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  <front>
    <journal-meta>
      <journal-id journal-id-type="nlm-ta">Arq Bras Cardiol</journal-id>
      <journal-id journal-id-type="publisher-id">abc</journal-id>
      <journal-title-group>
        <journal-title>Arquivos Brasileiros de Cardiologia</journal-title>
        <abbrev-journal-title abbrev-type="publisher">Arq. Bras. Cardiol.</abbrev-journal-title>
      </journal-title-group>
      <issn pub-type="ppub">0066-782X</issn>
      <issn pub-type="epub">1678-4170</issn>
      <publisher>
        <publisher-name>Sociedade Brasileira de Cardiologia - SBC</publisher-name>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id specific-use="scielo-v3" pub-id-type="publisher-id">zqjD699sjsZ6VLfjDGjvvgc</article-id>
      <article-id specific-use="scielo-v2" pub-id-type="publisher-id">S0066-782X2021001200845</article-id>
      <article-id pub-id-type="publisher-id">abc.20200266</article-id>
      <article-id pub-id-type="doi">10.36660/abc.20200266</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Posicionamento</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Posicionamento Brasileiro sobre o Uso da Multimodalidade de Imagens na Cardio-Oncologia &#8211; 2021</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-8809-8783</contrib-id>
          <name>
            <surname>Melo</surname>
            <given-names>Marcelo Dantas Tavares de</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Paiva</surname>
            <given-names>Marcelo Goulart</given-names>
          </name>
          <xref ref-type="aff" rid="aff2">
            <sup>2</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Santos</surname>
            <given-names>Maria Ver&#244;nica C&#226;mara</given-names>
          </name>
          <xref ref-type="aff" rid="aff3">
            <sup>3</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-4505-3344</contrib-id>
          <name>
            <surname>Rochitte</surname>
            <given-names>Carlos Eduardo</given-names>
          </name>
          <xref ref-type="aff" rid="aff4">
            <sup>4</sup>
          </xref>
          <xref ref-type="aff" rid="aff5">
            <sup>5</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Moreira</surname>
            <given-names>Val&#233;ria de Melo</given-names>
          </name>
          <xref ref-type="aff" rid="aff5">
            <sup>5</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Saleh</surname>
            <given-names>Mohamed Hassan</given-names>
          </name>
          <xref ref-type="aff" rid="aff4">
            <sup>4</sup>
          </xref>
          <xref ref-type="aff" rid="aff6">
            <sup>6</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Brand&#227;o</surname>
            <given-names>Simone Cristina Soares</given-names>
          </name>
          <xref ref-type="aff" rid="aff7">
            <sup>7</sup>
          </xref>
          <xref ref-type="aff" rid="aff8">
            <sup>8</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-6684-5952</contrib-id>
          <name>
            <surname>Gallafrio</surname>
            <given-names>Claudia Cosentino</given-names>
          </name>
          <xref ref-type="aff" rid="aff9">
            <sup>9</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Goldwasser</surname>
            <given-names>Daniel</given-names>
          </name>
          <xref ref-type="aff" rid="aff10">
            <sup>10</sup>
          </xref>
          <xref ref-type="aff" rid="aff11">
            <sup>11</sup>
          </xref>
          <xref ref-type="aff" rid="aff12">
            <sup>12</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-0477-480X</contrib-id>
          <name>
            <surname>Gripp</surname>
            <given-names>Eliza de Almeida</given-names>
          </name>
          <xref ref-type="aff" rid="aff13">
            <sup>13</sup>
          </xref>
          <xref ref-type="aff" rid="aff14">
            <sup>14</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-4154-3197</contrib-id>
          <name>
            <surname>Piveta</surname>
            <given-names>Rafael Bonafim</given-names>
          </name>
          <xref ref-type="aff" rid="aff15">
            <sup>15</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-9983-6438</contrib-id>
          <name>
            <surname>Silva</surname>
            <given-names>Tonnison Oliveira</given-names>
          </name>
          <xref ref-type="aff" rid="aff16">
            <sup>16</sup>
          </xref>
          <xref ref-type="aff" rid="aff17">
            <sup>17</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Santo</surname>
            <given-names>Thais Harada Campos Espirito</given-names>
          </name>
          <xref ref-type="aff" rid="aff18">
            <sup>18</sup>
          </xref>
          <xref ref-type="aff" rid="aff19">
            <sup>19</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-9748-1784</contrib-id>
          <name>
            <surname>Ferreira</surname>
            <given-names>Waldinai Pereira</given-names>
          </name>
          <xref ref-type="aff" rid="aff20">
            <sup>20</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-7152-1810</contrib-id>
          <name>
            <surname>Salemi</surname>
            <given-names>Vera Maria Cury</given-names>
          </name>
          <xref ref-type="aff" rid="aff4">
            <sup>4</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Cauduro</surname>
            <given-names>Sanderson A.</given-names>
          </name>
          <xref ref-type="aff" rid="aff21">
            <sup>21</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-0711-7995</contrib-id>
          <name>
            <surname>Barberato</surname>
            <given-names>Silvio Henrique</given-names>
          </name>
          <xref ref-type="aff" rid="aff22">
            <sup>22</sup>
          </xref>
          <xref ref-type="aff" rid="aff23">
            <sup>23</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Lopes</surname>
            <given-names>Helo&#237;sa M. Christovam</given-names>
          </name>
          <xref ref-type="aff" rid="aff24">
            <sup>24</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Pena</surname>
            <given-names>Jos&#233; Luiz Barros</given-names>
          </name>
          <xref ref-type="aff" rid="aff25">
            <sup>25</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-4207-4484</contrib-id>
          <name>
            <surname>Rached</surname>
            <given-names>Heron Rhydan Saad</given-names>
          </name>
          <xref ref-type="aff" rid="aff26">
            <sup>26</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-3314-9712</contrib-id>
          <name>
            <surname>Miglioranza</surname>
            <given-names>Marcelo Haertel</given-names>
          </name>
          <xref ref-type="aff" rid="aff27">
            <sup>27</sup>
          </xref>
          <xref ref-type="aff" rid="aff28">
            <sup>28</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Pinheiro</surname>
            <given-names>Aur&#233;lio Carvalho</given-names>
          </name>
          <xref ref-type="aff" rid="aff29">
            <sup>29</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-5611-4002</contrib-id>
          <name>
            <surname>Vrandecic</surname>
            <given-names>B&#225;rbara Athayde Linhares Martins</given-names>
          </name>
          <xref ref-type="aff" rid="aff30">
            <sup>30</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Cruz</surname>
            <given-names>Cecilia Beatriz Bittencourt Viana</given-names>
          </name>
          <xref ref-type="aff" rid="aff4">
            <sup>4</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-7131-6614</contrib-id>
          <name>
            <surname>Nomura</surname>
            <given-names>C&#233;sar Higa</given-names>
          </name>
          <xref ref-type="aff" rid="aff4">
            <sup>4</sup>
          </xref>
          <xref ref-type="aff" rid="aff31">
            <sup>31</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Cerbino</surname>
            <given-names>Fernanda Mello Erthal</given-names>
          </name>
          <xref ref-type="aff" rid="aff32">
            <sup>32</sup>
          </xref>
          <xref ref-type="aff" rid="aff33">
            <sup>33</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-1418-9361</contrib-id>
          <name>
            <surname>Costa</surname>
            <given-names>Isabela Bispo Santos da Silva</given-names>
          </name>
          <xref ref-type="aff" rid="aff34">
            <sup>34</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-4428-5186</contrib-id>
          <name>
            <surname>Coelho</surname>
            <given-names>Otavio Rizzi</given-names>
            <suffix>Filho</suffix>
          </name>
          <xref ref-type="aff" rid="aff35">
            <sup>35</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Carneiro</surname>
            <given-names>Adriano Camargo de Castro</given-names>
          </name>
          <xref ref-type="aff" rid="aff5">
            <sup>5</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-7234-4046</contrib-id>
          <name>
            <surname>Burgos</surname>
            <given-names>Ursula Maria Moreira Costa</given-names>
          </name>
          <xref ref-type="aff" rid="aff36">
            <sup>36</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-6726-5324</contrib-id>
          <name>
            <surname>Fernandes</surname>
            <given-names>Juliano Lara</given-names>
          </name>
          <xref ref-type="aff" rid="aff37">
            <sup>37</sup>
          </xref>
          <xref ref-type="aff" rid="aff38">
            <sup>38</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-7302-7448</contrib-id>
          <name>
            <surname>Uellendahl</surname>
            <given-names>Marly</given-names>
          </name>
          <xref ref-type="aff" rid="aff33">
            <sup>33</sup>
          </xref>
          <xref ref-type="aff" rid="aff39">
            <sup>39</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-7079-2600</contrib-id>
          <name>
            <surname>Calado</surname>
            <given-names>Eveline Barros</given-names>
          </name>
          <xref ref-type="aff" rid="aff40">
            <sup>40</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-6728-3565</contrib-id>
          <name>
            <surname>Senra</surname>
            <given-names>Tiago</given-names>
          </name>
          <xref ref-type="aff" rid="aff6">
            <sup>6</sup>
          </xref>
          <xref ref-type="aff" rid="aff31">
            <sup>31</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Assun&#231;&#227;o</surname>
            <given-names>Bruna Leal</given-names>
          </name>
          <xref ref-type="aff" rid="aff34">
            <sup>34</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Freire</surname>
            <given-names>Claudia Maria Vilas</given-names>
          </name>
          <xref ref-type="aff" rid="aff41">
            <sup>41</sup>
          </xref>
          <xref ref-type="aff" rid="aff42">
            <sup>42</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Martins</surname>
            <given-names>Cristiane Nunes</given-names>
          </name>
          <xref ref-type="aff" rid="aff30">
            <sup>30</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-6418-1424</contrib-id>
          <name>
            <surname>Sawamura</surname>
            <given-names>Karen Saori Shiraishi</given-names>
          </name>
          <xref ref-type="aff" rid="aff5">
            <sup>5</sup>
          </xref>
          <xref ref-type="aff" rid="aff14">
            <sup>14</sup>
          </xref>
          <xref ref-type="aff" rid="aff43">
            <sup>43</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Brito</surname>
            <given-names>M&#225;rcio Miranda</given-names>
          </name>
          <xref ref-type="aff" rid="aff44">
            <sup>44</sup>
          </xref>
          <xref ref-type="aff" rid="aff45">
            <sup>45</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Jardim</surname>
            <given-names>Maria Fernanda Silva</given-names>
          </name>
          <xref ref-type="aff" rid="aff46">
            <sup>46</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Bernardes</surname>
            <given-names>Renata Junqueira Moll</given-names>
          </name>
          <xref ref-type="aff" rid="aff47">
            <sup>47</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Di&#243;genes</surname>
            <given-names>Tereza Cristina</given-names>
          </name>
          <xref ref-type="aff" rid="aff48">
            <sup>48</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Vieira</surname>
            <given-names>Lucas de Oliveira</given-names>
          </name>
          <xref ref-type="aff" rid="aff49">
            <sup>49</sup>
          </xref>
          <xref ref-type="aff" rid="aff50">
            <sup>50</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-1466-9413</contrib-id>
          <name>
            <surname>Mesquita</surname>
            <given-names>Claudio Tinoco</given-names>
          </name>
          <xref ref-type="aff" rid="aff13">
            <sup>13</sup>
          </xref>
          <xref ref-type="aff" rid="aff51">
            <sup>51</sup>
          </xref>
          <xref ref-type="aff" rid="aff52">
            <sup>52</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Lopes</surname>
            <given-names>Rafael Willain</given-names>
          </name>
          <xref ref-type="aff" rid="aff5">
            <sup>5</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Segundo</surname>
            <given-names>Elry Medeiros Vieira</given-names>
            <suffix>Neto</suffix>
          </name>
          <xref ref-type="aff" rid="aff6">
            <sup>6</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Rigo</surname>
            <given-names>Let&#237;cia</given-names>
          </name>
          <xref ref-type="aff" rid="aff53">
            <sup>53</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Marin</surname>
            <given-names>Valeska Leite Siqueira</given-names>
          </name>
          <xref ref-type="aff" rid="aff54">
            <sup>54</sup>
          </xref>
          <xref ref-type="aff" rid="aff55">
            <sup>55</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Santos</surname>
            <given-names>Marcelo Jos&#233;</given-names>
          </name>
          <xref ref-type="aff" rid="aff56">
            <sup>56</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-6485-4900</contrib-id>
          <name>
            <surname>Grossman</surname>
            <given-names>Gabriel Blacher</given-names>
          </name>
          <xref ref-type="aff" rid="aff57">
            <sup>57</sup>
          </xref>
          <xref ref-type="aff" rid="aff58">
            <sup>58</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Quagliato</surname>
            <given-names>Priscila Cestari</given-names>
          </name>
          <xref ref-type="aff" rid="aff6">
            <sup>6</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Alcantara</surname>
            <given-names>Monica Luiza de</given-names>
          </name>
          <xref ref-type="aff" rid="aff59">
            <sup>59</sup>
          </xref>
          <xref ref-type="aff" rid="aff60">
            <sup>60</sup>
          </xref>
          <xref ref-type="aff" rid="aff61">
            <sup>61</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Teodoro</surname>
            <given-names>Jos&#233; Aldo Ribeiro</given-names>
          </name>
          <xref ref-type="aff" rid="aff62">
            <sup>62</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Albricker</surname>
            <given-names>Ana Cristina Lopes</given-names>
          </name>
          <xref ref-type="aff" rid="aff63">
            <sup>63</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Barros</surname>
            <given-names>Fanilda Souto</given-names>
          </name>
          <xref ref-type="aff" rid="aff64">
            <sup>64</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Amaral</surname>
            <given-names>Salomon Israel do</given-names>
          </name>
          <xref ref-type="aff" rid="aff65">
            <sup>65</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Porto</surname>
            <given-names>Carmen L&#250;cia Lascasas</given-names>
          </name>
          <xref ref-type="aff" rid="aff66">
            <sup>66</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Barros</surname>
            <given-names>Marcio Vin&#237;cius Lins</given-names>
          </name>
          <xref ref-type="aff" rid="aff67">
            <sup>67</sup>
          </xref>
          <xref ref-type="aff" rid="aff68">
            <sup>68</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Santos</surname>
            <given-names>Simone Nascimento dos</given-names>
          </name>
          <xref ref-type="aff" rid="aff69">
            <sup>69</sup>
          </xref>
          <xref ref-type="aff" rid="aff70">
            <sup>70</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Cantisano</surname>
            <given-names>Armando Lu&#237;s</given-names>
          </name>
          <xref ref-type="aff" rid="aff71">
            <sup>71</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-6186-1531</contrib-id>
          <name>
            <surname>Petisco</surname>
            <given-names>Ana Cl&#225;udia Gomes Pereira</given-names>
          </name>
          <xref ref-type="aff" rid="aff6">
            <sup>6</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Barbosa</surname>
            <given-names>Jos&#233; Eduardo Martins</given-names>
          </name>
          <xref ref-type="aff" rid="aff6">
            <sup>6</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Veloso</surname>
            <given-names>Orlando Carlos Gl&#243;ria</given-names>
          </name>
          <xref ref-type="aff" rid="aff72">
            <sup>72</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-4884-0223</contrib-id>
          <name>
            <surname>Spina</surname>
            <given-names>Salvador</given-names>
          </name>
          <xref ref-type="aff" rid="aff73">
            <sup>73</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Pignatelli</surname>
            <given-names>Ricardo</given-names>
          </name>
          <xref ref-type="aff" rid="aff74">
            <sup>74</sup>
          </xref>
          <xref ref-type="aff" rid="aff75">
            <sup>75</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-5645-2055</contrib-id>
          <name>
            <surname>Hajjar</surname>
            <given-names>Ludhmilla Abrah&#227;o</given-names>
          </name>
          <xref ref-type="aff" rid="aff4">
            <sup>4</sup>
          </xref>
          <xref ref-type="aff" rid="aff34">
            <sup>34</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-1033-3672</contrib-id>
          <name>
            <surname>Kalil</surname>
            <given-names>Roberto</given-names>
            <suffix>Filho</suffix>
          </name>
          <xref ref-type="aff" rid="aff4">
            <sup>4</sup>
          </xref>
          <xref ref-type="aff" rid="aff34">
            <sup>34</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-1253-1514</contrib-id>
          <name>
            <surname>Lopes</surname>
            <given-names>Marcelo Ant&#244;nio Cartaxo Queiroga</given-names>
          </name>
          <xref ref-type="aff" rid="aff76">
            <sup>76</sup>
          </xref>
          <xref ref-type="aff" rid="aff77">
            <sup>77</sup>
          </xref>
          <xref ref-type="aff" rid="aff78">
            <sup>78</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Vieira</surname>
            <given-names>Marcelo Luiz Campos</given-names>
          </name>
          <xref ref-type="aff" rid="aff4">
            <sup>4</sup>
          </xref>
          <xref ref-type="aff" rid="aff15">
            <sup>15</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-1777-477X</contrib-id>
          <name>
            <surname>Almeida</surname>
            <given-names>Andr&#233; Luiz Cerqueira</given-names>
          </name>
          <xref ref-type="aff" rid="aff79">
            <sup>79</sup>
          </xref>
          <xref ref-type="aff" rid="aff80">
            <sup>80</sup>
          </xref>
        </contrib>
        <aff id="aff1">
          <label>1</label>
          <institution content-type="orgname">Universidade Federal da Para&#237;ba</institution>
          <addr-line>
            <named-content content-type="city">Jo&#227;o Pessoa</named-content>
            <named-content content-type="state">PB</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Universidade Federal da Para&#237;ba, Jo&#227;o Pessoa, PB &#8211; Brasil</institution>
        </aff>
        <aff id="aff2">
          <label>2</label>
          <institution content-type="orgname">Hospital 9 de Julho</institution>
          <institution content-type="orgdiv1">Cardiologia</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">S&#227;o Paulo</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital 9 de Julho, Cardiologia, S&#227;o Paulo, S&#227;o Paulo &#8211; Brasil</institution>
        </aff>
        <aff id="aff3">
          <label>3</label>
          <institution content-type="orgname">Sociedade Brasileira de Oncologia Pedi&#225;trica</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Sociedade Brasileira de Oncologia Pedi&#225;trica, S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff4">
          <label>4</label>
          <institution content-type="orgname">Universidade de S&#227;o Paulo</institution>
          <institution content-type="orgdiv1">Hospital das Cl&#237;nicas da Faculdade de Medicina</institution>
          <institution content-type="orgdiv2">Instituto do Cora&#231;&#227;o (Incor)</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Instituto do Cora&#231;&#227;o (Incor) do Hospital das Cl&#237;nicas da Faculdade de Medicina da Universidade de S&#227;o Paulo (HCFMUSP), S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff5">
          <label>5</label>
          <institution content-type="orgname">Hospital do Cora&#231;&#227;o</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital do Cora&#231;&#227;o (HCOR), S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff6">
          <label>6</label>
          <institution content-type="orgname">Instituto Dante Pazzanese de Cardiologia</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Instituto Dante Pazzanese de Cardiologia, S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff7">
          <label>7</label>
          <institution content-type="orgname">Universidade Federal de Pernambuco</institution>
          <institution content-type="orgdiv1">Hospital das Cl&#237;nicas</institution>
          <addr-line>
            <named-content content-type="city">Recife</named-content>
            <named-content content-type="state">PE</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital das Cl&#237;nicas, Universidade Federal de Pernambuco, Recife, PE - Brasil</institution>
        </aff>
        <aff id="aff8">
          <label>8</label>
          <institution content-type="orgname">Cl&#237;nica Diagson</institution>
          <addr-line>
            <named-content content-type="city">Jo&#227;o Pessoa</named-content>
            <named-content content-type="state">PB</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Cl&#237;nica Diagson, Jo&#227;o Pessoa, PB &#8211; Brasil</institution>
        </aff>
        <aff id="aff9">
          <label>9</label>
          <institution content-type="orgname">Instituto de Oncologia Pedi&#225;trica</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Instituto de Oncologia Pedi&#225;trica, S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff10">
          <label>10</label>
          <institution content-type="orgname">Hospital Federal de Ipanema</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Federal de Ipanema, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff11">
          <label>11</label>
          <institution content-type="orgname">Hospital Copa D'Or</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Copa D'Or, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff12">
          <label>12</label>
          <institution content-type="orgname">Casa de Sa&#250;de S&#227;o Jos&#233;</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Casa de Sa&#250;de S&#227;o Jos&#233;, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff13">
          <label>13</label>
          <institution content-type="orgname">Hospital Pr&#243;-Card&#237;aco</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Pr&#243;-Card&#237;aco, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff14">
          <label>14</label>
          <institution content-type="orgname">Hospital Universit&#225;rio Ant&#244;nio Pedro</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Universit&#225;rio Ant&#244;nio Pedro, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff15">
          <label>15</label>
          <institution content-type="orgname">Hospital Israelita Albert Einstein</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Israelita Albert Einstein, S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff16">
          <label>16</label>
          <institution content-type="orgname">Hospital Cardio Pulmonar</institution>
          <institution content-type="orgdiv1">Centro de Estudos em Cardiologia</institution>
          <addr-line>
            <named-content content-type="city">Salvador</named-content>
            <named-content content-type="state">BA</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Cardio Pulmonar &#8211; Centro de Estudos em Cardiologia, Salvador, BA &#8211; Brasil</institution>
        </aff>
        <aff id="aff17">
          <label>17</label>
          <institution content-type="orgname">Escola Bahiana de Medicina e Sa&#250;de P&#250;blica</institution>
          <addr-line>
            <named-content content-type="city">Salvador</named-content>
            <named-content content-type="state">BA</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Escola Bahiana de Medicina e Sa&#250;de P&#250;blica, Salvador, BA &#8211; Brasil</institution>
        </aff>
        <aff id="aff18">
          <label>18</label>
          <institution content-type="orgname">Hospital Ana Nery</institution>
          <addr-line>
            <named-content content-type="city">Salvador</named-content>
            <named-content content-type="state">BA</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Ana Nery, Salvador, BA &#8211; Brasil</institution>
        </aff>
        <aff id="aff19">
          <label>19</label>
          <institution content-type="orgname">Diagnoson/Fleury</institution>
          <addr-line>
            <named-content content-type="city">Salvador</named-content>
            <named-content content-type="state">BA</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Diagnoson/Fleury, Salvador, BA &#8211; Brasil</institution>
        </aff>
        <aff id="aff20">
          <label>20</label>
          <institution content-type="orgname">ACCamargoCancer Center</institution>
          <institution content-type="orgdiv1">IMAGE</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">ACCamargoCancer Center &#8211; IMAGE, S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff21">
          <label>21</label>
          <institution content-type="orgname">Hospital Erasto Gaertner</institution>
          <addr-line>
            <named-content content-type="city">Curitiba</named-content>
            <named-content content-type="state">PR</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Erasto Gaertner, Curitiba, PR &#8211; Brasil</institution>
        </aff>
        <aff id="aff22">
          <label>22</label>
          <institution content-type="orgname">CardioEco Centro de Diagn&#243;stico Cardiovascular</institution>
          <addr-line>
            <named-content content-type="city">Curitiba</named-content>
            <named-content content-type="state">PR</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">CardioEco Centro de Diagn&#243;stico Cardiovascular, Curitiba, PR &#8211; Brasil</institution>
        </aff>
        <aff id="aff23">
          <label>23</label>
          <institution content-type="orgname">Quanta Diagn&#243;stico</institution>
          <addr-line>
            <named-content content-type="city">Curitiba</named-content>
            <named-content content-type="state">PR</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Quanta Diagn&#243;stico, Curitiba, PR &#8211; Brasil</institution>
        </aff>
        <aff id="aff24">
          <label>24</label>
          <institution content-type="orgname">Hospital de Amor</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital de Amor, Barretos, S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff25">
          <label>25</label>
          <institution content-type="orgname">Faculdade de Ci&#234;ncias M&#233;dicas de Minas Gerais</institution>
          <addr-line>
            <named-content content-type="city">Belo Horizonte</named-content>
            <named-content content-type="state">MG</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Faculdade de Ci&#234;ncias M&#233;dicas de Minas Gerais, Belo Horizonte, MG &#8211; Brasil</institution>
        </aff>
        <aff id="aff26">
          <label>26</label>
          <institution content-type="orgname">Hospital Leforte Liberdade</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Leforte Liberdade, S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff27">
          <label>27</label>
          <institution content-type="orgname">Instituto de Cardiologia do Rio Grande do Sul</institution>
          <institution content-type="orgdiv1">Laborat&#243;rio de Pesquisa e Inova&#231;&#227;o em Imagem Cardiovascular</institution>
          <addr-line>
            <named-content content-type="city">Porto Alegre</named-content>
            <named-content content-type="state">RS</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Instituto de Cardiologia do Rio Grande do Sul &#8211; Laborat&#243;rio de Pesquisa e Inova&#231;&#227;o em Imagem Cardiovascular, Porto Alegre, RS &#8211; Brasil</institution>
        </aff>
        <aff id="aff28">
          <label>28</label>
          <institution content-type="orgname">Hospital M&#227;e de Deus</institution>
          <addr-line>
            <named-content content-type="city">Porto Alegre</named-content>
            <named-content content-type="state">RS</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital M&#227;e de Deus, Porto Alegre, RS &#8211; Brasil</institution>
        </aff>
        <aff id="aff29">
          <label>29</label>
          <institution content-type="orgname">Hospital Adventista de Manaus</institution>
          <addr-line>
            <named-content content-type="city">Manaus</named-content>
            <named-content content-type="state">AM</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Adventista de Manaus, Manaus, AM &#8211; Brasil</institution>
        </aff>
        <aff id="aff30">
          <label>30</label>
          <institution content-type="orgname">Biocor Instituto</institution>
          <addr-line>
            <named-content content-type="city">Nova Lima</named-content>
            <named-content content-type="state">MG</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Biocor Instituto, Nova Lima, MG &#8211; Brasil</institution>
        </aff>
        <aff id="aff31">
          <label>31</label>
          <institution content-type="orgname">Hospital S&#237;rio-Liban&#234;s</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital S&#237;rio-Liban&#234;s, S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff32">
          <label>32</label>
          <institution content-type="orgname">Cl&#237;nica de Diagn&#243;stico por Imagem</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Cl&#237;nica de Diagn&#243;stico por Imagem, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff33">
          <label>33</label>
          <institution content-type="orgname">Diagn&#243;sticos da Am&#233;rica AS</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Diagn&#243;sticos da Am&#233;rica AS, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff34">
          <label>34</label>
          <institution content-type="orgname">Universidade de S&#227;o Paulo</institution>
          <institution content-type="orgdiv1">Instituto do C&#226;ncer do Estado de S&#227;o Paulo</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Universidade de S&#227;o Paulo Instituto do C&#226;ncer do Estado de S&#227;o Paulo, S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff35">
          <label>35</label>
          <institution content-type="orgname">Universidade Estadual de Campinas</institution>
          <addr-line>
            <named-content content-type="city">Campinas</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Universidade Estadual de Campinas (UNICAMP), Campinas, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff36">
          <label>36</label>
          <institution content-type="orgname">Universidade Tiradentes</institution>
          <addr-line>
            <named-content content-type="city">Aracaju</named-content>
            <named-content content-type="state">SE</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Universidade Tiradentes, Aracaju, SE &#8211; Brasil</institution>
        </aff>
        <aff id="aff37">
          <label>37</label>
          <institution content-type="orgname">Radiologia Cl&#237;nica de Campinas</institution>
          <addr-line>
            <named-content content-type="city">Campinas</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Radiologia Cl&#237;nica de Campinas, Campinas, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff38">
          <label>38</label>
          <institution content-type="orgname">Instituto de Ensino e Pesquisa Jos&#233; Michel Kalaf</institution>
          <addr-line>
            <named-content content-type="city">Campinas</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Instituto de Ensino e Pesquisa Jos&#233; Michel Kalaf, Campinas, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff39">
          <label>39</label>
          <institution content-type="orgname">Universidade Federal de S&#227;o Paulo</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Universidade Federal de S&#227;o Paulo (UNIFESP), S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff40">
          <label>40</label>
          <institution content-type="orgname">Universidade Federal de Pernambuco</institution>
          <institution content-type="orgdiv1">Hospital das Cl&#237;nicas</institution>
          <addr-line>
            <named-content content-type="city">Recife</named-content>
            <named-content content-type="state">PE</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital das Cl&#237;nicas da Universidade Federal de Pernambuco, Recife, PE &#8211; Brasil</institution>
        </aff>
        <aff id="aff41">
          <label>41</label>
          <institution content-type="orgname">Universidade Federal de Minas Gerais</institution>
          <addr-line>
            <named-content content-type="city">Belo Horizonte</named-content>
            <named-content content-type="state">MG</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG &#8211; Brasil</institution>
        </aff>
        <aff id="aff42">
          <label>42</label>
          <institution content-type="orgname">ECOCENTER</institution>
          <addr-line>
            <named-content content-type="city">Belo Horizonte</named-content>
            <named-content content-type="state">MG</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">ECOCENTER, Belo Horizonte, MG &#8211; Brasil</institution>
        </aff>
        <aff id="aff43">
          <label>43</label>
          <institution content-type="orgname">Universidade de S&#227;o Paulo</institution>
          <institution content-type="orgdiv1">Instituto da Crian&#231;a</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Instituto da Crian&#231;a da Universidade de S&#227;o Paulo (USP), S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff44">
          <label>44</label>
          <institution content-type="orgname">Universidade Federal do Tocantins</institution>
          <institution content-type="orgdiv1">Campus de Araguaina</institution>
          <addr-line>
            <named-content content-type="city">Araguaina</named-content>
            <named-content content-type="state">TO</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Universidade Federal do Tocantins &#8211; Campus de Araguaina, Araguaina, TO &#8211; Brasil</institution>
        </aff>
        <aff id="aff45">
          <label>45</label>
          <institution content-type="orgname">Hospital Municipal de Araguaina</institution>
          <addr-line>
            <named-content content-type="city">Araguaina</named-content>
            <named-content content-type="state">TO</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Municipal de Araguaina, Araguaina, TO &#8211; Brasil</institution>
        </aff>
        <aff id="aff46">
          <label>46</label>
          <institution content-type="orgname">Hospital Samaritano de S&#227;o Paulo</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Samaritano de S&#227;o Paulo, S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff47">
          <label>47</label>
          <institution content-type="orgname">Instituto D'Or de Pesquisa e Ensino</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Instituto D'Or de Pesquisa e Ensino, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff48">
          <label>48</label>
          <institution content-type="orgname">Hospital Infantil Albert Sabin</institution>
          <addr-line>
            <named-content content-type="city">Fortaleza</named-content>
            <named-content content-type="state">CE</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Infantil Albert Sabin, Fortaleza, CE &#8211; Brasil</institution>
        </aff>
        <aff id="aff49">
          <label>49</label>
          <institution content-type="orgname">Hospital S&#227;o Rafael</institution>
          <addr-line>
            <named-content content-type="city">Salvador</named-content>
            <named-content content-type="state">BA</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital S&#227;o Rafael, Salvador, BA &#8211; Brasil</institution>
        </aff>
        <aff id="aff50">
          <label>50</label>
          <institution content-type="orgname">Rede D'Or</institution>
          <addr-line>
            <named-content content-type="city">Salvador</named-content>
            <named-content content-type="state">BA</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Rede D'Or, Salvador, BA &#8211; Brasil</institution>
        </aff>
        <aff id="aff51">
          <label>51</label>
          <institution content-type="orgname">Universidade Federal Fluminense</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Universidade Federal Fluminense (UFF), Rio de Janeiro, RJ - Brasil</institution>
        </aff>
        <aff id="aff52">
          <label>52</label>
          <institution content-type="orgname">Hospital Vit&#243;ria</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Vit&#243;ria, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff53">
          <label>53</label>
          <institution content-type="orgname">Hospital Benefic&#234;ncia Portuguesa</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Benefic&#234;ncia Portuguesa, S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff54">
          <label>54</label>
          <institution content-type="orgname">Hospital Samaritano</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Samaritano, S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff55">
          <label>55</label>
          <institution content-type="orgname">Santa Casa de Miseric&#243;rdia</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Santa Casa de Miseric&#243;rdia, S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff56">
          <label>56</label>
          <institution content-type="orgname">Hospital de C&#226;ncer de Barretos</institution>
          <addr-line>
            <named-content content-type="city">Barretos</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital de C&#226;ncer de Barretos, Barretos, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff57">
          <label>57</label>
          <institution content-type="orgname">Cl&#237;nica Cardionuclear</institution>
          <addr-line>
            <named-content content-type="city">Porto Alegre</named-content>
            <named-content content-type="state">RS</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Cl&#237;nica Cardionuclear, Porto Alegre, RS &#8211; Brasil</institution>
        </aff>
        <aff id="aff58">
          <label>58</label>
          <institution content-type="orgname">Hospital Moinhos de Vento</institution>
          <addr-line>
            <named-content content-type="city">Porto Alegre</named-content>
            <named-content content-type="state">RS</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Moinhos de Vento, Porto Alegre, RS &#8211; Brasil</institution>
        </aff>
        <aff id="aff59">
          <label>59</label>
          <institution content-type="orgname">Americas Medical City</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Americas Medical City, Rio de Janeiro, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff60">
          <label>60</label>
          <institution content-type="orgname">Americas Servi&#231;os M&#233;dicos</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Americas Servi&#231;os M&#233;dicos, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff61">
          <label>61</label>
          <institution content-type="orgname">Rede D'Or</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Rede D'Or, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff62">
          <label>62</label>
          <institution content-type="orgname">Prenoto Medicina Diagn&#243;stica</institution>
          <addr-line>
            <named-content content-type="city">Ribeir&#227;o Preto</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Prenoto Medicina Diagn&#243;stica, Ribeir&#227;o Preto, SP &#8211; Brasil</institution>
        </aff>
        <aff id="aff63">
          <label>63</label>
          <institution content-type="orgname">Centro Universit&#225;rio Unihorizontes</institution>
          <addr-line>
            <named-content content-type="city">Belo Horizonte</named-content>
            <named-content content-type="state">MG</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Centro Universit&#225;rio Unihorizontes, Belo Horizonte, MG &#8211; Brasil</institution>
        </aff>
        <aff id="aff64">
          <label>64</label>
          <institution content-type="orgname">Angiolab Vit&#243;ria</institution>
          <addr-line>
            <named-content content-type="city">Vit&#243;ria</named-content>
            <named-content content-type="state">ES</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Angiolab Vit&#243;ria &#8211; Diagn&#243;stico Vascular, Vit&#243;ria, ES &#8211; Brasil</institution>
        </aff>
        <aff id="aff65">
          <label>65</label>
          <institution content-type="orgname">Casa de Sa&#250;de Nossa Senhora do Carmo</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Casa de Sa&#250;de Nossa Senhora do Carmo, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff66">
          <label>66</label>
          <institution content-type="orgname">Universidade do Estado do Rio de Janeiro</institution>
          <institution content-type="orgdiv1">Faculdade de Ci&#234;ncias M&#233;dicas</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Universidade do Estado do Rio de Janeiro Faculdade de Ci&#234;ncias M&#233;dicas, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff67">
          <label>67</label>
          <institution content-type="orgname">Mater Dei Rede de Sa&#250;de</institution>
          <addr-line>
            <named-content content-type="city">Belo Horizonte</named-content>
            <named-content content-type="state">MG</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Mater Dei Rede de Sa&#250;de, Belo Horizonte, MG &#8211; Brasil</institution>
        </aff>
        <aff id="aff68">
          <label>68</label>
          <institution content-type="orgname">Hospital Vera Cruz</institution>
          <addr-line>
            <named-content content-type="city">Belo Horizonte</named-content>
            <named-content content-type="state">MG</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Vera Cruz, Belo Horizonte, MG &#8211; Brasil</institution>
        </aff>
        <aff id="aff69">
          <label>69</label>
          <institution content-type="orgname">Hospital Bras&#237;lia &#8211; Ecocardiografia</institution>
          <addr-line>
            <named-content content-type="city">Bras&#237;lia</named-content>
            <named-content content-type="state">DF</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Bras&#237;lia &#8211; Ecocardiografia, Bras&#237;lia, DF &#8211; Brasil</institution>
        </aff>
        <aff id="aff70">
          <label>70</label>
          <institution content-type="orgname">Eccos Diagn&#243;stico Cardiovascular Avan&#231;ado</institution>
          <addr-line>
            <named-content content-type="city">Bras&#237;lia</named-content>
            <named-content content-type="state">DF</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Eccos Diagn&#243;stico Cardiovascular Avan&#231;ado, Bras&#237;lia, DF &#8211; Brasil</institution>
        </aff>
        <aff id="aff71">
          <label>71</label>
          <institution content-type="orgname">Hospital Barra D'Or</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Barra D'Or, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff72">
          <label>72</label>
          <institution content-type="orgname">Rede UHG</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Rede UHG, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff73">
          <label>73</label>
          <institution content-type="orgname">Hospital Aeron&#225;utico Central</institution>
          <addr-line>
            <named-content content-type="city">Buenos Aires</named-content>
          </addr-line>
          <country country="AR">Argentina</country>
          <institution content-type="original">Hospital Aeron&#225;utico Central, Buenos Aires &#8211; Argentina</institution>
        </aff>
        <aff id="aff74">
          <label>74</label>
          <institution content-type="orgname">Texas Children's Hospital</institution>
          <addr-line>
            <named-content content-type="city">Houston</named-content>
            <named-content content-type="state">Texas</named-content>
          </addr-line>
          <country country="US">EUA</country>
          <institution content-type="original">Texas Children's Hospital, Houston, Texas &#8211; EUA</institution>
        </aff>
        <aff id="aff75">
          <label>75</label>
          <institution content-type="orgname">Baylor College of Medicine</institution>
          <addr-line>
            <named-content content-type="city">Houston</named-content>
            <named-content content-type="state">Texas</named-content>
          </addr-line>
          <country country="US">EUA</country>
          <institution content-type="original">Baylor College of Medicine, Houston, Texas &#8211; EUA</institution>
        </aff>
        <aff id="aff76">
          <label>76</label>
          <institution content-type="orgname">Hospital Alberto Urquiza Wanderley</institution>
          <addr-line>
            <named-content content-type="city">Jo&#227;o Pessoa</named-content>
            <named-content content-type="state">PB</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Alberto Urquiza Wanderley &#8211; Hemodin&#226;mica e Cardiologia Intervencionista, Jo&#227;o Pessoa, PB &#8211; Brasil</institution>
        </aff>
        <aff id="aff77">
          <label>77</label>
          <institution content-type="orgname">Hospital Metropolitano Dom Jos&#233; Maria Pires</institution>
          <addr-line>
            <named-content content-type="city">Jo&#227;o Pessoa</named-content>
            <named-content content-type="state">PB</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Hospital Metropolitano Dom Jos&#233; Maria Pires, Jo&#227;o Pessoa, PB &#8211; Brasil</institution>
        </aff>
        <aff id="aff78">
          <label>78</label>
          <institution content-type="orgname">Sociedade Brasileira de Cardiologia</institution>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Sociedade Brasileira de Cardiologia, Rio de Janeiro, RJ &#8211; Brasil</institution>
        </aff>
        <aff id="aff79">
          <label>79</label>
          <institution content-type="orgname">Santa Casa de Miseric&#243;rdia de Feira de Santana</institution>
          <addr-line>
            <named-content content-type="city">Feira de Santana</named-content>
            <named-content content-type="state">BA</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Santa Casa de Miseric&#243;rdia de Feira de Santana &#8211; Cardiologia, Feira de Santana, BA &#8211; Brasil</institution>
        </aff>
        <aff id="aff80">
          <label>80</label>
          <institution content-type="orgname">Sociedade Brasileira de Cardiologia</institution>
          <institution content-type="orgdiv1">Departamento de Imagem Cardiovascular</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Departamento de Imagem Cardiovascular da Sociedade Brasileira de Cardiologia, S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
      </contrib-group>
      <author-notes>
        <corresp id="c1"><bold>Correspond&#234;ncia:</bold> Sociedade Brasileira de Cardiologia &#8211; Av. Marechal C&#226;mara, 360/330 &#8211; Centro &#8211; Rio de Janeiro &#8211; CEP: <postal-code>20020-907</postal-code> . E-mail: <email>diretrizes@cardiol.br</email> </corresp>
      </author-notes>
      <pub-date date-type="pub" publication-format="electronic">
        <day>25</day>
        <month>10</month>
        <year>2021</year>
      </pub-date>
      <pub-date date-type="collection" publication-format="electronic">
        <month>10</month>
        <year>2021</year>
      </pub-date>
      <volume>117</volume>
      <issue>4</issue>
      <fpage>845</fpage>
      <lpage>909</lpage>
      <permissions>
        <license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/" xml:lang="en">
          <license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License</license-p>
        </license>
      </permissions>
      <counts>
        <fig-count count="60"/>
        <table-count count="22"/>
        <equation-count count="0"/>
        <ref-count count="259"/>
        <page-count count="65"/>
      </counts>
    </article-meta>
  </front>
  <body>
    <table-wrap id="t1">
      <table frame="hsides" rules="rows">
        <colgroup width="12%">
          <col/>
          <col/>
          <col/>
          <col/>
          <col/>
          <col/>
          <col/>
          <col/>
        </colgroup>
        <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
          <tr>
            <th align="center" colspan="8" style="border-bottom: thin solid; border-color: #000000" valign="middle">Declara&#231;&#227;o de potencial conflito de interesses dos autores/colaboradores do Posicionamento Brasileiro sobre o Uso da Multimodalidade de Imagens na Cardio-Oncologia &#8211; 2021</th>
          </tr>
          <tr>
            <th align="center" colspan="8" style="border-bottom: thin solid; border-color: #000000" valign="middle">Se nos &#250;ltimos 3 anos o autor/colaborador do documento:</th>
          </tr>
          <tr>
            <th align="center" style="border-bottom: thin solid; border-color: #000000" valign="middle">Nomes Integrantes do Posicionamento</th>
            <th align="center" style="border-bottom: thin solid; border-color: #000000" valign="middle">Participou de estudos cl&#237;nicos e/ou experimentais subvencionados pela ind&#250;stria farmac&#234;utica ou de equipamentos relacionados ao posicionamento em quest&#227;o</th>
            <th align="center" style="border-bottom: thin solid; border-color: #000000" valign="middle">Foi palestrante em eventos ou atividades patrocinadas pela ind&#250;stria relacionados ao posicionamento em quest&#227;o</th>
            <th align="center" style="border-bottom: thin solid; border-color: #000000" valign="middle">Foi (&#233;) membro do conselho consultivo ou diretivo da ind&#250;stria farmac&#234;utica ou de equipamentos</th>
            <th align="center" style="border-bottom: thin solid; border-color: #000000" valign="middle">Participou de comit&#234;s normativos de estudos cient&#237;ficos patrocinados pela ind&#250;stria</th>
            <th align="center" style="border-bottom: thin solid; border-color: #000000" valign="middle">Recebeu aux&#237;lio pessoal ou institucional da ind&#250;stria</th>
            <th align="center" style="border-bottom: thin solid; border-color: #000000" valign="middle">Elaborou textos cient&#237;ficos em peri&#243;dicos patrocinados pela ind&#250;stria</th>
            <th align="center" style="border-bottom: thin solid; border-color: #000000" valign="middle">Tem a&#231;&#245;es da ind&#250;stria</th>
          </tr>
        </thead>
        <tbody style="border-bottom: thin solid; border-color: #000000">
          <tr>
            <td align="left" valign="middle">Adriano Camargo de Castro Carneiro</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Ana Cl&#225;udia Gomes Pereira Petisco</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Ana Cristina Lopes Albricker</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Andr&#233; Luiz Cerqueira de Almeida</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Armando Lu&#237;s Cantisano</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Aur&#233;lio Carvalho Pinheiro</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">B&#225;rbara Arhayde Lihares Martins Vrandecic</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Bruna Leal Assun&#231;&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Carlos Eduardo Rochitte</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Carmen Lucia Lascasas Porto</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Cecilia Beatriz Bittencourt Viana Cruz</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">C&#233;sar Higa Nomura</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Cl&#225;udia Cosentino Gallafrio</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Cl&#225;udia Maria Vilas Freire</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Claudio Tinoco Mesquita</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Cristiane Nunes Martins</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Daniel Goldwasser</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Eliza de Almeida Gripp</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Elry Medeiros Vieira Segundo Neto</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Eveline Barros Calado</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Fanilda Souto Barros</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Fernanda Mello Erthal Cerbino</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Gabriel Blacher Grossman</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Helo&#237;sa Helena M. Christovam Lopes</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Heron Rhydan Saad Rached</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Isabela Bispo Santos da Silva Costa</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Jos&#233; Aldo Ribeiro Teodoro</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Jos&#233; Eduardo Martins Barbosa</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Jos&#233; Luiz Barros Pena</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Juliano Lara Fernandes</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Karen Saori Shiraishi Sawamura</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Let&#237;cia Rigo</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Lucas de Oliveira Vieira</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Ludhmila Abrah&#227;o Hajjar</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Marcelo Ant&#244;nio Cartaxo Queiroga Lopes</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Marcelo Dantas Tavares de Melo</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Marcelo Goulart Paiva</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Marcelo Haertel Miglioranza</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Marcelo Luiz Campos Vieira</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Marcelo Santos</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">M&#225;rcio Miranda Brito</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">M&#225;rcio Vin&#237;cius Lins Barros</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Maria Fernanda Silva Jardim</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Maria Ver&#244;nica C&#226;mara dos Santos</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Marly Uellendahl</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Mohamed Hassan Saleh</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">M&#244;nica Luiza de Alcantara</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Orlando Carlos Gl&#243;ria Veloso</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Ot&#225;vio Rizzi Coelho-Filho</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Priscila Cestari Quagliato</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Rafael Bonafim Piveta</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Rafael Willain Lopes</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Renata Junqueira Moll Bernardes</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Ricardo Pignatelli</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Roberto Kalil Filho</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Salomon Israel do Amaral</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Salvador Spina</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Sanderson A. Cauduro</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Silvio Henrique Barberato</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Simone Cristina Soares Brand&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Simone Nascimento dos Santos</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Tereza Cristina Di&#243;genes</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Thais Harada Campos Espirito Santo</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Tiago Senra</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Tonnison de Oliveira Silva</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Ursula Maria Moreira Costa Burgos</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Val&#233;ria de Melo Moreira</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Valeska Leite</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Vera Maria Cury Salemi</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
          <tr>
            <td align="left" valign="middle">Waldinai P. Ferreira</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
            <td align="center" valign="middle">N&#227;o</td>
          </tr>
        </tbody>
      </table>
    </table-wrap>
    <sec>
      <title>1. Aspectos Gerais</title>
      <sec>
        <title>1.1. Situa&#231;&#227;o Atual da Cardio-Oncologia no Brasil e no Mundo</title>
        <p>Estima-se que a incid&#234;ncia de c&#226;ncer no Brasil seja de 600 mil casos/ano no bi&#234;nio 2018-2019. <xref ref-type="bibr" rid="B1"><sup>1</sup></xref> Somente a partir de 2005, a taxa de sobrevida superou a de mortalidade global por c&#226;ncer, levando a um aumento no n&#250;mero de sobreviventes expostos ao risco decardiotoxicidade (CTX), sendo atualmente a segunda causa de morbimortalidade nessa popula&#231;&#227;o. <xref ref-type="bibr" rid="B2"><sup>2</sup></xref> </p>
        <p>As complica&#231;&#245;es cardiovasculares decorrentes do seu tratamento, foco deste consenso, poder&#227;o resultar em mortes prematuras, interna&#231;&#245;es hospitalares custosas e afastamento do trabalho, o que leva &#224; necessidade de diagn&#243;stico e de interven&#231;&#245;es precoces. <xref ref-type="bibr" rid="B3"><sup>3</sup></xref> </p>
        <p>Idade (crian&#231;as e idosos), doen&#231;a mioc&#225;rdica ou coronariana pr&#233;via, hipertens&#227;o arterial sist&#234;mica (HAS), diabetes melito (DM), tabagismo, consumo de &#225;lcool e sedentarismo s&#227;o fatores associados ao risco aumentado de CTX. <xref ref-type="bibr" rid="B4"><sup>4</sup></xref> </p>
        <p>Estudos recentes sugerem que variantes genot&#237;picas possam modificar a suscetibilidade &#224; CTX, inserindo o mapeamento gen&#233;tico em campo promissor para identifica&#231;&#227;o de subgrupos de risco. <xref ref-type="bibr" rid="B5"><sup>5</sup></xref> </p>
        <p>Recomenda-se que sejam considerados pacientes de alto risco para o desenvolvimento de CTX aqueles cujo tratamento inclua: <xref ref-type="bibr" rid="B6"><sup>6</sup></xref> </p>
        <list list-type="bullet">
          <list-item>
            <p>Antraciclina em dose alta (doxorrubicina &gt; 250mg/m&#178; ou epirrubicina &gt; 600mg/m&#178;)</p>
          </list-item>
          <list-item>
            <p>Radioterapia (RT) em dose &#8805; 30 Gy (envolvendo o cora&#231;&#227;o) ou &gt; 2 Gy /sess&#227;o</p>
          </list-item>
          <list-item>
            <p>Doses menores de antraciclina e RT combinadas</p>
          </list-item>
          <list-item>
            <p>Doses menores de antraciclinas ou trastuzumabe isolados, por&#233;m associadas a:</p>
            <list list-type="simple">
              <list-item>
                <label>&#10146;</label>
                <p>Mais de dois fatores de risco cardiovascular (tabagismo, HAS, DM, dislipidemia, obesidade &#8211; durante ou ap&#243;s terapia)</p>
              </list-item>
              <list-item>
                <label>&#10146;</label>
                <p>Idade &#8805; 60 anos</p>
              </list-item>
              <list-item>
                <label>&#10146;</label>
                <p>Cardiopatia estrutural antes ou durante o tratamento (fra&#231;&#227;o de eje&#231;&#227;o [FE]: 50 a 55%, infarto agudo do mioc&#225;rdio [IAM], doen&#231;a valvar moderada/importante)</p>
              </list-item>
              <list-item>
                <label>&#10146;</label>
                <p>Combina&#231;&#227;o de doses baixas de antraciclina e trastuzumabe.</p>
              </list-item>
            </list>
          </list-item>
        </list>
      </sec>
      <sec>
        <title>1.2. Defini&#231;&#227;o de Cardiotoxicidade</title>
        <p>A defini&#231;&#227;o da CTX baseada no grau de redu&#231;&#227;o da fra&#231;&#227;o de eje&#231;&#227;o do ventr&#237;culo esquerdo (FEVE) omite, entretanto, as altera&#231;&#245;es que precedem a queda da FEVE e todos os outros efeitos t&#243;xicos que acontecem al&#233;m desse par&#226;metro. <xref ref-type="bibr" rid="B6"><sup>6</sup></xref><sup>-</sup><xref ref-type="bibr" rid="B8"><sup>8</sup></xref> A falta de uma defini&#231;&#227;o mais abrangente e, por vezes, a limita&#231;&#227;o cl&#237;nica, laboratorial e de imagem em documentar alguns eventos na sua fase inicial, fazem da CTX uma condi&#231;&#227;o cl&#237;nica subdiagnosticada. A Sociedade Europeia de Cardiologia, no ano de 2017, revisou a defini&#231;&#227;o de CTX e a estendeu para toda e qualquer altera&#231;&#227;o estrutural ou funcional do cora&#231;&#227;o e circula&#231;&#227;o, seja na vig&#234;ncia ou no p&#243;s-tratamento imediato ou tardio do c&#226;ncer, considerando como agentes agressores a quimioterapia (QT), a RT ou a pr&#243;pria doen&#231;a. <xref ref-type="bibr" rid="B4"><sup>4</sup></xref> </p>
      </sec>
      <sec>
        <title>1.3. Mecanismos de Cardiotoxicidade</title>
        <p>Apesar de termos conhecimento de alguns mecanismos relacionados &#224; CTX, ainda permanece um grande desafio a identifica&#231;&#227;o do mecanismo predominante, visto que a combina&#231;&#227;o de diferentes f&#225;rmacos e o protocolo de tratamento e fatores constitucionais inerentes ao pr&#243;prio paciente comp&#245;em uma complexa combina&#231;&#227;o que resulta na les&#227;odo sistema cardiovascular ( <xref ref-type="table" rid="t2">Tabela 1</xref> ). Na depend&#234;ncia da classe de quimioter&#225;picos, o dano celular pode acontecer de forma direta ou indireta e, ainda, com potencial ou n&#227;o de reversibilidade. <xref ref-type="bibr" rid="B9"><sup>9</sup></xref> Ewer et al. <xref ref-type="bibr" rid="B10"><sup>10</sup></xref> propuseram, em 2005, a classifica&#231;&#227;o da CTX em tipos 1 e 2, que embora venha sendo alvo de muitas cr&#237;ticas, tem ajudado a separar em danos celulares irrevers&#237;veis (Tipo 1), atribu&#237;dos ao grupo das antraciclinas, e disfun&#231;&#245;es revers&#237;veis (Tipo 2), atribu&#237;das ao trastuzumabe. Com o desenvolvimento de novas terapias antic&#226;ncer, incluindo os inibidores da tirosinoquinase de Bruton, inibidores de proteasomas, inibidores de <italic>checkpoints</italic> , dentre outros sabidamente com potencial cardiot&#243;xico, parece que tal proposta de classifica&#231;&#227;o merece ser revisada e ampliada.</p>
        <table-wrap id="t2">
          <label>Tabela 1</label>
          <caption>
            <title>Resumo dos principais mecanismos sugeridos de CTX por grupo de f&#225;rmacos</title>
          </caption>
          <table frame="hsides" rules="rows">
            <colgroup width="50%">
              <col/>
              <col/>
            </colgroup>
            <tbody style="border-bottom: thin solid; border-color: #000000">
              <tr>
                <td align="left" rowspan="6" valign="middle">Antraciclinas</td>
                <td align="left" valign="middle">Quebra da cadeia de dupla h&#233;lice do DNA (topoisomerase IIB)</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Estresse oxidativo (esp&#233;cies reativas de oxig&#234;nio)</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Hiperpermeabilidade da membrana celular (peroxida&#231;&#227;o lip&#237;dica)</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Altera&#231;&#245;es ultraestruturais</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Vacuoliza&#231;&#227;o citoplasm&#225;tica</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Apoptose celular</td>
              </tr>
              <tr>
                <td align="left" rowspan="3" valign="middle">Trastuzumabe</td>
                <td align="left" valign="middle">Interrup&#231;&#227;o de sinaliza&#231;&#227;o receptor HER 2/ERBB2 &#8211; Neuregulina 1</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Inibe repara&#231;&#227;o celular</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Disfun&#231;&#227;o celular</td>
              </tr>
              <tr>
                <td align="left" rowspan="3" valign="middle">Cisplatina <break/> Ciclofosfamida</td>
                <td align="left" valign="middle">Les&#227;o endotelial direta</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Ativa&#231;&#227;o e agrega&#231;&#227;o plaquet&#225;ria</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Trombose coronariana</td>
              </tr>
              <tr>
                <td align="left" rowspan="2" valign="middle">5- Fluoracil</td>
                <td align="left" valign="middle">Atua na via de sinaliza&#231;&#227;o molecular que regula o t&#244;nus muscular liso</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Vasospasmo&#8211; vasoconstric&#231;&#227;o</td>
              </tr>
              <tr>
                <td align="left" rowspan="4" valign="middle">Inibidores do fator de crescimento endotelial vascular (VEGF)</td>
                <td align="left" valign="middle">Inibe a atividade do &#243;xido n&#237;trico sintase</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Aumento na produ&#231;&#227;o de endotelina</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Inibe a ativa&#231;&#227;o da Rho-quinase</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Vasospasmo</td>
              </tr>
              <tr>
                <td align="left" rowspan="2" valign="middle">Inibidores do proteasoma</td>
                <td align="left" valign="middle">Interfer&#234;ncia na degrada&#231;&#227;o de prote&#237;nas disfuncionais</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Altera&#231;&#245;es funcionais do mi&#243;cito</td>
              </tr>
              <tr>
                <td align="left" rowspan="2" valign="middle">Inibidores do <italic>checkpoint</italic> imunol&#243;gico</td>
                <td align="left" valign="middle">Aumento de atividade dos linf&#243;citos T</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Atividade autoimune no m&#250;sculo card&#237;aco</td>
              </tr>
            </tbody>
          </table>
        </table-wrap>
      </sec>
      <sec>
        <title>1.4. Manifesta&#231;&#245;es Cl&#237;nicas de Cardiotoxicidade</title>
        <p>As manifesta&#231;&#245;es cl&#237;nicas cardiovasculares decorrentes do tratamento oncol&#243;gico remetem &#224; ponta de um <italic>iceberg</italic> , cuja base consiste em altera&#231;&#245;es estruturais e funcionais que precedem sinais e sintomas. Com prop&#243;sitos did&#225;ticos, optamos por dividir as manifesta&#231;&#245;es de CTX em tr&#234;s subgrupos: cl&#237;nicas, laboratoriais e imagens/tra&#231;ados ( <xref ref-type="table" rid="t3">Tabela 2</xref> ). Cabe ressaltar que tal proposta poder&#225;, a princ&#237;pio, ser alvo de cr&#237;ticas, uma vez que ainda n&#227;o &#233; fact&#237;vel o mapeamento gen&#233;tico de rotina, a fim de melhor atribuirmos a culpabilidade da express&#227;o fenot&#237;pica.</p>
        <table-wrap id="t3">
          <label>Tabela 2</label>
          <caption>
            <title>Fen&#243;tipos de cardiotoxicidade</title>
          </caption>
          <table frame="hsides" rules="rows">
            <colgroup width="50%">
              <col/>
              <col/>
            </colgroup>
            <tbody style="border-bottom: thin solid; border-color: #000000">
              <tr>
                <td align="left" rowspan="9" valign="middle">Quadro cl&#237;nico</td>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>HAS</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Hipertens&#227;o pulmonar</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Acidentes emb&#243;licos venosos e arteriais</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Doen&#231;a arterial carot&#237;dea</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Insufici&#234;ncia card&#237;aca/miocardite</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Derrame peric&#225;rdico/pericardite</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Disfun&#231;&#245;es valvares</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Isquemia mioc&#225;rdica/infarto</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Doen&#231;a peric&#225;rdica</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" rowspan="2" valign="middle">Laboratoriais</td>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Eleva&#231;&#227;o de troponinas (T ou I) e/ou CKMB</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Eleva&#231;&#227;o de pept&#237;dio natriur&#233;tico (BNP/NT-pr&#243;-BNP)</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" rowspan="8" valign="middle">Imagem/Tra&#231;ados</td>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Transtornos do ritmo card&#237;aco (extrass&#237;stoles, bloqueios, taquicardias supraventriculares e ventriculares, bradiarritmias, aumento do intervalo QT corrigido do eletrocardiograma)</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Dilata&#231;&#227;o das c&#226;maras card&#237;acas com FEVE preservada</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Redu&#231;&#227;o da FEVE &gt; 10% da basal ou &gt; 15% do strain longitudinal global</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Disfun&#231;&#227;o diast&#243;lica do ventr&#237;culo esquerdo</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Espessamento e/ou derrame peric&#225;rdico</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Disfun&#231;&#245;es valvares (estenoses, insufici&#234;ncias)</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Altera&#231;&#245;es em exames de imagem que indiquem sinais inflamat&#243;rios em atividades ou necrose (cintilografia/resson&#226;ncia card&#237;aca)</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">
                  <list list-type="bullet">
                    <list-item>
                      <p>Altera&#231;&#245;es em exames de angiotomografia das art&#233;rias coron&#225;rias ou escore de c&#225;lcio que teve seu in&#237;cio ou agravamento durante ou ap&#243;s o tratamento oncol&#243;gico (QT e/ou RT)</p>
                    </list-item>
                  </list>
                </td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="TFN1">
              <p>HAS: hipertens&#227;o arterial sist&#234;mica; BNP: pept&#237;d&#237;o natriur&#233;tico cerebral; FEVE: fra&#231;&#227;o de eje&#231;&#227;o do ventr&#237;culo esquerdo; QT: quimioterapia; RT: radioterapia</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
        <p>Antraciclinas e anticorpos monoclonais anti-HER2 respondem pela maior parte dos casos documentados de disfun&#231;&#227;o ventricular esquerda. Cardinale et al. <xref ref-type="bibr" rid="B11"><sup>11</sup></xref> demonstraram que a incid&#234;ncia de CTX por uso de antraciclinas em uma popula&#231;&#227;o de 2.625 pacientes foi de 9%, com 98% dos casos no primeiro ano de tratamento. <xref ref-type="bibr" rid="B11"><sup>11</sup></xref> Agentes alquilantes, inibidores do proteassoma e alguns inibidores da tirosinoquinase tamb&#233;m causam disfun&#231;&#227;o por diversos mecanismos. <xref ref-type="bibr" rid="B4"><sup>4</sup></xref> Miocardite inflamat&#243;ria grave pode estar associada ao uso de inibidores de <italic>checkpoint</italic> imunol&#243;gicos em 0,27% nos pacientes com associa&#231;&#227;o de nivolumab e ipilimumab. <xref ref-type="bibr" rid="B12"><sup>12</sup></xref> </p>
        <p>A doen&#231;a arterial coronariana (DAC) manifesta clinicamente como angina est&#225;vel, inst&#225;vel ou IAM, pode ser secund&#225;ria &#224;les&#227;o endotelial direta, trombose arterial aguda ou vasospasmo, dependendo da classe terap&#234;utica usada. Aterosclerose obstrutiva, rotura de placa e trombose coronariana, degenera&#231;&#245;es anulovalvares e pericardites est&#227;o relacionadas com RT mediastinal e s&#227;o dependentes da dose de radia&#231;&#227;o utilizada.HAS encontra-se intimamente ligada ao uso de inibidores do fator de crescimento endotelial. Trombose venosa profunda (TVP), doen&#231;a arterial perif&#233;rica e hipertens&#227;o pulmonar (HP) tamb&#233;m comp&#245;em o leque de manifesta&#231;&#245;es cl&#237;nicas da CTX. <xref ref-type="bibr" rid="B4"><sup>4</sup></xref> </p>
      </sec>
    </sec>
    <sec>
      <title>2. Cardiotoxicidade Mioc&#225;rdica</title>
      <sec>
        <title>2.1. Contribui&#231;&#227;o da Ecocardiografia</title>
        <sec>
          <title>2.1.1. Avalia&#231;&#227;o Estrutural e Funcional Mioc&#225;rdica do Ventr&#237;culo Esquerdo</title>
          <sec>
            <title>2.1.1.1. Ecodopplercardiografia Padr&#227;o</title>
            <p>A partir do momento que a disfun&#231;&#227;o mioc&#225;rdica foi reconhecida como um potencial efeito adverso do tratamento oncol&#243;gico, diversas estrat&#233;gias foram testadas para monitorar a fun&#231;&#227;o mioc&#225;rdica. Considerada como o m&#233;todo de maior acur&#225;cia, a bi&#243;psia endomioc&#225;rdica rapidamente caiu em desuso devido ao seu car&#225;ter invasivo, sendo substitu&#237;da ent&#227;o pelo monitoramento seriado da fun&#231;&#227;o sist&#243;lica ventricular esquerda por exames n&#227;o invasivos de imagem cardiovascular.</p>
            <p>A ecocardiografia consolidou-se como a base do monitoramento da CTX por meio da FEVE, por ser um m&#233;todo amplamente dispon&#237;vel, custo-efetivo e in&#243;cuo, possibilitando ser repetido in&#250;meras vezes, al&#233;m de fornecer diversas outras informa&#231;&#245;es anat&#244;micas e funcionais.</p>
            <p>A aplica&#231;&#227;o do m&#233;todo de Simpson melhora a estimativa dos volumes cavit&#225;rios, superando as limita&#231;&#245;es do encurtamento fracional e da f&#243;rmula de <italic>Teichholz</italic> , obtidos a partir de medidas lineares da ecocardiografia modo M ou bidimensional (2D). Entretanto, sua sensibilidade em detectar pequenas varia&#231;&#245;es longitudinais na fun&#231;&#227;o sist&#243;lica ainda &#233; baixa, principalmente devido a varia&#231;&#245;es frequentes de pr&#233; e p&#243;s-carga durante a QT e da variabilidade intra e interobservador que podem atingir at&#233; 10% (justamente um dos par&#226;metros mais aceitos para o diagn&#243;stico de CTX). <xref ref-type="bibr" rid="B13"><sup>13</sup></xref> Importante lembrar que, em virtude dessas varia&#231;&#245;es, exames com resultado fora dos par&#226;metros esperados devem ser repetidos e confirmados ap&#243;s 2 a 3 semanas do achado inicial.</p>
            <p>Considera-se que o risco de CTX varia de 3,6 a 11,8 vezes no caso do emprego de f&#225;rmacos cardiot&#243;xicos (em especial das antraciclinas) se a FEVE pr&#233;-tratamento estiver entre 50% e 55%. Durante o monitoramentoe ap&#243;s o tratamento oncol&#243;gico, sugere-se que a identifica&#231;&#227;o da CTX pelo bidimensional se baseie na queda da FEVE &gt; 10% (em rela&#231;&#227;o aos valores pr&#233;-tratamento) para menos de 50%. <xref ref-type="bibr" rid="B14"><sup>14</sup></xref> Essa situa&#231;&#227;o &#233; alvo de importante debate nas equipes m&#233;dicas no que tange a risco cardiol&#243;gico e benef&#237;cio oncol&#243;gico. Entre as condutas debatidas, encontram-se a troca por tratamentos com menor risco cardiot&#243;xico, o emprego de medidas cardioprotetoras e at&#233; mesmo a suspens&#227;o do tratamento sempre em acordo com o oncologista. <xref ref-type="bibr" rid="B14"><sup>14</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B15"><sup>15</sup></xref> </p>
            <p>O estudo da fun&#231;&#227;o sist&#243;lica longitudinal, em especial na indisponibilidade das metodologias avan&#231;adas (ecocardiografia tridimensional [3D] e estudo da deforma&#231;&#227;o mioc&#225;rdica) deve ser avaliado conjuntamente. Embora n&#227;o exista valores de refer&#234;ncia para o diagn&#243;stico, &#233; necess&#225;rio valorizar o progressivo decl&#237;nio da medida do pico de velocidade sist&#243;lica do anel mitral pelo Doppler tecidual (onda s&#8217;) e do deslocamento sist&#243;lico do anel mitral (MAPSE). <xref ref-type="bibr" rid="B16"><sup>16</sup></xref> </p>
            <p>O n&#250;mero de vezes que se faz necess&#225;ria a realiza&#231;&#227;o do estudo ecocardiogr&#225;fico ainda gera discuss&#227;o na literatura, variando conforme o risco individual, protocolo terap&#234;utico (f&#225;rmacos empregados e dosagem total) e identifica&#231;&#227;o de sinais e sintomas de CTX.</p>
            <p>&#201; importante lembrar que a CTX, na forma de altera&#231;&#245;es quantitativas nos par&#226;metros convencionais de avalia&#231;&#227;o da fun&#231;&#227;o sist&#243;lica, pode n&#227;o ser evidente at&#233; que haja uma redu&#231;&#227;o substancial na reserva mioc&#225;rdica. Assim, o dano card&#237;aco pode n&#227;o se tornar aparente por anos ou at&#233; mesmo d&#233;cadas ap&#243;s o t&#233;rmino do tratamento cardiot&#243;xico, fato que &#233; particularmente aplic&#225;vel a adultos sobreviventes de tumores durante a inf&#226;ncia.</p>
          </sec>
          <sec>
            <title>2.1.1.2. Strain Mioc&#225;rdico</title>
            <p>O <italic>strain</italic> , ou deforma&#231;&#227;o, &#233; definido como a quantidade de deforma&#231;&#227;o ou a mudan&#231;a fracional no comprimento de um segmento do mioc&#225;rdio, relacionada ao seu comprimento inicial. Tal par&#226;metro &#233; expresso em porcentagem (%) e com o sinal negativo. <xref ref-type="bibr" rid="B17"><sup>17</sup></xref> </p>
            <p>O <italic>strain</italic> 2D, derivado da t&#233;cnica do rastreamento de pontos ( <italic>speckle tracking</italic> ), n&#227;o sofre depend&#234;ncia do &#226;ngulo (fator limitante quando empregada a t&#233;cnica pelo Doppler tecidual), sendo mais reprodut&#237;vel e utilizada na pr&#225;tica cl&#237;nica geral com o intuito de se detectar precocemente as altera&#231;&#245;es da mec&#226;nica mioc&#225;rdica. <xref ref-type="bibr" rid="B17"><sup>17</sup></xref> O <italic>strain</italic> 3D representa um aprimoramento da t&#233;cnica. Nessa modalidade, todo um volume piramidal &#233; analisado, obtido pela captura registrada em posi&#231;&#227;o apical, de maneira bem mais r&#225;pida que as outras modalidades, mascom menor resolu&#231;&#227;o espacial e temporal.</p>
            <p>A queda da FEVE reflete um marcador de dano mioc&#225;rdico tardio, acompanhado por pior progn&#243;stico, com menor possibilidade de recupera&#231;&#227;o da fun&#231;&#227;o ventricular em 58% dos pacientes, apesar da interven&#231;&#227;o com medicamentos cardioprotetores. A disfun&#231;&#227;o card&#237;aca somente se torna evidente quando o dano mioc&#225;rdico &#233; significativo; por conseguinte, a aus&#234;ncia de redu&#231;&#227;o da FEVE n&#227;o exclui CTX. <xref ref-type="bibr" rid="B18"><sup>18</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B19"><sup>19</sup></xref> </p>
            <p>Deste modo, a aplica&#231;&#227;o do <italic>strain</italic> pela t&#233;cnica do <italic>speckle tracking</italic> para analisar a mec&#226;nica ventricular gradativamente est&#225; se estendendo a todas as cardiopatias, especialmente aquelas associadas ao uso de antineopl&#225;sicos, como antrac&#237;clicos e trastuzumabe. <xref ref-type="bibr" rid="B20"><sup>20</sup></xref> A possibilidade da detec&#231;&#227;o de les&#245;es subcl&#237;nicas tem sido uma das grandes vantagens na sua utiliza&#231;&#227;o. De um modo geral, embora a detec&#231;&#227;o precoce das mudan&#231;as seja conceitualmente importante, o valor dessas reais altera&#231;&#245;es deve comprovadamente se correlacionar com os desfechos.</p>
            <p>Revis&#227;o de v&#225;rios estudos demonstraram a capacidade do <italic>strain</italic> na detec&#231;&#227;o das altera&#231;&#245;es de deforma&#231;&#227;o mioc&#225;rdica de forma mais precoce que a queda da FEVE, seja imediatamente ap&#243;s a infus&#227;o da terapia ou em est&#225;gios mais tardios. <xref ref-type="bibr" rid="B21"><sup>21</sup></xref> </p>
            <p>Ganame et al. <xref ref-type="bibr" rid="B22"><sup>22</sup></xref> demonstraram os efeitos agudos dos antrac&#237;licos, capazes de induzir disfun&#231;&#227;o sist&#243;lica. <xref ref-type="bibr" rid="B22"><sup>22</sup></xref> O mesmo grupo estudou 56 pacientes sem fatores de risco para doen&#231;a cardiovascular (DCV), com diagn&#243;stico de linfoma, leucemia e outros tumores malignos, tratados somente com antrac&#237;clicos (dose menor que 300mg/m<sup>2</sup>) e comparados com um grupo controle. <xref ref-type="bibr" rid="B23"><sup>23</sup></xref> Ap&#243;s seguimento m&#233;dio de 5,2 anos, foi demonstrada uma redu&#231;&#227;o significativa do <italic>strain</italic> longitudinal global (SLG) em um momento em que a FEVE ainda era normal, sinalizando que novas ferramentas diagn&#243;sticas eram capazes de prever precocemente esse decl&#237;nio.</p>
            <p>Sawaya et al., <xref ref-type="bibr" rid="B24"><sup>24</sup></xref> utilizando o <italic>speckle tracking</italic> 2D, demonstraram que o SLG e a troponina foram preditores de disfun&#231;&#227;o sist&#243;lica em pacientes com c&#226;ncer de mama submetidos ao tratamento com antrac&#237;clicos e trastuzumabe. <xref ref-type="bibr" rid="B24"><sup>24</sup></xref> Quarenta e tr&#234;s pacientes realizaram ECO antes, no terceiro e sexto m&#234;s do tratamento. Foram avaliados FEVE pelo m&#233;todo de Simpson biplanar, SLG, radial, circunferencial e biomarcadores. Nesse estudo, o SLG foi capaz de prever CTX em sete dos nove pacientes, com sensibilidade de 78% e especificidade de 79%. O evento ocorreu no terceiro m&#234;s de seguimento em uma das pacientes e no sexto m&#234;s entre as demais.</p>
            <p>Tan et al. <xref ref-type="bibr" rid="B25"><sup>25</sup></xref> examinaram a FEVE e o SLG em 19 pacientes com c&#226;ncer de mama em uso de trastuzumabe, acompanhadas por um per&#237;odo de 34 meses (m&#233;dia de 24,7 meses). Observaram que as pacientes mantiveram altera&#231;&#245;es da fun&#231;&#227;o ventricular por longo per&#237;odo, com aumento dos di&#226;metros intracavit&#225;rios e redu&#231;&#227;o do SLG ao longo de todo o acompanhamento, questionando a reversibilidade da les&#227;o causada pelo trastuzumabe. <xref ref-type="bibr" rid="B25"><sup>25</sup></xref> </p>
            <p>Almeida et al. analisaram 40 pacientes com c&#226;ncer de mama que tinham usado a doxorrubicina dois anos antes do ecocardiograma e compararam com 41 mulheres saud&#225;veis. Os autores demonstraram que o SLG e a onda S&#180; do anel mitral estavam reduzidos nas pacientes que fizeram QT, apesar de manterem FEVE normal, sugerindo a presen&#231;a de disfun&#231;&#227;o ventricular subcl&#237;nica. Os autores mostraram ainda que a idade e o uso pr&#233;vio da doxorrubicina foram marcadores independentes de redu&#231;&#227;o do SLG. <xref ref-type="bibr" rid="B26"><sup>26</sup></xref> </p>
            <p>Recentemente, Piveta et al. <xref ref-type="bibr" rid="B27"><sup>27</sup></xref> avaliaram o papel do <italic>strain</italic> 3D em pacientes com c&#226;ncer de mama submetidos a tratamento com antrac&#237;clicos. Ap&#243;s exposi&#231;&#227;o &#224; baixa dose do quimioter&#225;pico (120 mg/m<sup>2</sup>) apenas o <italic>strain</italic> circunferencial 3D e a <italic>&#225;rea do strain</italic> 3D apresentaram altera&#231;&#227;o, enquanto os par&#226;metros derivados do <italic>strain</italic> 2D permaneceram inalterados. <xref ref-type="bibr" rid="B27"><sup>27</sup></xref> </p>
            <p>Revis&#227;o sistem&#225;tica com 1.504 pacientes mostrou que a redu&#231;&#227;o relativa de 10% a 15% do SLG em rela&#231;&#227;o ao valor basal foi importante preditor para o decl&#237;nio da FEVE. Medidas do strain radial e circunferencial tamb&#233;m apresentam altera&#231;&#227;o, por&#233;m tais vari&#225;veis ainda n&#227;o s&#227;o utilizadas rotineiramente. Na aus&#234;ncia de valores pr&#233;-QT para compara&#231;&#227;o, valores de SLG superiores a -19% s&#227;o sugestivos de CTX, sendo que a associa&#231;&#227;o com biomarcadores, em especial a troponina ultrassens&#237;vel, aumenta a sensibilidade para o diagn&#243;stico de CTX. &#201; importante ressaltar que os valores de refer&#234;ncia de normalidade sofrem varia&#231;&#245;es a depender dos <italic>softwares</italic> dos aparelhos, idade e sexo dos pacientes. Da&#237; a recomenda&#231;&#227;o para se repetir os exames sempre no mesmo aparelho e, de prefer&#234;ncia, com o mesmo examinador. <xref ref-type="bibr" rid="B21"><sup>21</sup></xref> </p>
            <p>Consenso das Sociedades Americana e Europeia de Imagem Cardiovascular sugere que as altera&#231;&#245;es de deforma&#231;&#227;o precedem a disfun&#231;&#227;o ventricular. <xref ref-type="bibr" rid="B28"><sup>28</sup></xref> Uma redu&#231;&#227;o de &gt;15% do SLG, imediatamente ap&#243;s ou durante o tratamento com antrac&#237;clicos, mostra-se o par&#226;metro mais &#250;til em predizer CTX, enquanto uma redu&#231;&#227;o menor que 8%, provavelmente, excluiria o diagn&#243;stico de CTX ( <xref ref-type="fig" rid="f1">Figura 1</xref> ).</p>
            <fig id="f1">
              <label>Figura 1</label>
              <caption>
                <title>Monitoramento e manejo cl&#237;nico durante terapia cardiot&#243;xica.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf01.tif"/></fig>
            <p>Em 2018, Liu et al. <xref ref-type="bibr" rid="B29"><sup>29</sup></xref> descreveram algoritmo de acompanhamento de pacientes submetidos a tratamento com antineopl&#225;sicos, no qual as ferramentas ecocardiogr&#225;ficas utilizadas foram a FEVE e o SLG. Nos pacientes que apresentaram FEVE &gt; 60%, a recomenda&#231;&#227;o foi otimizar o controle dos fatores de risco cardiovasculares existentes. Aqueles com FEVE entre 50% e 59% e com SLG menor que-16% ou no limite inferior da normalidade foram classificados como fun&#231;&#227;o mioc&#225;rdica preservada; j&#225; os que apresentavam o SLG maior que -16% ou uma redu&#231;&#227;o percentual de 15% em rela&#231;&#227;o ao valor basal foram considerados com disfun&#231;&#227;o subcl&#237;nica. Os pacientes que apresentaram FEVE entre 40% e 49% foram considerados portadores de disfun&#231;&#227;o mioc&#225;rdica, sendo indicados in&#237;cio de terapia cardioprotetora e avalia&#231;&#227;o em conjunto com o oncologista sobre riscos e benef&#237;cios da terapia antineopl&#225;sica nesse grupo espec&#237;fico, podendo eventualmente ser indicada redu&#231;&#227;o da dose ou troca da medica&#231;&#227;o. Empacientes com FE&lt;40%, recomenda-se iniciar terapia cardioprotetora e discutir com o oncologista o uso de terapia alternativa n&#227;o cardiot&#243;xica.</p>
            <p>N&#227;o h&#225; consenso a respeito dos &#237;ndices de fun&#231;&#227;o sist&#243;lica a serem acompanhadas ao longo do tratamento. <xref ref-type="bibr" rid="B14"><sup>14</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B15"><sup>15</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B29"><sup>29</sup></xref> Por&#233;m, recentemente, foi publicado o estudo SUCCOUR ( <italic>Strain sUrveillance of Chemotherapy for improving Cardiovascular Outcomes</italic> ) em que foi demonstrado que o tratamento guiado pela queda maior de 12% do strain global longitudinal do VE nos pacientes tratados com antrac&#237;clicos &#233; capaz de evitar a queda da fra&#231;&#227;o de eje&#231;&#227;o e de cardiotoxicidade em 1 ano. <xref ref-type="bibr" rid="B30"><sup>30</sup></xref> </p>
            <p>Al&#233;m do diagn&#243;stico de CTX, a identifica&#231;&#227;o da redu&#231;&#227;o do SLG apresenta valor progn&#243;stico, tendo sido associado &#224; maior mortalidade tardia em estudo retrospectivo, envolvendo 120 pacientes acompanhados por um per&#237;odo de 21,6 &#177; 13,9 meses. <xref ref-type="bibr" rid="B31"><sup>31</sup></xref> </p>
          </sec>
          <sec>
            <title>2.1.1.3. Fra&#231;&#227;o de Eje&#231;&#227;o do Ventr&#237;culo Esquerdo pelo M&#233;todo 3D</title>
            <p>O estudo 3D &#233; o m&#233;todo ecocardiogr&#225;fico de escolha para o c&#225;lculo da FEVE durante o tratamento oncol&#243;gico ( <xref ref-type="fig" rid="f2">Figura 2</xref> ). <xref ref-type="bibr" rid="B32"><sup>32</sup></xref> Ao proporcionar maior proximidade &#224; anatomia card&#237;aca, redunda em grande converg&#234;ncia com resultados obtidos pela resson&#226;ncia magn&#233;tica card&#237;aca (RMC) no c&#225;lculo dos volumes, massa e FEVE. <xref ref-type="bibr" rid="B33"><sup>33</sup></xref> O estudo 3D n&#227;o depende de presun&#231;&#245;es geom&#233;tricas, como ocorre com a an&#225;lise 2D, al&#233;m de minimizar limita&#231;&#245;es relacionadas a tal t&#233;cnica como o &#8220;encurtamento apical&#8221;.</p>
            <fig id="f2">
              <label>Figura 2</label>
              <caption>
                <title>Exemplo de estudo ecocardiogr&#225;fico tridimensional com an&#225;lise do full volume e estimativa dos volumes e FEVE.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf02.tif"/></fig>
            <p>A altera&#231;&#227;o predominante na CTX para consequente queda na FEVE &#233; o aumento do volume sist&#243;lico final do VE. <xref ref-type="bibr" rid="B15"><sup>15</sup></xref> Na popula&#231;&#227;o oncol&#243;gica, estudos sugerem que a t&#233;cnica 3D &#233; prefer&#237;vel &#224; 2D principalmente por ter demonstrado maior reprodutibilidade e maior acur&#225;cia no reconhecimento de FEVE lim&#237;trofe ou discretamente reduzida. Em sobreviventes de c&#226;ncer tratados com antrac&#237;clicos, Armstrong et al. <xref ref-type="bibr" rid="B34"><sup>34</sup></xref> demonstraram maior capacidade da t&#233;cnica 3D em identificar pacientes com FEVE &lt; 50% do que a avalia&#231;&#227;o 2D, com acur&#225;cia muito similar &#224; RMC, o que possibilita a identifica&#231;&#227;o mais precoce dos casos de CTX subcl&#237;nica. <xref ref-type="bibr" rid="B34"><sup>34</sup></xref> O estudo SUCCOUR utilizou dois crit&#233;rios de cardiotoxicidade pelo ecocardiograma preferencialmente 3D: queda maior de 5% nos pacientes com sintomas de insufici&#234;ncia card&#237;aca, ou maior de 10% nos assintom&#225;ticos, comparado com o exame inicial ( <italic>baseline</italic> ) para valores da fra&#231;&#227;o de eje&#231;&#227;o menores de 55%. <xref ref-type="bibr" rid="B30"><sup>30</sup></xref> </p>
            <p>Em pacientes sob tratamento quimioter&#225;pico, Thavendiranathan et al. <xref ref-type="bibr" rid="B13"><sup>13</sup></xref> compararam diferentes t&#233;cnicas ecocardiogr&#225;ficas para a avalia&#231;&#227;o seriada da FEVE ao longo de 1 ano e demonstraram que a t&#233;cnica 3D apresentou a menor variabilidade temporal intra e interobservador (5,6%). <xref ref-type="bibr" rid="B13"><sup>13</sup></xref> Este dado sugere que, al&#233;m de confi&#225;vel, o estudo 3D representa um m&#233;todo consistente e reprodut&#237;vel para a avalia&#231;&#227;o dos pacientes oncol&#243;gicos. <xref ref-type="bibr" rid="B32"><sup>32</sup></xref> Outros trabalhos tamb&#233;m destacam a maior reprodutibilidade da t&#233;cnica 3D no c&#225;lculo da FEVE, principalmente porque, tratando-se de t&#233;cnica semiautom&#225;tica para o tra&#231;ado endoc&#225;rdico, &#233; menos afetada pela variabilidade na aquisi&#231;&#227;o das imagens. <xref ref-type="bibr" rid="B35"><sup>35</sup></xref> </p>
          </sec>
          <sec>
            <title>2.1.1.4. Ecocardiografia com Contraste</title>
            <p>A visibiliza&#231;&#227;o inadequada das bordas endoc&#225;rdicas do VE ocorre frequentemente em pacientes sob tratamento quimioter&#225;pico de c&#226;ncer de mama, em particular ap&#243;s mastectomia e RT. Como consequ&#234;ncia, pode ocorrer subestimativa de volumes e determina&#231;&#227;o n&#227;o acurada da FEVE. De acordo com diretrizes internacionais, um agente ultras&#244;nico de contraste deve ser utilizado para a melhora do delineamento de bordas endoc&#225;rdicas e da an&#225;lise da fun&#231;&#227;o ventricular esquerda quando a visibiliza&#231;&#227;o endoc&#225;rdica em dois ou mais segmentos estiver limitada. <xref ref-type="bibr" rid="B36"><sup>36</sup></xref> Por outro lado, os agentes de contraste n&#227;o s&#227;o recomendados quando se estima a FEVE ao ecocardiograma 3D, pois acarretam menor reprodutibilidade e maior variabilidade temporal da FEVE do que ao se empregar o 3D isoladamente. <xref ref-type="bibr" rid="B13"><sup>13</sup></xref> </p>
          </sec>
          <sec>
            <title>2.1.1.5. Ecocardiografia sob Estresse</title>
            <p>A ecocardiografia sob estresse f&#237;sico ou farmacol&#243;gico &#233; um m&#233;todo estabelecido para detectar DAC obstrutiva e altera&#231;&#245;es subcl&#237;nicas da fun&#231;&#227;o mioc&#225;rdica. Pacientes oncol&#243;gicos frequentemente t&#234;m diminui&#231;&#227;o da reserva cardiovascular global, atribu&#237;da aos efeitos diretos da terapia adjuvante do c&#226;ncer e/ou aos efeitos indiretos das mudan&#231;as de estilo de vida associadas ao tratamento. <xref ref-type="bibr" rid="B37"><sup>37</sup></xref> Assim, as potenciais utilidades para o emprego da ecocardiografia sob estresse nos pacientes sob terapia do c&#226;ncer incluem: (a) investiga&#231;&#227;o inicial da presen&#231;a de DAC obstrutiva em pacientes com probabilidade pr&#233;-teste intermedi&#225;ria a alta, ECG n&#227;o interpret&#225;vel (f&#237;sico) ou incapazes de se exercitar (dobutamina), especialmente se recebendo quimioter&#225;picos associados &#224; isquemia ou ap&#243;s RT de longa data; (b) determina&#231;&#227;o da RCVE como preditor de CTX em pacientes com FEVE e SLG normais em repouso; (c) determina&#231;&#227;o da RCVE na CTX instalada, na medida em que a recupera&#231;&#227;o transit&#243;ria da fun&#231;&#227;o do VE durante o estresse poderia indicar melhor progn&#243;stico. <xref ref-type="bibr" rid="B28"><sup>28</sup></xref> Apesar dessas potencialidades, a ecocardiografia sob estresse tem sido pouco empregada no campo da cardio-oncologia.</p>
            <p>Utilizando o ecocardiograma sob estresse f&#237;sico em 57 mulheres assintom&#225;ticas com FEVE normal, tratadas de c&#226;ncer de mama com antraciclinas, Khouri et al. <xref ref-type="bibr" rid="B38"><sup>38</sup></xref> demonstraram redu&#231;&#227;o da RCVE por meio da redu&#231;&#227;o no volume sist&#243;lico em 12% e no &#237;ndice card&#237;aco em 24% em rela&#231;&#227;o ao repouso quando comparadas aos controles. <xref ref-type="bibr" rid="B38"><sup>38</sup></xref> </p>
            <p>Civelli et al. <xref ref-type="bibr" rid="B39"><sup>39</sup></xref> mediram prospectivamente a RCVE (definida pela diferen&#231;a entre a FEVE no pico e no repouso) por meio do ecocardiograma com dobutamina em baixa dose durante e ap&#243;s QT em alta dose em 49 mulheres com c&#226;ncer de mama avan&#231;ado. Um decl&#237;nio assintom&#225;tico &#8805; 5% da RCVE em rela&#231;&#227;o ao basal foi capaz de predizer queda na FEVE para &lt; 50%. <xref ref-type="bibr" rid="B39"><sup>39</sup></xref> </p>
            <p>A &#250;nica revis&#227;o sistem&#225;tica publicada sobre a utilidade dos m&#233;todos de estresse card&#237;aco para detec&#231;&#227;o de DCV em sobreviventes do c&#226;ncer de mama concluiu que parece haver evid&#234;ncias de que a ecocardiografia sob estresse traga benef&#237;cio para a avalia&#231;&#227;o progn&#243;stica precoce e seguimento tardio ap&#243;s terapia com antraciclinas. <xref ref-type="bibr" rid="B40"><sup>40</sup></xref> </p>
            <p>Antes que a incorpora&#231;&#227;o da ecocardiografia sob estresse possa ser rotineiramente adicionada &#224; pr&#225;tica cl&#237;nica cardio-oncol&#243;gica, mais estudos s&#227;o necess&#225;rios para determinar o melhor agente estressor, quaispar&#226;metros devem ser medidos durante o exame, o melhor momento em que deve ser realizado o exame de acordo com os diferentes tipos de tratamento, o custo-benef&#237;cio e a exequibilidade na popula&#231;&#227;o oncol&#243;gica e, finalmente, a presen&#231;a de valor incremental progn&#243;stico sobre os par&#226;metros tradicionais medidos no repouso (FEVE e SLG).</p>
          </sec>
          <sec>
            <title>2.1.1.6. Fun&#231;&#227;o Diast&#243;lica</title>
            <p>Anormalidades em par&#226;metros relacionados com a fun&#231;&#227;o diast&#243;lica, tais como ondas E e A, rela&#231;&#227;o E/A, tempo de relaxamento isovolum&#233;trico e &#237;ndice de <italic>performance</italic> mioc&#225;rdica, foram descritas precocemente ap&#243;s QT. <xref ref-type="bibr" rid="B41"><sup>41</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B42"><sup>42</sup></xref> Entretanto, estudos longitudinais n&#227;o foram capazes de reproduzir o valor progn&#243;stico desses achados e n&#227;o h&#225; evid&#234;ncias suficientes para recomendar essa an&#225;lise no diagn&#243;stico de CTX induzida por quimioter&#225;picos. <xref ref-type="bibr" rid="B43"><sup>43</sup></xref> </p>
            <p>Estudos demonstraram a utilidade da an&#225;lise derivada do Doppler tecidual (DT) durante a avalia&#231;&#227;o da fun&#231;&#227;o diast&#243;lica em pacientes sob tratamento contra o c&#226;ncer. Trabalhos revelaram redu&#231;&#227;o na velocidade diast&#243;lica precoce (onda e&#8217;) derivada do DT do anel mitral em pacientes tratados com antrac&#237;clicos, que permaneceu reduzida durante o tratamento e anos ap&#243;s seu t&#233;rmino, n&#227;o demonstrando, entretanto, valor preditivo de CTX. <xref ref-type="bibr" rid="B16"><sup>16</sup></xref> Negishi et al. <xref ref-type="bibr" rid="B44"><sup>44</sup></xref> revelaram que uma redu&#231;&#227;o de 10% na velocidade da onda e&#8217; foi observada em pacientes que desenvolveram CTX ap&#243;s tratamento com maiores doses cumulativas de doxorrubicina, mas esse par&#226;metro n&#227;o demonstrou papel preditivo de queda da FEVE. <xref ref-type="bibr" rid="B44"><sup>44</sup></xref> </p>
            <p>Questiona-se a utiliza&#231;&#227;o da disfun&#231;&#227;o diast&#243;lica como marcador espec&#237;fico de CTX. As altera&#231;&#245;es podem ocorrer por mudan&#231;as nas condi&#231;&#245;es de pr&#233;-carga, como resultado de reposi&#231;&#245;es vol&#234;micas associadas ao tratamento oncol&#243;gico ou deple&#231;&#227;o de volume devido a efeitos colaterais da QT, como n&#225;useas, v&#244;mito e diarreia. Nesses casos, podem n&#227;o representar uma mudan&#231;a real no desempenho diast&#243;lico do ventr&#237;culo esquerdo (VE).</p>
          </sec>
        </sec>
        <sec>
          <title>2.1.2. Avalia&#231;&#227;o Estrutural e Funcional Mioc&#225;rdica do Ventr&#237;culo Direito</title>
          <p>A preval&#234;ncia do envolvimento do ventr&#237;culo direito (VD) e seu valor progn&#243;stico ainda n&#227;o foram adequadamente estudados. Dados a respeito da influ&#234;ncia da QT no remodelamento, na fun&#231;&#227;o e na mec&#226;nica ventricular direita s&#227;o escassos e, por vezes, conflitantes.</p>
          <p>A dificuldade inerente &#224; avalia&#231;&#227;o do VD e &#224;s varia&#231;&#245;es determinadas pelas condi&#231;&#245;es hemodin&#226;micas sugerem que par&#226;metros tais como excurs&#227;o sist&#243;lica do anel tric&#250;spide (TAPSE), velocidade tecidual da regi&#227;o basal da parede livre do VD (onda S`), fra&#231;&#227;o da varia&#231;&#227;o da &#225;rea do VD (FAC), al&#233;m da deformidade mioc&#225;rdica pelo <italic>strain</italic> sejam os m&#233;todos ideais pela ecocardiografia, deixando a avalia&#231;&#227;o da fra&#231;&#227;o de eje&#231;&#227;o do ventr&#237;culo direito (FEVD) para a Resson&#226;ncia Magn&#233;tica Card&#237;aca, ou ecocardiografia 3D.</p>
          <p>Entre os f&#225;rmacos mais frequentemente relacionados com disfun&#231;&#227;o do VD e altera&#231;&#245;es na circula&#231;&#227;o pulmonar, temos: antraciclinas, trastuzumabe, ciclofosfamida e dasatinibe. <xref ref-type="bibr" rid="B45"><sup>45</sup></xref> Boczar et al, avaliaram o <italic>strain</italic> longitudinal do VD em pacientes com c&#226;ncer de mama tratadas com antraciclina. Ap&#243;s 3 meses, observaram uma redu&#231;&#227;o do <italic>strain</italic> de -16,2% para -13,81%. <xref ref-type="bibr" rid="B46"><sup>46</sup></xref> A diferen&#231;a do <italic>strain</italic> longitudinal do VD &#233; mais pronunciada quando desconsiderada a regi&#227;o septal, sugerindo uma sensibilidade maior do mioc&#225;rdico do VD. <xref ref-type="bibr" rid="B47"><sup>47</sup></xref> </p>
        </sec>
        <sec>
          <title>2.1.3. Seguimento Ecocardiogr&#225;fico Tardio</title>
          <p>As recomenda&#231;&#245;es acerca do acompanhamento dos pacientes ap&#243;s a finaliza&#231;&#227;o da QT variam de acordo com as caracter&#237;sticas cl&#237;nicas da popula&#231;&#227;o estudada, do protocolo utilizado na QT (com ou sem RT) e da dose cumulativa dos f&#225;rmacos (principalmente trastuzumabe e antrac&#237;clicos). Devido ao maior risco de desenvolver CTX nos primeiros 12 meses ap&#243;s antraciclina, &#224; queda da FEVE durante o uso de trastuzumabe e ao surgimento de complica&#231;&#245;es tardias p&#243;s RT, sugerimos o acompanhamento tardio, conforme mostrado na <xref ref-type="fig" rid="f3">Figura 3</xref> .</p>
          <fig id="f3">
            <label>Figura 3</label>
            <caption>
              <title>Recomenda&#231;&#245;es para o seguimento ecocardiogr&#225;fico tardio.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf03.tif"/></fig>
        </sec>
      </sec>
      <sec>
        <title>2.2. Contribui&#231;&#227;o da Medicina Nuclear</title>
        <sec>
          <title>2.2.1. Ventriculografia Radionucl&#237;dica ou Radiosiot&#243;pica</title>
          <p>A ventriculografia radioisot&#243;pica (do ingl&#234;s, <italic>multigated radionuclide angiography</italic> [MUGA]) &#233; um exame cintilogr&#225;fico, realizado em equipamento de gama-c&#226;mara, no servi&#231;o de medicina nuclear (MN). Trata-se de um m&#233;todo n&#227;o invasivo, com baixa taxa de exposi&#231;&#227;o &#224; radia&#231;&#227;o e que n&#227;o determina efeitos colaterais graves, com &#243;tima reprodutibilidade e baixa variabilidade inter e intraobservadores na avalia&#231;&#227;o da fun&#231;&#227;o ventricular. <xref ref-type="bibr" rid="B48"><sup>48</sup></xref> </p>
          <p>Juntamente com a ecocardiografia, a ventriculografia radioisot&#243;pica &#233; o m&#233;todo mais amplamente aceito para avaliar a FEVE de pacientes antes e durante tratamento do c&#226;ncer na identifica&#231;&#227;o do risco para IC cr&#244;nica (90% de sensibilidade e 72% de especificidade). <xref ref-type="bibr" rid="B49"><sup>49</sup></xref> </p>
          <p>Com uma FEVE basal normal, as pr&#243;ximas medi&#231;&#245;es devem ser feitas em doses cumulativas de 250 a 300 e 400 a 450mg/m<sup>2</sup>. Para pacientes com FEVE basal anormal (&lt; 50%), estudos seriados s&#227;o recomendados antes de cada dose subsequente de doxorrubicina. A <xref ref-type="fig" rid="f4">Figura 4</xref> mostra exemplos de comportamento da FEVE, avaliada pela ventriculografia radioisot&#243;pica, em pacientes realizando QT.</p>
          <fig id="f4">
            <label>Figura 4</label>
            <caption>
              <title>Exemplos de dois pacientes que realizaram ventriculografia radioisot&#243;pica para medi&#231;&#227;o da FEVE antes e ap&#243;s o t&#233;rmino da quimioterapia (QT) com antrac&#237;clicos. Na fileira superior, &#224; esquerda, est&#225; a FEVE basal do primeiro paciente, que foi de 71% (normal), e ap&#243;s o t&#233;rmino da QT e in&#237;cio de tratamento com trastuzumabe, houve queda da FEVE para 50% (superior &#224; direita). Na fileira inferior, paciente com c&#226;ncer de mama tinha uma FEVE de 52% antes do in&#237;cio da QT e, no acompanhamento, houve redu&#231;&#227;o da FEVE para 46%, o que motivou in&#237;cio de medica&#231;&#245;es cardioprotetoras. Imagens gentilmente cedidas pela Dra. M&#225;rcia Modesto (Servi&#231;o de Medicina Nuclear do Instituto Brasileiro de Controle do C&#226;ncer, S&#227;o Paulo, Brasil).</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf04.tif"/></fig>
        </sec>
        <sec>
          <title>2.2.2. Avalia&#231;&#227;o da Atividade Simp&#225;tica Card&#237;aca com mIBG</title>
          <p>A metaiodobenzilguanidina (mIBG) &#233; uma mol&#233;cula com estrutura similar a NE e age seletivamente sobre os nervos simp&#225;ticos sem, no entanto, ser metabolizada pela monoamina oxidase ou pela catecol-O-metil transferase, e n&#227;o exercendo efeito estimulat&#243;rio, como a norepinefrina (NE). A cintilografia card&#237;aca com mIBG-I <xref ref-type="bibr" rid="B123"><sup>123</sup></xref> avalia diretamente a fun&#231;&#227;o simp&#225;tica global e regional do cora&#231;&#227;o, incluindo a capta&#231;&#227;o, a recapta&#231;&#227;o, o armazenamento e os processos de libera&#231;&#227;o da NE nas termina&#231;&#245;es nervosas pr&#233;-sin&#225;pticas. <xref ref-type="bibr" rid="B50"><sup>50</sup></xref> </p>
          <p>Guimar&#227;es et al. <xref ref-type="bibr" rid="B51"><sup>51</sup></xref> realizaram a cintilografia card&#237;aca com mIBG-I <xref ref-type="bibr" rid="B123"><sup>123</sup></xref> em 20 mulheres com c&#226;ncer de mama e FEVE normal que tinham sido submetidas a tratamento com derivados das antraciclinas associado ou n&#227;o ao trastuzumabe. Os autores observaram que o uso da antraciclina com o trastuzumabe proporcionou maior frequ&#234;ncia e intensidade de hiperatividade adren&#233;rgica card&#237;aca. <xref ref-type="bibr" rid="B51"><sup>51</sup></xref> Outro estudo identificou capta&#231;&#227;o anormal de mIBG-I <xref ref-type="bibr" rid="B123"><sup>123</sup></xref> em pacientes que usaram antrac&#237;clico. Al&#233;m disso, a rela&#231;&#227;o da capta&#231;&#227;o entre o cora&#231;&#227;o e o mediastino (RC/M) de mIBG-I <xref ref-type="bibr" rid="B123"><sup>123</sup></xref> foi mais baixa &#224; medida que a dose cumulativa dessa medica&#231;&#227;o aumentava. <xref ref-type="bibr" rid="B52"><sup>52</sup></xref> Esses resultados d&#227;o suporte &#224; hip&#243;tese de que a institui&#231;&#227;o precoce de cardioprote&#231;&#227;o com f&#225;rmacosbetabloqueadores pode ser ben&#233;fica para esses pacientes.</p>
        </sec>
        <sec>
          <title>2.2.3. Metabolismo Mioc&#225;rdico &#8211; 18F-FDG PET-CT</title>
          <p>Recentemente, Borde et al. <xref ref-type="bibr" rid="B53"><sup>53</sup></xref> analisaram retrospectivamente a capta&#231;&#227;o mioc&#225;rdica de <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG em pacientes com linfoma tratados com QT&#224; base de adriamicina. <xref ref-type="bibr" rid="B53"><sup>53</sup></xref> Os autores demostraram que um aumento na atividade metab&#243;lica do mioc&#225;rdio pode ser um poss&#237;vel marcador de altera&#231;&#227;o celular que antecede a cascata de CTX. Neste estudo, o aumento do metabolismo glicol&#237;tico no m&#250;sculo card&#237;aco foi diretamente proporcional &#224; dose cumulativa de adriamicina recebida em mg/m<sup>2</sup>. Dados semelhantes tamb&#233;m foram propostos em pacientes com dano card&#237;aco induzido por radia&#231;&#227;o. <xref ref-type="bibr" rid="B54"><sup>54</sup></xref> Toubert et al. <xref ref-type="bibr" rid="B55"><sup>55</sup></xref> demonstraram modifica&#231;&#227;o na capta&#231;&#227;o mioc&#225;rdica de <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG em paciente tratado com uma combina&#231;&#227;o de inibidores de tirosina quinase (imatinibe e sorafenibe) que posteriormente desenvolveu IC fatal ( <xref ref-type="table" rid="t4">Tabela 3</xref> ). <xref ref-type="bibr" rid="B55"><sup>55</sup></xref> </p>
          <table-wrap id="t4">
            <label>Tabela 3</label>
            <caption>
              <title>Estudos com PET-CT que avaliaram a rela&#231;&#227;o da capta&#231;&#227;o mioc&#225;rdica de 18F-FDG em pacientes submetidos &#224; quimioterapia ou radioterapia <xref ref-type="bibr" rid="B55"><sup>55</sup></xref> </title>
            </caption>
            <table frame="hsides" rules="rows">
              <colgroup width="50%">
                <col/>
                <col/>
              </colgroup>
              <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
                <tr>
                  <th align="left" colspan="2" valign="middle">PET-CT <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG mioc&#225;rdico x f&#225;rmacos: o que dizem os estudos?</th>
                </tr>
              </thead>
              <tbody style="border-bottom: thin solid; border-color: #000000">
                <tr>
                  <td align="left" valign="middle">Borde et al. <xref ref-type="bibr" rid="B53"><sup>53</sup></xref> </td>
                  <td align="left" valign="middle">Adriamicina: aumento da concentra&#231;&#227;o de <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG no mioc&#225;rdio pode preceder a redu&#231;&#227;o da fun&#231;&#227;o ventricular esquerda e o grau de cardiotoxidade &#233; proporcional &#224; dose recebida.</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Toubert et al. <xref ref-type="bibr" rid="B55"><sup>55</sup></xref> </td>
                  <td align="left" valign="middle">Inibidores da tirosina quinase (imatinibe e sorafenibe): relato de caso que mostrou modifica&#231;&#227;o na concentra&#231;&#227;o mioc&#225;rdica de <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG previamente a evento card&#237;aco fatal.</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Evans et al. <xref ref-type="bibr" rid="B58"><sup>58</sup></xref> </td>
                  <td align="left" valign="middle">Aumento na concentra&#231;&#227;o <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG em pacientes que receberam radioterapiator&#225;cica &gt;20 Gy com &#225;rea card&#237;aca &gt; 5 cm<sup>2</sup>: indicador de les&#227;o mioc&#225;rdica.</td>
                </tr>
              </tbody>
            </table>
          </table-wrap>
          <p>As imagens de PET-CT utilizando o radiof&#225;rmaco <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG, bem como as obtidas pela resson&#226;ncia magn&#233;tica, podem ser &#250;teis no diagn&#243;stico da CTX induzida pelos inibidores dos <italic>checkpoints</italic> imunol&#243;gicos (ICI), visto que permitem detectar, avaliar a extens&#227;o e at&#233; mesmo quantificar o processo inflamat&#243;rio de diversas afec&#231;&#245;es cardiovasculares, tais como miocardite, pericardite e vasculites. <xref ref-type="bibr" rid="B56"><sup>56</sup></xref><sup>-</sup><xref ref-type="bibr" rid="B58"><sup>58</sup></xref> </p>
        </sec>
      </sec>
      <sec>
        <title>2.3. Contribui&#231;&#227;o da Resson&#226;ncia Magn&#233;tica Cardiovascular</title>
        <sec>
          <title>2.3.1. Avalia&#231;&#227;o da Cardiotoxicidadedurante o Tratamento Antineopl&#225;sico</title>
          <p>A RMC &#233; considerada o padr&#227;o-ouro para avalia&#231;&#227;o da FEVE, massa e volume das cavidades, sendo uma ferramente valiosa na avalia&#231;&#227;o de CTX induzida por QT. <xref ref-type="bibr" rid="B34"><sup>34</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B59"><sup>59</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B60"><sup>60</sup></xref> A FEVE pode reduzir a partir da altera&#231;&#227;o de um ou ambos os volumes. Em geral, a redu&#231;&#227;o do volume diast&#243;lico encontra-se relacionada com condi&#231;&#245;es de pr&#233;-carga que sofrem altera&#231;&#245;es din&#226;micas e constantes em um paciente oncol&#243;gico seja por v&#244;mitos, sangramentos, diarreia ou desidrata&#231;&#227;o. Estas s&#227;o prontamente revers&#237;veis com a restaura&#231;&#227;o da volemia. No entanto, o aumento progressivo do volume sist&#243;lico &#233; considerado um marcador de les&#227;omioc&#225;rdica relacionada &#224; QT. Outro par&#226;metro que merece aten&#231;&#227;o durante o acompanhamento quimioter&#225;pico &#233; a avalia&#231;&#227;o da massa ventricular. A CTX provoca aumento inicial da massa ventricular, provavelmente pela indu&#231;&#227;o da resposta inflamat&#243;ria pela QT, levando a aumento do volume do interst&#237;cio e dos cardiomi&#243;citos. No entnto, nas fases tardias, geralmente ap&#243;s 6 meses, ocorre um processo de redu&#231;&#227;o da massa ventricular (apoptose, fibrose, hipotrofia cardiomiocit&#225;ria etc.). Dessa forma, quando estamos diante de um aumento do volume sist&#243;lico e redu&#231;&#227;o da massa ventricular, tal combina&#231;&#227;o &#233; muito sugestiva de CTX, mesmo com fra&#231;&#227;ode eje&#231;&#227;o ainda preservada.</p>
          <p>Mais recentemente, a an&#225;lise de deforma&#231;&#227;o mioc&#225;rdica ( <italic>strain</italic> ) pela RMC vem ganhando destaque. Na popula&#231;&#227;o em tratamento quimioter&#225;pico, a literatura destaca o seu potencial em diagnosticar altera&#231;&#245;es subcl&#237;nicas. <xref ref-type="bibr" rid="B61"><sup>61</sup></xref><sup>-</sup><xref ref-type="bibr" rid="B63"><sup>63</sup></xref> Jolly et al. <xref ref-type="bibr" rid="B61"><sup>61</sup></xref> estudaram 72 pacientes em tratamento quimioter&#225;pico para c&#226;ncer de mama, sarcoma ou linfoma com RMC seriadas. <xref ref-type="bibr" rid="B61"><sup>61</sup></xref> Comparado com a RMC basal, houve uma piora significativa do <italic>strain</italic> circunferencial global (SCG) 3 meses ap&#243;s tratamento. Al&#233;m disso, o SCG se correlaciou fortemente com a queda subcl&#237;nica da FEVE. Em outro estudo com 41 pacientes portadoras de c&#226;ncer de mama em tratamento com trastuzumabe, tanto o SLG quanto o SCG reduziram durante o tratamento e correlacionaram-se com a queda da FEVE. <xref ref-type="bibr" rid="B62"><sup>62</sup></xref> O <italic>strain</italic> pela RMC ainda n&#227;o &#233; amplamente utilizado na pr&#225;tica cl&#237;nica, mas os estudos demonstram sua aplicabilidade potencial nos pacientes da cardio-oncologia.</p>
        </sec>
        <sec>
          <title>2.3.2. Resson&#226;ncia Magn&#233;tica Cardiovascular no Seguimento Tardio</title>
          <p>A avalia&#231;&#227;o tardia fornece importantes informa&#231;&#245;es diagn&#243;sticas e progn&#243;sticas pela RMC atrav&#233;s de sua complementa&#231;&#227;o com a an&#225;lise tecidual. &#201; importante compreender que altera&#231;&#245;es precoces durante o tratamento s&#227;o marcadores para algumas altera&#231;&#245;es tardias, como a presen&#231;a de realce tardio. O edema mioc&#225;rdico &#233; indicativo de processo inflamat&#243;rio no mioc&#225;rdio e, quanto maior for o conte&#250;do l&#237;quido, maior ser&#225; a intensidade de sinal local. <xref ref-type="bibr" rid="B64"><sup>64</sup></xref> A sequ&#234;ncia que auxilia neste contexto &#233; o <italic>triple-IR</italic> , que &#233; adquirida com a adi&#231;&#227;o de um terceiro pulso de satura&#231;&#227;o, para eliminar todo o sinal de tecido adiposo (satura&#231;&#227;o de gordura) da imagem. <xref ref-type="bibr" rid="B64"><sup>64</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B65"><sup>65</sup></xref> Alguns estudos t&#234;m demonstrado edema mioc&#225;rdico na RMC logo ap&#243;s a terapia com antraciclina, usando sequ&#234;ncias ponderadas em T2. <xref ref-type="bibr" rid="B66"><sup>66</sup></xref> O aumento precoce do edema e o aumento subagudo da fibrose vistos em ratos que receberam antraciclinas foram fortemente relacionados e s&#227;o ambos indicadores de mortalidade tardia. <xref ref-type="bibr" rid="B67"><sup>67</sup></xref> </p>
          <p>O realce tardio &#233; uma t&#233;cnica amplamente validada para identificar e quantificar a fibrose mioc&#225;rdica de maneira n&#227;o invasiva utilizando contraste paramagn&#233;tico de gadol&#237;neo. Padr&#245;es distintos de realce tardio s&#227;o reconhecidos na RMC permitindo diferenciar os diferentes tipos de acometimento mioc&#225;rdico, distinguindo entre miocardiopatias isqu&#234;micas e n&#227;o isqu&#234;micas. <xref ref-type="bibr" rid="B68"><sup>68</sup></xref> Isso &#233; de particular import&#226;ncia durante a avalia&#231;&#227;o da cardiomiopatia induzida por QT em indiv&#237;duos com condi&#231;&#245;es card&#237;acas preexistentes, como DAC.</p>
          <p>A preval&#234;ncia de realce tardio na CTX &#233; baixa. <xref ref-type="bibr" rid="B59"><sup>59</sup></xref> Embora seja o padr&#227;o-ouro para identificar &#225;reas focais de fibrose mioc&#225;rdica, ele n&#227;o &#233; adequado para avaliar a fibrose intersticial difusa, o que geralmente &#233; encontrado na cardiomiopatia causada por CTX.N&#227;o h&#225; um padr&#227;o t&#237;pico de realce tardio encontrado de CTX relacionada comantraciclinas e trastuzumabe, podendo haver queda da FEVE mesmo sem realce tardio. <xref ref-type="bibr" rid="B60"><sup>60</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B69"><sup>69</sup></xref> Quando presente, caracteristicamente, assemelha-se aos padr&#245;es j&#225; conhecidos das miocardiopatias n&#227;o isqu&#234;micas (epic&#225;rdico, mesoc&#225;rdico, focal e/ou juncional) ( <xref ref-type="fig" rid="f5">Figura 5</xref> ). <xref ref-type="bibr" rid="B68"><sup>68</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B70"><sup>70</sup></xref> </p>
          <fig id="f5">
            <label>Figura 5</label>
            <caption>
              <title>Realce tardio focal em parede &#237;nferolateral do ventr&#237;culo esquerdo em paciente com c&#226;ncer de mama tratada com antraciclina e trastuzumabe.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf05.tif"/></fig>
          <p>A miocardite &#233; uma complica&#231;&#227;o grave e potencialmente fatal nos pacientes em uso de imunoter&#225;picos, com mortalidade de aproximadamente 40%. <xref ref-type="bibr" rid="B71"><sup>71</sup></xref> Pode ter uma incid&#234;ncia mais elevada e at&#233; se manifestar como quadro fulminante naqueles pacientes em uso de inibidores de <italic>checkpoint</italic> imunol&#243;gico, principalmente se estiverem em terapia combinada e em m&#233;dia 34 dias ap&#243;s o in&#237;cio da terapia. <xref ref-type="bibr" rid="B72"><sup>72</sup></xref> </p>
        </sec>
        <sec>
          <title>2.3.3. Caracteriza&#231;&#227;o Tecidual pela RMC</title>
          <sec>
            <title>2.3.3.1. Mapas de T2</title>
            <p>A RMC tem a vantagem de fornecer informa&#231;&#245;es detalhadas sobre o remodelamento card&#237;aco, que s&#227;o complementares &#224; tradicional avalia&#231;&#227;o morfol&#243;gica e funcional do mioc&#225;rdio.Dados consistentes indicam que edema, inflama&#231;&#227;o, expans&#227;o da matriz de tecido conectivo e altera&#231;&#227;o da deforma&#231;&#227;o regional do mioc&#225;rdio ocorrem antes da disfun&#231;&#227;o mioc&#225;rdica em pacientes submetidos a tratamento cardiot&#243;xico, refor&#231;ando o potencial de aplicabilidade dessa modalidade em indiv&#237;duos expostos a terapias cardiot&#243;xicas.</p>
            <p>Estudos cl&#237;nicos mostraram, recentemente, que a utiliza&#231;&#227;o de protocolos de RMC que incorporam sequ&#234;ncias multiparam&#233;tricas com mapas de T1 e T2 proporcionoua detec&#231;&#227;o de altera&#231;&#245;es pr&#233;-cl&#237;nicas e precoces da CTX. <xref ref-type="bibr" rid="B73"><sup>73</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B74"><sup>74</sup></xref> A detec&#231;&#227;o de edema no mioc&#225;rdio, que normalmente &#233; baseada no aumento da intensidade de sinal nas imagens ponderadas em T2 no mioc&#225;rdio normalizadas para os valores do m&#250;sculo esquel&#233;tico, vem sendo aplicada com sucesso para doen&#231;a isqu&#234;mica e n&#227;o isqu&#234;mica do m&#250;sculo card&#237;aco. <xref ref-type="bibr" rid="B75"><sup>75</sup></xref><sup>-</sup><xref ref-type="bibr" rid="B77"><sup>77</sup></xref> </p>
            <p>Utilizando sequ&#234;ncias amplamente dispon&#237;veis e mais simples que os mapas de T2, Ferreira de Souza documentou aumento significativo da intensidade de sinal em T2 em mulheres tratadas com doses moderadas de doxorrubicina (240 mg/m<sup>2</sup>). <xref ref-type="bibr" rid="B74"><sup>74</sup></xref> Diversos grupos est&#227;o atualmente investigando a aplicabilidade dos mapas de T2 na avalia&#231;&#227;o de edema mioc&#225;rdico em sobreviventes de c&#226;ncer tratados com terapias antineopl&#225;sicas, mas, at&#233; o momento, poucos dados cl&#237;nicos est&#227;o dispon&#237;veis para justificar o seu emprego rotineiro na pratica do diaadia.</p>
          </sec>
          <sec>
            <title>2.3.3.2. Mapas de T1</title>
            <p>Apesar de a t&#233;cnica do realce tardio demonstrar de forma precisa a presen&#231;a de cicatriz e fibrose de substitui&#231;&#227;o, esta t&#233;cnica n&#227;o &#233; capaz de fornecer dados completos e definitivos a respeito da quantidade total de fibrose no mioc&#225;rdio, sobretudo sobre a fibrose intersticial. <xref ref-type="bibr" rid="B78"><sup>78</sup></xref> Como a t&#233;cnica do realce tardio &#233; fundamentadaem diferen&#231;as relativas da intensidade de sinal em T1 ap&#243;s a administra&#231;&#227;o de meio de contraste &#224; base de gadol&#237;nio, &#233; poss&#237;vel que a fibrose intersticial difusa seja visualizada de forma incompleta ou limitada por essa t&#233;cnica.</p>
            <p>Em diversos estudos, incluindo observa&#231;&#245;es retrospectivas e prospectivas, o realce tardio n&#227;o foi uniformemente detectado em pacientes submetidos ao tratamento com QT &#224; base de antrac&#237;clico. <xref ref-type="bibr" rid="B79"><sup>79</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B80"><sup>80</sup></xref> De fato, um exame de RMC com realce tardio negativo ou sem a presen&#231;a de &#225;reas com fibrose n&#227;o excluinecessariamente a presen&#231;a de fibrose mioc&#225;rdica, refor&#231;ando a limita&#231;&#227;o dessa metodologia nesse contexto. Apesar de Fallah-Rad ter demonstrado a presen&#231;a de realce tardio subepic&#225;rdico em todos os pacientes que apresentaram disfun&#231;&#227;o ventricular esquerda induzida pelo trastuzumabe, <xref ref-type="bibr" rid="B79"><sup>79</sup></xref> diversos outros estudos evidenciaram resultados conflitantes, sendo que os dados de Lawley et al. <xref ref-type="bibr" rid="B81"><sup>81</sup></xref> mostraram que apenas &lt; 10% das mulheres tratadas com trastuzumabe apresentaramrealce tardio positivo. <xref ref-type="bibr" rid="B81"><sup>81</sup></xref> </p>
            <p>Novas t&#233;cnicas baseadas em medidas sucessivas de T1 realizada antes e ap&#243;s a administra&#231;&#227;o de meio de contraste &#224; base de gadol&#237;nio proporcionam uma avalia&#231;&#227;o mais precisa e acurada acerca do volume extracelular no mioc&#225;rdio (ECV), um marcador da matriz de tecido conectivo no mioc&#225;rdio e da fibrose intersticial. Mesmo antes do advento dos mapas de T1, autores j&#225; mostravam que medidas de T1 no mioc&#225;rdio conseguem detectar o aumento da distribui&#231;&#227;o do gadol&#237;nio no mioc&#225;rdio em sobreviventes de c&#226;ncer tratados com QT. <xref ref-type="bibr" rid="B79"><sup>79</sup></xref> Esses achados indicam que a expans&#227;o da matriz de tecido conectivo avaliado por mapas de T1 emerge como um marcador precoce da CTX, e que &#233; capaz de predizer inclusive a piora da capacidade funcional.</p>
            <p>Pacientes previamente expostos a antrac&#237;clicosapresentam valores de ECV significativamente maiores quando comparados a controles saud&#225;veis pareados para idade e sexo.Jordan et al. investigaram pacientes com e sem c&#226;ncer, incluindo indiv&#237;duos tratados e n&#227;o tratados com antraciclina, assim como indiv&#237;duos tratados com outros quimioter&#225;picos. <xref ref-type="bibr" rid="B82"><sup>82</sup></xref> Os valores do T1 nativo (antes da administra&#231;&#227;o de contraste) foram consistentemente maiores antes e ap&#243;s o tratamento nos indiv&#237;duos com c&#226;ncer comparado aos indiv&#237;duos sem c&#226;ncer.Nesse estudo ainda foi demonstrado que o ECV aumentou significativamente ap&#243;s o tratamento com antrac&#237;clicos (30,4 &#177; 0,7% <italic>vs.</italic> 27,8 &#177; 0,7%; p &lt; 0,01). Al&#233;m disso, utilizando modelos estat&#237;sticos multivariados, tanto os valores de T1 nativo como do ECV permaneceram consistentemente maiores nos pacientes com c&#226;ncer independentemente do ajuste para diversas outras vari&#225;veis.</p>
            <p>Recentemente, foi demonstrado que a quantifica&#231;&#227;o do tempo intracelular da &#225;gua (T<sub>1</sub>) no mioc&#225;rdio emerge como uma abordagem inovadora para detectar o remodelamento mioc&#225;rdico ap&#243;s o tratamento de c&#226;ncer, oferecendo informa&#231;&#245;es complementares &#224; avalia&#231;&#227;o isolada do ECV. <xref ref-type="bibr" rid="B15"><sup>15</sup></xref> Estudo recente avaliou 27 mulheres com c&#226;ncer de mama antes e ap&#243;s dose cumulativa de doxorrubicinade 240mg/m<sup>2</sup>, incluindo a realiza&#231;&#227;o de biomarcadores. No per&#237;odo de 1 a 2 anos ap&#243;s doxorrubicina, observou-se queda da FEVE e da massa indexada do VE. Por outro lado, houve aumento do ECV e redu&#231;&#227;o do tempo intracelular da &#225;gua. <xref ref-type="bibr" rid="B74"><sup>74</sup></xref> </p>
          </sec>
        </sec>
      </sec>
    </sec>
    <sec>
      <title>3.Toxicidade Vascular</title>
      <sec>
        <title>3.1. Contribui&#231;&#227;o da Ultrassonografia Vascular</title>
        <sec>
          <title>3.1.1. Tromboembolismo Venoso e C&#226;ncer</title>
          <sec>
            <title>3.1.1.1. Introdu&#231;&#227;o</title>
            <p>A associa&#231;&#227;o entre c&#226;ncer e TVP e/ou superficial foi relatada pela primeira vez por Armand Trousseau em 1865. <xref ref-type="bibr" rid="B83"><sup>83</sup></xref> O risco relativo de tromboembolismo venoso (TEV) &#233; cerca de sete vezes maior em pacientes com c&#226;ncer ativo, sendo que o TEV pode ser a primeira manifesta&#231;&#227;o de um c&#226;ncer oculto (7% a 12% dos casos), constituindo um &#8220;fen&#244;meno paraneopl&#225;sico&#8221;. <xref ref-type="bibr" rid="B84"><sup>84</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B85"><sup>85</sup></xref> </p>
            <p>Ocorr&#234;ncia de trombose complica o manejo do paciente com c&#226;ncer em virtudeda necessidade de terapia anticoagulante e o risco potencial de sangramento. Portadores de neoplasia e TEV aguda apresentam risco maior de recorr&#234;ncia de trombose do que os n&#227;oportadores. Por fim, um epis&#243;dio de TEV aumenta a mortalidade dos pacientes oncol&#243;gicos e isso pode ser resultado de embolia pulmonar maci&#231;a ou avan&#231;o do tumor. <xref ref-type="bibr" rid="B86"><sup>86</sup></xref> </p>
          </sec>
          <sec>
            <title>3.1.1.2. Epidemiologia</title>
            <p>Existem diversos fatores associados que podem aumentar o risco de trombose em pacientes com c&#226;ncer: tratamento (RT e/ou QT), p&#243;s-operat&#243;rio e dispositivos intravasculares. <xref ref-type="bibr" rid="B87"><sup>87</sup></xref> A incid&#234;ncia de TVP em pacientes com c&#226;ncer &#233; 4,7 vezes maior do que na popula&#231;&#227;o sem c&#226;ncer, ap&#243;s ajustes para comorbidades, como foi demonstrado na popula&#231;&#227;o da Dinamarca. <xref ref-type="bibr" rid="B88"><sup>88</sup></xref> A incid&#234;ncia nos primeiros 2anos varia de 0,8% a 8,0% e est&#225; associada a altas taxas de recorr&#234;ncia e mortalidade. A maior incid&#234;ncia de TEV no primeiro ano ap&#243;s o diagn&#243;stico ocorre naqueles com doen&#231;a avan&#231;ada do c&#233;rebro, pulm&#227;o, &#250;tero, bexiga, p&#226;ncreas, est&#244;mago e rim (4 a 13 vezes maior na doen&#231;a metast&#225;tica do que naqueles com doen&#231;a localizada). QT aumenta em 7 vezes o risco de ocorr&#234;ncia de TEV em paciente com c&#226;ncer.</p>
          </sec>
          <sec>
            <title>3.1.1.3. Diagn&#243;stico de TVP</title>
            <p>Ultrassonografia venosa &#233; o exame de imagem padr&#227;o indicado para os pacientes com suspeita de trombose venosa (profunda e/ou superficial), seja em vasos centrais, abdominais ou extremidades (regi&#227;o cervical, membros superiores e membros inferiores). Al&#233;m de confirmar ou afastar a presen&#231;a de trombos, permite diagn&#243;stico diferencial com outras patologias.</p>
            <p>Na pr&#225;tica cl&#237;nica, a defini&#231;&#227;o do segmento do corpo a ser examinado depende dos sinais e sintomas apresentados pelo paciente. Nos casos de suspeita de embolismo pulmonar e aus&#234;ncia de ind&#237;cios da localiza&#231;&#227;o da fonte de trombos, o rastreamento com ultrassom venoso dever&#225; dar prioridade aos vasos dos membros inferiores (s&#237;tio de 85% dos casos de TVP). Se a pesquisa for negativa nesse territ&#243;rio, a sequ&#234;ncia da investiga&#231;&#227;o incluir&#225; as veias il&#237;acas e cava inferior; por fim, vasos cervicais e de membros superiores.</p>
          </sec>
          <sec>
            <title>3.1.1.4. Protocolos de Ultrassonografia Venosa</title>
            <p>Recomenda-se que pacientes com &#8220;escore de Wells&#8221; &#8805; 2 devem realizar a ultrasonografia venosa (envolvendo a compress&#227;o de todo o membro inferior a cada 2 cm desde o ligamento inguinal at&#233; o tornozelo, incluindo-se as veias tibiais posteriores, fibulares e musculares da panturrilha &#8211; gastrocn&#234;mias e soleares; e as imagens coloridas com a an&#225;lise espectral pelo menos das veias femoral comum e popl&#237;tea), pois se somente o segmento femoropopl&#237;teo tiver sido examinado e restar d&#250;vida, o exame completo dever&#225; ser repetido em 5 a 7 dias para afastar TVP (retardando diagn&#243;stico e aumentando riscos e custos). Se houver &#225;reas sintom&#225;ticas n&#227;o inclu&#237;das no protocolo, estas dever&#227;o obrigatoriamente ser avaliadas (p. ex., veias tibiais anteriores, veias plantares etc). <xref ref-type="bibr" rid="B89"><sup>89</sup></xref> </p>
            <p>Caso n&#227;o haja possibilidade de realiza&#231;&#227;o do exame completo, &#233; aceito que inicialmente seja feito o exame de dois pontos (CUS) at&#233; que novo estudo (protocolo completo) possa ser efetuado. &#201; sabido que a disponibilidade dessa modalidade de diagn&#243;stico &#233; limitada em centros m&#233;dicos menores, ambulat&#243;rios, nas noites e finais de semana.</p>
            <p>Exames espec&#237;ficos das veias il&#237;acas e da veia cava inferior devem ser reservados para casos duvidosos; tromboses rizom&#233;licas, desde a raiz da coxa ( <xref ref-type="fig" rid="f6">Figura 6 A-B</xref> ); ou quando as curvas espectrais de fluxo (Doppler puls&#225;til) em femoral comum apresentarem padr&#227;o cont&#237;nuo (perda de fasicidade), sugerindo comprometimento proximal.</p>
            <fig id="f6">
              <label>Figura 6</label>
              <caption>
                <title>A e B &#8211; Edema rizom&#233;lico em paciente adolescente com c&#226;ncer e trombo ocluindo veia il&#237;aca direita.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf06.tif"/></fig>
          </sec>
          <sec>
            <title>3.1.1.5. Diagn&#243;stico Diferencialde TVP</title>
            <p>Portadores de neoplasia (oculta ou em atividade, acamados ou n&#227;o, em QT ou RT, em uso de anticoagulantes, com cateter venoso para infus&#227;o de medicamento) e outras comorbidades podem apresentar complica&#231;&#245;es que exigem diagn&#243;stico diferencial com trombose venosa. Dentre essas, as mais frequentes s&#227;o edema (uni ou bilateral) em qualquer localiza&#231;&#227;o e dor na panturrilha.</p>
            <p>A ultrassonografia, al&#233;m de afastar a presen&#231;a de trombos na luz dos vasos em segmentos edemaciados, possibilita o diagn&#243;stico de massas tumorais compressivas de veias il&#237;acas como causa de edema uni ou bilateral; &#8220;s&#237;ndrome de May-Turner&#8221; e edema de membro inferior esquerdo; celulites extensas; massas mediastinais comprimindo veia cava superior, com edema de membros superiores e pesco&#231;o. Edema bilateral raramente &#233; causado por trombose, devendo-se afastar condi&#231;&#245;es sist&#234;micas (insufici&#234;ncia card&#237;aca, insufici&#234;ncia hep&#225;tica, fal&#234;ncia renal, hipotireoidismo) ou uso de medicamentos.</p>
            <p>Outra vantagem da ultrassonografia nos casos de aumento significativo de volume dos membros decorrentes de compress&#227;o por massas tumorais, TVP extensa ou hematomas volumosos &#233; a avalia&#231;&#227;o r&#225;pida de poss&#237;vel comprometimento associado ao fluxo arterial regional (&#8220;s&#237;ndrome compartimental&#8221;), que pode levar &#224; isquemia grave.</p>
          </sec>
        </sec>
        <sec>
          <title>3.1.2. Trombose Relacionada a Cateter em Pacientes com C&#226;ncer</title>
          <sec>
            <title>3.1.2.1. Introdu&#231;&#227;o</title>
            <p>A utiliza&#231;&#227;o de cateteres de longa perman&#234;ncia &#233; frequente na popula&#231;&#227;o de pacientes com c&#226;ncer devido &#224; necessidade de infus&#227;o de quimioter&#225;picos, al&#233;m da administra&#231;&#227;o endovenosa de terapias de suporte. A trombose relacionada ao cateter (TRC) &#233; definida como um trombo mural que se estende do cateter ao l&#250;men do vaso, levando &#224; obstru&#231;&#227;o parcial ou oclus&#227;o do cateter, com ou sem sintomas cl&#237;nicos. <xref ref-type="bibr" rid="B90"><sup>90</sup></xref> </p>
            <p>A maioria dos casos de TRC ocorre dentro dos primeiros 100 dias ap&#243;s a inser&#231;&#227;o do cateter. A taxa de TRC situa-se na faixa de 14% e 18% quando realizado rastreamento com venografia ou ultrassonografia vascular (USV). Destes, menos de 5% dos pacientes s&#227;o sintom&#225;ticos. <xref ref-type="bibr" rid="B91"><sup>91</sup></xref> </p>
            <p>A TRC pode causar embolia pulmonar em 15% e perda do acesso em 10% dos pacientes, elevando significantemente os custos relacionados ao tratamento e manuseio desses pacientes. <xref ref-type="bibr" rid="B92"><sup>92</sup></xref> </p>
          </sec>
          <sec>
            <title>3.1.2.2. Fatores de Risco</title>
            <p>Uma metan&#225;lise que incluiu cinco estudos randomizados de indiv&#237;duos com e sem c&#226;ncer avaliou prospectivamente as vari&#225;veis relacionadas com TRC, sendo significantes: <xref ref-type="bibr" rid="B93"><sup>93</sup></xref> </p>
            <list list-type="alpha-lower">
              <list-item>
                <p>Inser&#231;&#227;o em veia subcl&#225;via &#215; membro superior (OR 2,16; 95% IC 1,07-4,34).</p>
              </list-item>
              <list-item>
                <p>Hist&#243;ria pr&#233;via de TVP (OR 2,03; 95% IC 1,05-3,92).</p>
              </list-item>
              <list-item>
                <p>Posi&#231;&#227;o impr&#243;pria da ponta do cateter (OR 1,92; 95% IC 1,22-3,02).</p>
              </list-item>
            </list>
            <p>Em an&#225;lise multivariada, o cateter <italic>port-a-cath</italic> apresentou uma redu&#231;&#227;o de 57% no risco de TRC quando comparado ao cateter <italic>PICC (peripherallyinserted central catheter)</italic> . <xref ref-type="bibr" rid="B93"><sup>93</sup></xref> </p>
          </sec>
          <sec>
            <title>3.1.2.3. Diagn&#243;stico e Complica&#231;&#245;es</title>
            <p>Na trombose envolvendo as veias do bra&#231;o, axilar, subcl&#225;via distal ou jugular, a sensibilidade e a especificidade s&#227;obastante elevadas (&gt; 95%) ( <xref ref-type="fig" rid="f7">Figura 7</xref> ). Esses valores, contudo, caem para a faixa de 55% nas tromboses envolvendo a veia subcl&#225;via proximal, o tronco venoso braquiocef&#225;lico e a veia cava superior. Isso ocorre devido &#224; natural dificuldade de abordagem, imposta pela barreira anat&#244;mica de osso e pulm&#227;o nesta regi&#227;o. Uma alternativa &#233; o uso de sondas com menor &#225;rea de superf&#237;cie de contato como sondas setoriais pedi&#225;tricas e/ou adultas e sondas microconvexas.As complica&#231;&#245;es mais frequentes dos trombos s&#227;o infec&#231;&#227;o secund&#225;ria (coloniza&#231;&#227;o bacteriana), embolia pulmonar e s&#237;ndrome p&#243;s-tromb&#243;tica. <xref ref-type="bibr" rid="B94"><sup>94</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B95"><sup>95</sup></xref> </p>
            <fig id="f7">
              <label>Figura 7</label>
              <caption>
                <title>Ultrassonografia vascular (USV) na regi&#227;o supraclavicular proximal, evidenciando trombose na veia jugular interna direita (VJID) proximal, tronco venoso braquiocef&#225;lico (TBC) e veia subcl&#225;via direita proximal (VSCD). Observa-se o cateter central em VSCD direcionado ao TBC.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf07.tif"/></fig>
          </sec>
        </sec>
        <sec>
          <title>3.1.3. Hipertens&#227;o Pulmonar no Paciente Oncol&#243;gico</title>
          <p>Conceitualmente, a HP &#233; definida por um aumento da press&#227;o arterial m&#233;dia superior a 20 mmHg durante estudo hemodin&#226;mico invasivo. A forma mais comum &#233; decorrente do acometimento do VE (Tipo II da Organiza&#231;&#227;o Mundial de Sa&#250;de).</p>
          <p>O ecocardiograma continua sendo a ferramenta de primeira linha na investiga&#231;&#227;o diagn&#243;stica de HP, por&#233;m &#233; importante refor&#231;ar a complexidade cl&#237;nica do diagn&#243;stico etiol&#243;gico da HP nos pacientes oncol&#243;gicos, em que podemos encontrar:</p>
          <list list-type="simple">
            <list-item>
              <label>-</label>
              <p>Massas ou tumores no &#225;trio esquerdo, causando efeito obstrutivo e, com isso, levar a um aumento da press&#227;o capilar;</p>
            </list-item>
            <list-item>
              <label>-</label>
              <p>Compress&#227;o tumoral extr&#237;nseca, como visto nos casos de grandes timomas, linfomas ou mediastinite fibrosante;</p>
            </list-item>
            <list-item>
              <label>-</label>
              <p>Tromboembolismo pulmonar, secund&#225;rio aos inibidores de tirosina-quinase como o dasatinibe ou ao acometimento do VE (CTX, cardiopatia preexistente, valvopatias etc.). <xref ref-type="bibr" rid="B96"><sup>96</sup></xref> </p>
            </list-item>
          </list>
          <p>Em pacientes com HP, a tomografia computadorizada tem um valor especial na avalia&#231;&#227;o da vasculariza&#231;&#227;o pulmonar e do par&#234;nquima pulmonar, fornecendo informa&#231;&#245;es sobre poss&#237;veis mecanismos e consequ&#234;ncias da HP. Os achados parenquimatosos pulmonares podem ser variados e dependem de sua etiologia. <xref ref-type="bibr" rid="B97"><sup>97</sup></xref> </p>
          <p>A tomografia sem contraste permite a detec&#231;&#227;o de anormalidades relacionadas com HP como aumento das dimens&#245;es do tronco pulmonar, dilata&#231;&#227;o de c&#226;maras direitas e identifica quadros secund&#225;rios &#224; doen&#231;a pulmonar, sendo suficiente para a avalia&#231;&#227;o da maioria das doen&#231;as pulmonares. &#201; indicada na avalia&#231;&#227;o do par&#234;nquima pulmonar em doen&#231;as pulmonares difusas, como pneumopatias intersticiais e doen&#231;a pulmonar obstrutiva cr&#244;nica, detec&#231;&#227;o de malforma&#231;&#245;es arteriovenosas e no diagn&#243;stico de doen&#231;a veno-oclusiva ou hemangiomatose capilar pulmonar.</p>
          <p>A tomografia com contraste define a anatomia e a estrutura vascular pulmonar, obtendo imagens angiogr&#225;ficas precisas do tronco pulmonar at&#233; o n&#237;vel vascular subsegmentar. &#201; amplamente dispon&#237;vel, de f&#225;cil execu&#231;&#227;o e mais sens&#237;vel que a angiografia invasiva na detec&#231;&#227;o de &#234;mbolos pulmonares e, assim, tornou-se a modalidade padr&#227;o para o diagn&#243;stico n&#227;o invasivo de embolia pulmonar aguda.</p>
          <p>No cen&#225;rio de HP, o VD vai refletir a sobrecarga press&#243;rica com hipertrofia e dilata&#231;&#227;o, podendo apresentar disfun&#231;&#227;o ventricular. Distor&#231;&#227;o significativa da geometria ventricular pode estar presente, com o VD assumindo conforma&#231;&#227;o globosa, levando &#224; compress&#227;o ventricular esquerda em est&#225;gios mais avan&#231;ados.Pacientes com HP com dilata&#231;&#227;o de VD e fra&#231;&#227;o de eje&#231;&#227;o reduzida de VD t&#234;m pior progn&#243;stico. <xref ref-type="bibr" rid="B98"><sup>98</sup></xref> </p>
          <p>A aquisi&#231;&#227;o em cine fornece uma avalia&#231;&#227;o precisa da morfologia e fun&#231;&#227;o ventricular com imagens adquiridas em eixo curto, obtendo-se uma cobertura volum&#233;trica completa do VD, embora imagens adquiridas em orienta&#231;&#227;o transaxial tamb&#233;m possam ser usadas. V&#225;rias informa&#231;&#245;es s&#227;o obtidas como os volumes sist&#243;lico e diast&#243;lico final, fra&#231;&#227;o de eje&#231;&#227;o, d&#233;bito card&#237;aco e massa mioc&#225;rdica. <xref ref-type="bibr" rid="B99"><sup>99</sup></xref> A massa do VD &#233; medida tra&#231;ando as bordas epic&#225;rdica e endoc&#225;rdica, e o &#237;ndice de massa ventricular &#233; normalmente calculado como a raz&#227;o da massa do VD para a massa do VE.</p>
          <p>A avalia&#231;&#227;o da geometria do septo interventricular tamb&#233;m &#233; avaliada na resson&#226;ncia e a sua proje&#231;&#227;o para a esquerda durante a s&#237;stole denota aumento press&#243;rico de c&#226;maras direitas. &#192; medida que a press&#227;o no territ&#243;rio pulmonar aumenta, a press&#227;o sist&#243;lica do VD pode exceder a do VE e levar a um comprometimento do volume sist&#243;lico do VE. Em quadros de HP mais grave, a fal&#234;ncia progressiva do VD acomete a fun&#231;&#227;o diast&#243;lica do VE devido &#224; proje&#231;&#227;o do septo interventricular tamb&#233;m durante a di&#225;stole, comprometendo o enchimento diast&#243;lico do VE, reduzindo ainda mais o d&#233;bito cad&#237;aco. A curvatura interventricular septal &#233; uma medida efetiva da deforma&#231;&#227;o geom&#233;trica envolvendo os ventr&#237;culos, existindo forte correla&#231;&#227;o entre a curvatura paradoxal do septo interventricular e a gravidade da HP. <xref ref-type="bibr" rid="B100"><sup>100</sup></xref> </p>
          <p>Novas t&#233;cnicas est&#227;o sendo implementadas como a avalia&#231;&#227;o do <italic>strain</italic> mioc&#225;rdico, imagem de contraste de fase ( <italic>phasecontrast</italic> ) e o estudo do realce tardio com poss&#237;vel aplica&#231;&#227;o nos casos de pacientes com HP, permitindo a an&#225;lise da fun&#231;&#227;o mioc&#225;rdica regional, repercuss&#227;o hemodin&#226;mica e extens&#227;o do comprometimento do VD. <xref ref-type="bibr" rid="B101"><sup>101</sup></xref> </p>
        </sec>
      </sec>
    </sec>
    <sec>
      <title>4. Cardiotoxicidade Induzida por Radioterapia</title>
      <sec>
        <title>4.1. Papel da Ecocardiografia</title>
        <sec>
          <title>4.1.1.Epidemiologia</title>
          <p>A RT ocupa espa&#231;o importante no tratamento do c&#226;ncer. Nos EUA, mais de 3 milh&#245;es de pacientes sobreviventes de c&#226;ncer foram submetidos &#224; RT em 2016, n&#250;mero correspondente a 29% da totalidade dos sobreviventes ap&#243;s 5 anos do diagn&#243;stico inicial. A propor&#231;&#227;o de pacientes com c&#226;ncer submetidos &#224; RT tor&#225;cica chega a 45,6% se agruparmos os pacientes com neoplasia de mama e linfoma. V&#225;rios estudos demonstram incid&#234;ncia aumentada de DAC, IAM e morte s&#250;bita card&#237;aca em pacientes submetidos &#224; RT, em especial nos pacientes com linfoma de Hodgkin ou neoplasia de mama, refor&#231;ando o potencial de efeitos colaterais desse tratamento. <xref ref-type="bibr" rid="B102"><sup>102</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B103"><sup>103</sup></xref> </p>
          <p>Denomina-se doen&#231;a card&#237;aca induzida por radia&#231;&#227;o (DCIR) os diversos efeitos delet&#233;rios no sistema cardiovascular gerados pela dosagem cumulativa total de RT e potencializados pela QT adjuvante. Seu espectro &#233; altamente vari&#225;vel e engloba o acometimento de qualquer estrutura do sistema cardiovascular, sendo a manifesta&#231;&#227;o tardia muito mais frequente. Perfazem as complica&#231;&#245;es agudas, geralmente mais sutis e clinicamente menos importantes, os quadros de miopericardite e de pericardite. J&#225; os achados tardios, que se apresentam anos ou d&#233;cadas ap&#243;s sua a exposi&#231;&#227;o, costumam ser clinicamente mais relevantes e incluem os quadros de pericardite cr&#244;nica, valvulopatias, vasculopatia de grandes e m&#233;dios vasos (aorta em porcelana e estenose carot&#237;dea), miocardiopatias (formas dilatada e restritiva), doen&#231;as do sistema de condu&#231;&#227;o e DAC. <xref ref-type="bibr" rid="B104"><sup>104</sup></xref> &#201; farta a literatura demonstrando que a exposi&#231;&#227;o &#224; radia&#231;&#227;o, especialmente do t&#243;rax esquerdo, est&#225; associada a um aumento da mortalidade cardiovascular, atribu&#237;da principalmente &#224; DAC e ao maior risco de desenvolvimento de insufici&#234;ncia card&#237;aca. <xref ref-type="bibr" rid="B105"><sup>105</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B106"><sup>106</sup></xref> Os fatores de risco mais relevantes ao desenvolvimento de DCIR est&#227;o ilustrados na <xref ref-type="table" rid="t5">Tabela 4</xref> .</p>
          <table-wrap id="t5">
            <label>Tabela 4</label>
            <caption>
              <title>Fatores de risco para doen&#231;a card&#237;aca induzida pela radioterapia (RT)</title>
            </caption>
            <table frame="hsides" rules="rows">
              <colgroup width="99%">
                <col width="1%"/>
                <col/>
              </colgroup>
              <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
                <tr>
                  <th align="left" colspan="2" valign="middle">FATORES DE RISCO PARA DOEN&#199;AS CARD&#205;ACAS INDUZIDA PELA RT</th>
                </tr>
              </thead>
              <tbody style="border-bottom: thin solid; border-color: #000000">
                <tr>
                  <td align="left" valign="middle"/>
                  <td align="left" valign="middle">Idade &lt; 50 anos</td>
                </tr>
                <tr>
                  <td align="left" valign="middle"/>
                  <td align="left" valign="middle">Dose cumulativa de radia&#231;&#227;o &gt; 30 Gy</td>
                </tr>
                <tr>
                  <td align="left" valign="middle"/>
                  <td align="left" valign="middle">Altas doses fracionadas de radia&#231;&#227;o &gt; 2 Gy/dia</td>
                </tr>
                <tr>
                  <td align="left" valign="middle"/>
                  <td align="left" valign="middle">Presen&#231;a e extens&#227;o do tumor pr&#243;ximo ao cora&#231;&#227;o</td>
                </tr>
                <tr>
                  <td align="left" valign="middle"/>
                  <td align="left" valign="middle">Uso concomitante de quimioter&#225;picos (principalmente antrac&#237;clicos)</td>
                </tr>
                <tr>
                  <td align="left" valign="middle"/>
                  <td align="left" valign="middle">Fatores de risco para doen&#231;a cardiovascular (HAS, DM, DLP, tabagismo)</td>
                </tr>
                <tr>
                  <td align="left" valign="middle"/>
                  <td align="left" valign="middle">Doen&#231;a cardiovascular preexistente</td>
                </tr>
                <tr>
                  <td align="left" valign="middle"/>
                  <td align="left" valign="middle">Inadequada prote&#231;&#227;o da &#225;rea card&#237;aca</td>
                </tr>
                <tr>
                  <td align="left" valign="middle"/>
                  <td align="left" valign="middle">Irradia&#231;&#227;o na regi&#227;o anterior ou hemit&#243;rax esquerdo</td>
                </tr>
                <tr>
                  <td align="left" colspan="2" valign="middle">
                    <bold>Defini&#231;&#227;o de alto risco: exposi&#231;&#227;o &#224; radia&#231;&#227;o tor&#225;cica em regi&#227;o anterior ou tor&#225;cica esquerda adicionalmente a pelo menos um dos fatores listados</bold>
                  </td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="TFN2">
                <p>RT: radioterapia; HAS: hipertens&#227;o arterial sist&#234;mica; DM: diabetes melito; DLP: dislipidemia.</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
        </sec>
        <sec>
          <title>4.1.2. Fisiopatologia</title>
          <p>Os cardiomi&#243;citos s&#227;o relativamente resistentes ao dano provocado pela radia&#231;&#227;o, pelo seu estado p&#243;s-mit&#243;tico. Entretanto, c&#233;lulas endoteliais continuam sens&#237;veis &#224; radia&#231;&#227;o, e a fisiopatologia da maioria das formas de DCIR parece estar relacionada a essas c&#233;lulas. Outros mecanismos perpetuadores da agress&#227;o celular tamb&#233;m parecem estar relacionados, como a isquemia e a hip&#243;xia tecidual, al&#233;m da agress&#227;o direta manifestada por aterosclerose acelerada, trombose, indu&#231;&#227;o ao estresse oxidativo, miocit&#243;lise e ativa&#231;&#227;o de mecanismos neuro-humorais levando &#224; aterosclerose e, finalmente, &#224; fibrose. <xref ref-type="bibr" rid="B107"><sup>107</sup></xref> </p>
        </sec>
        <sec>
          <title>4.1.3. Avalia&#231;&#227;o Inicial e Seguimento</title>
          <p>Em se tratando de pacientes oncol&#243;gicos, a avalia&#231;&#227;o complementar cardiovascular &#233; classicamente ditada pelo <italic>status</italic> sintom&#225;tico ou pela presen&#231;a de achados sugestivos no exame f&#237;sico. A ecocardiografia assume um papel central na avalia&#231;&#227;o da morfologia e fun&#231;&#227;o do cora&#231;&#227;o e representa a primeira modalidade de imagem na maioria dos casos.</p>
          <p>Em rela&#231;&#227;o ao seguimento p&#243;s-tratamento com RT, recomendam-se avalia&#231;&#245;es cl&#237;nicas anuais contemplando anamnese dirigida, exame cl&#237;nico e eletrocardiograma de repouso. Na presen&#231;a de sintomas e/ou novos achados sugestivos ao exame f&#237;sico, sugere-se a realiza&#231;&#227;o de novo ecocardiograma transtor&#225;cico (ETT). Nos pacientes que permanecem assintom&#225;ticos e categorizados como de baixo risco para desenvolvimento de DCIR, o ETT de vigil&#226;ncia &#233; recomendado ap&#243;s 10 anos da exposi&#231;&#227;o e reavalia&#231;&#245;es seguintes a cada 5 anos. J&#225; em indiv&#237;duos assintom&#225;ticos, no entanto, classificados como de alto risco, sugere-se a antecipa&#231;&#227;o da avalia&#231;&#227;o, incluindo a pesquisa de isquemia mioc&#225;rdica por meio de teste funcional n&#227;o invasivo, conforme ilustrado na <xref ref-type="fig" rid="f8">Figura 8</xref> . <xref ref-type="bibr" rid="B104"><sup>104</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B108"><sup>108</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B109"><sup>109</sup></xref> </p>
          <fig id="f8">
            <label>Figura 8</label>
            <caption>
              <title>Algoritmo de acompanhamento evolutivo ecocardiogr&#225;fico ap&#243;s radioterapia tor&#225;cica.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf08.tif"/></fig>
        </sec>
        <sec>
          <title>4.1.4. DCIR e o Papel do Ecocardiograma</title>
          <sec>
            <title>4.1.4.1. Doen&#231;a Peric&#225;rdica e Mioc&#225;rdica Induzida pela Radia&#231;&#227;o</title>
            <p>A doen&#231;a peric&#225;rdica &#233; descrita como o efeito colateral mais comum da RT tor&#225;cica, surgindo habitualmente algumas semanas ap&#243;s o tratamento. Novos protocolos, incluindo doses mais baixas e implementa&#231;&#227;o de t&#233;cnicas cardioprotetoras,diminu&#237;ram a incid&#234;ncia de 20% para 2,5%, guardando correla&#231;&#227;o proporcional &#224; dose e ao volume exposto durante o tratamento. <xref ref-type="bibr" rid="B103"><sup>103</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B104"><sup>104</sup></xref> A pericardite geralmente &#233; autolimitada. No entanto, 10% a 20% dos pacientes desenvolvem pericardite cr&#244;nica ou constritiva 5 a 10 anos ap&#243;s o tratamento, o que sinaliza para um progn&#243;stico mais reservado. <xref ref-type="bibr" rid="B109"><sup>109</sup></xref> O ETT, al&#233;m do diagn&#243;stico, permite a quantifica&#231;&#227;o de derrames peric&#225;rdicos e auxilia pericardiocentese. Uma das grandes vantagens do m&#233;todo &#233; permitir a an&#225;lise da sua fisiologia constrictiva, caracterizada por achados ecocardiogr&#225;ficos como espessamento peric&#225;rdico, <italic>bounce</italic> septal, padr&#227;o de enchimento diast&#243;lico restritivo, varia&#231;&#227;o inspirat&#243;ria significativa do influxo mitral (&gt; 25%), pletora de veia cava inferior, redu&#231;&#227;o do <italic>strain</italic> circunferencial e revers&#227;o do fluxo diast&#243;lico expirat&#243;rio nas veias hep&#225;ticas. O impacto na sobrevida tem sido atribu&#237;do ao encontro concomitante de outras les&#245;es card&#237;acas associadas &#224; radia&#231;&#227;o, sendo comumente acompanhado por fibrose mioc&#225;rdica, estenose prematura da art&#233;ria coron&#225;ria e les&#245;es valvares importantes.</p>
          </sec>
          <sec>
            <title>4.1.4.2. Doen&#231;a Coron&#225;ria Induzida por Radia&#231;&#227;o</title>
            <p>Habitualmente, o tratamento de linfoma de Hodgkin e c&#226;ncer de mama inclue a RT tor&#225;cica, resultando na exposi&#231;&#227;o dos tecidos card&#237;acos &#224; radia&#231;&#227;o. A incid&#234;ncia cumulativa de doen&#231;a arterial coronariana induzida por radia&#231;&#227;o (DACIR) &#233; estimada em quase 60% em sobreviventes do linfoma de Hodgkin, com um risco relativo de 3,2 vezes maior em compara&#231;&#227;o com a popula&#231;&#227;o em geral. <xref ref-type="bibr" rid="B109"><sup>109</sup></xref> J&#225; em rela&#231;&#227;o ao c&#226;ncer de mama, o mais frequente entre as mulheres, metan&#225;lises mostraram que o risco relativo de desenvolver DACIR &#233; mais alto em pacientes que recebem RT tor&#225;cica esquerda. <xref ref-type="bibr" rid="B110"><sup>110</sup></xref> </p>
            <p>Portanto, pacientes com neoplasias tor&#225;cicas t&#234;m um risco consideravelmente maior de desenvolver DACIR em compara&#231;&#227;o com a popula&#231;&#227;o em geral, em especial na presen&#231;a de fatores de risco como dose cumulativa utilizada (em geral &gt; 30 Gy), idade precoce durante a exposi&#231;&#227;o, volume de tecido acometido, falta de prote&#231;&#227;o card&#237;aca e presen&#231;a de fatores de risco cardiovasculares tradicionais preexistentes. <xref ref-type="bibr" rid="B104"><sup>104</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B105"><sup>105</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B109"><sup>109</sup></xref> </p>
            <p>Apesar de a DCIR se manifestar tardiamente, a DAC, em especial, pode ter surgimento mais precocemente, j&#225; a partir do quinto ano p&#243;s-exposi&#231;&#227;o. <xref ref-type="bibr" rid="B105"><sup>105</sup></xref> &#201; sabido que as les&#245;es coronarianas induzidas pela radia&#231;&#227;o exibem, em sua maioria, acometimento ostial e proximal, caracteristicamente envolvendo o tronco da coron&#225;ria esquerda, art&#233;ria descendente anterior ou a art&#233;ria coron&#225;ria direita. <xref ref-type="bibr" rid="B107"><sup>107</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B111"><sup>111</sup></xref> A RT predisp&#245;e ou acelera a aterosclerose, inclusive naqueles pacientes sem fatores de riscos cardiovasculares cl&#225;ssicos, e pode ter como primeira apresenta&#231;&#227;o cl&#237;nica a morte s&#250;bita. Dessa forma, considerando-se a alta morbimortalidade, apresenta&#231;&#227;o cl&#237;nica heterog&#234;nea e por vezes at&#237;pica, advoga-se a realiza&#231;&#227;o de rastreamento por meio do ecocardiograma de estresse (ETT estresse), utilizando-se estresse f&#237;sico ou farmacol&#243;gico (dobutamina) quando pertinente. Esse m&#233;todo funcional n&#227;o invasivo oferece vantagens como acur&#225;cia satisfat&#243;ria, aus&#234;ncia de radia&#231;&#227;o, relativo baixo custo e disponibilidade.</p>
          </sec>
          <sec>
            <title>4.1.4.3. Doen&#231;a Valvular Induzida pela Radia&#231;&#227;o (DVIR)</title>
            <p>Relata-se maior preval&#234;ncia de DVIR nos subgrupos de portadores de linfoma de Hodgkin (17%) e neoplasia de mama (4,2%). Assim como na DACIR, o seu risco est&#225; relacionado com dose total de radia&#231;&#227;o e campo de exposi&#231;&#227;o.</p>
            <p>O acometimento valvar com repercuss&#227;o hemodin&#226;mica geralmente ocorre ap&#243;s 10 anos da RT e mais comumente acomete as valvas do lado esquerdo do cora&#231;&#227;o. A valva a&#243;rtica &#233; mais frequentemente acometida que a mitral. O surgimento de regurgita&#231;&#245;es valvares &#233; mais precoce que as les&#245;es esten&#243;ticas, que costumam aparecer cerca de 20 anos ap&#243;s a RT. Os achados ecocardiogr&#225;ficos s&#227;o vari&#225;veis e incluem desde altera&#231;&#245;es m&#237;nimas sem disfun&#231;&#227;o valvar associada, at&#233; fibrose difusa, espessamento e calcifica&#231;&#227;o. S&#227;o caracter&#237;sticos o acometimento de qualquer componente do aparato valvar, poupando comissuras, permitindo assim diferencia&#231;&#227;o sobretudo da etiologia reum&#225;tica. O comprometimento da cortina mitroa&#243;rtica (espessamento e calcifica&#231;&#227;o) &#233; um achado caracter&#237;stico p&#243;s-RT e est&#225; associado &#224; pior sobrevida a longo prazo. <xref ref-type="bibr" rid="B103"><sup>103</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B108"><sup>108</sup></xref> </p>
            <p>Com a progress&#227;o dos sintomas e gravidade das les&#245;es, pode haver necessidade de interven&#231;&#227;o cir&#250;rgica ou manejo percut&#226;neo. T&#233;cnicas ecocardiogr&#225;ficas diferenciadas como o eco 3D e o eco transesof&#225;gico (ETE) auxiliam na melhora da avalia&#231;&#227;o anat&#244;mica e funcional, especialmente nas les&#245;es valvares de maior repercuss&#227;o hemodin&#226;mica e estrutural. Recomenda-se, entretanto, cuidado na realiza&#231;&#227;o do ETE em pacientes submetidos &#224; RT tor&#225;cica, dada a possibilidade de comprometimento associado da estrutura esof&#225;gica nesses pacientes.</p>
          </sec>
        </sec>
      </sec>
      <sec>
        <title>4.2. Arterite Induzida por Radia&#231;&#227;o &#8211; Arterite Act&#237;nica</title>
        <p>A arterite induzida por radia&#231;&#227;o, tamb&#233;m chamada de arterite act&#237;nica, se d&#225; por altera&#231;&#227;o da estrutura da parede arterial e aparecimento de estenoses ou oclus&#245;es arteriais. Esses fen&#244;menos podem resultar em um processo ateroscler&#243;tico acelerado, de car&#225;ter inflamat&#243;rio, por les&#227;o das cel&#250;las endoteliais, podendo acometer art&#233;rias de m&#233;dio ou grande calibre. Nos casos de radioterapida para tumores da cabe&#231;a e pesco&#231;o, as art&#233;rias comprometidas podem estar nos segmentos intra e extracranianos.</p>
        <p>A estenose carot&#237;dea induzida pela RT teve sua evolu&#231;&#227;o estudada por Cheng et al, <xref ref-type="bibr" rid="B112"><sup>112</sup></xref> estes autores demonstraram que, comparados com controles n&#227;o submetidos &#224; irradia&#231;&#227;o, houve progress&#227;o anual do grau de estenose, de menor que 50% para maior que 50%, em 15,4% <italic>versus</italic> 4,8% (pacientes n&#227;o irradiados). Nesse estudo, n&#227;o houve diferen&#231;a no surgimentos de sintomas ou mortalidade entre os grupos estudados. Por&#233;m, tais altera&#231;&#245;es podem levar, segundo outros autores, ao aparecimento de sintomas cerebrovasculares, tendo sido demonstrado que pacientes sintom&#225;ticos, com les&#245;es carot&#237;deas p&#243;s-RT, exibem fluxo cerebral reduzido. <xref ref-type="bibr" rid="B113"><sup>113</sup></xref> </p>
        <p>Arteriopatia perif&#233;rica, apesar de mais rara, tamb&#233;m tem sido relacionada ap&#243;s a radioterapia, como por exemplo ap&#243;s o tratamento de c&#226;nceres da c&#233;rvix uterina, com acometimento de art&#233;rias il&#237;acas e femorais; os sintomas podem ser de isquemia cr&#244;nica, por&#233;m, tamb&#233;m podem ocorrer casos de oclus&#227;o arterial aguda. <xref ref-type="bibr" rid="B114"><sup>114</sup></xref> </p>
        <sec>
          <title>4.2.1. Diagn&#243;stico</title>
          <p>O diagn&#243;stico da estenose carot&#237;dea pode ser feito clinicamente, inferido pela ausculta de sopro na regi&#227;o do pesco&#231;o que recebeu a RT. Os exames de imagem, incluindo a ultrassonografia vascular, a angiotomografia, a resson&#226;ncia nuclear magn&#233;tica ou a angiografia convencional contrastada, podem, al&#233;m de detectar e estenose, tamb&#233;m quantific&#225;-la. <xref ref-type="bibr" rid="B115"><sup>115</sup></xref> </p>
          <p>A ultrassonografia vascular tem vantagens por ser n&#227;o invasiva, de baixo custo, sem uso de contraste nefrot&#243;xico, podendo assim ser utilizada, se de forma segura, no seguimento a m&#233;dio e longo prazo dos pacientes.</p>
        </sec>
        <sec>
          <title>4.2.2. Caracter&#237;sticas Ultrassonogr&#225;ficas</title>
          <p>As les&#245;es arteriais induzidas pela radia&#231;&#227;o ionizante podem ocorrer nas diversas art&#233;rias do corpo, tendo sido descritas, principalmente, nos troncos supra a&#243;rticos (art&#233;rias car&#243;tidas e subcl&#225;vias). Ap&#243;s o primeiro ano do uso da RT para o tratamento de c&#226;nceres localizados na cabe&#231;a e no pesco&#231;o, h&#225; um espessamento acelerado e progressivo da camada mediointimal de ambas as art&#233;rias car&#243;tidas, podendo levar a importante redu&#231;&#227;o luminal. <xref ref-type="bibr" rid="B116"><sup>116</sup></xref> Wilbers et al. <xref ref-type="bibr" rid="B117"><sup>117</sup></xref> encontraram resultados semelhantes ap&#243;s 7 anos do uso da radioterapia nessa regi&#227;o. Estudo realizado com jovens submetidos &#224; radioterapia, em um seguimento de 20 anos, mostrou os seguintes achados: maior preval&#234;ncia de placas ateroscler&#243;ticas no lado irradiado do que no contralateral (18% versus 2%), maior espessura mediointimal (EMI) em pacientes tratados que nos controles e um aumento linear da EMI pelo tempo desde a realiza&#231;&#227;o da RT <xref ref-type="bibr" rid="B118"><sup>118</sup></xref> ( <xref ref-type="fig" rid="f9">Figuras 9</xref> e <xref ref-type="fig" rid="f10">10</xref> ).</p>
          <fig id="f9">
            <label>Figura 9</label>
            <caption>
              <title>Art&#233;ria car&#243;tida comum direita em corte transverso com importante espessamento da camada mediointimal levando &#224; grande redu&#231;&#227;o luminal.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf09.tif"/></fig>
          <fig id="f10">
            <label>Figura 10</label>
            <caption>
              <title>Paciente com arterite act&#237;nica, 6 anos ap&#243;s a radioterapia. A. Estenose maior que 70% da art&#233;ria car&#243;tida comum direita ao Doppler colorido &#8211; observa-se grande redu&#231;&#227;o luminal e turbul&#234;ncia do fluxo. B. Art&#233;ria car&#243;tida comum direita com grande aumento da espessura mediointimal (EMI) ao modo B causando com redu&#231;&#227;o luminal. C. Doppler pulsado com eleva&#231;&#227;o da velocidade de fluxo. D. Car&#243;tida comum esquerda oclu&#237;da.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf10.tif"/></fig>
          <p>&#201; frequente o acometimento da art&#233;ria car&#243;tida comum por um processo ateroscler&#243;tico acelerado, que tamb&#233;m pode ser observado na art&#233;ria car&#243;tida interna. O diagn&#243;stico diferencial apenas pela imagem ultrassonogr&#225;fica nem sempre &#233; poss&#237;vel, sendo que a hist&#243;ria de radioterapia na regi&#227;o acometida &#233; fundamental para que o diagn&#243;stico seja estabelecido. A doen&#231;a ateroscler&#243;tica e a arterite de Takayassu s&#227;o os principais diagn&#243;sticos diferenciais. Na doen&#231;a ateroscler&#243;tica, em geral, o acometimento se d&#225; mais comumente na bifurca&#231;&#227;o carot&#237;dea e na car&#243;tida interna, mas tamb&#233;m pode ocorrer na car&#243;tida comum ( <xref ref-type="fig" rid="f11">Figura 11</xref> ). Nos casos da arterite act&#237;nica, o acometimento da art&#233;ria car&#243;tida comum &#233; mais evidente, apresentando uma aterosclerose mais difusa, acentuada e progressiva. <xref ref-type="bibr" rid="B112"><sup>112</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B115"><sup>115</sup></xref> </p>
          <fig id="f11">
            <label>Figura 11</label>
            <caption>
              <title>Placa ateroscler&#243;tica na bifurca&#231;&#227;o carot&#237;dea.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf11.tif"/></fig>
          <p>Na arterite de Takayassu, h&#225; um espessamento homog&#234;neo e conc&#234;ntrico que pode levar &#224; estenose significativa e oclus&#227;o do vaso, podendo tamb&#233;m haver dilata&#231;&#245;es (aneurismas). Caracteristicamente acomete a car&#243;tida comum at&#233; a bifurca&#231;&#227;o, mas poupa a car&#243;tida interna <xref ref-type="bibr" rid="B119"><sup>119</sup></xref> ( <xref ref-type="fig" rid="f12">Figura 12 A -B</xref> ).</p>
          <fig id="f12">
            <label>Figura 12</label>
            <caption>
              <title>Arterite de Takayassu, sexo feminino, 17 anos de idade. A. Corte longitudinal da art&#233;ria car&#243;tida comum esquerda mostra importante espessamento conc&#234;ntrico da parede. B.119 Imagem ao powerDoppler com grande redu&#231;&#227;o luminal da art&#233;ria car&#243;tida comum, com l&#250;men preservado a partir da bifurca&#231;&#227;o carot&#237;dea.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf12.tif"/></fig>
        </sec>
        <sec>
          <title>4.2.3. Seguimento das Estenoses Arteriais</title>
          <p>Em fun&#231;&#227;o do car&#225;ter progressivo das estenoses arteriais induzidas pela radia&#231;&#227;o, sugere-se um seguimento mais rigorosos por m&#233;todos de imagem a fim de detectar as estenoses significativas pass&#237;veis de tratamento. Inicialmente, a ultrassonografia vascular pede ser realizada anualmente e ter seu uso individualizado, com intervalos menores caso haja mais r&#225;pida progress&#227;o da doen&#231;a e tamb&#233;m ap&#243;s o tratamento. <xref ref-type="bibr" rid="B120"><sup>120</sup></xref> </p>
          <p>A endarterectomia de car&#243;tida (ECA) e a abordagem via endovascular (angioplastia carot&#237;dea com STENT) se mostraram op&#231;&#245;es eficazes no tratamento das estenoses induzidas pela RT. <xref ref-type="bibr" rid="B121"><sup>121</sup></xref> A extens&#227;o da doen&#231;a e a grande &#225;rea arterial acometida podem favorecer fen&#244;menos emb&#243;licos durante o tratamento com STENT e levar ao surgimento de eventos cerebrovasculares. Al&#233;m disso, os STENTS podem apresentar hiperplasia intimal com recorr&#234;ncia da estenose ( <xref ref-type="fig" rid="f13">Figura 13</xref> ). O mecanismo que leva ao surgimento da hiperplasia intimal intra STENT nesses pacientes parece estar relacionado &#224; prolifera&#231;&#227;o de c&#233;lulas musculares lisas. <xref ref-type="bibr" rid="B122"><sup>122</sup></xref> A recorr&#234;ncia da estenose tem se mostrado um problema ap&#243;s o tratamento endovascular, aparentando ser maior nos pacientes com radioterapia pr&#233;via quando comparados com os controles. Comparados com os pacientes submetidos &#224; ECA, a taxa de reestenose acima de 50% &#233; maior nos tratados com STENT. <xref ref-type="bibr" rid="B123"><sup>123</sup></xref> </p>
          <fig id="f13">
            <label>Figura 13</label>
            <caption>
              <title>Paciente ap&#243;s 10 anos de radioterapia, com stent na art&#233;ria car&#243;tida comum esquerda; corte longitudinal demostrando a hiperplasia intimal e fluxo intrastent ao Doppler colorido; Doppler pulsado demonstrando aumento da velocidade local.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf13.tif"/></fig>
          <p>O acometimento de outras art&#233;rias, que n&#227;o as art&#233;rias cervicais, deve ser individualizado, tendo, na literatura, casos relatados com tratamento cir&#250;rgico e, via endovascular, angioplastia com STENT. <xref ref-type="bibr" rid="B114"><sup>114</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B124"><sup>124</sup></xref> </p>
        </sec>
      </sec>
      <sec>
        <title>4.3. Avalia&#231;&#227;o Cardiovascular ap&#243;s Radioterapia | Papel da Medicina Nuclear</title>
        <sec>
          <title>4.3.1. Avalia&#231;&#227;o e Seguimento de DAC ap&#243;s RT</title>
          <p>Lind et al. <xref ref-type="bibr" rid="B125"><sup>125</sup></xref> avaliaram 69 mulheres submetidas &#224; RT tor&#225;cica nas doses de 46 a 50 Gy, com fra&#231;&#245;es de at&#233; 2 Gy por sess&#227;o, utilizando blindagem card&#237;aca adequada. Estas foram submetidas &#224; cintilografia de perfus&#227;o mioc&#225;rdica em repouso com sestamibi-<sup>99m</sup>Tc ou tetrofosmin-<sup>99m</sup>Tc antes e com 6, 12 e 18 meses ap&#243;s RT. Com 6 meses foram observadas altera&#231;&#245;es perfusionais, em especial no territ&#243;rio da art&#233;ria coron&#225;ria descendente anterior. <xref ref-type="bibr" rid="B125"><sup>125</sup></xref> Este achado tamb&#233;m foi corroborado por Hardenbergh et al., <xref ref-type="bibr" rid="B126"><sup>126</sup></xref> que mostraram altera&#231;&#245;es perfusionais em cerca de 60% dos indiv&#237;duos 6meses ap&#243;s irradia&#231;&#227;o tor&#225;cica. <xref ref-type="bibr" rid="B126"><sup>126</sup></xref> A an&#225;lise da fun&#231;&#227;o ventricular ao ecocardiograma mostrou que somente um desses pacientes apresentou redu&#231;&#227;o de mais de 10% da FEVE. Mesmo associado ao dano de microcircula&#231;&#227;o, os autores destacam a import&#226;ncia deste achado, que pode levar &#224; disfun&#231;&#227;o diast&#243;lica e sist&#243;lica, subsequentemente.</p>
          <p>As altera&#231;&#245;es coron&#225;rias tanto micro quanto macrovasculares s&#227;o sequelas tardias reconhecidas da RT tor&#225;cica. &#201; conhecida a import&#226;ncia de uma triagem regular para os efeitos coron&#225;rios da RT. No entanto, ainda n&#227;o h&#225; regimes de rastreamento espec&#237;fico para essa popula&#231;&#227;o, mesmo diante do grande arsenal de m&#233;todos n&#227;o invasivos dispon&#237;veis. <xref ref-type="bibr" rid="B127"><sup>127</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B128"><sup>128</sup></xref> </p>
        </sec>
      </sec>
      <sec>
        <title>4.4. Avalia&#231;&#227;o de DAC ap&#243;s Radioterapia &#8211; Papel da Tomografia Computadorizada</title>
        <p>A cardiotoxicidade induzida pelo tratamento radioter&#225;pico apresenta v&#225;rios mecanismos fisiopatol&#243;gicos que desencadeiam diversas inj&#250;rias ao sistema cardiovascular: nas art&#233;rias coron&#225;rias, podem ocorrer um efeito vasoesp&#225;stico direto, les&#227;o endotelial ou altera&#231;&#245;es no metabolismo lip&#237;dico e aterosclerose prematura consequente. O risco de eventos coron&#225;rios subsequentes &#233; proporcional &#224; dose de radia&#231;&#227;o.</p>
        <p>A elevada acur&#225;cia na detec&#231;&#227;o de DAC pela angiotomografia coron&#225;ria confere ao m&#233;todo o potencial de fornecer informa&#231;&#245;es precisas na suspeita de DAC nos pacientes com c&#226;ncer, especialmente na dor tor&#225;cica e nos sintomas de insufici&#234;ncia card&#237;aca potencialmente relacionados &#224; etiologia isqu&#234;mica.</p>
        <p>Numerosos estudos demonstram incid&#234;ncia aumentada de DAC, infarto agudo do mioc&#225;rdio e morte s&#250;bita card&#237;aca em pacientes submetidos &#224; radioterapia, em especial nos pacientes com linfoma de Hodgkin ou neoplasia de mama, refor&#231;ando o potencial nocivo deste tratamento. As diretrizes atuais sugerem triagem para DAC no per&#237;odo de 5 a 10 anos ap&#243;s a irradia&#231;&#227;o tor&#225;cica como vigil&#226;ncia para cardiotoxicidade tardia. <xref ref-type="bibr" rid="B129"><sup>129</sup></xref> </p>
        <p>Diversos estudos incluindo a tomografia confirmam esses achados cl&#237;nico-epidemiol&#243;gicos em pacientes com linfoma de Hodgkin. Mulrooney et al. <xref ref-type="bibr" rid="B130"><sup>130</sup></xref> identificaram placas pela angiotomografia coron&#225;ria em 39% dos sobreviventes. J&#225; Girinsky et al. <xref ref-type="bibr" rid="B131"><sup>131</sup></xref> encontraram placas em 26% dos pacientes submetidos &#224; radioterapia num estudo prospectivo com seguimento m&#233;dio de 9,5 anos incluindo 179 pacientes. Na an&#225;lise multivariada, a dose de radia&#231;&#227;o aplicada na origem das art&#233;rias coron&#225;rias associou-se ao achado de placas. Van Rosendael et al. <xref ref-type="bibr" rid="B132"><sup>132</sup></xref> compararam 71 pacientes submetidos &#224; radioterapia com 237 controles n&#227;o irradiados pareados para m&#250;ltiplos fatores de risco para DAC e encontraram maior preval&#234;ncia de placas, doen&#231;a mais proximal, maior grau de estenose e n&#250;mero de vasos com les&#245;es importantes no grupo submetido &#224; radioterapia.</p>
      </sec>
      <sec>
        <title>4.5. Avalia&#231;&#227;o de DAC ap&#243;s Radioterapia &#8211; Papel da Resson&#226;ncia Magn&#233;tica</title>
        <p>A RMC tem excelente acur&#225;cia no diagn&#243;stico de isquemia mioc&#225;rdica quando associada ao estresse farmacol&#243;gico, e &#233; considerada o padr&#227;o-ouro na avalia&#231;&#227;o de infarto e viabilidade mioc&#225;rdica, al&#233;m da an&#225;lise da fun&#231;&#227;o ventricular, apresentando valor progn&#243;stico na predi&#231;&#227;o eventos cardiovasculares.</p>
        <p>O estudo CE-MARC comparou a pesquisa de isquemia da perfus&#227;o sob estresse pela RMC com a da perfus&#227;o sob estresse pela cintilografia em 628 pacientes submetidos &#224; cinecoronariografia como refer&#234;ncia, em uma popula&#231;&#227;o com preval&#234;ncia de DAC obstrutiva de 39%. <xref ref-type="bibr" rid="B133"><sup>133</sup></xref> Ambos os m&#233;todos apresentaram especificidades semelhantes (RMC 83,4% x SPECT 82,6%, p = 0,916), por&#233;m a RMC foi significativamente mais sens&#237;vel para o diagn&#243;stico de isquemia mioc&#225;rdica (RMC 86,5% x SPECT 66,5%, p &lt; 0,0001).</p>
        <p>A t&#233;cnica de realce tardio, em que as imagens s&#227;o adquiridas ap&#243;s a infus&#227;o de gadol&#237;nio e sem a necessidade de agentes estressores, &#233; considerada o principal meio n&#227;o invasivo para a detec&#231;&#227;o de fibrose mioc&#225;rdica. A an&#225;lise da extens&#227;o do infarto do mioc&#225;rdio prediz a viabilidade mioc&#225;rdica relacionada ao segmento em investiga&#231;&#227;o. A presen&#231;a e a extens&#227;o do infarto pela RMC apresenta estabelecido valor progn&#243;stico, inclusive a presen&#231;a de infartos desconhecidos em pacientes submetidos &#224; RMC est&#225; associada com pior progn&#243;stico cardiovascular e mortalidade. <xref ref-type="bibr" rid="B134"><sup>134</sup></xref> </p>
      </sec>
    </sec>
    <sec>
      <title>5. Tumores e Massas Card&#237;acas</title>
      <sec>
        <title>5.1. Contribui&#231;&#227;o da Ecocardiografia</title>
        <p>Massas card&#237;acas costumam ser desafiadoras ao diagn&#243;stico ecocardiogr&#225;fico. Trombos, vegeta&#231;&#245;es e pseudotumores representam 75% dos casos. Os tumores card&#237;acos prim&#225;rios (TCP) propriamente ditos s&#227;o extremamente raros com frequ&#234;ncia estimada de 0,02%, podendo ser benignos ou malignos quanto &#224; histologia. J&#225; as met&#225;stases card&#237;acas s&#227;o at&#233; 100 vezes mais frequentes. Recentemente, a Organiza&#231;&#227;o Mundial da Sa&#250;de atualizou a classifica&#231;&#227;o de tumores card&#237;acos e peric&#225;rdicos. <xref ref-type="bibr" rid="B135"><sup>135</sup></xref> </p>
        <p>O ecocardiograma transtor&#225;cico (ETT) avalia localiza&#231;&#227;o, morfologia, dimens&#245;es, ecogenicidade, mobilidade, extens&#227;o, calcifica&#231;&#245;es, tipo de inser&#231;&#227;o e presen&#231;a ou n&#227;o de derrame peric&#225;rdico (DP). <xref ref-type="bibr" rid="B136"><sup>136</sup></xref> As diferentes modalidades de Doppler permitem avalia&#231;&#227;o do fluxo sangu&#237;neo e consequente repercuss&#227;o hemodin&#226;mica, como obstru&#231;&#227;o ao fluxo ou disfun&#231;&#227;o valvar. O mapeamento de fluxo em cores pode revelar apresen&#231;a de vasculariza&#231;&#227;o em certos tipos de tumores, assim como o uso de contrastes de perfus&#227;o, permitindo identifica&#231;&#227;o e diferencia&#231;&#227;o entre trombos e tumores. Em geral, trombos n&#227;o real&#231;am e s&#227;o bem delineados na cavidade contrastada. O contraste auxilia tamb&#233;m na diferencia&#231;&#227;o entre tumores benignos e malignos. <xref ref-type="bibr" rid="B137"><sup>137</sup></xref> Tumores malignos tendem a apresentar realce completo, enquanto tumores benignos apenas parcialmente. A an&#225;lise da perfus&#227;o p&#243;s-impulso ( <italic>replenishment</italic> ) pode ser qualitativa (visual) ou quantitativa, por meio de curvas de capta&#231;&#227;o de intensidade tempo-sinal e atrav&#233;s de mapas param&#233;tricos (codifica&#231;&#227;o colorida da intensidade de sinal). A diferen&#231;a entre o n&#237;vel m&#225;ximo de intensidade de <italic>pixel</italic> estacion&#225;rio p&#243;s-impulso ( <italic>A</italic> ) da massa e o mioc&#225;rdio vizinho pode ser calculada (Delta <italic>A</italic> <sub>massa-mioc&#225;rdio</sub>). A sensibilidade e a especificidade relatadas do Delta <italic>A</italic> <sub>massa-mioc&#225;rdio</sub> em diferenciar um trombo de tumores benignos e malignos foram 93% e 100%, respectivamente, com valores de corte de 23,2 dB e de 100% e 97%, com valor de corte de 0,45 dB. <xref ref-type="bibr" rid="B138"><sup>138</sup></xref> Estimativas do volume, velocidade e fluxo sangu&#237;neo microvascular das massas tamb&#233;m podem ser obtidas. Imagens com <italic>strain</italic> podem diferenciar a natureza e o padr&#227;o contr&#225;til de certos tipos de tumores, como fibroma e rabdomioma. Rabdomiomas apresentam deforma&#231;&#227;o oposta &#224; do mioc&#225;rdio, enquanto fibromas n&#227;o apresentam deforma&#231;&#227;o. <xref ref-type="bibr" rid="B139"><sup>139</sup></xref> O ETE tem maior sensibilidade (&gt;95%) e melhor resolu&#231;&#227;o ac&#250;stica que o ETT, permitindo melhor caracteriza&#231;&#227;o de tumores e massas quanto &#224; localiza&#231;&#227;o, inser&#231;&#227;o e rela&#231;&#227;o com a veia cava, especialmente nas les&#245;es atriais e valvares. O ETE tem papel importante em casos com emboliza&#231;&#227;o sist&#234;mica, na avalia&#231;&#227;o intraoperat&#243;ria de ressec&#231;&#227;o tumoral, bem como nas les&#245;es ventriculares em pacientes com janela ac&#250;stica tor&#225;cica limitada. O ecocardiograma 3D em tempo real &#233; a mais nova ferramenta de avalia&#231;&#227;o de massas card&#237;acas, fornecendo dados mais acurados sobre volume, morfologia e rela&#231;&#227;o com estruturas vizinhas, al&#233;m de aspectos como local e tipo de inser&#231;&#227;o, homogeneidade, vasculariza&#231;&#227;o, calcifica&#231;&#227;o e &#225;reas de necrose. <xref ref-type="bibr" rid="B140"><sup>140</sup></xref> </p>
        <p>Toda massa card&#237;aca encontrada ao ecocardiograma deve ser colocada no contexto cl&#237;nico e epidemiol&#243;gico. Idade, sexo, sintomatologia e doen&#231;a oncol&#243;gica concomitante s&#227;o elementos importantes para o diagn&#243;stico. Artefatos devem ser exclu&#237;dos analisando m&#250;ltiplos planos de corte e fazendo ajustes nos par&#226;metros de imagem. Valva de Eust&#225;quio e crista terminalis proeminentes, rede de Chiari e crista coumad&#237;nica s&#227;o variantes anat&#244;micas que podem ser mal interpretadas e confundidas com massas. Escresc&#234;ncias de Lambl s&#227;o estruturas filiformes que variam entre 3 e 5mm, encontradas no local de fechamento das valvas, a jusante do fluxo. N&#227;o causam disfun&#231;&#227;o valvar, mas podem embolizar. Hipertrofia lipomatosa do septo interatrial se caracteriza por infiltra&#231;&#227;o de gordura madura, que poupa a fossa oval conferindo-lhe t&#237;pica forma de haltere. Tumores amorfos calcificados s&#227;o massas n&#227;o neopl&#225;sicas heterog&#234;neas, hiperecoicas, com &#225;reas hipo ou isoecoicas, de mobilidade vari&#225;vel, frequentemente associados &#224; calcifica&#231;&#227;o do anel mitral e que podem ser fontes de embolias. <xref ref-type="bibr" rid="B141"><sup>141</sup></xref> Cistos peric&#225;rdicos s&#227;o hipoecoicos, usualmente loculados, com dimens&#245;es variadas e adjacentes &#224; borda card&#237;aca.Trombos podem ser encontrados em qualquer cavidade e variam em tamanho, morfologia e mobilidade, mas n&#227;o costumam ocorrer fora de condi&#231;&#245;es predisponentes. Quando no interior do &#225;trio esquerdo, ocorrem principalmente em pacientes que apresentam contraste espont&#226;neo, fibrila&#231;&#227;o atrial, estenose ou pr&#243;tese mitral. No &#225;trio direito (AD), s&#227;o relativamente comuns em pacientes oncol&#243;gicos com cateter de longa perman&#234;ncia e estado de hipercoagulabilidade. Trombos migrantes s&#227;o vistos no lado direito do cora&#231;&#227;o em pacientes com TVP e contexto de embolia pulmonar. Trombo no VE associa-se a altera&#231;&#245;es da contratilidade segmentar e cardiomiopatia dilatada. Vegeta&#231;&#245;es acometem principalmente as valvas card&#237;acas esquerdas, apresentam grande mobilidade e movimenta&#231;&#227;o independente. S&#227;o encontradas na superf&#237;cie atrial das valvas atrioventriculares e na superf&#237;cie ventricular das valvas semilunares, frequentemente causando disfun&#231;&#227;o valvar, em um contexto de endocardite.</p>
        <sec>
          <title>5.1.1. Tumores Card&#237;acos Prim&#225;rios Benignos (TCPB)</title>
          <p>Representam 85% a 90% de todos os TCP. Destes, cerca de 50% s&#227;o mixomas. <xref ref-type="bibr" rid="B136"><sup>136</sup></xref> Rabdomioma &#233; o tipo mais frequente na inf&#226;ncia, correspondendo a aproximadamente 50% dos casos, seguido por fibroma e mixoma. <xref ref-type="bibr" rid="B142"><sup>142</sup></xref> </p>
          <sec>
            <title>5.1.1.1. Mixomas Card&#237;acos</title>
            <p>S&#227;o mais frequentes entre 30 e 60 anos, apresentando sintomas constitucionais, obstrutivos ou emb&#243;licos. Localizam-se no AE em 75% dos casos, 20% no AD e 5% nos ventr&#237;culos. Tipicamente, caracterizam-se como massas polipoides oscilantes, fixadas no septo interatrial atrav&#233;s de ped&#237;culo estreito. S&#227;o heterog&#234;neos, com n&#250;cleos ecog&#234;nicos, &#225;reas c&#237;sticas e superf&#237;cies lisas. Dependendo do tamanho, podem obstruir o fluxo da valva atrioventricular. Mixomas papilares s&#227;o menores, com apar&#234;ncia esticada, superf&#237;cie irregular, maior mobilidade e maior risco de emboliza&#231;&#227;o. O ETE (2D ou 3D) e o uso de contrastes de perfus&#227;o auxiliam na caracteriza&#231;&#227;o desses tumores. Mixomas card&#237;acos podem ser recorrentes, quando associados ao Complexo de Carney. Nesses casos, o ETT &#233; a t&#233;cnica de imagem ideal para o seguimento. <xref ref-type="bibr" rid="B143"><sup>143</sup></xref> </p>
          </sec>
          <sec>
            <title>5.1.1.2. Fibroelastomas Papilares</title>
            <p>S&#227;o pequenos tumores avasculares (em geral, &lt; 10mm), s&#233;sseis ou pedunculados, arredondados, gelatinosos, com m&#250;ltiplas proje&#231;&#245;es papilares estreitas, alongadas e ramificadas. Lembram an&#234;monas do mar quando colocados sob a &#225;gua. Essas caracter&#237;sticas lhes conferem friabilidade e predisposi&#231;&#227;o para ades&#227;o de trombos. <xref ref-type="bibr" rid="B144"><sup>144</sup></xref> Epis&#243;dios de emboliza&#231;&#227;o s&#227;o mais comuns em tumores maiores que 10mm e podem ocorrer a partir de trombos aderidos ou da fragmenta&#231;&#227;o de papilas. Geralmente s&#227;o &#250;nicos, m&#243;veis e fixos a qualquer superf&#237;cie endoc&#225;rdica por um ped&#237;culo curto. Acometem a superf&#237;cie endoc&#225;rdica valvular em 77% dos casos e ocorrem principalmente em idosos. Comumente s&#227;o vistos na por&#231;&#227;o m&#233;dia dos folhetos das valvas card&#237;acas esquerdas. Na valva a&#243;rtica, costumam protrair no l&#250;men arterial e na mitral, na superf&#237;cie atrial. <xref ref-type="bibr" rid="B144"><sup>144</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B145"><sup>145</sup></xref> Ao ecocardiograma, exibem mobilidade independente, bordas pontilhadas e cintilantes e ped&#237;culo central estreito. Usualmente, n&#227;o causam disfun&#231;&#227;o valvar. O ETE apresenta papel importante na avalia&#231;&#227;o desses tumores.</p>
          </sec>
          <sec>
            <title>5.1.1.3. Rabdomiomas</title>
            <p>Geralmente s&#227;o diagnosticados no primeiro ano de vida ou na vida fetal. Associam-se &#224; esclerose tuberosa, costumam ser m&#250;ltiplos e tendem a regredir espontaneamente. <xref ref-type="bibr" rid="B146"><sup>146</sup></xref> Acometem principalmente o septo interventricular, paredes ventriculares e valvas atrioventriculares. Aparecem como m&#250;ltiplas massas nodulares ou pedunculadas, lobuladas, bem delimitadas, homog&#234;neas e hiperecog&#234;nicas em rela&#231;&#227;o ao mioc&#225;rdio circundante. Apresentam deforma&#231;&#227;o oposta &#224; do mioc&#225;rdio nas imagens com <italic>strain</italic> . <xref ref-type="bibr" rid="B139"><sup>139</sup></xref> </p>
          </sec>
          <sec>
            <title>5.1.1.4. Fibromas Card&#237;acos</title>
            <p>Raramente ocorrem em adultos. Aproximadamente 3% a 5% s&#227;o associados &#224; s&#237;ndrome de Gorlin (s&#237;ndrome do carcinoma basocelular). <xref ref-type="bibr" rid="B147"><sup>147</sup></xref> Caracterizam-se como massa s&#243;lida intramural, &#250;nica, hiperecog&#234;nica, bem delimitada, n&#227;o contr&#225;til, com calcifica&#231;&#245;es e que se estendem para a cavidade do VE. Podem provocar arritmias, disfun&#231;&#227;o ventricular e obstru&#231;&#227;o ao fluxo. N&#227;o apresentam deforma&#231;&#227;o nas imagens com <italic>strain</italic> . <xref ref-type="bibr" rid="B139"><sup>139</sup></xref> </p>
          </sec>
          <sec>
            <title>5.1.1.5. Lipomas Card&#237;acos</title>
            <p>S&#227;o massas de tecido adiposo encapsulado, localizadas principalmente no subendoc&#225;rdio do VE, mas ocorre em outras c&#226;maras, no peric&#225;rdio e valvas card&#237;acas, podendo atingir v&#225;rios cent&#237;metros. Apresentam-se com base larga, homog&#234;neas, im&#243;veis e sem calcifica&#231;&#227;o. Na cavidade, s&#227;o hiperecoicase, no peric&#225;rdio, hipoecoicas. <xref ref-type="bibr" rid="B148"><sup>148</sup></xref> </p>
          </sec>
          <sec>
            <title>5.1.1.6. Teratomas</title>
            <p>S&#227;o tumores de c&#233;lulas germinativas encontrados em lactentes, crian&#231;as e fetos. <xref ref-type="bibr" rid="B147"><sup>147</sup></xref> Podem ser maduros ou imaturos e raramente ocorrem em adultos.Localizam-se preferencialmente no espa&#231;o peric&#225;rdico e podem provocar tamponamento card&#237;aco ou compress&#227;o de estruturas adjacentes. <xref ref-type="bibr" rid="B149"><sup>149</sup></xref> Caracterizam-se como massas heterog&#234;neas contendo &#225;reas s&#243;lidas, c&#237;sticas e calcifica&#231;&#245;es, frequentemente acompanhadas de derrame peric&#225;rdico.</p>
          </sec>
          <sec>
            <title>5.1.1.7. Hemangiomas Card&#237;acos</title>
            <p>S&#227;o tumores vasculares raramente encontrados. Ocorrem em qualquer idade, inclusive na vida fetal. Localizam-se principalmente no VE e AD, medindo entre 2 e 10 cm na maioria dos casos. S&#227;o pedunculados e m&#243;veis na metade dos casos. Aparecem como massas bem circunscritas, c&#237;sticas ou s&#243;lidas, uni ou multilobuladas, dependendo do tipo: cavernoso, capilar ou arteriovenoso. <xref ref-type="bibr" rid="B150"><sup>150</sup></xref> </p>
          </sec>
          <sec>
            <title>5.1.1.8. Paragangliomas Card&#237;acos</title>
            <p>S&#227;o tumores neuroend&#243;crinos muito raros. Associam-se a v&#225;rias s&#237;ndromes, como doen&#231;a de Von HippelLindau, neurofibromatose I, complexo de Carney, entre outras. Podem ser benignos ou malignos e hormonalmente ativos ou inativos. S&#227;o extremamente vascularizados e n&#227;o encapsulados. Ocorrem mais frequentemente entre a 4&#170; e 5&#170; d&#233;cadas de vida e se localizam principalmente no espa&#231;o peric&#225;rdico, junto ao sulco atrioventricular, raiz dos grandes vasos e AE. Caracterizam-se como massas ecog&#234;nicas, com base larga, usualmente de forma ovoide, bem delimitadas, com tamanho m&#233;dio de 5cm, circundando art&#233;ria coron&#225;ria, podendo comprimir estruturas adjacentes. <xref ref-type="bibr" rid="B151"><sup>151</sup></xref> </p>
          </sec>
          <sec>
            <title>5.1.1.9. Schwanomas Card&#237;acos</title>
            <p>S&#227;o tumores de crescimento lento, extremamente raros, com apenas 25 casos relatados na literatura inglesa (18 intracard&#237;acos e 7 intraperic&#225;rdicos). Originam-se do plexo card&#237;aco ou de ramos do nervo vago e envolvem mais o lado direito do cora&#231;&#227;o. S&#227;o benignos, mas podem assumir comportamento maligno. Constituem massas ecog&#234;nicas, hipodensas, n&#227;o pedunculadas, delimitadas, podendo atingir v&#225;rios cent&#237;metros, causando sinais e sintomas relacionados &#224; compress&#227;o de estruturas adjacentes. <xref ref-type="bibr" rid="B152"><sup>152</sup></xref> </p>
          </sec>
        </sec>
        <sec>
          <title>5.1.2. Tumores Card&#237;acos Prim&#225;rios Malignos (TCPM)</title>
          <p>S&#227;o extremamente raros com frequ&#234;ncia de 0,008%. Correspondem a 10% a 15% de todos os TCP. S&#227;o representados por diferentes tipos de sarcomas, linfomas e mesoteliomas. Acometem principalmente adultos na quinta d&#233;cada de vida. Sarcomas representam 65% a 95% dos casos em adultos e 70% em crian&#231;as e adolescentes (&lt; 18 anos). <xref ref-type="bibr" rid="B143"><sup>143</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B154"><sup>154</sup></xref> Angiossarcoma &#233; o tipo mais comum. Geralmente produz sintomas como dispneia e dor tor&#225;cica pleur&#237;tica. <xref ref-type="bibr" rid="B155"><sup>155</sup></xref> </p>
          <sec>
            <title>5.1.2.1. Angiossarcomas</title>
            <p>Apresentam comportamento agressivo e podem metastatizar. Localizam-se preferencialmente no AD. Apresentam-se como volumosas massas ecog&#234;nicas lobuladas, homog&#234;neas, im&#243;veis, n&#227;o pedunculadas e sem hastes, com ampla base de inser&#231;&#227;o endoc&#225;rdica e bordas intracard&#237;acas lisas. Devido &#224; sua localiza&#231;&#227;o junto ao sulco atrioventricular, costumam causar obstru&#231;&#245;es na valva tric&#250;spide e, na maioria dos casos, acometem o peric&#225;rdio originando derrames hemorr&#225;gicos. Devido, em parte, &#224; sua vasculariza&#231;&#227;o esguia, n&#227;o real&#231;am significativamente com o uso de contrastes de perfus&#227;o. A sensibilidade do ETT em sua identifica&#231;&#227;o &#233; de 75%. <xref ref-type="bibr" rid="B155"><sup>155</sup></xref> </p>
            <sec>
              <title>5.1.2.1.1. Sarcomas Indiferenciados</title>
              <p>Tipicamente se localizam no AE, podendo mimetizar mixomas. Tendem a envolver a valva mitral causando obstru&#231;&#227;o ao fluxo. Apresentam bases largas, certa mobilidade, aspecto macio e homog&#234;neo. <xref ref-type="bibr" rid="B156"><sup>156</sup></xref> </p>
            </sec>
            <sec>
              <title>5.1.2.1.2. Rabdomiossarcoma</title>
              <p>&#201; o tipo mais comum em crian&#231;as. Usualmente surge nas paredes ventriculares e frequentemente interferem na fun&#231;&#227;o valvar devido ao crescimento intracavit&#225;rio. <xref ref-type="bibr" rid="B148"><sup>148</sup></xref> Tendem a ocorrer em mais de um local, podendo ocasionar obstru&#231;&#227;o em m&#250;ltiplos n&#237;veis. Crescem rapidamente e costumam invadir o peric&#225;rdio. <xref ref-type="bibr" rid="B136"><sup>136</sup></xref> </p>
            </sec>
            <sec>
              <title>5.1.2.1.3. Leiomiossarcomas</title>
              <p>Surgem mais comumente em vasos como a veia cava inferior e art&#233;ria pulmonar, mas podem ocorrer no AE.</p>
            </sec>
          </sec>
          <sec>
            <title>5.1.2.2. Linfomas Card&#237;acos Prim&#225;rios</title>
            <p>Representam aproximadamente 27% dos TCPM, sendo o linfoma n&#227;oHodgkin de grandes c&#233;lulas B o tipo mais comum. <xref ref-type="bibr" rid="B153"><sup>153</sup></xref> Predominam na 6&#170; d&#233;cada de vida, mas ocorrem entre a 1&#170; e 9&#170; d&#233;cadas, sendo frequentes em pacientes imunocomprometidos. Localizam-se principalmente no lado direito do cora&#231;&#227;o e no peric&#225;rdio. Envolvem a veia cava superior em 25% dos casos e o septo interatrial em 48%. Aparecem como massas infiltrativas ou nodulares. Formas infiltrativas s&#227;o homog&#234;neas, promovendo espessamento da parede e hemodin&#226;mica restritiva. Formas nodulares adentram a cavidade e podem comprometer o n&#243; atrioventricular, art&#233;ria coron&#225;ria direita e peric&#225;rdio. <xref ref-type="bibr" rid="B136"><sup>136</sup></xref> Em 75% dos casos, mais de uma c&#226;mara est&#225; envolvida. Dependendo da localiza&#231;&#227;o e dimens&#245;es, pode causar obstru&#231;&#227;o ao fluxo de entrada, s&#237;ndrome da veia cava superior, arritmias, bloqueio atrioventricular, s&#237;ndromes restritivas ou constritivas, DP e fen&#244;menos emb&#243;licos. O ETE (2D ou 3D) e o uso de contrastes de perfus&#227;o s&#227;o &#250;teis na caracteriza&#231;&#227;o desses tumores. <xref ref-type="bibr" rid="B157"><sup>157</sup></xref> </p>
          </sec>
          <sec>
            <title>5.1.2.3. Mesoteliomas Peric&#225;rdicos Malignos Prim&#225;rios</title>
            <p>Representam 8% dos TCPM e aproximadamente 50% dos tumores prim&#225;rios do peric&#225;rdio. <xref ref-type="bibr" rid="B153"><sup>153</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B158"><sup>158</sup></xref> S&#227;o mais frequentes entre a quinta e s&#233;tima d&#233;cadas de vida e apresentam baixa sobrevida. Associam-se, em muitos casos, com exposi&#231;&#227;o ao asbesto e RT. <xref ref-type="bibr" rid="B159"><sup>159</sup></xref> A sintomatologia &#233; vaga e inclui sintomas de pericardite constritiva e DP com tamponamento card&#237;aco. Infiltra&#231;&#227;o mioc&#225;rdica pode ocorrer e resultar em anormalidades de condu&#231;&#227;o. O ETT tem baixa sensibilidade em sua detec&#231;&#227;o. <xref ref-type="bibr" rid="B158"><sup>158</sup></xref> </p>
          </sec>
        </sec>
        <sec>
          <title>5.1.3. Tumores Card&#237;acos Metast&#225;ticos</title>
          <p>S&#227;o por defini&#231;&#227;o malignos e sua incid&#234;ncia tem aumentado nas &#250;ltimas d&#233;cadas, chegando a 18,35% em pacientes com doen&#231;a oncol&#243;gica avan&#231;ada. <xref ref-type="bibr" rid="B159"><sup>159</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B160"><sup>160</sup></xref> Predominam entre a sexta e s&#233;tima d&#233;cada de vida. Met&#225;stases card&#237;acas podem ocorrer por extens&#227;o direta do tumor, via hematog&#234;nica, linf&#225;tica e por difus&#227;o intracavit&#225;ria atrav&#233;s da veia cava inferior ou de veias pulmonares. Com exce&#231;&#227;o dos tumores do sistema nervoso central, qualquer tumor maligno pode enviar met&#225;stases para o cora&#231;&#227;o, mas carcinomas de pulm&#227;o, mama, es&#244;fago, melanoma e neoplasias hematol&#243;gicas (leucemia e linfoma) s&#227;o respons&#225;veis pela maioria dos casos. <xref ref-type="bibr" rid="B159"><sup>159</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B161"><sup>161</sup></xref> Melanomas malignos s&#227;o os mais propensos a acometerem o cora&#231;&#227;o. Peric&#225;rdio, epic&#225;rdio, mioc&#225;rdio e endoc&#225;rdio, em ordem decrescente de frequ&#234;ncia, s&#227;o os locais que podem ser acometidos. Quando intracavit&#225;rios, localizam-se preferencialmente nas c&#226;maras direitas. Derrames peric&#225;rdicos s&#227;o frequentes e podem ser assintom&#225;ticos. Deve-se suspeitar de envolvimento card&#237;aco em todos os pacientes com doen&#231;a oncol&#243;gica que desenvolvam novos sintomas cardiovasculares. <xref ref-type="bibr" rid="B162"><sup>162</sup></xref> O ETT &#233; o m&#233;todo de avalia&#231;&#227;o inicial para detec&#231;&#227;o de trombos tumorais na veia cava inferior, c&#226;maras card&#237;acas e presen&#231;a de DP. Outras modalidades de imagem s&#227;o necess&#225;rias para melhor caracteriza&#231;&#227;o das les&#245;es, sua extens&#227;o e rela&#231;&#227;o com estruturas vizinhas, bem como para revelar o s&#237;tio tumoral prim&#225;rio. <xref ref-type="bibr" rid="B161"><sup>161</sup></xref> </p>
        </sec>
      </sec>
      <sec>
        <title>5.2. Contribui&#231;&#227;o da Resson&#226;ncia Magn&#233;tica Card&#237;aca</title>
        <p>A RMC, sobretudopela propriedade de caracteriza&#231;&#227;o tecidual, tem se estabelecido como uma metodologia robusta na avalia&#231;&#227;o das massas card&#237;acas, especialmente na diferencia&#231;&#227;o entre tumores benignos e malignos. Al&#233;m da caracteriza&#231;&#227;o tecidual, a RMC poder&#225; fornecer importantes informa&#231;&#245;es quanto a localiza&#231;&#227;o, dimens&#245;es, extens&#227;o e sinais de compress&#227;o ou obstru&#231;&#227;o das estruturas card&#237;acas. <xref ref-type="bibr" rid="B163"><sup>163</sup></xref> </p>
        <p>As sequ&#234;ncias de cinerresson&#226;ncia SSFP ( <italic>steady-state-free-precession</italic> ) s&#227;o utilizadas para avalia&#231;&#227;o da morfologia e mobilidade da massa e sua rela&#231;&#227;o com o mioc&#225;rdio; e ainda se causa obstru&#231;&#227;o hemodin&#226;mica &#224;s estruturas valvares. As sequ&#234;ncias de sangue escuro pr&#233;-contraste ponderadas em T1 e T2 auxiliam na defini&#231;&#227;o da rela&#231;&#227;o com a anatomia adjacente, o tamanho, a extens&#227;o e a caracteriza&#231;&#227;o da massa. A intensidade de sinal da massa na resson&#226;ncia depende do tempo de relaxamento T1 e T2. Esta intensidade de sinal deve ser avaliada em rela&#231;&#227;o &#224; intensidade de sinal do mioc&#225;rdio, se &#233; isointenso, hipointenso ou hiperintenso em rela&#231;&#227;o ao sinal do mioc&#225;rdio. <xref ref-type="bibr" rid="B164"><sup>164</sup></xref> </p>
        <p>A satura&#231;&#227;o de gordura permite a identifica&#231;&#227;o do sinal da gordura na composi&#231;&#227;o da massa, uma vez que estase apresenta hiperintensa nas sequ&#234;ncias ponderadas em T1 e T2; a satura&#231;&#227;o deste sinal sugere componente gorduroso na massa. Esta t&#233;cnica permite identificar estruturas benignas como a infiltra&#231;&#227;o lipomatosa do septo interatrial, tumores benignos como o lipoma e detectar a presen&#231;a de gordura como componente de um lipossarcoma.</p>
        <p>A vasculariza&#231;&#227;o do tumor pode ser avaliada por meio da perfus&#227;o de primeira passagem do gadol&#237;nio quanto &#224; presen&#231;a ou n&#227;o de perfus&#227;o e se &#233; isoperfundida, hipoperfundida ou hiperperfundida em rela&#231;&#227;o ao mioc&#225;rdio do VE; enquanto o realce tardio detecta a presen&#231;a de fibrose na composi&#231;&#227;o da massa. <xref ref-type="bibr" rid="B165"><sup>165</sup></xref> </p>
        <p>O protocolo da RMC para avalia&#231;&#227;o de massa card&#237;aca ou peric&#225;rdica deve come&#231;ar com cortes axiais de alta resolu&#231;&#227;o, seguidos de sequ&#234;ncias de cinerresson&#226;ncia para sua localiza&#231;&#227;o e an&#225;lise da fun&#231;&#227;o card&#237;aca e da sua repercuss&#227;o hemodin&#226;mica. A seguir, de acordo com a suspeita diagn&#243;stica, s&#227;o realizados cortes sobre a massa para sua adequada caracteriza&#231;&#227;o tecidual. Podem ser usadas sequ&#234;ncias ponderadas em T1 e T2, sequ&#234;ncias com supress&#227;o de gordura para avaliar o componente lip&#237;dico da massa suspeita, perfus&#227;o de primeira passagem com gadol&#237;nio para estudo da sua vasculariza&#231;&#227;o e sequ&#234;ncias de realce tardio para avalia&#231;&#227;o de fibrose.</p>
        <p>Na suspeita de trombo, sequ&#234;ncias de realce tardio com longo tempo de invers&#227;o tamb&#233;m podem ser usadas para confirmar o diagn&#243;stico. A RMC permite a diferencia&#231;&#227;o entre trombo e tumor, uma vez que, no trombo, n&#227;o h&#225; perfus&#227;o pelo agente paramagn&#233;tico, apresentando um aspecto muito escuro nas sequ&#234;ncias de realce tardio, mesmo com tempo de invers&#227;o prolongado de at&#233; 600ms, podendo ser observada &#225;rea adjacente de hipersinal pelo sangue circunjacente ou tardiamente apresentar leve contraste de permeio em trombos antigos, muito organizados.</p>
        <sec>
          <title>5.2.1. Tumores Prim&#225;rios Benignos</title>
          <sec>
            <title>5.2.1.1. Mixoma</title>
            <p>Os achados pr&#233;-contraste podem ser explicados por sua histologia: hipersinal em sequ&#234;ncias ponderadas em T2 est&#225; relacionado com a matriz mixoide com alto conte&#250;do de &#225;gua e polissacar&#237;deos, enquantoos focos de hipossinal est&#227;o relacionados a &#225;reas de hemorragia, hemossiderina (degrada&#231;&#227;o da hemogolobina), calcifica&#231;&#245;es e trombos de superf&#237;cie. Os mixomas s&#227;o isointensos nas imagens ponderadas em T1 e hiperintensos nas ponderadas em T2 ( <xref ref-type="fig" rid="f14">Figura 14</xref> ). Observamos um discreto realce nas imagens de perfus&#227;o de primeira passagem em 16% a 66% dos casos.O realce tardio tem um padr&#227;o vari&#225;vel e heterog&#234;neo, podendo ser observados uma distribui&#231;&#227;o mais difusa (&gt;50% do tumor &#8211; mais frequente) e um padr&#227;o menos intenso (&lt; 50% do tumor). <xref ref-type="bibr" rid="B166"><sup>166</sup></xref> Cerca de 10% a 20% dos mixomas apresentam calcifica&#231;&#245;es e alguns podem ter trombos em sua superf&#237;cie.</p>
            <fig id="f14">
              <label>Figura 14</label>
              <caption>
                <title>Mixoma em &#225;trio esquerdo.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf14.tif"/></fig>
          </sec>
          <sec>
            <title>5.2.1.2. Lipoma</title>
            <p>Em 50% dos casos, tem origem na camada subendoc&#225;rdica; os outros 50%, mesoc&#225;rdica ou epic&#225;rdica. Pode determinar altera&#231;&#245;es hemodin&#226;micas, a depender do tamanho. Apresentam sinal homog&#234;neo semelhante aotecido gorduroso: hiperintenso em T1 e com queda do sinal nas sequ&#234;ncias de satura&#231;&#227;o de gordura e iso/hipersinal em T2. <xref ref-type="bibr" rid="B167"><sup>167</sup></xref> N&#227;o ocorre perfus&#227;o de primeira passagem nem realce tardio em sequ&#234;ncias contrastadas <xref ref-type="bibr" rid="B168"><sup>168</sup></xref> ( <xref ref-type="fig" rid="f15">Figura 15</xref> ).</p>
            <fig id="f15">
              <label>Figura 15</label>
              <caption>
                <title>Lipoma em &#225;trio direito. A. Cinerresson&#226;ncia em quatro c&#226;maras mostrando grande lipoma em &#225;trio direito. B. Imagem ponderada em T1 demonstrando que o lipoma &#233; hiperintenso. C. Aus&#234;ncia de realcetardio local.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf15.tif"/></fig>
          </sec>
          <sec>
            <title>5.2.1.3. Fibroelastoma Papilar</title>
            <p>Nas imagens de cinerresson&#226;ncia, apresenta-se como uma massa hipointensa e extremamente m&#243;vel, sem necessariamente causar impacto funcional na valva. Avaliar as caracter&#237;sticas teciduais da tumora&#231;&#227;o &#233; dif&#237;cil pelo pequeno tamanho e grande mobilidade, mas pode ser observado um sinal isointenso em T1 e hiperintenso em T2, com aus&#234;ncia deperfus&#227;o de primeira passageme hipersinal nas imagens de realce tardio <xref ref-type="bibr" rid="B167"><sup>167</sup></xref> ( <xref ref-type="fig" rid="f16">Figura 16</xref> ).</p>
            <fig id="f16">
              <label>Figura 16</label>
              <caption>
                <title>Fibroelastoma papil&#237;fero em valva mitral. A. Cinerresson&#226;ncia em quatro c&#226;maras em que se observa a massa hiposinal. B. Imagem ponderada em T1 demonstrando isossinal. C. Sequ&#234;ncia de realce tardio precoce com gadol&#237;nio demostrando realce leve local.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf16.tif"/></fig>
          </sec>
          <sec>
            <title>5.2.1.4. Rabdomioma</title>
            <p>Discretamente hiperintenso em imagens ponderadas em T1 e hiperintenso em imagens ponderadas em T2. Apresenta m&#237;nimo realce ou at&#233; mesmo aus&#234;ncia ap&#243;s o gadol&#237;nio ( <xref ref-type="fig" rid="f17">Figura 17</xref> ).</p>
            <fig id="f17">
              <label>Figura 17</label>
              <caption>
                <title>Rabdomioma de ventr&#237;culo esquerdo: A. Cinerresson&#226;ncia em eixo curto demonstrando a massa de localiza&#231;&#227;o intramural no septo interventricular. B. Imagem ponderada em T2 demonstrando hipersinal. C. Sequ&#234;ncia de realce tardio demostrando leve realce local.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf17.tif"/></fig>
          </sec>
          <sec>
            <title>5.2.1.5. Fibromas</title>
            <p>S&#227;o geralmente iso/hipointensos nas imagens ponderadas em T1 e homogeneinamentehipointensos nas imagens ponderadas em T2. O aspecto na perfus&#227;o de primeira passagem gerelmente &#233; ausente pela sua baixa vasculariza&#231;&#227;o. No realce tardio, os fibromas apresentam um realce homog&#234;neo intenso, embora algumas vezes as les&#245;es possam apresentar um componente central de baixo sinal que pode estar associado &#224; calcifica&#231;&#227;o local <xref ref-type="bibr" rid="B169"><sup>169</sup></xref> ( <xref ref-type="fig" rid="f18">Figura 18</xref> ).</p>
            <fig id="f18">
              <label>Figura 18</label>
              <caption>
                <title>Fibroma intramural. A. Cinerresson&#226;ncia em quatro c&#226;maras mostrando tumor intramural em parede lateral. B. Imagem ponderada em T2 mostrando a massa com hipossinal em rela&#231;&#227;o ao mioc&#225;rdio. C e D. Imagem de realce tardio em eixo curto e eixo longo mostrando hipersinal homog&#234;neo do tumor compat&#237;vel com tecido fibroso.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf18.tif"/></fig>
          </sec>
          <sec>
            <title>5.2.1.6. Hemangioma</title>
            <p>Apresentar&#227;o um aspecto heterog&#234;neo iso ou hiperintenso nas imagens ponderadas em T1 e usualmente hiperintenso em pT2, podendo tamb&#233;m ocorrer heterogeneidade com &#225;reas de baixo sinal. O padr&#227;o do realce tardio &#233; caracteristicamente heterog&#234;neo e hiperintenso com uma marcada perfus&#227;o de primeira passagem. <xref ref-type="bibr" rid="B168"><sup>168</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B169"><sup>169</sup></xref> </p>
          </sec>
        </sec>
        <sec>
          <title>5.2.2. Tumores Malignos</title>
          <p>Os tumores malignos costumam ser maiores, apresentam mais frequentemente perfus&#227;o de primeira passagem do gadol&#237;nio e maior preval&#234;ncia de realce tardio. <xref ref-type="bibr" rid="B170"><sup>170</sup></xref> </p>
          <sec>
            <title>5.2.2.1. Sarcomas</title>
            <p>A maioria dos sarcomas mostra caracter&#237;sticas sugestivas de malignidade como um sinal heterog&#234;neo em virtude de necrose e hemorragia em seu interior, formato nodular ou irregular, bordas mal definidas, infiltra&#231;&#227;o do mioc&#225;rdio e das estruturas adjacentes, extens&#227;o para o peric&#225;rdio e derrame peric&#225;rdico associado.O angiossarcoma corresponde a 40% dos sarcomas card&#237;acos e localiza-se, em sua maioria, no &#225;trio direito com infiltra&#231;&#227;o da parede atrial e do peric&#225;rdio associado a derrame peric&#225;rdico ( <xref ref-type="fig" rid="f19">Figura 19</xref> ). Na RMC, mostra-se como uma grande massa lobular heterog&#234;nea com iso/hipersinal em T1, hipersinal em T2, perfus&#227;o de primeira passagem com gadol&#237;nio e hipersinal heterog&#234;neo nas imagens de realce tardio ( <xref ref-type="fig" rid="f20">Figura 20</xref> ). <xref ref-type="bibr" rid="B147"><sup>147</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B169"><sup>169</sup></xref> </p>
            <fig id="f19">
              <label>Figura 19</label>
              <caption>
                <title>Angiossarcoma em &#225;trio direito. A. Cinerresson&#226;ncia em quatro c&#226;maras mostrando sarcoma com origem na parede posterior do &#225;trio direito com infiltra&#231;&#227;o das suas paredes, da por&#231;&#227;o basal do ventr&#237;culo direito e do peric&#225;rdio. B. Imagem de realce tardio com hipersinal heterog&#234;neo da massa em corte axial mais superior.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf19.tif"/></fig>
            <fig id="f20">
              <label>Figura 20</label>
              <caption>
                <title>Rabdomiossarcoma em ventr&#237;culo direito. A. Cinerresson&#226;ncia em quatro c&#226;maras mostrando massa multilobulada intracavit&#225;ria em ventr&#237;culo direito, de grandes dimens&#245;es. B. Imagem de realce tardio com hipersinal heterog&#234;neo da massa.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf20.tif"/></fig>
          </sec>
          <sec>
            <title>5.2.2.2. Linfoma</title>
            <p>Apresentam iso/hipossinal nas imagens ponderadas em T1, iso/hipersinal nas imagens ponderadas em T2 e realce tardio heterog&#234;neo.</p>
          </sec>
        </sec>
      </sec>
      <sec>
        <title>5.3. Contribui&#231;&#227;o da Medicina Nuclear</title>
        <sec>
          <title>5.3.1. <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG PET-CT</title>
          <p>A <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG PET-CT ainda &#233; pouco utilizada nos tumores card&#237;acos, principalmente nos tumores card&#237;acos malignos prim&#225;rios. Em rela&#231;&#227;o &#224;s neoplasias card&#237;acas metast&#225;ticas (secund&#225;rias), que s&#227;o as mais frequentes, a <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG PET-CT &#233; uma t&#233;cnica j&#225; estabelecida. <xref ref-type="bibr" rid="B171"><sup>171</sup></xref> </p>
          <p>Em um estudo tipo s&#233;rie de casos, Rahbar et al. <xref ref-type="bibr" rid="B172"><sup>172</sup></xref> avaliaram 24 pacientes consecutivos com tumores card&#237;acos com <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG PET-CT antes do tratamento. <xref ref-type="bibr" rid="B172"><sup>172</sup></xref> Os pacientes foram divididos de acordo com o subtipo histol&#243;gico dos tumores, obtidos por ressec&#231;&#227;o cir&#250;rgica ou bi&#243;psia, resultando em: benignos (n = 07), malignos prim&#225;rios (n = 08) e malignos secund&#225;rios (n = 09). A capta&#231;&#227;o tumoral de <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG foi observada entre os grupos. Posteriormente, para avaliar sensibilidade e especificidade do m&#233;todo na diferencia&#231;&#227;o entre benigno e maligno, foram separados apenas em malignos (n = 17) e benignos (n = 7). A capta&#231;&#227;o de <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG foi quantificada de acordo com o &#237;ndice do valor m&#225;ximo de capta&#231;&#227;o padronizada (do ingl&#234;s, <italic>Maximum Standard Uptake Value</italic> &#8211; SUV max) de volumes tridimensionais abrangendo a massa tumoral. No caso de baixa capta&#231;&#227;o tumoral de <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG, as imagens da TC foram utilizadas para identificar e obter os volumes do tumor. Al&#233;m disso, em virtude de capta&#231;&#227;o mioc&#225;rdica fisiol&#243;gica de <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG, capta&#231;&#227;o no mioc&#225;rdio normal e <italic>pool</italic> sangu&#237;neo foram medidos e comparados com os SUVs max dos tumores. Observou-se que a capta&#231;&#227;o de <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG foi baixa no <italic>pool</italic> sangu&#237;neo e no mioc&#225;rdio normal, e significativamente alta nos tumores prim&#225;rios malignos em rela&#231;&#227;o aos benignos. Os tumores malignos secund&#225;rios apresentaram uma capta&#231;&#227;o compar&#225;vel a dos malignos prim&#225;rios; no entanto, com uma varia&#231;&#227;o de SUV max consideravelmente maior. A m&#233;dia do SUV max foi de 2,8 &#177; 0,6 no grupo de tumores card&#237;acos benignos. Esses tumores geralmente n&#227;o apresentam contraste positivo em rela&#231;&#227;o ao mioc&#225;rdio normal e s&#227;o visualizados apenas nas imagens morfol&#243;gicas da TC. Em contrapartida, os tumores malignos prim&#225;rios apresentam SUV max 2,5 vezes maior em rela&#231;&#227;o aos benignos. Entre os tumores card&#237;acos metast&#225;ticos, a SUV max foi de 10,8 &#177; 4,9 com uma varia&#231;&#227;o significativa na capta&#231;&#227;o de <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG de 3,4 a 16,7. Em rela&#231;&#227;o aos tumores malignos prim&#225;rios, a capta&#231;&#227;o de <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG foi maior do que os benignos e semelhante aos malignos secund&#225;rios. <xref ref-type="bibr" rid="B172"><sup>172</sup></xref> </p>
          <sec>
            <title>5.3.1.1. Valor de Ponto de Corte do SUV max de <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG para Melhor Diferenciar Tumor Card&#237;aco Benigno de Maligno</title>
            <p>Diferentes pontos de corte do SUV max t&#234;m sido sugeridos na determina&#231;&#227;o de malignidade por meio da <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG PET-CT. No estudo de Rahbar et al., <xref ref-type="bibr" rid="B172"><sup>172</sup></xref> um valor de 3,5 alcan&#231;ou uma sensibilidade de 100%, especificidade de 86%, valor preditivo positivo de 94% e negativo de 100%. <xref ref-type="bibr" rid="B172"><sup>172</sup></xref> Quando aumentaram esse valor para 4,6 encontraram uma especificidade de 100%, sensibilidade de 94% e um valor preditivo positivo de 100% para malignidade. Dentre as principais limita&#231;&#245;es deste estudo, est&#227;o a natureza retrospectiva, a falta de um padr&#227;o diagn&#243;stico para tumores card&#237;acos e a heterogeneidade dos resultados. Al&#233;m disso, diversos mixomas n&#227;o foram inclu&#237;dos na an&#225;lise por terem sido diagnosticados ao ecocardiograma e &#224; RMC.</p>
          </sec>
        </sec>
      </sec>
    </sec>
    <sec>
      <title>6. Situa&#231;&#245;es Especiais</title>
      <sec>
        <title>6.1. Doen&#231;a Card&#237;aca Carcinoide</title>
        <p>Os tumores neuroend&#243;crinos s&#227;o neoplasias raras (2,5 a 5 casos por 100.000 habitantes), podendo surgir em qualquer lugar, sendo mais frequentes no trato gastrointestinal (carcinoides). <xref ref-type="bibr" rid="B173"><sup>173</sup></xref> Cerca de 30% a 40% dos casos, em sua maioria localizado no intestino delgado e c&#243;lon proximal, manifestam altera&#231;&#245;es vasomotoras (hipotens&#227;o, hipertens&#227;o, <italic>flushing</italic> ), diarreia e broncospasmo, chamada s&#237;ndrome carcinoide, geralmente associada &#224; met&#225;stase hep&#225;tica. <xref ref-type="bibr" rid="B174"><sup>174</sup></xref> A presen&#231;a de biomarcadores como NT-proBNP, cromagraninaA e 5 &#8211; hidroxindolac&#233;tico (5-HIAA) &#233; &#250;til tanto no diagn&#243;stico quanto no progn&#243;stico da doen&#231;a carcinoide. <xref ref-type="bibr" rid="B175"><sup>175</sup></xref> </p>
        <p>A doen&#231;a card&#237;aca carcinoide (DCC), manifestada pela forma&#231;&#227;o de placas, espessamento e fibrose endoc&#225;rdica, acomete preferencialmente as cavidades direitas, valvas tric&#250;spide e pulmonar, sendo provavelmente relacionada com a exposi&#231;&#227;o cr&#244;nica ao 5-HIAA. O comprometimento das cavidades esquerdas (15% dos casos), valvas mitral e a&#243;rtica &#233; visto na presen&#231;a de <italic>shunt</italic> direita/esquerda (p. ex., forame oval patente) ou na presen&#231;a de tumor carcinoide br&#244;nquico. <xref ref-type="bibr" rid="B176"><sup>176</sup></xref> O diagn&#243;stico precoce e o monitoramento da progress&#227;o da DCC impactam drasticamente no progn&#243;stico e na sobrevida alongo prazo (sobrevida m&#233;dia de 1,6 ano <italic>vs.</italic> 4,6 anos na aus&#234;ncia de DCC), uma vez que o tratamento cir&#250;rgico precoce &#233; fundamental para o sucesso.</p>
        <p>A ecocardiografia &#233; o padr&#227;o-ouro para o diagn&#243;stico e acompanhamento da DCC. <xref ref-type="bibr" rid="B173"><sup>173</sup></xref> A avalia&#231;&#227;o de cavidades card&#237;acas direitas (&#225;trio e ventr&#237;culo), fun&#231;&#227;o ventricular direita, espessamento, mobilidade dos folhetos e presen&#231;a de regurgita&#231;&#227;o ou estenose valvar (analisadas individualmente) deve ser realizada na suspeita cl&#237;nica inicial, no surgimento de novo sopro card&#237;aco, novos sintomas ou a cada 3 a 6 meses conforme a severidade da DCC ( <xref ref-type="fig" rid="f21">Figura 21</xref> ).</p>
        <fig id="f21">
          <label>Figura 21</label>
          <caption>
            <title>Paciente com tumor carcinoide, met&#225;stase hep&#225;tica, quadro cl&#237;nico de insufici&#234;ncia card&#237;aca direita. VD: ventr&#237;culo direito, AD: &#225;trio direito, IT: insufici&#234;ncia tric&#250;spide, VCI: veia cava inferior.</title>
          </caption>
          <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf21.tif"/></fig>
        <p>O comprometimento da valva tric&#250;spide levando &#224; regurgita&#231;&#227;o &#233; a altera&#231;&#227;o mais frequente, seguida da regurgita&#231;&#227;o pulmonar, estenose tric&#250;spide e, por &#250;ltimo, estenose pulmonar. Na valva tric&#250;spide ocorre principalmente o envolvimento dos folhetos septal e anterior, ficando o folheto posterior relativamente preservado. Dilata&#231;&#227;o e disfun&#231;&#227;o do VD s&#227;o consequ&#234;ncias da gravidade das les&#245;es valvares. A identifica&#231;&#227;o de met&#225;stase card&#237;aca (4% dos casos) tamb&#233;m &#233; poss&#237;vel pela ecocardiografia, entretanto &#233; mais bem visualizada pela RNM. <xref ref-type="bibr" rid="B173"><sup>173</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B176"><sup>176</sup></xref> </p>
        <p>Diversos escores ecocardiogr&#225;ficos foram propostos para avalia&#231;&#227;o da DCC.Dentre os escores mais simples, o descrito por Westberg et al. <xref ref-type="bibr" rid="B177"><sup>177</sup></xref> ( <xref ref-type="table" rid="t6">Tabela 5</xref> ) avalia apenas a anatomia e regurgita&#231;&#227;o da valva tric&#250;spide. A soma dos pontos &gt; 1 &#233; considerada como patol&#243;gica (acur&#225;cica 87%). A sobrevida em 3 anos &#233; inferior a 45% quando escore &gt; 4 contra 75% no escore 0. <xref ref-type="bibr" rid="B177"><sup>177</sup></xref> </p>
        <table-wrap id="t6">
          <label>Tabela 5</label>
          <caption>
            <title>Escore de Westberg <xref ref-type="bibr" rid="B171"><sup>171</sup></xref> </title>
          </caption>
          <table frame="hsides" rules="rows">
            <colgroup width="16%">
              <col/>
              <col/>
              <col/>
              <col/>
              <col/>
              <col/>
            </colgroup>
            <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
              <tr>
                <th align="left" valign="middle">Caracter&#237;stica</th>
                <th align="center" colspan="5" valign="middle">Severidade e pontua&#231;&#227;o</th>
              </tr>
            </thead>
            <tbody style="border-bottom: thin solid; border-color: #000000">
              <tr>
                <td align="left" valign="middle">Espessamento valvar</td>
                <td align="center" valign="middle">Normal <break/> 0</td>
                <td align="center" valign="middle">Leve <break/> 1</td>
                <td align="center" valign="middle">Moderada <break/> 2</td>
                <td align="center" valign="middle">Severa <break/> 3</td>
                <td align="center" valign="middle">Severa com retra&#231;&#227;o valvar <break/> 4</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Regurgita&#231;&#227;o</td>
                <td align="center" valign="middle">Normal <break/> 0</td>
                <td align="center" valign="middle">Leve <break/> 1</td>
                <td align="center" valign="middle">Moderado <break/> 2</td>
                <td align="center" valign="middle">Importante <break/> 3</td>
                <td align="center" valign="middle">Extrema <break/> 4</td>
              </tr>
            </tbody>
          </table>
        </table-wrap>
        <p>Escores mais complexos como o de Bhattacharyya et al. <xref ref-type="bibr" rid="B173"><sup>173</sup></xref> ( <xref ref-type="table" rid="t7">Tabela 6</xref> ) oferecem um n&#250;mero maior de informa&#231;&#245;es, sendo &#250;teis no acompanhamento e planejamento cir&#250;rgico. Nele, um escore &gt; 8 apresenta uma acur&#225;cia de 96% para o diagn&#243;stico de DCC, sendo que o aumento de 5 pontos no escore foi preditor independente da progress&#227;o da DCC (RR 2,95) e de mortalidade (RR 2,66) segundo Dobson et al. <xref ref-type="bibr" rid="B176"><sup>176</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B178"><sup>178</sup></xref> </p>
        <table-wrap id="t7">
          <label>Tabela 6</label>
          <caption>
            <title>Escore de Bhattacharyya <xref ref-type="bibr" rid="B167"><sup>167</sup></xref> </title>
          </caption>
          <table frame="hsides" rules="rows">
            <colgroup width="20%">
              <col/>
              <col/>
              <col/>
              <col/>
              <col/>
            </colgroup>
            <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
              <tr>
                <th align="left" valign="middle">Caracter&#237;stica</th>
                <th align="center" colspan="4" valign="middle">Severidade e pontua&#231;&#227;o</th>
              </tr>
            </thead>
            <tbody style="border-bottom: thin solid; border-color: #000000">
              <tr>
                <td align="left" valign="middle">Espessamento valvar</td>
                <td align="center" valign="middle">&lt; 3 mm <break/> 0</td>
                <td align="center" valign="middle">&#8805; 3 e &lt; 4 mm <break/> 1</td>
                <td align="center" valign="middle">&#8805; 4 e &lt; 5 mm <break/> 2</td>
                <td align="center" valign="middle">&#8805; 5mm <break/> 3</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Mobilidade valvar</td>
                <td align="center" valign="middle">Normal <break/> 0</td>
                <td align="center" valign="middle">Leve <break/> 1</td>
                <td align="center" valign="middle">Moderada <break/> 2</td>
                <td align="center" valign="middle">Severa/fixa <break/> 3</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Morfologia valvar</td>
                <td align="center" valign="middle">Normal <break/> 0</td>
                <td align="center" valign="middle">Retificada <break/> 1</td>
                <td align="center" valign="middle">Retra&#231;&#227;o leve <break/> 2</td>
                <td align="center" valign="middle">Retra&#231;&#227;o moderada/severa <break/> 3</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Estenose valvar</td>
                <td align="center" valign="middle">Normal <break/> 0</td>
                <td align="center" valign="middle">Leve <break/> 1</td>
                <td align="center" valign="middle">Moderado <break/> 2</td>
                <td align="center" valign="middle">Importante <break/> 3</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Regurgita&#231;&#227;o valvar</td>
                <td align="center" valign="middle">Normal <break/> 0</td>
                <td align="center" valign="middle">Leve <break/> 1</td>
                <td align="center" valign="middle">Moderado <break/> 2</td>
                <td align="center" valign="middle">Importante <break/> 3</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Di&#226;metro do ventr&#237;culo direito</td>
                <td align="center" valign="middle">Normal <break/> 0</td>
                <td align="center" valign="middle">Aumento leve <break/> 1</td>
                <td align="center" valign="middle">Aumento moderado <break/> 2</td>
                <td align="center" valign="middle">Aumento importante <break/> 3</td>
              </tr>
              <tr>
                <td align="left" valign="middle">Fun&#231;&#227;o do ventr&#237;culo direito</td>
                <td align="center" valign="middle">Normal <break/> 0</td>
                <td align="center" valign="middle">Redu&#231;&#227;o leve <break/> 1</td>
                <td align="center" valign="middle">Redu&#231;&#227;o moderada <break/> 2</td>
                <td align="center" valign="middle">Redu&#231;&#227;o importante <break/> 3</td>
              </tr>
            </tbody>
          </table>
        </table-wrap>
        <p>Tratamento cir&#250;rgico card&#237;aco est&#225; indicado por ocasi&#227;o da dilata&#231;&#227;o e disfun&#231;&#227;o do VD e sinais de insufici&#234;ncia card&#237;aca refrat&#225;ria ao tratamento medicamentoso. O fechamento de FOP com o objetivo de reduzir o <italic>shunt</italic> direita/esquerda e a remo&#231;&#227;o das met&#225;stases devem ser recomendados durante a abordagem. <xref ref-type="bibr" rid="B175"><sup>175</sup></xref> </p>
      </sec>
      <sec>
        <title>6.2. Amiloidose Card&#237;aca (AC)</title>
        <sec>
          <title>6.2.1. Introdu&#231;&#227;o</title>
          <p>A amiloidose &#233; uma doen&#231;a multissist&#234;mica, decorrente do dep&#243;sito no espa&#231;o extracelular de material protein&#225;ceo composto, de dif&#237;cil diagn&#243;stico, e, uma vez comprovado o acometimento card&#237;aco, progn&#243;stico reservado. De acordo com o tipo de prote&#237;na precursora, pode ser chamada de amiloidose de cadeia leve (AL), quando os dep&#243;sitos se originam de prote&#237;nas de cadeia leve, e amiloidose relacionada &#224; transtirretina (ATTR), cuja prote&#237;na se origina da prote&#237;na transportadora de horm&#244;nio tiroxina e retinol. <xref ref-type="bibr" rid="B179"><sup>179</sup></xref> </p>
        </sec>
        <sec>
          <title>6.2.2. Tipos Cl&#237;nicos e Envolvimento Card&#237;aco</title>
          <p>A forma AL pode envolver v&#225;rios &#243;rg&#227;os como os rins, trato gastrointestinal e sistema nervoso aut&#244;nomo, al&#233;m do pr&#243;prio cora&#231;&#227;o. &#201; causada pelo dep&#243;sito de prote&#237;nas derivadas das imunoglobulinas de cadeia leve produzidas pelas c&#233;lulas plasm&#225;ticas em quadros de discrasia plasmocit&#225;ria como no mieloma m&#250;ltiplo (MM). Cerca de 10% dos pacientes com MM podem desenvolver AL e, destes, mais da metade pode apresentar AC. O acometimento card&#237;aco est&#225; em segundo lugar depois do envolvimento dos rins na AL. <xref ref-type="bibr" rid="B180"><sup>180</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B181"><sup>181</sup></xref> </p>
          <p>O mecanismo patol&#243;gico do tipo ATTR &#233; o dep&#243;sito de derivados da transtirretina, produzida pelo f&#237;gado.&#201; subdividida em dois outros tipos: a) ATTR do tipo selvagem, com a sigla ATTRwt (sigla em ingl&#234;s, &#8220; <italic>wild type</italic> &#8221;), com acometimento predominante do cora&#231;&#227;o, al&#233;m de frequentemente causar s&#237;ndrome do t&#250;nel do carpo, ruptura do tend&#227;o do b&#237;ceps e estenose espinhal; b) ATTR mutante (ATTRm), associada a substitui&#231;&#245;es espec&#237;ficas dos genes que codificam a transtirretina e podem acometer o sistema nervoso aut&#244;nomo e perif&#233;rico al&#233;m do pr&#243;prio cora&#231;&#227;o. <xref ref-type="bibr" rid="B182"><sup>182</sup></xref> </p>
        </sec>
        <sec>
          <title>6.2.3. Contribui&#231;&#227;o da Ecocardiografia</title>
          <p>O ETT &#233; a op&#231;&#227;o diagn&#243;stica mais usada quando se suspeita do diagn&#243;stico de AC e &#233; usado tamb&#233;m para rastrear casos em familiares. &#201; altamente dispon&#237;vel em servi&#231;os m&#233;dicos de complexidade vari&#225;vel, custo relativamente baixo e com a possibilidade de ser repetido de forma seriada com boa reprodutibilidade e consist&#234;ncia dos seus achados. A presen&#231;a de acometimento card&#237;aco guarda em si o pior progn&#243;stico deste grupo de pacientes.</p>
          <sec>
            <title>6.2.3.1. Aumento da Espessura Mioc&#225;rdica</title>
            <p>O mioc&#225;rdio apresenta aspecto brilhante ou cintilante granular, melhor apreciado na imagem fundamental, sem o uso da harm&#244;nica. O aumento da espessura mioc&#225;rdica &#233; frequentemente conc&#234;ntrico e sim&#233;trico, diferentemente dos casos de cardiomiopatia hipertr&#243;fica que tendem a exibir maior assimetria na distribui&#231;&#227;o da mesma ( <xref ref-type="fig" rid="f22">Figura 22</xref> ). A presen&#231;a de aumento da espessura mioc&#225;rdica e de ondas de baixa voltagem ao eletrocardiograma consiste em achados que levam &#224; suspeita para AC. <xref ref-type="bibr" rid="B183"><sup>183</sup></xref> O termo &#8220;aumento da espessura mioc&#225;rdica&#8221; deve ser diferenciado da hipertrofia mioc&#225;rdica secund&#225;ria, em que h&#225; hipertrofia miocelular, uma vez que, na AC, &#233; o espa&#231;o extracelular que se encontra aumentado pela deposi&#231;&#227;o do material amiloide proteico. <xref ref-type="bibr" rid="B184"><sup>184</sup></xref> O aumento da espessura mioc&#225;rdica &#233; difuso e pode incluir todas as paredes do VE, parede livre do VD, septo interatrial e valvas com ou sem regurgita&#231;&#227;o associada. A espessura mioc&#225;rdica de 12mm ou superior pode ser usada como valor de corte para suspeita diagn&#243;stica de AC. <xref ref-type="bibr" rid="B185"><sup>185</sup></xref> O valor cl&#237;nico e o progn&#243;stico do aumento da espessura mioc&#225;rdica j&#225; s&#227;o conhecidos. Quanto mais exuberante, maior ser&#225; a ocorr&#234;ncia de insufici&#234;ncia card&#237;aca congestiva (ICC) e pior a sobrevida.</p>
            <fig id="f22">
              <label>Figura 22</label>
              <caption>
                <title>Paciente portador de hipertrofia do ventr&#237;culo esquerdo (VE) sem causa determinada. Ecocardiograma evidencia aspecto brilhante ou cintilante granular do mioc&#225;rdio, sugestivo de amiloidose card&#237;aca.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf22.tif"/></fig>
          </sec>
          <sec>
            <title>6.2.3.2. &#193;trio Esquerdo</title>
            <p>Altera&#231;&#245;es no &#225;trio esquerdo tamb&#233;m podem ser encontradas e o aumento do volume atrial esquerdo pode ser devido n&#227;o somente a graus elevados de disfun&#231;&#227;o diast&#243;lica, mas tamb&#233;m &#224; pr&#243;pria deposi&#231;&#227;o de fibrilas amiloides.</p>
            <p>Altera&#231;&#245;es na deforma&#231;&#227;o mioc&#225;rdica atrial (s <italic>train</italic> e <italic>strain rate)</italic> , assim como em par&#226;metros de fun&#231;&#227;o sist&#243;lica atrial, s&#227;o frequentemente observadas em pacientes com poucas caracter&#237;sticas ecocardiogr&#225;ficas devido &#224; AC, e tamb&#233;m em indiv&#237;duos com sintomas de ICC, estando associadas &#224; piora no progn&#243;stico. <xref ref-type="bibr" rid="B186"><sup>186</sup></xref> </p>
          </sec>
          <sec>
            <title>6.2.3.3. Fun&#231;&#227;o Diast&#243;lica</title>
            <p>Em fases mais avan&#231;adas a avalia&#231;&#227;o da fun&#231;&#227;o diast&#243;lica costuma apresentar rela&#231;&#227;o E/e&#8217; aumentada, compat&#237;vel com aumento das press&#245;es de enchimento do VE. Entretanto, par&#226;metros da fun&#231;&#227;o diast&#243;lica encontram-se alteradas mesmo nas fases iniciais da AC. A presen&#231;a da disfun&#231;&#227;o diast&#243;lica est&#225; associada &#224; piora na evolu&#231;&#227;o cl&#237;nica, como j&#225; demonstrado, al&#233;m sugerir um maior risco de tromboembolismo. <xref ref-type="bibr" rid="B187"><sup>187</sup></xref><sup>-</sup><xref ref-type="bibr" rid="B189"><sup>189</sup></xref> </p>
          </sec>
          <sec>
            <title>6.3.3.4. Fun&#231;&#227;o Sist&#243;lica do Ventr&#237;culo Esquerdo</title>
            <p>A FEVE pode ainda estar dentro dos limites da normalidade e esta caracter&#237;stica permite incluir a AC dentro das causas de insufici&#234;ncia card&#237;aca com fra&#231;&#227;o de eje&#231;&#227;o preservada (ICFEP). A piora da fun&#231;&#227;o sist&#243;lica ocorre em fases mais tardias e est&#225; associada &#224; piora cl&#237;nica e progn&#243;stica. <xref ref-type="bibr" rid="B187"><sup>187</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B189"><sup>189</sup></xref> </p>
            <p>Considerando as medidas de deforma&#231;&#227;o mioc&#225;rdica, a AC exibe redu&#231;&#227;o no <italic>SLG</italic> mioc&#225;rdico principalmente nas regi&#245;es basais e m&#233;dias do VE com preserva&#231;&#227;o dos valores na regi&#227;o apical (preserva&#231;&#227;o apical). <xref ref-type="bibr" rid="B188"><sup>188</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B190"><sup>190</sup></xref> &#201; &#250;til calcular a rela&#231;&#227;o da m&#233;dia dos valores do SLG apical pela m&#233;dia da soma dos valores do SLG nas regi&#245;es basal e m&#233;dia do VE. Esta rela&#231;&#227;o&gt; 1 apresenta alta especificidade para o diagn&#243;stico de AC. <xref ref-type="bibr" rid="B190"><sup>190</sup></xref> Quando se considera a rela&#231;&#227;o entre as medidas da FEVE e valores de <italic>strain</italic> mioc&#225;rdico (da sigla em ingl&#234;s <italic>&#8220;EFS&#8221;</italic> ou <italic>ejection fraction and strain relation</italic> ), h&#225; uma invers&#227;o desta rela&#231;&#227;o com menores valores de deforma&#231;&#227;o mioc&#225;rdica e FEVE preservada, independentemente dos sintomas claros de ICC. EFS igual ou superior a quatro &#233; util na diferencia&#231;&#227;o entre AC e CMH, com valores de sensibilidade iguaisa 89,7% e especificidade de 91,7%. <xref ref-type="bibr" rid="B187"><sup>187</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B188"><sup>188</sup></xref> </p>
            <p>Valores isolados de <italic>SLG</italic> mioc&#225;rdico maiores que-15% est&#227;o associados a maior gravidade nos casos de AC, bem como aumento na mortalidade. <xref ref-type="bibr" rid="B191"><sup>191</sup></xref> Em outro estudo, o valor de <italic>strain superior</italic> a -17% conseguiu separar grupos de pacientes com resposta cl&#237;nica desfavor&#225;vel ap&#243;s transplante de medula &#243;ssea aut&#243;logo. O &#237;ndice de preserva&#231;&#227;o apical ( <italic>apical sparring</italic> ) com resultado igual ou superior a 1,19 se associou a maior mortalidade e necessidade de transplante card&#237;aco em 5 anos de seguimento. Este mesmo &#237;ndice mostrou valor preditivo nas curvas de sobrevida e necessidade de transplante card&#237;aco quando em associa&#231;&#227;o a menor valor de FEVE. <xref ref-type="bibr" rid="B192"><sup>192</sup></xref> </p>
            <p>Liu et al. <xref ref-type="bibr" rid="B193"><sup>193</sup></xref> analisaram o valor do pico da onda diast&#243;lica da curva de <italic>strain rate</italic> isoladamente (fase r&#225;pida de enchimento diast&#243;lico) em 41 pacientes com AC, demonstrando que o valor global do <italic>strain rate</italic> diast&#243;lico (LSR<sub>dias</sub> global &gt; -0,85 S<sup>&#8722;1</sup>) foi preditivo de aumento em 4x na mortalidade em pacientes com AC com FEVE preservada (FEVE &gt; 50%). <xref ref-type="bibr" rid="B193"><sup>193</sup></xref> </p>
            <p>As medidas de <italic>strain</italic> s&#227;o altamente sens&#237;veis e exibem boa especificidade nos casos de AC, por&#233;m h&#225; que se destacar que medidas ecocardiogr&#225;ficas convencionais da fun&#231;&#227;o sist&#243;lica ainda s&#227;o importantes e demonstram &#243;tima correla&#231;&#227;o progn&#243;stica nesses casos. Assim, o volume sist&#243;lico indexado (VSi) e a medida que integra volume sist&#243;lico e o volume total da massa mioc&#225;rdica (denominada fra&#231;&#227;o de contra&#231;&#227;o mioc&#225;rdica, do ingl&#234;s <italic>myocardial contraction fraction</italic> ou <italic>MCF</italic> ) mostraram bom valor progn&#243;stico em pacientes com AC independentemente do tipo e compar&#225;veis &#224;s medidas do <italic>strain</italic> . Assim, neste grupo de pacientes, o VSi&lt;33mL/min e a MCF &lt;34% com &#237;ndice card&#237;aco &lt;2,4 L/min/m<sup>2</sup> foram os melhores preditores de sobrevida global com acur&#225;cia compar&#225;vel &#224;s medidas de <italic>strain</italic><xref ref-type="bibr" rid="B194"><sup>194</sup></xref> ( <xref ref-type="fig" rid="f23">Figura 23</xref> ).</p>
            <fig id="f23">
              <label>Figura 23</label>
              <caption>
                <title>Strain global longitudinal do ventr&#237;culo esquerdo em um paciente com amiloidose por transtirretina, demonstrando o seu padr&#227;o peculiar que poupa o &#225;pice e acomete mais as por&#231;&#245;es mediobasais.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf23.tif"/></fig>
          </sec>
          <sec>
            <title>6.2.3.5. Outros Achados</title>
            <p>Apesar de n&#227;o apresentar incid&#234;ncia not&#225;vel em casos de AC, a presen&#231;a de trombos intracard&#237;acos j&#225; foi relatada e deve ser destacado que n&#227;o tem necessariamente associa&#231;&#227;o com a presen&#231;a de fibrila&#231;&#227;o atrial. <xref ref-type="bibr" rid="B195"><sup>195</sup></xref> Alguns autores j&#225; demonstraram que o tipo AL e a presen&#231;a de disfun&#231;&#227;o diast&#243;lica s&#227;o fatores de risco independentes para presen&#231;a de trombos intracard&#237;acos. <xref ref-type="bibr" rid="B196"><sup>196</sup></xref> A pesquisa por trombos deve ser sempre considerada em pacientes que apresentam crit&#233;rios de gravidade da AC (altos graus de aumento da espessura mioc&#225;rdica, diminui&#231;&#227;o da FEVE e est&#225;gios avan&#231;ados de disfun&#231;&#227;o diast&#243;lica, por exemplo). V&#225;rios mecanismos j&#225; foram propostos para explicar a ocorr&#234;ncia de trombos, al&#233;m da pr&#243;pria presen&#231;a da fibrila&#231;&#227;o atrial. Assim, podem ser citados: dep&#243;sitos de subst&#226;ncias amiloides em regi&#227;o subendoc&#225;rdica que produzem les&#227;o e maior enrijecimento parietal; estase hemodin&#226;mica como consequ&#234;ncia da disfun&#231;&#227;o diast&#243;lica importante geralmente do tipo restritiva; e hipercoagulabilidade plasm&#225;tica, como mecanismo sist&#234;mico decorrente de v&#225;rias condi&#231;&#245;es.</p>
            <p>Tamponamento card&#237;aco devido a derrame peric&#225;rdico importante &#233; raro e o seu diagn&#243;stico &#233; predominantemente cl&#237;nico, visto que as press&#245;es elevadas nas c&#226;maras direitas diminuem as chances de colabamento cl&#225;ssico ao ecocardiograma. O derrame peric&#225;rdico de menor intensidade &#233; mais comum. As valvas card&#237;acas tamb&#233;m podem estar infiltradas, por&#233;m raramente exibem regurgita&#231;&#227;o valvar severa. <xref ref-type="bibr" rid="B187"><sup>187</sup></xref> </p>
          </sec>
          <sec>
            <title>6.2.3.6. Abordagem Diagn&#243;stica</title>
            <p>O diagn&#243;stico da AC se inicia com o exame de ecocardiograma em in&#250;meras situa&#231;&#245;es cl&#237;nicas, mas muito frequentemente se d&#225; em uma das duas circunst&#226;ncias de avalia&#231;&#227;o pelo cardiologista.</p>
            <p>A primeira diz respeito &#224; necessidade da avalia&#231;&#227;o cardiol&#243;gica em pacientes com mieloma m&#250;ltiplo. Nesses casos, &#233; imperativa a confirma&#231;&#227;o do acometimento card&#237;aco, visto que a sobrevida nos casos de AC do tipo AL pode ser extremamente desfavor&#225;vel. Mesmo que os achados ecocardiogr&#225;ficos cl&#225;ssicos estejam ausentes no primeiro exame, recomenda-se repetir no seguimento do paciente.</p>
            <p>Na segunda situa&#231;&#227;o, pacientes s&#227;o submetidos &#224; avalia&#231;&#227;o cardiol&#243;gica seja por apresentarem quadro cl&#237;nico de ICFEP ou, ainda, pela presen&#231;a de &#8220;hipertrofia&#8221; no exame de ecocardiografia (frequentemente associada a complexos com baixa voltagem no ECG).</p>
            <p>Nestes casos, al&#233;m da pesquisa dos achados ecocardiogr&#225;ficos descritos anteriormente, sugere-se prosseguir investiga&#231;&#227;o com outros exames de imagem (RNM e MN) e investiga&#231;&#227;o laboratorial como eletroforese de prote&#237;nas e teste de prote&#237;nas de cadeia leve.</p>
            <p>Nos centros em que o estudo da deformidade mioc&#225;rdica est&#225; dispon&#237;vel, a presen&#231;a de preserva&#231;&#227;o apical &#233; t&#237;pica, por&#233;m n&#227;o &#233; exclusiva. Outras causas de hipertrofia ventricular esquerda podem exibir o mesmo padr&#227;o, como hipertrofia secund&#225;ria &#224; HAS e &#224; estenose a&#243;rtica.</p>
          </sec>
        </sec>
        <sec>
          <title>6.2.4. Contribui&#231;&#227;o da Resson&#226;ncia Magn&#233;tica Card&#237;aca</title>
          <p>A RMC permite o diagn&#243;stico de AC pelas altera&#231;&#245;es morfol&#243;gicas e funcionais nas sequ&#234;ncias de cinerresson&#226;ncia, assim como o ETT, e de forma mais acurada atrav&#233;s das sequ&#234;ncias de realce tardio e de mapa T1.</p>
          <p>A sequ&#234;ncia de realce tardio geralmente detecta o dep&#243;sito de prote&#237;na amiloide no espa&#231;o intersticial do mioc&#225;rdio atrav&#233;s do hipersinal (cor branca) presente no m&#250;sculo normalmente preto nessas imagens. <xref ref-type="bibr" rid="B197"><sup>197</sup></xref> Syed et al. <xref ref-type="bibr" rid="B198"><sup>198</sup></xref> analisaram a RMC em 120 pacientes com amiloidose. <xref ref-type="bibr" rid="B198"><sup>198</sup></xref> Destes, 35 tinham confirma&#231;&#227;o de envolvimento card&#237;aco pela histologia. Os outros 85 foram divididos naqueles com ou sem evid&#234;ncia ecocardiogr&#225;fica de AC. Nos 35 pacientes com diagn&#243;stico histol&#243;gico, 97% tinhamrealce tardio e 91% apresentavamaumento da espessura parietal pela ecocardiografia. Realce tardio transmural ou subendoc&#225;rdico foi o padr&#227;o mais comumente encontrado (83%), sendo associado a maior dep&#243;sito intersticial de amiloide; realce tardio focal (6%) e dificuldade de anular o sinal do mioc&#225;rdico (8%) tamb&#233;m foram padr&#245;es associados ao envolvimento card&#237;aco. Nos 85 pacientes sem histologia, o realce tardio esteve presente em 86% dos pacientes com altera&#231;&#227;o ecocardiogr&#225;fica e em 47% dos pacientes sem evid&#234;ncia de AC pela ETT. A presen&#231;a e o padr&#227;o de realce tardio foram associados &#224; classe funcional pela NYHA, &#224; baixa voltagem no ECG, ao &#237;ndice de massa do VE, ao espessamento parietal do VD e aos valores de troponina e pept&#237;dio natriur&#233;tico do tipo B (BNP) s&#233;ricos. <xref ref-type="bibr" rid="B198"><sup>198</sup></xref> </p>
          <p>Austin et al. <xref ref-type="bibr" rid="B199"><sup>199</sup></xref> estudaram 47 pacientes com suspeita de AC que foram submetidos a RMC, ECG, ETT e bi&#243;psia. <xref ref-type="bibr" rid="B199"><sup>199</sup></xref> Em compara&#231;&#227;o &#224; bi&#243;psia, o realce tardio teve sensibilidade de 88%, especificidade de 90%, valor preditivo positivo de 88% e valor preditivo negativo de 90%, sendo o &#250;nico com acur&#225;cia diagn&#243;stica significativa na an&#225;lise multivariada. Ap&#243;s 1 ano da bi&#243;psia, 19% dos pacientes faleceram, sendo o realce tardio o &#250;nico fator preditor significativo de mortalidade no per&#237;odo, mostrando o papel progn&#243;stico deste par&#226;metro na amiloidose.</p>
          <p>Comrela&#231;&#227;o &#224; diferencia&#231;&#227;o dos tipos de AC, a RMC pode ajudar na predi&#231;&#227;o da AL e da ATTR. Dungu et al. <xref ref-type="bibr" rid="B200"><sup>200</sup></xref> mostraram maior aumento da espessura mioc&#225;rdica (228g x 167g) e maior extens&#227;o do realce tardio nos pacientes com ATTR, apesar da pior mortalidade dos pacientes com AL. Neste estudo, 90% dos pacientes com ATTR apresentaram algum segmento com realce tardio transmural em compara&#231;&#227;o com 37% dos pacientes com AL. Al&#233;m disso, 100% tiveram realce tardio no VD na ATTR em compara&#231;&#227;o com 72% na AL. Os autores criaram um escore, o qual denominaram QALE (Query Amyloid Late Enhancement), com valores variando de 0 a 18. Valores superiores ou igual a 13 s&#227;o capazes de predizer ATTR em vez de AL, com sensibilidade de 82% e especificidade de 76%.</p>
          <p>A sequ&#234;ncia de mapa T1, t&#233;cnica mais recente na RNM, tamb&#233;m pode ajudar no diagn&#243;stico e progn&#243;stico de pacientes com AC, al&#233;m de servir no futuro para monitorar o tratamento de novos agentes terap&#234;uticos nesta doen&#231;a. Os valores de T1 pr&#233;-contraste est&#227;o aumentados em pacientes com AC, sendo esta uma op&#231;&#227;o diagn&#243;stica em pacientes ainda sem realce tardio, ou naqueles que n&#227;o realizam a sequ&#234;ncia de realce tardio por contraindica&#231;&#227;o &#224; inje&#231;&#227;o de gadol&#237;nio. Al&#233;m disso, com a inje&#231;&#227;o de gadol&#237;nio, &#233; poss&#237;vel calcular o volume extracelular do mioc&#225;rdio (ECV), que est&#225; expandido na AC pelo dep&#243;sito de fibrilas amiloides no interst&#237;cio, apresentando boa correla&#231;&#227;o com a bi&#243;psia, tendo valor progn&#243;stico comprovado. <xref ref-type="bibr" rid="B201"><sup>201</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B202"><sup>202</sup></xref> </p>
        </sec>
        <sec>
          <title>6.2.5. Contribui&#231;&#227;o da Medicina Nuclear</title>
          <p>A medicina nuclear (MN) ganhou uma nova relev&#226;ncia na detec&#231;&#227;o da AC com os estudos que demonstraram que os radiotra&#231;adores com afinidade &#243;ssea, como o &#225;cido 3,3-difosfono-1,2-propanodicarbox&#237;lico (DPD) e o pirofosfato (ambos marcados com Tecn&#233;cio-99 m), apresentam sensibilidade bastante importante para detec&#231;&#227;o da ATTR. A cintilografia com esses tra&#231;adores permite a diferencia&#231;&#227;o dos subtipos de prote&#237;na amiloide, de forma n&#227;o invasiva, baseada nos graus de concentra&#231;&#227;o do tra&#231;ador na &#225;rea card&#237;aca. Essa diferencia&#231;&#227;o tem implica&#231;&#245;es progn&#243;sticas e terap&#234;uticas. <xref ref-type="bibr" rid="B203"><sup>203</sup></xref> O mais importante estudo sobre o tema at&#233; o momento &#233; o de Gilmore et al. <xref ref-type="bibr" rid="B204"><sup>204</sup></xref> Eles avaliaram os resultados da cintilografia com radiotra&#231;adores de afinidade &#243;ssea em 1.217 pacientes com suspeita de AC encaminhados para avalia&#231;&#227;o em centros especializados, obtendo valores de sensibilidade de at&#233; 99% quando j&#225; descartada a forma AL pela an&#225;lise bioqu&#237;mica. <xref ref-type="bibr" rid="B204"><sup>204</sup></xref> A t&#233;cnica do exame consiste na inje&#231;&#227;o do tra&#231;ador em veia perif&#233;rica com aquisi&#231;&#227;o de imagens planares do t&#243;rax na proje&#231;&#227;o anterior ap&#243;s uma hora da administra&#231;&#227;o do radiof&#225;rmaco ( <xref ref-type="fig" rid="f24">Figura 24</xref> ). Essa imagem permite a realiza&#231;&#227;o da an&#225;lise quantitativa na qual duas regi&#245;es de interesse (ROI &#8211; region of interest) s&#227;o desenhadas, uma sobre a &#225;rea card&#237;aca no hemit&#243;rax esquerdo (HTE) e outra no hemit&#243;rax direito (HTD), em imagem espelhada. A rela&#231;&#227;o entre as contagens (representando a quantidade do tra&#231;ador presente em cada &#225;rea) do HTE e HTD maior que 1,5 tem elevada sensibilidade diagn&#243;stica (95% de sensibilidade e 79% de especifidade). <xref ref-type="bibr" rid="B203"><sup>203</sup></xref> Esta rela&#231;&#227;o do HTE/HTD possui poder diagn&#243;stico, mas tamb&#233;m progn&#243;stico, considerando que valores maiores que 1,6 conferem pior progn&#243;stico em seguimento de 5 anos. Ap&#243;s 3 horas s&#227;o adquiridas imagens do t&#243;rax (sendo opcional as imagens de corpo inteiro) nas proje&#231;&#245;es anterior e posterior, obl&#237;qua e lateral esquerdas. O grau de concentra&#231;&#227;o do tra&#231;ador na &#225;rea card&#237;aca &#233; avaliado em compara&#231;&#227;o ao gradeado costal, variando de grau 0 a 3: grau 0, aus&#234;ncia de concentra&#231;&#227;o card&#237;aca; grau 1, concentra&#231;&#227;o card&#237;aca discreta e menor que ao gradeado costal; grau 2, igual ao gradeado costal; e grau 3, maior que o gradeado costal. Os graus 2 e 3 est&#227;o fortemente associados &#224; forma ATTR (&gt; 99% de sensibilidade e 86% de especificidade) no contexto de cadeias leves j&#225; exclu&#237;da ( <xref ref-type="fig" rid="f25">Figura 25</xref> ). Os graus 0 e 1 podem ainda estar relacionados &#224; forma AL ( <xref ref-type="fig" rid="f26">Figura 26</xref> ) ou TTRm em fase inicial da doen&#231;a. A imagem de 3 horas possui maior especificidade diagn&#243;stica para ATTR (sensibilidade de 58% e especifidade de 100%). <xref ref-type="bibr" rid="B205"><sup>205</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B206"><sup>206</sup></xref> As imagens tomogr&#225;ficas, imagens SPECT (do ingl&#234;s, <italic>Single Photon Emission Tomography</italic> ), da regi&#227;o do t&#243;rax no tempo de 3 horas t&#234;m sido utilizadas com mais frequ&#234;ncia por melhorar a capacidade de distin&#231;&#227;o da presen&#231;a de atividade na cavidade ventricular esquerda ( <italic>blood pool)</italic> e melhorar a avalia&#231;&#227;o do septo interventricular, s&#237;tio pass&#237;vel de bi&#243;psia mioc&#225;rdica nos casos em que essa ainda se faz necess&#225;ria. Essa imagem adicional tamb&#233;m possibilita a compara&#231;&#227;o quantitativa da concentra&#231;&#227;o mioc&#225;rdica com o gradeado costal de forma mais precisa. A <xref ref-type="fig" rid="f27">Figura 27</xref> evidencia acometimento do VD por ATTRm, melhor avaliado &#224;s imagens tomogr&#225;ficas. O metileno difosfonado marcado com Tecn&#233;cio-99m (MDP-99mTc) &#233; o tra&#231;ador &#243;sseo de maior disponibilidade no territ&#243;rio nacional, mas a sua utiliza&#231;&#227;o para fins de avalia&#231;&#227;o de AC &#233; desencorajada. Estudo comparou os f&#225;rmacos MPD e DPD marcados com Tecn&#233;cio-99m em um grupo de pacientes com amiloidose familiar e a performance diagn&#243;stica deste tra&#231;ador &#233; considerada sub&#243;tima, com eventuais falsos negativos. <xref ref-type="bibr" rid="B207"><sup>207</sup></xref> A <xref ref-type="fig" rid="f28">Figura 28</xref> representa uma sequ&#234;ncia diagn&#243;stica para casos suspeitos de AC atrav&#233;s da MN.</p>
          <fig id="f24">
            <label>Figura 24</label>
            <caption>
              <title>Imagem na proje&#231;&#227;o anterior do t&#243;rax realizada uma hora ap&#243;s a administra&#231;&#227;o intravenosa do pirofosfatomarcado com Tecn&#233;cio-99m (<sup>99m</sup>Tc). Cada um dos c&#237;rculos representa uma regi&#227;o de interesse (ROI) e permite quantificar a concentra&#231;&#227;o do tra&#231;ador. A rela&#231;&#227;o das contagens entre hemit&#243;rax esquerdo e direito (HTE/HTD) deste caso foi de 1,75, sendo, portanto, positiva para amiloidose card&#237;aca forma transtirretina (ATTR).</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf24.tif"/></fig>
          <fig id="f25">
            <label>Figura 25</label>
            <caption>
              <title>Cintilografia de corpo inteiro e imagens planares do t&#243;rax com pirofosfato<sup>99m</sup>Tc demonstrando ac&#250;mulo anormal do radiof&#225;rmaco na proje&#231;&#227;o do cora&#231;&#227;o (setas) em paciente com insufici&#234;ncia card&#237;aca avan&#231;ada com fra&#231;&#227;o de eje&#231;&#227;o preservada. As dosagens s&#233;ricas de cadeias leves foram negativas e uma bi&#243;psia de gordura abdominal foi positiva para amiloidose. O diagn&#243;stico definitivo foi de amiloidose card&#237;aca por transtirretina.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf25.tif"/></fig>
          <fig id="f26">
            <label>Figura 26</label>
            <caption>
              <title>Cintilografia de corpo inteiro e imagens planares do t&#243;rax com pirofosfato<sup>99m</sup>Tc demonstrando ac&#250;mulo de intensidade leve (grau 1) na proje&#231;&#227;o do cora&#231;&#227;o ( <italic>seta</italic> ) em paciente com posterior confirma&#231;&#227;o de amiloidose de cadeia leve (AL) por achado de pico monoclonal na eletroforese de prote&#237;nas s&#233;ricas e urin&#225;rias, aumento da dosagem s&#233;rica da forma livre dos anticorpos ( <italic>freelight</italic> ) e aspirado de medula &#243;ssea demonstrando infiltra&#231;&#227;o plasmocit&#225;ria com celularidade inferior a 10%. A confirma&#231;&#227;o final foi realizada por bi&#243;psia de gordura abdominal, que foi positiva para amiloidose.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf26.tif"/></fig>
          <fig id="f27">
            <label>Figura 27</label>
            <caption>
              <title>Imagens tomogr&#225;ficas (SPECT) reconstru&#237;das nos eixos axial, coronal e sagital, identificando concentra&#231;&#227;o do pirofosfato<sup>99m</sup>Tc no ventr&#237;culo esquerdo e acometimento simult&#226;neo do ventr&#237;culo direito (setas) em paciente com suspeita de amiloidose card&#237;aca forma transtirretina (TTR) mutada, confirmada por teste gen&#233;tico.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf27.tif"/></fig>
          <fig id="f28">
            <label>Figura 28</label>
            <caption>
              <title>Sequ&#234;ncia diagn&#243;stica proposta atrav&#233;s da medicina nuclear para casos suspeitos de amiloidose card&#237;aca (AC). TTR: transtirretina (TTRm: TTR mutada; TTRs: TTR selvagem); AL: amiloidose card&#237;aca de cadeia leve; PYP: pirofosfato; DPD: &#225;cido 3,3-difosfono-1,2-propanodicarbox&#237;lico; <sup>99m</sup>Tc: tecn&#233;cio-99m.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf28.tif"/></fig>
        </sec>
      </sec>
      <sec>
        <title>6.3. S&#237;ndrome de Takotsubo</title>
        <p>A s&#237;ndrome de Takotsubo (ST) &#233; caracterizada por disfun&#231;&#227;o ventricular esquerda aguda e revers&#237;vel com comportamento semelhante &#224; s&#237;ndrome coronariana aguda, geralmente com in&#237;cio abrupto de dor precordial e dispneia. &#201; uma s&#237;ndrome card&#237;aca induzida por estresse sem a evid&#234;ncia de DAC obstrutiva, que geralmente tem recupera&#231;&#227;o espont&#226;nea dentro de dias ou semanas.</p>
        <p>Nos &#250;ltimos anos, tem havido um grande interesse em estudar a rela&#231;&#227;o entre c&#226;ncer e ST. Isso aconteceu principalmente ap&#243;s alguns estudos publicados mostrarem uma forte associa&#231;&#227;o entre essas duas condi&#231;&#245;es. <xref ref-type="bibr" rid="B208"><sup>208</sup></xref> </p>
        <p>A preval&#234;ncia de neoplasias parece ser maior em pacientes com ST quando comparada com indiv&#237;duos na mesma faixa et&#225;ria e sexo, tanto no momento do diagn&#243;stico desta doen&#231;a como no seguimento desses pacientes. Enquanto, na popula&#231;&#227;o geral, o diagn&#243;stico de ST gira em torno de 1% a 2%, em indiv&#237;duos com malignidade essa condi&#231;&#227;o chega a 10%. <xref ref-type="bibr" rid="B209"><sup>209</sup></xref> </p>
        <p>Na maioria dos casos, a ST envolve segmentos apicais e m&#233;dios do VE, que se mostram acin&#233;ticos ou discin&#233;ticos (padr&#227;o de &#8220;balonismo apical&#8221;), em oposi&#231;&#227;o aos segmentos basais, que em geral encontram-se hipercin&#233;ticos. Algumas formas com padr&#227;o variante foram descritas como a forma &#8220;medio ventricular&#8221; e &#8220;invertida&#8221;. A &#8220;medio ventricular&#8221; se caracteriza por acinesia dos segmentos medio ventricular, com hipocinesia ou contra&#231;&#227;o normal dos segmentos apicais e hipercontratilidade da base. O padr&#227;o &#8220;invertido&#8221; caracteriza-se por duas formas diferentes, a primeira definida pela caracter&#237;stica de poupar a regi&#227;o apical,apresentando-se com hipocinesia das paredes remanescentes, e a segunda com hipocinesia limitada aos segmentos basais.</p>
        <p>A ecocardiografia com <italic>speckle tracking</italic> permite a avalia&#231;&#227;o da deforma&#231;&#227;o multidirecional do VE. Nos casos t&#237;picos (&#8220;balonismo apical&#8221;), h&#225; um comprometimento da deforma&#231;&#227;o longitudinal apical e m&#233;dia,com um gradiente de deforma&#231;&#227;o base-&#225;pice.Ainda nessa fase,todos os componentes da mec&#226;nica de tor&#231;&#227;o do VE envolvendo as fases sist&#243;lica e diast&#243;lica est&#227;o comprometidos. Dada a sua maior sensibilidade na detec&#231;&#227;o de anormalidades sutis em compara&#231;&#227;o aos par&#226;metros mais tradicionais, como FEVE e &#237;ndice de motilidade de parede, a ecocardiografia com <italic>speckle tracking</italic> pode ajudar no diagn&#243;stico de ST. <xref ref-type="bibr" rid="B210"><sup>210</sup></xref> </p>
        <p>A ecocardiografia 3D trouxe a possibilidade de demonstra&#231;&#227;o mais acurada de volumes do VE e FEVE em compara&#231;&#227;o com a ecocardiografia 2De angiografia. No entanto, estudos adicionais usando essa tecncologia no curso da ST ainda s&#227;o nescess&#225;rios para estabelecer o seu papel na pr&#225;tica cl&#237;nica.</p>
        <p>Os tumores mais prevalentes entre pacientes com ST foram: colorretal, mam&#225;rio, br&#244;nquico e melanoma. <xref ref-type="bibr" rid="B208"><sup>208</sup></xref> As neoplasias hematol&#243;gicas foram menos prevalentes.Em rela&#231;&#227;o aos potenciais fatores desencadeantes, identificou-se uma rela&#231;&#227;o com o tratamento oncol&#243;gico em 57% dos casos: estresse cir&#250;rgico (33%), QT (17%) e RT (7%); os demais foram estresse emocional (30%) e presen&#231;a de outra doen&#231;a aguda (13%). <xref ref-type="bibr" rid="B209"><sup>209</sup></xref> </p>
        <p>Os pacientes com malignidade t&#234;m um limiar de toler&#226;ncia reduzido para estressores e um aumento da sensibilidade dos receptores adren&#233;rgicos card&#237;acos. Nesse cen&#225;rio, a adi&#231;&#227;o de estressores f&#237;sicos (dor secund&#225;ria ao c&#226;ncer, procedimentos diagn&#243;sticos, cirurgias oncol&#243;gicas) e estressores emocionais (medo de doen&#231;a ou morte, mudan&#231;as na din&#226;mica familiar), comuns &#224; doen&#231;a, contribuem para uma maior predisposi&#231;&#227;o paraapresentar a ST. Algumas malignidades, como feocromocitoma e paraganglioma, causam hipercatecolaminemia e podem ser um gatilho da ST. <xref ref-type="bibr" rid="B211"><sup>211</sup></xref> </p>
      </sec>
      <sec>
        <title>6.4. Miocardiopatia Sider&#243;tica (Sobrecarga de Ferro)</title>
        <p>A preval&#234;ncia de anemia nos pacientes com c&#226;ncer &#233; elevada, estando presente em mais da metade dos pacientes durante o curso da doen&#231;a, especialmente em pacientes com neoplasia de origem hematol&#243;gica. A anemia considerada moderada a grave ocorre em aproximadamente 40% dos pacientes, sendo de causa multifatorial, podendo ser secund&#225;ria &#224; mielossupress&#227;o relacionada com tratamento, sangramento oculto, defici&#234;ncia funcional de ferro, defici&#234;ncia de eritropoetina devido &#224; doen&#231;a renal e/ou envolvimento medular com tumor. <xref ref-type="bibr" rid="B212"><sup>212</sup></xref> A principal doen&#231;a oncol&#243;gica que leva &#224; sobrecarga de ferro &#233; a s&#237;ndrome mielodispl&#225;sica (SMD), tanto pelo aumento da absor&#231;&#227;o quanto pelas transfus&#245;es regulares. Como consequ&#234;ncia, esses pacientes com c&#226;ncer ou sobreviventes podem sofrer sobrecarga de ferro em &#243;rg&#227;os como f&#237;gado, cora&#231;&#227;o e adrenal. A sobrecarga de ferro card&#237;aca usualmente implica pior progn&#243;stico cardiovascular quando comparada &#224; popula&#231;&#227;o geral com desfechos presentes em 73,2% <italic>versus</italic> 54,5% em um per&#237;odo de 3 anos. <xref ref-type="bibr" rid="B213"><sup>213</sup></xref> </p>
        <p>A miocardiopatia por dep&#243;sito de ferro, em fases iniciais, comumente se apresenta com fun&#231;&#227;o ventricular normal. O diagn&#243;stico pelo ecocardiograma &#233; muitas vezes um desafio, mas alguns achados podem sugerir o diagn&#243;stico com hist&#243;ria cl&#237;nica compat&#237;vel.Disfun&#231;&#227;o diast&#243;lica ventricular pode evoluir para fisiologia restritiva, progredindo at&#233; cardiopatia dilatada com FEVE reduzida. &#201; poss&#237;vel a apresenta&#231;&#227;o como constri&#231;&#227;o peric&#225;rdica causado pela deposi&#231;&#227;o de ferro no peric&#225;rdio. A t&#233;cnica de <italic>speckle tracking</italic> (STE) apresenta ainda papel conflitante nesse cen&#225;rio, mas a maior sobrecarga card&#237;aca de ferro pode estar associada a um valor absoluto reduzido de SLG. N&#227;o h&#225; descri&#231;&#227;o pela literatura de um padr&#227;o de <italic>strain</italic> que seja espec&#237;fico de sobrecarga de ferro no mioc&#225;rdio. Os resultados dos estudos que tentaram correlacionar <italic>strain</italic> circunferencial e radial com dep&#243;sito de ferro foram conflitantes. O <italic>speckle tracking</italic> pelo ecocardiograma 3D tamb&#233;m n&#227;o tem papel estabelecido nesses pacientes, mas vem demostrando resultados favor&#225;veis &#224; detec&#231;&#227;o de disfun&#231;&#227;o subcl&#237;nica precoce. <xref ref-type="bibr" rid="B214"><sup>214</sup></xref><sup>-</sup><xref ref-type="bibr" rid="B216"><sup>216</sup></xref> </p>
        <p>Embora a ecocardiografia possa ser usada para rastrear a sobrecarga de ferro, esse m&#233;todo n&#227;o pode prever com precis&#227;o o conte&#250;do de ferro no mioc&#225;rdio, diferentemente da RMC ( <xref ref-type="table" rid="t8">Tabela 7</xref> ).</p>
        <table-wrap id="t8">
          <label>Tabela 7</label>
          <caption>
            <title>Classifica&#231;&#227;o da sobrecarga de ferro mioc&#225;rdica (MIC) e hep&#225;tica (LIC) pela resson&#226;ncia magn&#233;tica</title>
          </caption>
          <table frame="hsides" rules="rows">
            <colgroup width="16%">
              <col/>
              <col/>
              <col/>
              <col/>
              <col/>
              <col/>
            </colgroup>
            <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
              <tr>
                <th align="left" valign="middle">T2* (ms) 1.5T</th>
                <th align="center" valign="middle">R2* (Hz) 1.5T</th>
                <th align="center" valign="middle">T2* (ms) 3.0T</th>
                <th align="center" valign="middle">R2* (Hz) 3.0T</th>
                <th align="center" valign="middle">MIC/LIC (mg/g dw)</th>
                <th align="center" valign="middle">Classifica&#231;&#227;o</th>
              </tr>
            </thead>
            <tbody style="border-bottom: thin solid; border-color: #000000">
              <tr>
                <td align="center" colspan="6" valign="middle">
                  <bold>Cora&#231;&#227;o</bold>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">&gt; 20</td>
                <td align="center" valign="middle">&#8804; 50</td>
                <td align="center" valign="middle">&gt;12,6</td>
                <td align="center" valign="middle">&#8804; 79</td>
                <td align="center" valign="middle">&#8804; 1,16</td>
                <td align="center" valign="middle">Normal</td>
              </tr>
              <tr>
                <td align="left" valign="middle">10 a 20</td>
                <td align="center" valign="middle">50 a 100</td>
                <td align="center" valign="middle">5,8 a 12,6</td>
                <td align="center" valign="middle">79 a 172</td>
                <td align="center" valign="middle">1,16 a 2,71</td>
                <td align="center" valign="middle">Sobrecargaleve/moderada</td>
              </tr>
              <tr>
                <td align="left" valign="middle">&lt; 10</td>
                <td align="center" valign="middle">&gt; 100</td>
                <td align="center" valign="middle">&lt; 5,8</td>
                <td align="center" valign="middle">&gt; 172</td>
                <td align="center" valign="middle">&gt; 2,71</td>
                <td align="center" valign="middle">Sobrecarga grave</td>
              </tr>
              <tr>
                <td align="center" colspan="6" valign="middle">
                  <bold>F&#237;gado</bold>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">&gt;15,4</td>
                <td align="center" valign="middle">&#8804; 65</td>
                <td align="center" valign="middle">&gt; 8,4</td>
                <td align="center" valign="middle">&#8804; 119</td>
                <td align="center" valign="middle">&#8804; 2,0</td>
                <td align="center" valign="middle">Normal</td>
              </tr>
              <tr>
                <td align="left" valign="middle">4,5 a 15,4</td>
                <td align="center" valign="middle">66 a 224</td>
                <td align="center" valign="middle">2,3 a 8,4</td>
                <td align="center" valign="middle">120 a 435</td>
                <td align="center" valign="middle">2,0 a 7,0</td>
                <td align="center" valign="middle">Leve</td>
              </tr>
              <tr>
                <td align="left" valign="middle">2,1 a 4,5</td>
                <td align="center" valign="middle">225 a 475</td>
                <td align="center" valign="middle">1,05 a 2,3</td>
                <td align="center" valign="middle">436 a 952</td>
                <td align="center" valign="middle">7,0 a 15</td>
                <td align="center" valign="middle">Moderada</td>
              </tr>
              <tr>
                <td align="left" valign="middle">&lt; 2,1</td>
                <td align="center" valign="middle">&gt; 475</td>
                <td align="center" valign="middle">&lt; 1,05</td>
                <td align="center" valign="middle">&gt; 952</td>
                <td align="center" valign="middle">&gt; 15</td>
                <td align="center" valign="middle">Grave</td>
              </tr>
            </tbody>
          </table>
        </table-wrap>
        <p>Devido a essa limita&#231;&#227;o, as diretrizes atuais de diversas sociedades internacionais e diferentes patologias recomendam o uso de rotina da resson&#226;ncia magn&#233;tica para determina&#231;&#227;o e seguimento do grau de sobrecarga de ferro nos diferentes &#243;rg&#227;os. A indica&#231;&#227;o de resson&#226;ncia magn&#233;tica para esses pacientes dever&#225; ser iniciada a partir da detec&#231;&#227;o de graus elevados de ferritina s&#233;rica &gt; 1.000ng/mL ou recebimento de &gt; 10 bolsas transfusionais naqueles pacientes com expectativa de vida superior a 12 meses. <xref ref-type="bibr" rid="B217"><sup>217</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B218"><sup>218</sup></xref> </p>
        <p>O exame de resson&#226;ncia deve avaliar simultaneamente f&#237;gado e cora&#231;&#227;o, sendo repetido anualmente ou conforme mudan&#231;as terap&#234;uticas do quelante de ferro ou da carga transfusional. A quantifica&#231;&#227;o &#233; feita pelo efeito indireto que as mol&#233;culas de ferro exercem sobre o campo magn&#233;tico local no tecido estudado. Logo, quanto maior a concentra&#231;&#227;o de ferro tecidual, menor ser&#225; o sinal do tecido medido (mais escuro) ( <xref ref-type="fig" rid="f29">Figura 29</xref> ).</p>
        <fig id="f29">
          <label>Figura 29</label>
          <caption>
            <title>Exemplo de pacientes oncol&#243;gicos com n&#237;veis normais de ferro mioc&#225;rdico (A) e sobrecarga de ferro significativa (B). O paciente A tem T2* calculado em 22,8 ms com MIC (Myocardial Iron Concentration) = 0,98 mg/g; o paciente B tem T2* de 11,9ms com MIC de 2,2 mg/g. Observa-se o grau maior de escurecimento mioc&#225;rdico no paciente B com o aumento dos valores de tempo de eco (TE), determinando visualmente o maior grau de sobrecarga mioc&#225;rdica. O paciente B iniciou terapia de quela&#231;&#227;o oral de ferro ap&#243;s a determina&#231;&#227;o da sobrecarga mioc&#225;rdica pela resson&#226;ncia.</title>
          </caption>
          <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf29.tif"/></fig>
        <p>Atualmente, o exame de resson&#226;ncia n&#227;o tem substituto espec&#237;fico, sendo o &#250;nico exame capaz de determinar quantitativamente a sobrecarga de ferro em diferentes &#243;rg&#227;os ao mesmo tempo de forma n&#227;o invasiva, sem contraste ou radia&#231;&#227;o ionizante.</p>
      </sec>
    </sec>
    <sec>
      <title>7. Pericardiopatias</title>
      <sec>
        <title>7.1. Tumores do Peric&#225;rdio</title>
        <p>Embora geralmente assintom&#225;tica, a doen&#231;a maligna peric&#225;rdica pode apresentar sintomas inespec&#237;ficos, como dispneia e taquicardia, que costumam estar relacionados com pericardite, constri&#231;&#227;o peric&#225;rdica, invas&#227;o mioc&#225;rdica ou, mais comumente, derrame peric&#225;rdico (com ou sem tamponamento). O tamponamento ocorre em pacientes com derrame importante, sem sintomas pr&#233;vios, em at&#233; 1/3 dos casos. <xref ref-type="bibr" rid="B219"><sup>219</sup></xref> </p>
        <p>Em cerca de 20% a 50% dos pacientes com c&#226;ncer e derrame peric&#225;rdico, a causa deste &#233; envolvimento neopl&#225;sico, podendo em outros 30% ser decorrente do comprometimento linf&#225;tico secund&#225;rio &#224; RT ou infec&#231;&#227;o viral. Em 10% a 25% dos casos, a presen&#231;a de derrame peric&#225;rdico &#233; o primeiro sinal de neoplasia. <xref ref-type="bibr" rid="B220"><sup>220</sup></xref> </p>
        <p>Os tumores podem ser neoplasia peric&#225;rdica prim&#225;ria ou met&#225;stase envolvendo o peric&#225;rdio (neoplasia peric&#225;rdica secund&#225;ria). A dissemina&#231;&#227;o pode ocorrer via hematog&#234;nica, linf&#225;tica ou invas&#227;o direta do pulm&#227;o e mediastino. Os tumores que causam mais met&#225;stases ao peric&#225;rdio s&#227;o mama, pulm&#227;o, carcinoma de c&#233;lulas renais, linfomas e melanomas, sendo o padr&#227;o histol&#243;gico mais comum o adenocarcinoma. <xref ref-type="bibr" rid="B221"><sup>221</sup></xref> </p>
        <p>Estudo recente mostrou que a presen&#231;a de neoplasia hematol&#243;gica, colorretal, ovariana, renal, p&#226;ncreas, mama e bexiga ocultos deve ser suspeitada em pacientes idosos, obesos e/ou tabagistas que apresentem quadro de pericardite aguda e necessidade de interna&#231;&#227;o. O diagn&#243;stico oncol&#243;gico geralmente foi feito 3 a 12 meses ap&#243;s o epis&#243;dio de pericardite. <xref ref-type="bibr" rid="B222"><sup>222</sup></xref> </p>
        <sec>
          <title>7.1.1. Ecocardiograma em Pacientes com Neoplasia Peric&#225;rdica</title>
          <p>O derrame peric&#225;rdico pode ser avaliado de forma semiquantitativa pelo ETT. O aumento r&#225;pido do volume e a presen&#231;a de contraste espont&#226;neo no mesmo, com ou sem a visualiza&#231;&#227;o de massa peric&#225;rdica, s&#227;o sugestivos de neoplasia peric&#225;rdica. Esta costuma apresentar aspecto s&#243;lido, ecogenicidade aumentada, podendo infiltrar o mioc&#225;rdio. <xref ref-type="bibr" rid="B220"><sup>220</sup></xref> Como diagn&#243;stico diferencial, a gordura peric&#225;rdica tem baixa ecogenicidade e pode ser observada adjacente &#224; parede livre do VD e jun&#231;&#227;o atrioventricular.</p>
          <p>Entre os tumores prim&#225;rios, o mesotelioma, origin&#225;rio das c&#233;lulas mesoteliais do peric&#225;rdio visceral ou parietal, se apresenta com derrame peric&#225;rdico, tamponamento ou constri&#231;&#227;o, sendo que os n&#243;dulos no peric&#225;rdio podem invadir o mioc&#225;rdio. Estudo retrospectivo com 64 pacientes com mesotelioma peric&#225;rdico maligno prim&#225;rio mostrou que as apresenta&#231;&#245;es ecocardiogr&#225;ficas foram inespec&#237;ficas, com derrame peric&#225;rdico em 86% dos casos, sendo importantes em 67%, hemorr&#225;gicos em 95%, com presen&#231;a de massas peric&#225;rdicas em 36% e espessamento em 17% dos casos.Tamponamento e pericardite constritiva ocorreram em 37% e 27%, respectivamente, sendo que o tamponamento pode estar relacionado com prolifera&#231;&#227;o das c&#233;lulas mesoteliais difusas e infiltra&#231;&#227;o mioc&#225;rdica, reduzindo o relaxamento e a complac&#234;ncia. Reac&#250;mulo de l&#237;quido ap&#243;s a pericardiocentese ocorreu em 73% dos casos. <xref ref-type="bibr" rid="B223"><sup>223</sup></xref> </p>
          <p>A mensura&#231;&#227;o da espessura do peric&#225;rdio &#233; limitada pelo ecocardiograma. Esta limita&#231;&#227;o &#233; superada quando as medidas s&#227;o superiores a 5mm. De forma geral, a medida da espessura peric&#225;rdica &#233; melhor realizada por tomografia computadorizada ou RMC, que permitem uma melhor avalia&#231;&#227;o do implante e da extens&#227;o tumoral. Assim, a associa&#231;&#227;o dos m&#233;todos de multimodalidade mostra valor incremental. J&#225; a t&#233;cnica do <italic>speckle tracking</italic> permite a detec&#231;&#227;o de disfun&#231;&#227;o mioc&#225;rdica subcl&#237;nica por infiltra&#231;&#227;o mioc&#225;rdica precoce.</p>
          <p>Normalmente, o l&#237;quido peric&#225;rdico s&#243; deve ser observado na s&#237;stole, mas, com o ac&#250;mulo, ele pode ser observado durante todo o ciclo card&#237;aco. O derrame peric&#225;rdico &#233; considerado importante na presen&#231;a de pelo menos 2cm de l&#237;quido peric&#225;rdico em volta do cora&#231;&#227;o. No tamponamento card&#237;aco, h&#225; a compress&#227;o do cora&#231;&#227;o pelo ac&#250;mulo de l&#237;quido no espa&#231;o peric&#225;rdico, o que leva ao aumento da press&#227;o intraperic&#225;rdica que excede a intracavit&#225;ria. Tal ac&#250;mulo pode ocorrer r&#225;pida ou gradualmente.O consequente colapso das cavidades card&#237;acas direitas, secund&#225;rio ao aumento da press&#227;o intraperic&#225;rdica, &#233; mais proeminente na expira&#231;&#227;o, quando o enchimento de AD e VD &#233; reduzido. Entretanto, em presen&#231;a de HP, o colapso do AD &#233; mais tardio, resistindo at&#233; que a press&#227;o intraperic&#225;rdica supere as press&#245;es elevadas nas cavidades direitas. Em casos de derrames volumosos, o cora&#231;&#227;o costuma &#8220;balan&#231;ar&#8221; dentro do l&#237;quido peric&#225;rdico a cada batimento card&#237;aco, podendo apresentar altern&#226;ncia el&#233;trica no registro eletrocardiogr&#225;fico. Observam-se ainda mudan&#231;as respirat&#243;rias dos fluxos card&#237;acos. O aumento das press&#245;es no interior do VD durante a inspira&#231;&#227;o conduz a um desvio do septo interventricular para a esquerda e consequente aumento do fluxo e volume das c&#226;maras direitas, al&#233;m da dilata&#231;&#227;o da veia cava inferior ( <xref ref-type="fig" rid="f30">Figura 30 A-B</xref> ).</p>
          <fig id="f30">
            <label>Figura 30</label>
            <caption>
              <title>A. Varia&#231;&#227;o do fluxo tric&#250;spide maior que 40%. B. Veia cava inferior t&#250;rgida sem varia&#231;&#227;o de seu calibre com manobras respirat&#243;rias (paciente com c&#226;ncer de mama).</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf30.tif"/></fig>
          <p>A incis&#227;o subxifoide &#233; padr&#227;o-ouro para acesso cir&#250;rgico para realiza&#231;&#227;o de bi&#243;psia ou drenagem peric&#225;rdica. Entretanto, rotineiramente, a pericardiocentese &#233; guiada por fluoroscopia ou ecocardiografia, com taxa de complica&#231;&#245;es de 4% a 10% dos casos. Durante a pericardiocentese guiada por ecocardiografia, o uso da solu&#231;&#227;o salina agitada &#233; &#250;til para avaliar a posi&#231;&#227;o da agulha antes de inserir o cateter e, depois, para avaliar a posi&#231;&#227;o do cateter. <xref ref-type="bibr" rid="B224"><sup>224</sup></xref> O derrame peric&#225;rdico &#233; considerado recorrente se ocorre ac&#250;mulo de l&#237;quido dentro de 3meses p&#243;s-drenagem.</p>
        </sec>
      </sec>
    </sec>
    <sec>
      <title>8. Cardio-Oncologia na Popula&#231;&#227;o Infantojuvenil</title>
      <sec>
        <title>8.1. Considera&#231;&#245;es Gerais</title>
        <p>O n&#250;mero de casos novos de c&#226;ncer infantojuvenis esperados para o Brasil, para cada ano do tri&#234;nio 2020-2022, ser&#225; de 4.310 casos novos no sexo masculino e de 4.150 para o sexo feminino. Esses valores correspondem a um risco estimado de 137 casos novos por milh&#227;o no sexo masculino e de 139 por milh&#227;o para o sexo feminino. O c&#226;ncer infantojuvenil consiste em um conjunto de doen&#231;as que apresentam caracter&#237;sticas pr&#243;prias, em rela&#231;&#227;o &#224; histopatologia e ao comportamento cl&#237;nico. Os tipos predominantes de c&#226;nceres pedi&#225;tricos (entre 0 a 19 anos) s&#227;o leucemia (28%), sistema nervoso central (26%) e linfomas (8%). Consecutivamente, observam-se tumores do sistema nervoso perif&#233;rico (neuroblastomas), tumor de Wilms, retinoblastoma, tumores de c&#233;lulas germinativas (ov&#225;rios e test&#237;culos), sarcomas de partes moles e osteossarcoma. <xref ref-type="bibr" rid="B225"><sup>225</sup></xref> </p>
        <p>As perspectivas de cura do c&#226;ncer infantojuvenil s&#227;o promissoras, com taxa atual de sobrevida na ordem de 80% em institui&#231;&#245;es qualificadas e diante do diagn&#243;stico precoce. <xref ref-type="bibr" rid="B226"><sup>226</sup></xref> Apesar do sucesso terap&#234;utico, complica&#231;&#245;es inerentes aos f&#225;rmacos quimioter&#225;picos e/ou &#224; RT comprometem v&#225;rios sistemas org&#226;nicos em curto, m&#233;dio ou longo prazo. Existem evid&#234;ncias claras de que os sobreviventes de c&#226;ncer tratados na inf&#226;ncia com antraciclinas e/ou RT apresentam chances significativamente maiores de desenvolver complica&#231;&#245;es cardiovasculares ao longo de suas vidas, com estimativa que varia entre 5%e 30%, especialmente diante do protocolo utilizado e determinados fatores de risco. A incid&#234;ncia cumulativa de problemas cr&#244;nicos graves pode chegar a 40% no intervalo de 30 anos de seguimento dos sobreviventes. <xref ref-type="bibr" rid="B227"><sup>227</sup></xref> </p>
        <p>O c&#226;ncer &#233; a segunda causa mais comum de morte entre crian&#231;as de 1 a 14 anos nos EUA, perdendo apenas para os acidentes e mortes violentas. No Brasil, o c&#226;ncer foi respons&#225;vel por 8% do total de mortes entre crian&#231;as e adolescentes de 1 a 19 anos e 12% dos &#243;bitos na faixa de 1 a 14 anos entre 2009 e 2013. Em 2014, 2.724 mortes por c&#226;ncer infantojuvenil ocorreram no Brasil. <xref ref-type="bibr" rid="B225"><sup>225</sup></xref> Essa realidade demonstra o quanto &#233; importante essa intera&#231;&#227;o entre onco-hematologistas e cardiologistas na seguran&#231;a do tratamento do c&#226;ncer infantojuvenil.</p>
        <p>As complica&#231;&#245;es cardiovasculares s&#227;o as principais causas de morbimortalidade nos sobreviventes de c&#226;ncer tratados na inf&#226;ncia, perdendo apenas para recorr&#234;ncias da pr&#243;pria doen&#231;a e neoplasias secund&#225;rias. Os mecanismos de a&#231;&#227;o dos diversos quimioter&#225;picos, bem como as les&#245;es f&#237;sicas determinadas pela RT, comportam-se de modo semelhante entre adultos, crian&#231;as e adolescentes. No entanto, a vulnerabilidade dessa faixa et&#225;ria mais jovem &#233;, particularmente, maior, por estarem em constante processo de crescimento e desenvolvimento f&#237;sico. Al&#233;m disso, os cardiomi&#243;citosapresentam uma limitada capacidade de regenera&#231;&#227;o, e o metabolismo dos f&#225;rmacos nessa popula&#231;&#227;o comporta-se de modo diferente, quando comparados aos adultos. <xref ref-type="bibr" rid="B228"><sup>228</sup></xref> Desse modo, les&#245;es consideradas de pequena gravidade na &#233;poca do tratamento podem comprometer evolutivamente a fun&#231;&#227;o mioc&#225;rdica ao longo do tempo e virem a descompensar na idade adulta.O inadequado ganho de massa ventricular esquerda e a queda da fun&#231;&#227;o contr&#225;til, bem como a poss&#237;vel evolu&#231;&#227;o para o modo restritivo de cardiomiopatia progressiva no decorrer dos anos, trazem sequelas cardiovasculares muitas vezes irrevers&#237;veis em alguns desses pacientes.</p>
        <p>Al&#233;m da disfun&#231;&#227;o mioc&#225;rdica ventricular, outras complica&#231;&#245;es podem decorrer do emprego dos quimioter&#225;picos: les&#245;es do endot&#233;lio arterial (relacionadas ao efeito hipertensivo sist&#234;mico e pulmonar), acometimento da circula&#231;&#227;o coronariana, les&#245;es do endot&#233;lio venoso (relacionadas aos efeitos tromb&#243;ticos), disfun&#231;&#245;es valvares, arritmias e pericardiopatias. <xref ref-type="bibr" rid="B229"><sup>229</sup></xref> </p>
        <p>O comprometimento peric&#225;rdico pode estar relacionado &#224; pr&#243;pria neoplasia, como tamb&#233;m ser consequ&#234;ncia da a&#231;&#227;o de alguns quimioter&#225;picos ou secund&#225;rios &#224; met&#225;stase card&#237;aca. A pericardite, com ou sem derrame, poder&#225; estar associada ou n&#227;o &#224; miocardite. A pericardite constritiva &#233; mais associada &#224; cardiotoxicidade induzida pela RT, sendo necess&#225;rio diferenci&#225;-la da miocardite restritiva. Os exames de imagem cardiovascular s&#227;o essenciais na elucida&#231;&#227;o dessas altera&#231;&#245;es, especialmente em est&#225;gios subcl&#237;nicos.</p>
        <p>As antraciclinas (doxorrubicina, daunorrubicina, epirrubicina, idarrubicina e mitoxantrone) s&#227;o agentes quimioter&#225;picos extremamente potentes e amplamente usados na maioria dos protocolos de tratamento de neoplasias na inf&#226;ncia. Existe uma forte rela&#231;&#227;o entre a dose cumulativa de antraciclinas e o risco de insufici&#234;ncia card&#237;aca, podendo haver, em alguns casos, um longo per&#237;odo de lat&#234;ncia entre a exposi&#231;&#227;o ao quimioter&#225;pico e o aparecimento de sintomas cardiovasculares. <xref ref-type="bibr" rid="B227"><sup>227</sup></xref> A les&#227;o mioc&#225;rdica &#233; progressiva e geralmente irrevers&#237;vel, culminando com disfun&#231;&#227;o card&#237;aca grave. A a&#231;&#227;o cardiot&#243;xica das antraciclinasocorre atrav&#233;s de v&#225;rios mecanismos, sendo os mais evidentes a forma&#231;&#227;o de radicais livres citoplasm&#225;ticos, resultando em estresse oxidativo nos mi&#243;citos, e &#224; a&#231;&#227;o direta no n&#250;cleo, em que as antraciclinas agem sobre a topoisomerase-2 (Top2), impedindo a replica&#231;&#227;o do DNA que induz &#224; morte celular. Apesar de a fra&#231;&#227;o Top2&#945;, foco do tratamento antineopl&#225;sico, estar expressa nas c&#233;lulas tumorais, a fra&#231;&#227;o Top2&#946; se expressa nos cardiomi&#243;citos, permitindo a&#231;&#227;o t&#243;xica semelhante. <xref ref-type="bibr" rid="B230"><sup>230</sup></xref> Os protocolos de tratamento onco-hematol&#243;gicos atuais seguem uma tend&#234;ncia ao emprego de doses menores de antrac&#237;clicos. No entanto, mesmo com doses consideradas baixas, alguns pacientes pedi&#225;tricos apresentam rea&#231;&#245;es cardiot&#243;xicas durante a evolu&#231;&#227;o do tratamento e/ou no seguimento tardio, de forma que alguns autores consideram n&#227;o haver dose segura. <xref ref-type="bibr" rid="B231"><sup>231</sup></xref> A suscetibilidade individual ainda n&#227;o est&#225; completamente elucidada, mas h&#225; hip&#243;teses de que algumas caracter&#237;sticas gen&#233;ticas aumentem a vulnerabilidade e a precocidade da disfun&#231;&#227;o mioc&#225;rdica. Algumas a&#231;&#245;es preventivas s&#227;o recomendadas, especialmente nos pacientes estratificados como de alto risco de desenvolver complica&#231;&#245;es cardiovasculares. Estrat&#233;gia prim&#225;ria, espec&#237;fica contra os efeitos cardiot&#243;xicos das antraciclinas, &#233; dada atrav&#233;s da infus&#227;o do dexrazoxano, ou pela op&#231;&#227;o da doxorrubicinalipossomal (pouco utilizada entre pacientes jovens). Estrat&#233;gia secund&#225;ria, representada pela administra&#231;&#227;o de f&#225;rmacos com efeitos hemodin&#226;micos como os betabloqueadores, em especial, o carvedilol, inibidores da enzima conversora da angiotensina (IECA), e espironolactona, tem sido considerada como coadjuvante no cen&#225;rio da preven&#231;&#227;o ou no tratamento de les&#245;es estabelecidas, cujos estudos prospectivos em crian&#231;as ainda est&#227;o em andamento. <xref ref-type="bibr" rid="B228"><sup>228</sup></xref> </p>
        <p>Outras subst&#226;ncias potencialmente cardiot&#243;xicas s&#227;o usadas para o tratamento de neoplasias em crian&#231;as e adolescentes, muitas vezes em associa&#231;&#227;o com antraciclinas. A cardiotoxicidade n&#227;o &#233; rara com o uso de agentes alquilantes, como a ciclofosfamida, a cisplatina e a ifosfamida, sendo as apresenta&#231;&#245;es mais frequentes a miocardite, as arritmias e a insufici&#234;ncia card&#237;aca. A complica&#231;&#227;o cardiovascular mais comum dos antimetab&#243;litos, como o 5-fluorouracil, &#233; a isquemia mioc&#225;rdica, relatada principalmente em adultos. Agentes biol&#243;gicos como os inibidores da tirosino-quinase podem causar prolongamento do intervalo QT, insufici&#234;ncia card&#237;aca, hipertens&#227;o arterial e IAM. O etoposido &#233; uma podofilotoxina sint&#233;tica aprovada para o tratamento de algumas neoplasias como sarcoma de Ewing e linfomas. As complica&#231;&#245;es cardiovasculares s&#227;o raras, por&#233;m dor tor&#225;cica, angina e IAM t&#234;m sido relatados em adultos recebendo etoposido em associa&#231;&#227;o com bleomicina, cisplatina e ifosfamida. Agentes biol&#243;gicos como as interleucinas e o interferon podem causar hipotens&#227;o ou arritmias. Os alcaloides da vinca, como a vincristina e a vimblastina, t&#234;m como principal efeito cardiovascular a isquemia mioc&#225;rdica por vasospasmo coronariano. A imunoterapia tamb&#233;m vem ocupando lugar no tratamento do c&#226;ncer infantojuvenil, com potencial para desencadear miocardite, apesar de rara (&lt; 1%) e pericardite. <xref ref-type="bibr" rid="B232"><sup>232</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B233"><sup>233</sup></xref> </p>
        <p>A RT &#233; um m&#233;todo terap&#234;utico frequentemente utilizado no tratamento oncol&#243;gico pedi&#225;trico (cerca de 40% dos protocolos). As complica&#231;&#245;es card&#237;acas decorrentes da RT devem-se &#224; inflama&#231;&#227;o e &#224; fibrose das estruturas card&#237;acas, podendo envolver peric&#225;rdio, mioc&#225;rdio, valvas card&#237;acas e art&#233;rias coron&#225;rias. O peric&#225;rdio &#233; a estrutura acometida com maior frequ&#234;ncia. As les&#245;es podem permanecer assintom&#225;ticas por 5 a 15 anos, mas geralmente s&#227;o progressivas. A gravidade das les&#245;es &#233; proporcional &#224; dose, volume irradiado e &#224; associa&#231;&#227;o com os quimioter&#225;picos, o que confere maior risco. Os avan&#231;os nas t&#233;cnicas de RT, nas duas &#250;ltimas d&#233;cadas, permitiram uma redu&#231;&#227;o no volume e nas doses de radia&#231;&#227;o na &#225;rea card&#237;aca. Com o surgimento de t&#233;cnicas de planejamento 3D, o delineamento das estruturas adjacentes, o ajuste de doses e a modifica&#231;&#227;o de campos permitiram a redu&#231;&#227;o significativa da dose sobre &#243;rg&#227;os de risco, como o cora&#231;&#227;o. <xref ref-type="bibr" rid="B227"><sup>227</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B234"><sup>234</sup></xref> </p>
      </sec>
      <sec>
        <title>8.2. Principais Fatores de Risco para o Desenvolvimento de Cardiotoxicidade entre Crian&#231;as e Adolescentes</title>
        <p><bold>Dose cumulativa:</bold> mesmo doses relativamente baixas de antraciclinas t&#234;m sido relatadas como desencadeantes de cardiotoxicidade. O conceito de dose segura de antraciclinas tem sido desconsideradopor alguns autores, como observadoem estudo que mostrou um aumento de 30% de anormalidades ecocardiogr&#225;ficas subcl&#237;nicas 13 anos ap&#243;s o tratamento de leucemia, mesmo com doses cumulativas de antraciclinas entre 180 e 240mg/m<sup>2</sup>. <xref ref-type="bibr" rid="B234"><sup>234</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B235"><sup>235</sup></xref> </p>
        <p><bold>Associa&#231;&#227;o entre agentes quimioter&#225;picos:</bold> a administra&#231;&#227;o concomitante de mais de um agente quimioter&#225;pico sabidamente cardiot&#243;xico n&#227;o s&#243; facilita, como potencializa os efeitos cardiovasculares adversos.</p>
        <p><bold>Idade ao tratamento:</bold> crian&#231;as tratadas antes dos 5 anos de idade apresentam maiores chances de complica&#231;&#245;es cardiovasculares em curto ou em longo prazo, especialmente devido&#224; limita&#231;&#227;o funcional mioc&#225;rdica progressiva diante da demanda do crescimento f&#237;sico.</p>
        <p><bold>Sexo:</bold> meninas apresentam duas vezes maior incid&#234;ncia de cardiotoxicidade que meninos, provavelmente devido ao maior percentual de gordura corporal que permite maior tempo de exposi&#231;&#227;o e concentra&#231;&#227;o corporal das antraciclinas.</p>
        <p><bold>Velocidade de infus&#227;o:</bold> alguns estudos, em adultos, sugeriram uma redu&#231;&#227;o na preval&#234;ncia de cardiotoxicidade atrav&#233;s da infus&#227;o cont&#237;nua de antrac&#237;clicos, quando comparada com a administra&#231;&#227;o em <italic>bolus.</italic> Este modo de infus&#227;o, por&#233;m, n&#227;o foi cardioprotetor alongo prazo na popula&#231;&#227;o pedi&#225;trica. <xref ref-type="bibr" rid="B231"><sup>231</sup></xref> </p>
        <p><bold>Radioterapia mediastinal e neuroeixo:</bold> doses radioter&#225;picas &#8805; 30 Gy ou a combina&#231;&#227;o de antraciclina com RT, mesmo em baixas doses, tamb&#233;m representam um agravante ao risco de desenvolvimento de complica&#231;&#245;es cardiovasculares. A baixa idade quando da exposi&#231;&#227;o &#224; radia&#231;&#227;o tamb&#233;m &#233; fator importante. Esses pacientes podem evoluir com complica&#231;&#245;es valvares, peric&#225;rdicas, miocardiopatia restritiva, coronariopatias e arritmias que podem induzir &#224; morte s&#250;bita. <xref ref-type="bibr" rid="B227"><sup>227</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B234"><sup>234</sup></xref> </p>
        <p><bold>Radioterapia do sistema nervoso central:</bold> a longo prazo, crian&#231;as que receberam irradia&#231;&#227;o cranial apresentaram maior perda de massa ventricular, fato atribu&#237;do ao comprometimento da hip&#243;fise com consequente defici&#234;ncia secund&#225;ria da produ&#231;&#227;o de IGF-1, precursor do horm&#244;nio do crescimento (GH). <xref ref-type="bibr" rid="B236"><sup>236</sup></xref> </p>
        <p><bold>Comorbidades:</bold> a presen&#231;a de duas ou mais comorbidades incrementam o risco cardiovascular nos adultos sobreviventes ao tratamento do c&#226;ncer na idade pedi&#225;trica. O desenvolvimento de hipertens&#227;o arterial sist&#234;mica, DM, dislipidemia e DAC, especialmente em associa&#231;&#227;o&#224; obesidade e ao tabagismo, incrementa a precocidade do surgimento das complica&#231;&#245;es quando comparado aos seus irm&#227;os. A presen&#231;a de disfun&#231;&#227;o hep&#225;tica, disfun&#231;&#227;o renal e dist&#250;rbios eletrol&#237;ticos compromete o <italic>clearance</italic> do f&#225;rmaco, lentifica sua elimina&#231;&#227;o e aumenta o tempo de exposi&#231;&#227;o ao medicamento.</p>
        <p><bold>Variantes gen&#233;ticas:</bold> a predisposi&#231;&#227;o individual &#224; cardiotoxicidade tem sido reportada em diversos estudos. Algumas variantes gen&#233;ticas, como a RARG e UGT1A6, aumentam a Top2 ou lentificam o metabolismo dos f&#225;rmacos. A incid&#234;ncia de disfun&#231;&#227;o mioc&#225;rdica aumenta nove vezes em pacientes portadores da muta&#231;&#227;o do gene C282Y para hemocromatose heredit&#225;ria. Portadores de trissomia 21 trazem consigo maiores chances de desenvolver leucemia mieloide aguda e s&#227;o mais sens&#237;veis aos efeitos t&#243;xicos dos quimioter&#225;picos. Cardiomiopatias familiares (hipertr&#243;ficas, arritmog&#234;nicas) e portadores de cardiopatias cong&#234;nitas podem apresentar mioc&#225;rdios mais vulner&#225;veis. <xref ref-type="bibr" rid="B237"><sup>237</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B238"><sup>238</sup></xref> </p>
      </sec>
      <sec>
        <title>8.3. Monitoramento Cardiol&#243;gico durante o Tratamento</title>
        <p>A metodologia aplicada aos exames de imagem cardiovascular, defini&#231;&#245;es e par&#226;metros utilizados na avalia&#231;&#227;o de pacientes infantojuvenis ou sobreviventes ao tratamento do c&#226;ncer na idade pedi&#225;trica s&#227;o os mesmos aplicados &#224; popula&#231;&#227;o adulta.</p>
        <p>A ecocardiografia &#233; o principal m&#233;todo indicado para o monitoramento desses pacientes, pois permite a an&#225;lise dos principais par&#226;metros de fun&#231;&#227;o diast&#243;lica e sist&#243;lica de ambos os ventr&#237;culos, estado anat&#244;mico e funcional das estruturas valvares e do peric&#225;rdio, al&#233;m da investiga&#231;&#227;o de massas, trombos e vegeta&#231;&#245;es. A fun&#231;&#227;o mioc&#225;rdica ventricular &#233; quantificada atrav&#233;s de diversos par&#226;metros e metodologias. Os mais preconizados s&#227;o a FEVE atrav&#233;s do m&#233;todo de Simpson biplanar e a an&#225;lise dos &#237;ndices de deforma&#231;&#227;o mioc&#225;rdica ( <italic>strain</italic> ), pela t&#233;cnica de <italic>speckle tracking</italic> . As medidas de deforma&#231;&#227;o mioc&#225;rdica podem ser obtidas por ecocardiografia 2De 3De analisadas nos modos longitudinal, radial ou circunferencial, uma vez que n&#227;o dependem do &#226;ngulo de incid&#234;ncia do ultrassom. Esse m&#233;todo tem sido alvo de v&#225;rios estudos que procuram detectar precocemente altera&#231;&#245;es subcl&#237;nicas que podem ser preditoras de cardiotoxicidade na popula&#231;&#227;o infantojuvenil. <xref ref-type="bibr" rid="B239"><sup>239</sup></xref> O modo longitudinal tem sido o de melhor reprodutibilidade utilizado na grande maioria dos estudos. Apesar de suas vantagens (disponibilidade, acessibilidade e baixo custo), a ecocardiografia apresenta algumas limita&#231;&#245;es, em especial a variabilidade inter-observador e o comprometimento da qualidade das imagens obtidas diante de janelas ac&#250;sticas inadequadas. Outra limita&#231;&#227;o est&#225; relacionada com fra&#231;&#227;o de eje&#231;&#227;o, comprovadamente de baixa sensibilidade no contexto da detec&#231;&#227;o precoce de altera&#231;&#245;es funcionais mioc&#225;rdicas. Em contrapartida, a an&#225;lise da deforma&#231;&#227;o mioc&#225;rdica atrav&#233;s da t&#233;cnica de <italic>speckletracking</italic> permite identificar les&#245;es subcl&#237;nicas que precedem a queda da FEVE. <xref ref-type="bibr" rid="B239"><sup>239</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B240"><sup>240</sup></xref> </p>
        <p>A RMC &#233; outro importante m&#233;todo diagn&#243;stico no contexto cardio-oncol&#243;gico infantojuvenil. Al&#233;m de ser opadr&#227;o-ouro na quantifica&#231;&#227;o da FEVE, permite tamb&#233;m a detec&#231;&#227;o de edema intersticial precoce e fibrose mioc&#225;rdica atrav&#233;s de m&#233;todos contempor&#226;neos associados &#224; utiliza&#231;&#227;o de contraste (gadol&#237;nio) pelo mapeamento em T1 e identifica&#231;&#227;o de realce tardio. Al&#233;m disso, tem importante papel na caracteriza&#231;&#227;o de massas intra e extracard&#237;acas. Entretanto, devido &#224;s suas caracter&#237;sticas intr&#237;nsecas, temlimita&#231;&#245;es quanto ao seu uso como rotina.</p>
        <p>A aplicabilidade da MN na &#225;rea pedi&#225;trica exige, al&#233;m do conhecimento t&#233;cnico, a necess&#225;ria avalia&#231;&#227;o conjunta com a equipe pedi&#225;trica sobre o risco <italic>versus</italic> benef&#237;cio da exposi&#231;&#227;o do paciente infantojuvenil &#224;s doses de radia&#231;&#227;o (embora baixas, com base nos princ&#237;pios de seguran&#231;a de radia&#231;&#227;o). <xref ref-type="bibr" rid="B241"><sup>241</sup></xref> A ventriculografia radioisot&#243;pica (VR), t&#233;cnica n&#227;o invasiva que utiliza as hem&#225;cias marcadas com <sup>99m</sup>Tc como radiof&#225;rmaco, permite a an&#225;lise de v&#225;rios par&#226;metros da fun&#231;&#227;o ventricular (curva de atividade <italic>vs.</italic> tempo, an&#225;lise de fase e amplitude), possibilitando uma refinada avalia&#231;&#227;o das regi&#245;es de melhor desempenho contr&#225;til (amplitude) e o momento temporal em que esta contra&#231;&#227;o ocorreu (an&#225;lise de fase), detectando a presen&#231;a de assincronismo contr&#225;til entre os ventr&#237;culos direito e esquerdo e intraventricular esquerdo. No entanto, em rela&#231;&#227;o &#224; fun&#231;&#227;o diast&#243;lica, as informa&#231;&#245;es fornecidas s&#227;o limitadas. &#201; discut&#237;vel o momento ideal da realiza&#231;&#227;o da VR durante o tratamento oncol&#243;gico a fim de minimizar as vari&#225;veis que possam confundir a investiga&#231;&#227;o. Segere-se a realiza&#231;&#227;o da mesma pelo menos 3 semanas ap&#243;s a terapia com antraciclina, quando os pacientes est&#227;o afebris e com hemoglobina superior a 9 g/dL. <xref ref-type="bibr" rid="B242"><sup>242</sup></xref> Com rela&#231;&#227;o aos outros m&#233;todos nucleares empregados na detec&#231;&#227;o de cardiotoxicidade como a capta&#231;&#227;o mioc&#225;rdica de mIBG <xref ref-type="bibr" rid="B123"><sup>123</sup></xref> I e PET-CT, ainda n&#227;o h&#225; dados robustos para indica&#231;&#227;o na popula&#231;&#227;o pedi&#225;trica.</p>
        <p>O diagn&#243;stico de cardiotoxicidade atrav&#233;s dos m&#233;todos de imagem cardiovascular &#233; feito com base nas altera&#231;&#245;es detectadas em rela&#231;&#227;o ao exame basal. Desse modo, recomenda-se realizar a avalia&#231;&#227;o funcional antes do in&#237;cio do tratamento antineopl&#225;sico e durante a evolu&#231;&#227;o, como an&#225;lise comparativa, procurando sempre utilizar os mesmos equipamentos, os mesmos m&#233;todos e as mesmas vari&#225;veis utilizadas nas avalia&#231;&#245;es anteriores.</p>
        <p>A <xref ref-type="table" rid="t9">Tabela 8</xref> mostra as recomenda&#231;&#245;es internacionais de monitoramento ecocardiogr&#225;fico de pacientes durante e ap&#243;s o tratamento com antraciclinas (principais representantes da cardiotoxicidade na faixa et&#225;ria infantojuvenil).</p>
        <table-wrap id="t9">
          <label>Tabela 8</label>
          <caption>
            <title>Monitoramento ecocardiogr&#225;fico de pacientes tratados com antraciclinas na inf&#226;ncia</title>
          </caption>
          <table frame="hsides" rules="rows">
            <colgroup width="20%">
              <col/>
              <col/>
              <col/>
              <col/>
              <col/>
            </colgroup>
            <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
              <tr>
                <th align="left" rowspan="2" valign="middle">DC (mg/m<sup>2</sup>)</th>
                <th align="center" colspan="2" valign="middle">Durante o tratamento</th>
                <th align="center" colspan="2" valign="middle">Ap&#243;s o tratamento</th>
              </tr>
              <tr>
                <th align="center" valign="middle">Sem FRP</th>
                <th align="center" valign="middle">01 ou + FRP</th>
                <th align="center" valign="middle">Sem FRP</th>
                <th align="center" valign="middle">01 ou + FRP</th>
              </tr>
            </thead>
            <tbody style="border-bottom: thin solid; border-color: #000000">
              <tr>
                <td align="left" valign="middle">Inicial</td>
                <td align="center" valign="middle">Sim</td>
                <td align="center" valign="middle">Sim</td>
                <td align="center" valign="middle">NA</td>
                <td align="center" valign="middle">NA</td>
              </tr>
              <tr>
                <td align="left" valign="middle">&lt; 200</td>
                <td align="center" valign="middle">
                  <list list-type="simple">
                    <list-item>
                      <label>&#8211;</label>
                      <p>Crit&#233;rio cl&#237;nico</p>
                    </list-item>
                  </list>
                </td>
                <td align="center" valign="middle">
                  <list list-type="simple">
                    <list-item>
                      <label>&#8211;</label>
                      <p>Cada 2/3 ciclos</p>
                    </list-item>
                  </list>
                </td>
                <td align="center" valign="middle">
                  <list list-type="simple">
                    <list-item>
                      <label>&#8211;</label>
                      <p>1 m&#234;sp&#243;s-TT</p>
                    </list-item>
                    <list-item>
                      <label>&#8211;</label>
                      <p>Avaliar em 1, 2 e 5 anos</p>
                    </list-item>
                    <list-item>
                      <label>&#8211;</label>
                      <p>Individualizar SN</p>
                    </list-item>
                  </list>
                </td>
                <td align="center" valign="middle">
                  <list list-type="simple">
                    <list-item>
                      <label>&#8211;</label>
                      <p>1 m&#234;s p&#243;s-TT</p>
                    </list-item>
                    <list-item>
                      <label>&#8211;</label>
                      <p>Avaliar em 1, 2 e 5 anos</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">200 a 300</td>
                <td align="center" valign="middle">
                  <list list-type="simple">
                    <list-item>
                      <label>&#8211;</label>
                      <p>Crit&#233;rio cl&#237;nico</p>
                    </list-item>
                  </list>
                </td>
                <td align="center" valign="middle">
                  <list list-type="simple">
                    <list-item>
                      <label>&#8211;</label>
                      <p>Cada 2/3 ciclos</p>
                    </list-item>
                  </list>
                </td>
                <td align="center" valign="middle">
                  <list list-type="simple">
                    <list-item>
                      <label>&#8211;</label>
                      <p>1, 6 e 12 meses p&#243;s-TT</p>
                    </list-item>
                    <list-item>
                      <label>&#8211;</label>
                      <p>Depois: a cada 2 anos (assintom&#225;tico)</p>
                    </list-item>
                  </list>
                </td>
                <td align="center" valign="middle">
                  <list list-type="simple">
                    <list-item>
                      <label>&#8211;</label>
                      <p>1, 6 e 12 meses p&#243;s-TT</p>
                    </list-item>
                    <list-item>
                      <label>&#8211;</label>
                      <p>Depois: anual</p>
                    </list-item>
                    <list-item>
                      <label>&#8211;</label>
                      <p>Individualizar</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">300 a 450</td>
                <td align="center" valign="middle">
                  <list list-type="simple">
                    <list-item>
                      <label>&#8211;</label>
                      <p>Crit&#233;rio cl&#237;nico</p>
                    </list-item>
                    <list-item>
                      <label>&#8211;</label>
                      <p>Individualizar SN</p>
                    </list-item>
                  </list>
                </td>
                <td align="center" valign="middle">
                  <list list-type="simple">
                    <list-item>
                      <label>&#8211;</label>
                      <p>Cada 2 ciclos</p>
                    </list-item>
                  </list>
                </td>
                <td align="center" valign="middle">
                  <list list-type="simple">
                    <list-item>
                      <label>&#8211;</label>
                      <p>1, 6 e 12 meses p&#243;s-TT</p>
                    </list-item>
                    <list-item>
                      <label>&#8211;</label>
                      <p>Depois: anual</p>
                    </list-item>
                    <list-item>
                      <label>&#8211;</label>
                      <p>Individualizar</p>
                    </list-item>
                  </list>
                </td>
                <td align="center" valign="middle">
                  <list list-type="simple">
                    <list-item>
                      <label>&#8211;</label>
                      <p>01 m&#234;s p&#243;s-TT</p>
                    </list-item>
                    <list-item>
                      <label>&#8211;</label>
                      <p>Depois: 6/6 meses</p>
                    </list-item>
                    <list-item>
                      <label>&#8211;</label>
                      <p>Individualizar SN</p>
                    </list-item>
                  </list>
                </td>
              </tr>
              <tr>
                <td align="left" valign="middle">&gt; 450</td>
                <td align="center" valign="middle">
                  <list list-type="simple">
                    <list-item>
                      <label>&#8211;</label>
                      <p>Metade do TT</p>
                    </list-item>
                    <list-item>
                      <label>&#8211;</label>
                      <p>Individualizar SN</p>
                    </list-item>
                  </list>
                </td>
                <td align="center" valign="middle">
                  <list list-type="simple">
                    <list-item>
                      <label>&#8211;</label>
                      <p>Cada 2 ciclos</p>
                    </list-item>
                    <list-item>
                      <label>&#8211;</label>
                      <p>Individualizar SN</p>
                    </list-item>
                  </list>
                </td>
                <td align="center" colspan="2" valign="middle">
                  <list list-type="simple">
                    <list-item>
                      <label>&#8211;</label>
                      <p>1 m&#234;s p&#243;s-TT</p>
                    </list-item>
                    <list-item>
                      <label>&#8211;</label>
                      <p>Depois: 6/6 meses</p>
                    </list-item>
                    <list-item>
                      <label>&#8211;</label>
                      <p>Individualizar SN</p>
                    </list-item>
                  </list>
                </td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="TFN3">
              <p>DC: dose cumulativa; FRP: fatores de risco preexistentes; TT: tratamento; SN: se necess&#225;rio; NA: n&#227;o se aplica.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
        <p>&#201; necess&#225;rio levar em considera&#231;&#227;o o estado hemodin&#226;mico do paciente no momento da avalia&#231;&#227;o. Sempre que poss&#237;vel, considerar o estado mais est&#225;vel poss&#237;vel. A fragilidade do paciente pedi&#225;trico diante de determinadas situa&#231;&#245;es, como altera&#231;&#245;es da volemia (desidrata&#231;&#227;o, hiper-hidrata&#231;&#227;o), anemia, febre, hipotermia, choque, sepse, frequ&#234;ncia card&#237;aca e altera&#231;&#245;es do ritmo, pode influenciar, pontualmente, na interpreta&#231;&#227;o dos resultados. Essas condi&#231;&#245;es afetam a pr&#233; e p&#243;s-carga e s&#227;o suficientes para promover uma varia&#231;&#227;o de 5% a 10% no volume sist&#243;lico por ciclo card&#237;aco, com influ&#234;ncia na fra&#231;&#227;o de eje&#231;&#227;o. As altera&#231;&#245;es da contratilidade global e segmentar, durante a QT, podem estar relacionadas &#224; cardiomiopatia secund&#225;ria induzida por estresse transit&#243;rio (idiop&#225;tica, sepse, les&#227;o neurol&#243;gica, libera&#231;&#227;o de catecolaminas). <xref ref-type="bibr" rid="B243"><sup>243</sup></xref> As altera&#231;&#245;es funcionais diante de intercorr&#234;ncias cl&#237;nicas poder&#227;o ser transit&#243;rias ou definitivas. Recomenda-se a reavalia&#231;&#227;o logo ap&#243;s a compensa&#231;&#227;o do quadro.</p>
        <p>A defini&#231;&#227;o de cardiotoxicidade subcl&#237;nica continua sendo um desafio tamb&#233;m para a popula&#231;&#227;o infantojuvenil. Alguns estudos relatam altera&#231;&#245;es segmentares mesmo antes da queda do <italic>strain</italic> global longitudinal, o que tem levantado a aten&#231;&#227;o quanto &#224; maior acur&#225;cia desse m&#233;todo na detec&#231;&#227;o precoce de disfun&#231;&#227;o mioc&#225;rdica. As atuais recomenda&#231;&#245;es internacionais consideram a queda percentual de 15% do <italic>strain</italic> global longitudinal, comparados com os valores iniciais (basais), como indicativa de disfun&#231;&#227;o subcl&#237;nica, desde que em condi&#231;&#245;es hemodin&#226;micas comparativamente semelhantes. <xref ref-type="bibr" rid="B239"><sup>239</sup></xref> </p>
      </sec>
      <sec>
        <title>8.4. Seguimento a Longo Prazo dos Sobreviventes</title>
        <p>O risco de desenvolvimento de complica&#231;&#245;es cardiovasculares e a gravidade das les&#245;es aumentam com o passar do tempo. Estudos demonstraram que, entre sobreviventes de c&#226;ncer tratados na inf&#226;ncia e acompanhados por 30 anos, 8% apresentaram insufici&#234;ncia card&#237;aca. A detec&#231;&#227;o precoce da cardiotoxicidade induzida pelos tratamentos antineopl&#225;sicos parece ter um efeito significativo no controle da evolu&#231;&#227;o e nos efeitos hemodin&#226;micos decorrentes da les&#227;o mioc&#225;rdica. A identifica&#231;&#227;o do melhor m&#233;todo para a detec&#231;&#227;o precoce da cardiotoxicidade nesses pacientes &#233; de extrema import&#226;ncia. A ecocardiografia e a RMC s&#227;o os m&#233;todos mais recomendados pelas principais diretrizes e estudos internacionais. <xref ref-type="bibr" rid="B28"><sup>28</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B227"><sup>227</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B239"><sup>239</sup></xref> </p>
        <p>Apesar da escassez de estudos controlados e randomizados na popula&#231;&#227;o infantojuvenil, a detec&#231;&#227;o precoce das les&#245;es desde o est&#225;gio subcl&#237;nico &#233; de fundamental import&#226;ncia para impedir a sua progress&#227;o, prevenindo ou revertendo o remodelamento patol&#243;gico do VE. <xref ref-type="bibr" rid="B228"><sup>228</sup></xref> </p>
        <p>A Sociedade Americana de Oncologia Cl&#237;nica (ASCO) prop&#245;e cinco quest&#245;es cl&#237;nicas que podem orientar no planejamento e monitoramento das complica&#231;&#245;es cardiovasculares dos sobreviventes: <xref ref-type="bibr" rid="B6"><sup>6</sup></xref> </p>
        <list list-type="order">
          <list-item>
            <p>Quais pacientes t&#234;m risco aumentado de evoluir com disfun&#231;&#227;o card&#237;aca?</p>
          </list-item>
          <list-item>
            <p>Quais as estrat&#233;gias preventivas para minimizar o risco ANTES do in&#237;cio do tratamento?</p>
          </list-item>
          <list-item>
            <p>Quais as estrat&#233;gias preventivas para minimizar os riscos DURANTE o tratamento com f&#225;rmacospotencialmente cardiot&#243;xicos?</p>
          </list-item>
          <list-item>
            <p>Quais os m&#233;todos de escolha para monitorar os pacientes de risco DURANTE o tratamento?</p>
          </list-item>
          <list-item>
            <p>Quais os m&#233;todos de escolha para monitorar os pacientes de risco AP&#211;S o tratamento?</p>
          </list-item>
        </list>
        <p>O planejamento de seguimento tardio com basena estratifica&#231;&#227;o dos riscos permite a escolha do melhor m&#233;todo de monitoramento da fun&#231;&#227;o mioc&#225;rdica (biomarcadores e exames de imagem), visando &#224; detec&#231;&#227;o precoce de disfun&#231;&#227;o subcl&#237;nica, com consequente utiliza&#231;&#227;o de f&#225;rmacosque possam prevenir ou reverter o remodelamento do cora&#231;&#227;o.</p>
        <p>Com rela&#231;&#227;o ao seguimento tardio ap&#243;s a RT &#8211; um dos pilares do tratamento oncol&#243;gico pedi&#225;trico, onde cerca de 40% das crian&#231;as, adolescentes e adultos jovens s&#227;o submetidos em alguma etapa do tratamento da doen&#231;a &#8211; a incid&#234;ncia e a gravidades&#227;o diretamente proporcionais &#224; dose e ao volume irradiado e inversamente proporcionais &#224; idade. A ocorr&#234;ncia tamb&#233;m aumenta com o tempo decorrido da RT e uso associado de agentes cardiot&#243;xicos, em particular as antraciclinas, al&#233;m de eventual doen&#231;a card&#237;aca pr&#233;via. <xref ref-type="bibr" rid="B34"><sup>34</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B234"><sup>234</sup></xref> A radia&#231;&#227;o leva &#224; fibrose mioc&#225;rdica intersticial difusa, especialmente da parede anterior do VE, relacionada &#224; &#225;rea irradiada, cuja manifesta&#231;&#227;o cl&#237;nica ser&#225; expressa como cardiomiopatia restritiva. Diante da dificuldade de avalia&#231;&#227;o da fun&#231;&#227;o diast&#243;lica em crian&#231;as, os valores encontrados devem ser comparados com os valores basais do pr&#243;prio paciente. O dano endotelial favorece o desenvolvimento precoce de placas ateroscler&#243;ticas complicadas por hemorragia e inflama&#231;&#227;o com riscos de ruptura e trombose. O peric&#225;rdio &#233; o principal alvo de les&#227;ousualmente iniciada por pericardite fibrinosa e derrame peric&#225;rdico, seguidos por espessamento fibroso preferencialmente no peric&#225;rdio parietal e VD, podendo estender-se ao mediastino. O comprometimento valvar &#233; menos frequente e, ao contr&#225;rio do que ocorre no peric&#225;rdio, atinge mais o lado esquerdo do cora&#231;&#227;o. As c&#250;spides tornam-se espessadas, podem calcificar e levar &#224; insufici&#234;ncia e estenose, principalmente das valvas mitral e a&#243;rtica, poupando as pontas das c&#250;spides e a regi&#227;o das comissuras valvares. <xref ref-type="bibr" rid="B244"><sup>244</sup></xref> </p>
        <p>Os sobreviventes ao tratamento do c&#226;ncer na fase infantojuvenil s&#227;o mais vulner&#225;veis ao desenvolvimento de DAC prematura, inclusive subcl&#237;nica, com risco de infarto do mioc&#225;rdio 2 a 8 vezes maior que a popula&#231;&#227;o geral. Como os eventos coronarianos s&#227;o raros em pacientes mais jovens, mesmo naqueles em risco aumentado, o ecocardiograma com estresse farmacol&#243;gico e exames de imagem nuclear para avalia&#231;&#227;o da perfus&#227;o e viabilidade mioc&#225;rdicas est&#227;o recomendados. <xref ref-type="bibr" rid="B245"><sup>245</sup></xref> </p>
        <p>Os controles tardios em indiv&#237;duos sem disfun&#231;&#227;o ventricular devem ser realizados de rotina ap&#243;s 6 meses a 1 ano e, depois, periodicamente, uma vez que a incid&#234;ncia de insufici&#234;ncia card&#237;aca relacionada ao uso de antraciclina, assim como ap&#243;s RT, aumenta com o acompanhamento tardio, podendo surgir depois de 15 anos ou mais.Embora a frequ&#234;ncia ideal para avalia&#231;&#227;o da estrutura e fun&#231;&#227;o do VE em sobreviventes expostos &#224; radia&#231;&#227;o card&#237;aca n&#227;o esteja ainda bem estabelecida entre os consensos, quanto maior o n&#250;mero defatores de risco, mais frequentes essas avalia&#231;&#245;es dever&#227;o ser realizadas. <xref ref-type="bibr" rid="B246"><sup>246</sup></xref> </p>
      </sec>
      <sec>
        <title>8.5. Gravidez nas Sobreviventes do C&#226;ncer Infantojuvenil</title>
        <p>Com os avan&#231;os no tratamento oncol&#243;gico e o not&#225;vel n&#250;mero de sobreviventes do c&#226;ncer infantojuvenil, um grande n&#250;mero de mulheres atinge a idade f&#233;rtil e muitas optar&#227;o por engravidar. Algumas s&#227;o portadoras de les&#245;es subcl&#237;nicas n&#227;o diagnosticadas e outras se encontram na vig&#234;ncia de tratamento para insufici&#234;ncia card&#237;aca ou outras complica&#231;&#245;es tardias do tratamento antineopl&#225;sico. A gravidez est&#225; associada a mudan&#231;as substanciais no sistema cardiovascular, uma vez que existe um aumento da demanda metab&#243;lica no cora&#231;&#227;o da gestante. Aumentos marcantes no volume sangu&#237;neo circulante contribuem para um incremento de 30% a 40% no d&#233;bito card&#237;aco em um per&#237;odo relativamente precoce da gesta&#231;&#227;o (20 a 24 semanas), altera&#231;&#245;es que influenciam na interpreta&#231;&#227;o do <italic>status</italic> cardiovascular. Como consequ&#234;ncia, h&#225; taquicardia e anemia relativa, al&#233;m de fen&#244;menos de hipercoagulabilidade.O risco de desenvolvimento de eventos card&#237;acos durante a gravidez de mulheres previamente expostas a antraciclinas e/ou RT tor&#225;cica na inf&#226;ncia n&#227;o &#233; claramente conhecido, com poucos dados dispon&#237;veis na literatura. <xref ref-type="bibr" rid="B247"><sup>247</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B248"><sup>248</sup></xref> </p>
        <p>Regurgita&#231;&#245;es multivalvulares fisiol&#243;gicas, especialmente nas c&#226;maras direitas, por aumento volum&#233;trico das c&#226;maras card&#237;acas, dilata&#231;&#227;o dos an&#233;is valvares, bem como derrame peric&#225;rdico discreto, s&#227;o frequentes no final da gesta&#231;&#227;o e no per&#237;odo p&#243;s-parto, e parecem ser causados por hipervolemia decorrente desse per&#237;odo.</p>
        <p>A <xref ref-type="table" rid="t10">Tabela 9</xref> relaciona as altera&#231;&#245;es cardiovasculares fisiol&#243;gicas maternas de acordo com o trimestre da gesta&#231;&#227;o.</p>
        <table-wrap id="t10">
          <label>Tabela 9</label>
          <caption>
            <title>Mudan&#231;as ecocardiogr&#225;ficas fisiol&#243;gicas durante a gravidez</title>
          </caption>
          <table frame="hsides" rules="rows">
            <colgroup width="12%">
              <col/>
              <col/>
              <col/>
              <col/>
              <col/>
              <col/>
              <col/>
              <col/>
            </colgroup>
            <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
              <tr>
                <th align="center" colspan="2" style="border-right: thin solid; border-color: #000000" valign="middle">1&#176; Trimestre</th>
                <th align="center" colspan="2" style="border-right: thin solid; border-color: #000000" valign="middle">2&#176; Trimestre</th>
                <th align="center" colspan="2" style="border-right: thin solid; border-color: #000000" valign="middle">3&#176; Trimestre</th>
                <th align="center" colspan="2" valign="middle">P&#243;s-parto</th>
              </tr>
            </thead>
            <tbody style="border-bottom: thin solid; border-color: #000000">
              <tr>
                <td align="center" valign="middle">&#8595;</td>
                <td align="center" style="border-right: thin solid; border-color: #000000" valign="middle">RVS</td>
                <td align="center" valign="middle">&#8595;</td>
                <td align="center" style="border-right: thin solid; border-color: #000000" valign="middle">RVS</td>
                <td align="center" valign="middle">&#8595;</td>
                <td align="center" style="border-right: thin solid; border-color: #000000" valign="middle">RVS <break/> SLG</td>
                <td align="center" valign="middle">&#8595;</td>
                <td align="center" valign="middle">FC <break/> DDVE <break/> Massa VE <break/> DC</td>
              </tr>
              <tr>
                <td align="center" valign="middle">&#8593;</td>
                <td align="center" style="border-right: thin solid; border-color: #000000" valign="middle">FC <break/> DDVE <break/> Massa VE <break/> DC</td>
                <td align="center" valign="middle">&#8593;</td>
                <td align="center" style="border-right: thin solid; border-color: #000000" valign="middle">FC <break/> DDVE <break/> Massa VE <break/> DC</td>
                <td align="center" valign="middle">&#8593;</td>
                <td align="center" style="border-right: thin solid; border-color: #000000" valign="middle">FC <break/> DDVE <break/> Massa VE <break/> DC</td>
                <td align="center" valign="middle">&#8593;</td>
                <td align="center" valign="middle">RVS <break/> SLG</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="TFN4">
              <p>RVS:resist&#234;ncia vascular sist&#234;mica; FC: frequ&#234;ncia card&#237;aca; DDVE: di&#226;metro diast&#243;lico do VE; VE: ventr&#237;culo esquerdo; SLG: <italic>strain</italic> longitudinal global; DC: d&#233;bito card&#237;aco; &#8593; = aumenta;&#8595; = diminui.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
        <sec>
          <title>8.5.1. Desfechos Card&#237;acos em Gestantes Sobreviventes do C&#226;ncer Infantojuvenil</title>
          <p>Alguns estudos cl&#237;nicos avaliaram desfechos card&#237;acos durante a gravidez em mulheres previamente expostas &#224; terapia oncol&#243;gica cardiot&#243;xica.</p>
          <p>Van Dalen et al. <xref ref-type="bibr" rid="B247"><sup>247</sup></xref> avaliaram, retrospectivamente,53 mulheres sobreviventes ao c&#226;ncer infantojuvenil que tiveram um ou mais filhos. Dados da fun&#231;&#227;o sist&#243;lica ventricular esquerda e outros par&#226;metros ecocardiogr&#225;ficos n&#227;o estavam dispon&#237;veis para an&#225;lise. O diagn&#243;stico de insufici&#234;ncia card&#237;aca foi definido com base em sinais e sintomas. Nenhuma paciente desenvolveu insufici&#234;ncia card&#237;aca durante a gravidez ou nos 5 meses ap&#243;s o parto. <xref ref-type="bibr" rid="B247"><sup>247</sup></xref> </p>
          <p>Hines et al. <xref ref-type="bibr" rid="B248"><sup>248</sup></xref> aplicaram um question&#225;rio a 847 mulheres sobreviventes ao c&#226;ncer infantojuvenil que tiveram pelo menos uma gravidez completa. Os autores constataram que a maioria das mulheres sobreviventes ao c&#226;ncer infantojuvenil n&#227;o apresentoucomplica&#231;&#245;es card&#237;acas durante ou ap&#243;s o parto; no entanto, gestantes com hist&#243;rico de terapias cardiot&#243;xicas devem ser seguidas cuidadosamente durante a gravidez, principalmente aquelas com hist&#243;rico de exposi&#231;&#245;es &#224; antraciclina e queforamdiagnosticadas com cardiomiopatia subcl&#237;nica ou sintom&#225;tica anterior ou atual. <xref ref-type="bibr" rid="B248"><sup>248</sup></xref> </p>
          <p>Em outro estudo, 37 mulheres que receberam doxorrubicina como parte de um protocolo de QT para um dist&#250;rbio neopl&#225;sico na inf&#226;ncia foram acompanhadas no mesmo centro durante as gravidezes (72 gesta&#231;&#245;es) e ap&#243;s o parto.Os autores conclu&#237;ram que o resultado da gravidez em mulheres que receberam doxorrubicina por malignidade na inf&#226;ncia &#233; geralmente favor&#225;vel. No entanto, aquelas com disfun&#231;&#227;o ventricular esquerda antes da gesta&#231;&#227;o devem ser consideradas com risco aumentado para pior resultado na gravidez e deteriora&#231;&#227;o adicional da fun&#231;&#227;o mioc&#225;rdica. <xref ref-type="bibr" rid="B249"><sup>249</sup></xref> </p>
          <p>Thompson et al. <xref ref-type="bibr" rid="B250"><sup>250</sup></xref> avaliaram uma coorte de 58 mulheres que foram tratadas com antraciclinas e/ou radia&#231;&#227;o tor&#225;cica antes dos 20 anos de idade, no <italic>MD Anderson Cancer Center</italic> . A incid&#234;ncia de eventos card&#237;acos adversos (definidos como FEVE &lt; 50% em pelo menos dois ecocardiogramas ou DAC) foi significativamente maior nas mulheres que tiveram pelo menos uma gravidez (29%) em compara&#231;&#227;o com um grupo controle de nul&#237;paras pareadas por dose de antraciclina e per&#237;odo de acompanhamento (15%), p &lt; 0,05. Dentre as 58 mulheres gr&#225;vidas, nove foram diagnosticadas com doen&#231;a cardiovascular durante a gravidez e cinco foram diagnosticadas posteriormente &#224; gravidez. Nessa pequena coorte, o intervalo entre a exposi&#231;&#227;o &#224;s antraciclinas at&#233; a primeira gravidez, bem como a dose total de antraciclinas, esteve associado a um risco aumentado de eventos card&#237;acos adversos. Al&#233;m disso, a pr&#243;pria gravidez esteva associada a um aumento de 2,4 vezes no risco de desenvolvimento de eventos card&#237;acos adversos (IC 95%:1,02-5,41, p = 0,045). <xref ref-type="bibr" rid="B250"><sup>250</sup></xref> </p>
        </sec>
        <sec>
          <title>8.5.2. Recomenda&#231;&#227;o de Monitoramento Cardiovascular em Sobreviventes do C&#226;ncer Infantojuvenil com Desejo de Gestar</title>
          <p>Estudos em popula&#231;&#245;es n&#227;o oncol&#243;gicas com cardiomiopatias preexistentes relataram um alto risco de descompensa&#231;&#227;o card&#237;aca devido &#224;s mudan&#231;as na fisiologia card&#237;aca durante a gravidez.A gravidez n&#227;o est&#225; recomendada em portadoras de cardiomiopatias com FEVE &lt; 40%. <xref ref-type="bibr" rid="B251"><sup>251</sup></xref> </p>
          <p>Em sobreviventes do c&#226;ncer infantojuvenil, existem evid&#234;ncias limitadas sobre monitoramento card&#237;aco na gravidez. Diretrizes internacionais recomendam uma avalia&#231;&#227;o cardiovascular antes da gravidez e no primeiro trimestre para todas as mulheres que foram tratadas durante a inf&#226;ncia com antraciclinas e/ou RT tor&#225;cica. <italic>Children&#8217;s Oncology Group</italic> recomenda a realiza&#231;&#227;o de um ecocardiograma antes e periodicamente durante a gravidez (especialmente durante o terceiro trimestre), al&#233;m do monitoramento card&#237;aco durante o trabalho de parto e parto em pacientes que receberam doses de antraciclinas&gt; 300 mg/m<sup>2</sup>, doses de radia&#231;&#227;o tor&#225;cica &gt; 30 Gy, e que receberam ambos tratamentos oncol&#243;gicos, antraciclinas e RT tor&#225;cica. <xref ref-type="bibr" rid="B246"><sup>246</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B251"><sup>251</sup></xref> </p>
          <p>Recomenda-se ent&#227;o:</p>
          <list list-type="bullet">
            <list-item>
              <p>Avalia&#231;&#227;o da fun&#231;&#227;o card&#237;aca pelo ecocardiograma antes da gravidez e, periodicamente, a cada trimestre, em mulheres que foram tratadas com antraciclinas (principalmente em doses &gt; 300mg/m<sup>2</sup>) e/ou RT tor&#225;cica (especialmente em doses &gt; 30 Gy) com FEVE pr&#233;via &#8805; 50%;</p>
            </list-item>
            <list-item>
              <p>Avalia&#231;&#227;o da fun&#231;&#227;o card&#237;aca pelo ecocardiograma antes da gravidez e no &#250;ltimo trimestre de gesta&#231;&#227;o, ou quando indica&#231;&#227;o cl&#237;nica, em mulheres que foram tratadas com antraciclinas (doses &lt; 300mg/m<sup>2</sup>) e/ou RT tor&#225;cica (doses &lt; 30 Gy) com FEVE pr&#233;via &#8805; 50%;</p>
            </list-item>
            <list-item>
              <p>Avalia&#231;&#227;o da fun&#231;&#227;o card&#237;aca pelo ecocardiograma antes da gravidez e, periodicamente, a cada trimestre, ou quando indica&#231;&#227;o cl&#237;nica, al&#233;m de monitoramento card&#237;aco durante o trabalho de parto e parto em mulheres com FEVE entre 40 e 50%. Considerar a repeti&#231;&#227;o do ecocardiograma um m&#234;s ap&#243;s o parto;</p>
            </list-item>
            <list-item>
              <p>Gravidez n&#227;o &#233; recomend&#225;vel em pacientes com FEVE &lt; 40%.</p>
            </list-item>
          </list>
        </sec>
      </sec>
      <sec>
        <title>8.6. Situa&#231;&#245;es Predisponentes a Eventos Tromb&#243;ticos Relacionados ao Tratamento de C&#226;ncer Infantojuvenil</title>
        <sec>
          <title>8.6.1. Trombo Intracard&#237;aco</title>
          <p>Grande parte do tratamento quimioter&#225;pico dos pacientes com c&#226;ncer infantojuvenil &#233; realizada por via endovenosa atrav&#233;s de cateteres de longa perman&#234;ncia, aumentando o risco para forma&#231;&#227;o de trombos ou vegeta&#231;&#245;es. Al&#233;m disso, as propriedades pr&#243;-coagulantes das c&#233;lulas tumorais facilitam a invas&#227;o tumoral e as met&#225;stases. <xref ref-type="bibr" rid="B252"><sup>252</sup></xref> </p>
          <p>Na popula&#231;&#227;o pedi&#225;trica, a incid&#234;ncia m&#233;dia de eventos tromb&#243;ticos (ET) associados ao c&#226;ncer &#233; de 8%, com maior frequ&#234;ncia nasleucemias linfobl&#225;sticas agudas (LLA), seguida porsarcomas, linfomas, leucemia mieloide aguda (LMA), tumor de Wilms, neuroblastomas e tumor de sistema nervoso central.Entre as leucemias, a ocorr&#234;ncia pode atingir 36,7%; linfomas (devido &#224; compress&#227;o extr&#237;nseca de massa no mediastino), tumores s&#243;lidos e tumores do sistema nervoso central, at&#233; 16%; dentre os sarcomas, o de Ewing &#233; o que mais apresenta riscos para ET, seguido porrabdomiossarcoma e osteossarcoma. <xref ref-type="bibr" rid="B253"><sup>253</sup></xref> </p>
          <p>V&#225;rias condi&#231;&#245;es cl&#237;nicas s&#227;o relacionadas &#224; etiologia dos ET em crian&#231;as e adolescentes: cirurgias recentes, doen&#231;a card&#237;aca cong&#234;nita, imobiliza&#231;&#227;o, trauma, s&#237;ndrome nefr&#243;tica, uso de contraceptivos orais, trombofilia cong&#234;nita e presen&#231;a de cateter venoso central (CVC), que &#233; o fator predisponente isolado mais importante. <xref ref-type="bibr" rid="B252"><sup>252</sup></xref> A L-asparaginase, utilizada em protocolos de leucemia linfobl&#225;stica aguda (LLA), pode suprimir anticoagulantes naturais, particularmente antitrombina e plasminog&#234;nio. Uso de corticosteroide pode levar &#224; ativa&#231;&#227;o do complexo FVIII-von Willebrande &#224; ativa&#231;&#227;o do inibidor plasminog&#234;nio (PAI-1). A combina&#231;&#227;o de L-asparaginase e corticosteroide&#233; um fator de alto risco para o desenvolvimento de ET, principalmente na fase de indu&#231;&#227;o, em queocorre uma redu&#231;&#227;o da capacidade de inibir a trombina. <xref ref-type="bibr" rid="B253"><sup>253</sup></xref> </p>
          <p>O tromboembolismo pulmonar &#233; bem menos relatado entre crian&#231;as e adolescentes, quando comparados aos adultos. Em estudo canadense, foi demonstrada a incid&#234;ncia de 0,86 por 10.000 admiss&#245;es hospitalares; por&#233;m, h&#225; escassez de registros de seguimento alongo prazo. <xref ref-type="bibr" rid="B254"><sup>254</sup></xref> </p>
          <p>As caracter&#237;sticas gen&#233;ticas do hospedeiro tamb&#233;m influenciam na maior vulnerabilidade aos ET. A defici&#234;ncia de anticoagulantes naturais como antitrombina, prote&#237;na C e prote&#237;na S &#233;o fator gen&#233;tico mais frequentemente relacionado comET na popula&#231;&#227;o pedi&#225;trica. <xref ref-type="bibr" rid="B252"><sup>252</sup></xref> </p>
          <p>O ecocardiograma transtor&#225;cico (ETT) &#233; uma importante ferramenta para a pesquisa de trombos e vegeta&#231;&#245;es intracard&#237;acas, complementado pela ecocardiografia transesof&#225;gica (ETE), que apresenta maior sensibilidade. O uso de contraste de microbolhas pode ajudar a detectar trombos e diferenciar trombo avascular de tumores vascularizados. Os trombos intracard&#237;acos s&#227;o caracterizados por terem aspecto hiperecog&#234;nico e bordas geralmente regulares. A resson&#226;ncia magn&#233;tica e a angiotomografia podem ser adjuvantes para elucida&#231;&#227;o diagn&#243;stica; mesmo assim, pode ser dif&#237;cil diferenciar trombos de outros tumores card&#237;acos. O diagn&#243;stico de trombo intracard&#237;aco &#233; fruto da combina&#231;&#227;o da apresenta&#231;&#227;o da imagem, localiza&#231;&#227;o e quadro cl&#237;nico. Em casos incertos, o diagn&#243;stico &#233; frequentemente realizado ap&#243;s um ciclo de anticoagula&#231;&#227;o e reavalia&#231;&#227;o pelo m&#233;todo de imagem. <xref ref-type="bibr" rid="B255"><sup>255</sup></xref> </p>
        </sec>
        <sec>
          <title>8.6.2. Cateter Venoso Central</title>
          <p>Estima-se que, nos EUA, mais de 5 milh&#245;es de cateteres venosos centrais (CVC) sejam implantados anualmente. Crian&#231;as com c&#226;ncer requerem administra&#231;&#227;o endovenosa de quimioter&#225;picos por per&#237;odo consider&#225;vel de tempo. O uso de CVC ap&#243;s a d&#233;cada de 80 melhorou a qualidade de vida desses pacientes, por&#233;m o uso est&#225; associado a complica&#231;&#245;es mec&#226;nicas, infecciosas e tromb&#243;ticas. A incid&#234;ncia de TRC em pacientes oncol&#243;gicos pedi&#225;tricos relatada nos &#250;ltimos anos variou de 4,6% a 7%. <xref ref-type="bibr" rid="B252"><sup>252</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B256"><sup>256</sup></xref> </p>
          <p>O ecocardiograma tem papel fundamental na avalia&#231;&#227;o deste dispositivo. A ponta do cateter deve estar idealmente localizada na veia cava superior pr&#243;ximo &#224; jun&#231;&#227;o com o &#225;trio direito para evitar arritmias e forma&#231;&#227;o de trombos. Deve-se avaliar todo o trajeto venoso vis&#237;vel, bem como o comportamento do fluxo pr&#243;ximo ao dispositivo, nas cavidades card&#237;acas e nas valvas. <xref ref-type="bibr" rid="B256"><sup>256</sup></xref> </p>
        </sec>
        <sec>
          <title>8.6.3. Diagn&#243;stico Diferencial de Massa Intracard&#237;aca</title>
          <sec>
            <title>8.6.3.1. Crista Terminalis Proeminente</title>
            <p>A <italic>crista terminalis</italic> &#233; um tecido fibromuscular que demarca os limites do seio venoso embriol&#243;gico e a parede muscular do &#225;trio direito. Quando proeminente, pode ser equivocadamente diagnosticada como uma massa intracard&#237;aca. Ao ecocardiograma, apresenta-se como uma imagem hiperecog&#234;nica na por&#231;&#227;o posterolateral do &#225;trio direito. Seu conhecimento evita o diagn&#243;stico incorreto de trombo intracard&#237;aco.</p>
          </sec>
          <sec>
            <title>8.6.3.2. Calcifica&#231;&#227;o do Anel Mitral</title>
            <p>A calcifica&#231;&#227;o do anel mitral (CAM) &#233; a deposi&#231;&#227;o de c&#225;lcio e de gordura ao longo do anel fibroso, mais comumente na por&#231;&#227;o posterior do anel valvar mitral, com aspecto hiperecog&#234;nico. Pode ser base para forma&#231;&#227;o de trombos ou vegeta&#231;&#245;es e apresentar componentes m&#243;veis calcificados com potencial para emboliza&#231;&#227;o.</p>
          </sec>
          <sec>
            <title>8.6.3.3. Endocardite Infecciosa</title>
            <p>Em pacientes em tratamento de c&#226;ncer, com hemocultura positiva, deve-se suspeitar do diagn&#243;stico de endocardite infecciosa (EI), visto que esses doentes t&#234;malto risco para infec&#231;&#245;es hospitalares pelo n&#250;mero de interna&#231;&#245;es e pela imunossupress&#227;o. O ETT &#233; mandat&#243;rio nesses casos. A investiga&#231;&#227;o inclui as valvas card&#237;acas em busca de sinais de vegeta&#231;&#227;o, abscessos ou f&#237;stulas card&#237;acas, presen&#231;a de nova regurgita&#231;&#227;o valvar, al&#233;m da apar&#234;ncia dos dispositivos endovenosos de longa perman&#234;ncia. A especificidade para o diagn&#243;stico de vegeta&#231;&#227;o endoc&#225;rdica atrav&#233;s do ETT &#233; superior a 90%, por&#233;m a sensibilidade varia de 62% a 79%, vistoque imagens menores que 2 a 3mm podem n&#227;o ser visibilizadas. O ETE possui tamb&#233;m especificidade superior a 90%; contudo, temsensibilidade maior para o diagn&#243;stico de EI (&gt; 80% a 90%).</p>
            <p>As vegeta&#231;&#245;es endoc&#225;rdicas t&#234;m como caracter&#237;sticas o formato bastante irregular, movimento ca&#243;tico que independe do movimento valvar, localizam-se habitualmente no lado atrial das valvas atrioventriculares e no lado ventricular das valvas semilunares e associam-se &#224; destrui&#231;&#227;o do aparato valvar, levando &#224; regurgita&#231;&#227;o ou abscesso valvar. Os abscessos valvares acometem mais comumente a valva a&#243;rtica e podem fistulizar para o VE ou para o &#225;trio. H&#225; risco aumentado para acidente vascular encef&#225;lico (AVE) e IAM nos pacientes diagnosticados com EI. Os principais agentes respons&#225;veis pelos AVE s&#227;o as vegeta&#231;&#245;es endoc&#225;rdicas com dimens&#245;es maiores que 10 a 15mm, que acometem mais de uma valva, t&#234;mmobilidade excessiva, hemocultura positiva para fungo, <italic>S. aureus</italic> e <italic>S. bovis</italic> .</p>
          </sec>
          <sec>
            <title>8.6.3.4. Endocardite Tromb&#243;tica N&#227;o Bacteriana</title>
            <p><bold>Libman-Sacks:</bold> composta por material granular com imunocomplexos e plaquetas, sem bact&#233;rias; geralmente tem dimens&#245;es pequenas (1 a 4 mm), localiza-se nos mesmos locais que a endocardite, por&#233;m &#233; usualmente menos irregular e mais bem delimitada e n&#227;o est&#225; associada &#224; destrui&#231;&#227;o valvar. S&#227;o les&#245;es, habitualmente, assintom&#225;ticas e mais comuns em pacientes com diagn&#243;stico de l&#250;pus.</p>
            <p><bold>Endocardite mar&#226;ntica:</bold> a endocardite mar&#226;ntica &#233; um tipo de endocardite n&#227;o infecciosa associada &#224; malignidade relacionada com carcinomas s&#243;lidos metast&#225;ticos e adenocarcinomas de pulm&#227;o, p&#226;ncreas, g&#225;strico e outros adenocarcinomas. H&#225; descri&#231;&#245;es de associa&#231;&#227;o com s&#237;ndromes mielodispl&#225;sicas. As vegeta&#231;&#245;es mar&#226;nticas s&#227;o compostas por fibrina e plaquetas e raramente leva &#224; disfun&#231;&#227;o valvar; classicamente, afeta a face atrial da valva mitral e a face ventricular da valva a&#243;rtica. Pode embolizar em mais de 50% dos casos. A ecotextura, as dimens&#245;es e a localiza&#231;&#227;o n&#227;o s&#227;o diferentes da EI. No entanto, observa-se frequentemente espessamento valvar difuso significativo, o que pode ajudar no diagn&#243;stico.</p>
          </sec>
          <sec>
            <title>8.6.3.5. Excresc&#234;ncia de Lambl</title>
            <p>A excresc&#234;ncia de Lambl pode ser definida como estrutura filiforme, menor que 2 mm de largura e 3 a 10mm de comprimento, com movimento ondulante localizado na face atrial da valva mitral e na face ventricular da valva a&#243;rtica. N&#227;o est&#225; associada a eventos tromboemb&#243;licos.</p>
          </sec>
        </sec>
      </sec>
      <sec>
        <title>8.6. Avalia&#231;&#227;o Cardiovascular Diante do Transplante de Medula &#211;ssea em Pacientes Infantojuvenis</title>
        <p>O transplante de medula &#243;ssea (TMO), ou transplante de c&#233;lulas-tronco hematopoi&#233;ticas, seja do tipo aut&#243;logo ou do tipo alog&#234;nico, tem participa&#231;&#227;o importante no tratamento de diversas neoplasias na inf&#226;ncia e adolesc&#234;ncia. As mais frequentes s&#227;o as leucemias, alguns tumores s&#243;lidos, aplasia de medula &#243;ssea, imunodefici&#234;ncias, al&#233;m de algumas doen&#231;as heredit&#225;rias que acometem o sistema hematopoi&#233;tico.</p>
        <p>Os transplantes aut&#243;logos s&#227;o, em geral, menos pass&#237;veis de complica&#231;&#245;es cardiovasculares, diferentemente dos alog&#234;nicos. A incid&#234;ncia de complica&#231;&#245;es cardiovasculares aumenta de acordo com o tempo de cura desses pacientes, podendo atingir at&#233; 17% a partir de 15 anos ap&#243;s o tratamento. Os sobreviventes de TMO apresentam 13 vezes mais risco de complica&#231;&#245;es cardiovasculares quando comparados aos seus irm&#227;os. <xref ref-type="bibr" rid="B257"><sup>257</sup></xref> </p>
        <p>Fatores que favorecem a toxicidade cardiovascular ap&#243;s o TMO:</p>
        <list list-type="bullet">
          <list-item>
            <p>Idade ao TMO;</p>
          </list-item>
          <list-item>
            <p>QTcardiot&#243;xica anterior (p. ex., antraciclinas);</p>
          </list-item>
          <list-item>
            <p>Regime de condicionamento mieloablativo (p. ex., ciclofosfamida);</p>
          </list-item>
          <list-item>
            <p>Irradia&#231;&#227;o tor&#225;cica pr&#233;via;</p>
          </list-item>
          <list-item>
            <p>Irradia&#231;&#227;o corporal total ( <italic>total body irradiation</italic> [TBI]);</p>
          </list-item>
          <list-item>
            <p>Tipo de transplante;</p>
          </list-item>
          <list-item>
            <p>Presen&#231;a de doen&#231;a do enxerto contra o hospedeiro (DECH);</p>
          </list-item>
          <list-item>
            <p>Comorbidades (hipertens&#227;o arterial, DM, dislipidemia, tabaco, obesidade).</p>
          </list-item>
        </list>
        <p>A DECH &#233; a complica&#231;&#227;o mais frequentemente relacionada ao TMO alog&#234;nico e requer avalia&#231;&#245;es regulares atrav&#233;s dos m&#233;todos de imagem cardiovascular. Ela desencadeia rea&#231;&#245;es imunol&#243;gicas que levam ao dano endotelial e processos inflamat&#243;rios cr&#244;nicos, acomete v&#225;rios &#243;rg&#227;os, inclusive os pulm&#245;es, podendo simular quadro de hipertens&#227;o arterial pulmonar. Favorece o desenvolvimento de vasculite, aterosclerose precoce, hipertens&#227;o arterial sist&#234;mica, doen&#231;as cerebrovasculares, angina e IAM. <xref ref-type="bibr" rid="B258"><sup>258</sup></xref> O uso prolongado de corticosteroide e de outros imunossupressores no tratamento da DECH acelera esses eventos, e a presen&#231;a de fatores de riscos cardiovasculares convencionais contribuicom o surgimento dessas complica&#231;&#245;es. O comprometimento card&#237;aco isolado da DECH &#233; raro e pode se apresentar na forma de pericardite, arritmias e DAC. <xref ref-type="bibr" rid="B257"><sup>257</sup></xref> </p>
        <p>Outro fator a ser considerado &#233; o dep&#243;sito de ferro no mioc&#225;rdio, decorrente das m&#250;ltiplas transfus&#245;es sangu&#237;neas, que pode persistir por anos ap&#243;s o TMO e usualmente &#233; avaliadopor meiode resson&#226;ncia magn&#233;tica card&#237;aca e hep&#225;tica. <xref ref-type="bibr" rid="B259"><sup>259</sup></xref> </p>
        <p>Os sobreviventes de TMO tratados com antraciclinas e/ou irradia&#231;&#227;o tor&#225;cica devem ser examinados anualmente, em busca desinais de complica&#231;&#245;es cardiovasculares. A fun&#231;&#227;o card&#237;aca (sist&#243;lica e diast&#243;lica) dever&#225; ser avaliada por meioda ecocardiografia, anualmente ou a cada 5 anos, dependendo das doses e da idade a que foram submetidos. Devem ser orientados, preventivamente, quanto aos fatores de risco cardiovasculares modific&#225;veis (hipertens&#227;o arterial, DM, dislipidemia, tabagismo).</p>
      </sec>
    </sec>
  </body>
  <back>
    <fn-group>
      <fn fn-type="other" id="fn1">
        <p><bold>Realiza&#231;&#227;o:</bold> Departamento de Imagem Cardiovascular (DIC) da Sociedade Brasileira de Cardiologia (SBC) e endossado pela Sociedad Interamericanana de Im&#225;genes Cardiovasculares (SiSIAC) da Sociedad Interamericana de Cardiolog&#237;a (SIAC)</p>
      </fn>
      <fn fn-type="other" id="fn2">
        <p><bold>Conselho de Normatiza&#231;&#245;es e Diretrizes (2020-2021):</bold> Brivaldo Markman Filho, Antonio Carlos Sobral Sousa, Aurora Felice Castro Issa, Bruno Ramos Nascimento, Harry Correa Filho, Marcelo Luiz Campos Vieira</p>
      </fn>
      <fn fn-type="other" id="fn3">
        <p><bold>Coordenador de Normatiza&#231;&#245;es e Diretrizes (2020-2021):</bold> Brivaldo Markman Filho</p>
      </fn>
      <fn fn-type="other" id="fn4">
        <p><bold>Nota:</bold> Estes posicionamentos se prestam a informar e n&#227;o a substituir o julgamento cl&#237;nico do m&#233;dico que, em &#250;ltima an&#225;lise, deve determinar o tratamento apropriado para seus pacientes.</p>
      </fn>
    </fn-group>
    <glossary>
      <title>Lista de Abreviaturas</title>
      <def-list>
        <def-item>
          <term id="G1"><xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG</term>
          <def>
            <p><xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-Fluordesoxiglicose</p>
          </def>
        </def-item>
        <def-item>
          <term id="G2">APBI</term>
          <def>
            <p>Accelerated partial-breast irradiation</p>
          </def>
        </def-item>
        <def-item>
          <term id="G3">AVE</term>
          <def>
            <p>Acidente vascular encef&#225;lico</p>
          </def>
        </def-item>
        <def-item>
          <term id="G4">AC</term>
          <def>
            <p>Amiloidose card&#237;aca</p>
          </def>
        </def-item>
        <def-item>
          <term id="G5">AL</term>
          <def>
            <p>Amiloidose de cadeia leve</p>
          </def>
        </def-item>
        <def-item>
          <term id="G6">ATTr</term>
          <def>
            <p>Amiloidose transtirretina</p>
          </def>
        </def-item>
        <def-item>
          <term id="G7">ACD</term>
          <def>
            <p>Art&#233;ria coron&#225;ria direita</p>
          </def>
        </def-item>
        <def-item>
          <term id="G8">ADA</term>
          <def>
            <p>Art&#233;ria descendente anterior</p>
          </def>
        </def-item>
        <def-item>
          <term id="G9">AIT</term>
          <def>
            <p>Ataque isqu&#234;mico transit&#243;rio</p>
          </def>
        </def-item>
        <def-item>
          <term id="G10">CTX</term>
          <def>
            <p>Cardiotoxicidade</p>
          </def>
        </def-item>
        <def-item>
          <term id="G11">DM</term>
          <def>
            <p>Diabetes melito</p>
          </def>
        </def-item>
        <def-item>
          <term id="G12">DAC</term>
          <def>
            <p>Doen&#231;a arterial coronariana</p>
          </def>
        </def-item>
        <def-item>
          <term id="G13">DACIR</term>
          <def>
            <p>Doen&#231;a arterial coronariana induzida por radia&#231;&#227;o</p>
          </def>
        </def-item>
        <def-item>
          <term id="G14">DCC</term>
          <def>
            <p>Doen&#231;a card&#237;aca carcinoide</p>
          </def>
        </def-item>
        <def-item>
          <term id="G15">DCIR</term>
          <def>
            <p>Doen&#231;a card&#237;aca induzida por radia&#231;&#227;o</p>
          </def>
        </def-item>
        <def-item>
          <term id="G16">DCV</term>
          <def>
            <p>Doen&#231;a cardiovascular</p>
          </def>
        </def-item>
        <def-item>
          <term id="G17">DECH</term>
          <def>
            <p>Doen&#231;a do enxerto contra o hospedeiro</p>
          </def>
        </def-item>
        <def-item>
          <term id="G18">DVIR</term>
          <def>
            <p>Doen&#231;a valvular induzida por radia&#231;&#227;o</p>
          </def>
        </def-item>
        <def-item>
          <term id="G19">DVP</term>
          <def>
            <p>Doen&#231;a vascular perif&#233;rica</p>
          </def>
        </def-item>
        <def-item>
          <term id="G20">ETE</term>
          <def>
            <p>Ecocardiograma transesof&#225;gico</p>
          </def>
        </def-item>
        <def-item>
          <term id="G21">ETT</term>
          <def>
            <p>Ecocardiograma transtor&#225;cico</p>
          </def>
        </def-item>
        <def-item>
          <term id="G22">ECA</term>
          <def>
            <p>Endarterectomia de car&#243;tida</p>
          </def>
        </def-item>
        <def-item>
          <term id="G23">EI</term>
          <def>
            <p>Endocardite infecciosa</p>
          </def>
        </def-item>
        <def-item>
          <term id="G24">EMI</term>
          <def>
            <p>Espessura mediointimal</p>
          </def>
        </def-item>
        <def-item>
          <term id="G25">ET</term>
          <def>
            <p>Eventos tromb&#243;ticos</p>
          </def>
        </def-item>
        <def-item>
          <term id="G26">FEVE</term>
          <def>
            <p>Fra&#231;&#227;o de eje&#231;&#227;o do ventr&#237;culo esquerdo</p>
          </def>
        </def-item>
        <def-item>
          <term id="G27">HAS</term>
          <def>
            <p>Hipertens&#227;o arterial sist&#234;mica</p>
          </def>
        </def-item>
        <def-item>
          <term id="G28">HP</term>
          <def>
            <p>Hipertens&#227;o pulmonar</p>
          </def>
        </def-item>
        <def-item>
          <term id="G29">IAM</term>
          <def>
            <p>Infarto agudo do mioc&#225;rdio</p>
          </def>
        </def-item>
        <def-item>
          <term id="G30">IC</term>
          <def>
            <p>Insufici&#234;ncia card&#237;aca</p>
          </def>
        </def-item>
        <def-item>
          <term id="G31">ICFEP</term>
          <def>
            <p>Insufici&#234;ncia card&#237;aca com fra&#231;&#227;o de eje&#231;&#227;o preservada</p>
          </def>
        </def-item>
        <def-item>
          <term id="G32">IMRT</term>
          <def>
            <p>Intensive-modulated radiation therapy</p>
          </def>
        </def-item>
        <def-item>
          <term id="G33">SUV max</term>
          <def>
            <p>Maximum standard uptake value</p>
          </def>
        </def-item>
        <def-item>
          <term id="G34">MN</term>
          <def>
            <p>Medicinal nuclear</p>
          </def>
        </def-item>
        <def-item>
          <term id="G35">MM</term>
          <def>
            <p>Mieloma m&#250;ltiplo</p>
          </def>
        </def-item>
        <def-item>
          <term id="G36">NE</term>
          <def>
            <p>Norepinefrina</p>
          </def>
        </def-item>
        <def-item>
          <term id="G37">PSAP</term>
          <def>
            <p>Press&#227;o sist&#243;lica da art&#233;ria pulmonar</p>
          </def>
        </def-item>
        <def-item>
          <term id="G38">QT</term>
          <def>
            <p>Quimioterapia</p>
          </def>
        </def-item>
        <def-item>
          <term id="G39">RT</term>
          <def>
            <p>Radioterapia</p>
          </def>
        </def-item>
        <def-item>
          <term id="G40">RCVE</term>
          <def>
            <p>Reserva contr&#225;til do ventr&#237;culo esquerdo</p>
          </def>
        </def-item>
        <def-item>
          <term id="G41">RMC</term>
          <def>
            <p>Resson&#226;ncia magn&#233;tica card&#237;aca</p>
          </def>
        </def-item>
        <def-item>
          <term id="G42">SVC</term>
          <def>
            <p>S&#237;ndrome da veia cava inferior</p>
          </def>
        </def-item>
        <def-item>
          <term id="G43">SVCS</term>
          <def>
            <p>S&#237;ndrome da veia cava superior</p>
          </def>
        </def-item>
        <def-item>
          <term id="G44">ST</term>
          <def>
            <p>S&#237;ndrome de Takotsubo</p>
          </def>
        </def-item>
        <def-item>
          <term id="G45">STE</term>
          <def>
            <p>Speckle tracking echocardiography</p>
          </def>
        </def-item>
        <def-item>
          <term id="G46">SLG</term>
          <def>
            <p>Strainlongitudinal global</p>
          </def>
        </def-item>
        <def-item>
          <term id="G47">TC</term>
          <def>
            <p>Tomografia computadorizada</p>
          </def>
        </def-item>
        <def-item>
          <term id="G48">TMO</term>
          <def>
            <p>Transplante de medula &#243;ssea</p>
          </def>
        </def-item>
        <def-item>
          <term id="G49">TRC</term>
          <def>
            <p>Trombose relacionada ao cateter</p>
          </def>
        </def-item>
        <def-item>
          <term id="G50">TAC</term>
          <def>
            <p>Tumor amorfo calcificado</p>
          </def>
        </def-item>
        <def-item>
          <term id="G51">TCPB</term>
          <def>
            <p>Tumores card&#237;acos prim&#225;rios benignos</p>
          </def>
        </def-item>
        <def-item>
          <term id="G52">TCPM</term>
          <def>
            <p>Tumores card&#237;acos prim&#225;rios malignos</p>
          </def>
        </def-item>
        <def-item>
          <term id="G53">USV</term>
          <def>
            <p>Ultrassonografia vascular</p>
          </def>
        </def-item>
        <def-item>
          <term id="G54">VCI</term>
          <def>
            <p>Veia cava inferior</p>
          </def>
        </def-item>
        <def-item>
          <term id="G55">VJID</term>
          <def>
            <p>Veia jugular interna direita</p>
          </def>
        </def-item>
        <def-item>
          <term id="G56">VD</term>
          <def>
            <p>Ventr&#237;culo direito</p>
          </def>
        </def-item>
        <def-item>
          <term id="G57">VE</term>
          <def>
            <p>Ventr&#237;culo esquerdo</p>
          </def>
        </def-item>
        <def-item>
          <term id="G58">WR</term>
          <def>
            <p>Washout Rate</p>
          </def>
        </def-item>
      </def-list>
    </glossary>
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    <app-group>
      <app id="app1">
        <label>ANEXO 1</label>
        <sec>
          <title>SUGEST&#195;O DE LAUDO DE ECOCARDIOGRAMA NA CARDIO-ONCOLOGIA</title>
          <list list-type="roman-upper">
            <list-item>
              <p>
                <bold>Identifica&#231;&#227;o do paciente:</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>Nome:</p>
                </list-item>
                <list-item>
                  <p>Registro hospitalar/Identidade pessoal:</p>
                </list-item>
                <list-item>
                  <p>G&#234;nero:</p>
                </list-item>
                <list-item>
                  <p>Data de nascimento: / / (&#8230;.. anos)</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>Diagn&#243;stico oncol&#243;gico:</p>
            </list-item>
            <list-item>
              <p>Comorbidades:</p>
            </list-item>
            <list-item>
              <p>Tratamento:</p>
              <list list-type="bullet">
                <list-item>
                  <p>Data do in&#237;cio do tratamento: / /</p>
                </list-item>
                <list-item>
                  <p>Data do t&#233;rmino do tratamento: / /</p>
                </list-item>
                <list-item>
                  <p>Protocolo de tratamento (f&#225;rmacosusados):</p>
                </list-item>
                <list-item>
                  <p>Dose cumulativa de antraciclina:mg/m<sup>2</sup></p>
                </list-item>
                <list-item>
                  <p>Radioterapia tor&#225;cica:Gy</p>
                </list-item>
                <list-item>
                  <p>Outros medicamentos em uso:</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>Momento (timing) do exame:</p>
              <list list-type="simple">
                <list-item>
                  <label>&#9633;</label>
                  <p>Exame do in&#237;cio do tratamento (basal)</p>
                </list-item>
                <list-item>
                  <label>&#9633;</label>
                  <p>Exame intermedi&#225;rio (avalia&#231;&#227;o de rotina). Delta QT: &#8230;&#8230;. dias</p>
                </list-item>
                <list-item>
                  <label>&#9633;</label>
                  <p>Exame por intercorr&#234;ncia. Qual:&#8230;.</p>
                </list-item>
                <list-item>
                  <label>&#9633;</label>
                  <p>Exame de t&#233;rmino de tratamento</p>
                </list-item>
                <list-item>
                  <label>&#9633;</label>
                  <p>Exame fora de tratamento (FT): &#8230;&#8230;. meses / &#8230;&#8230;. anos</p>
                  <p>Data do &#250;ltimo exame: / /</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>Dados antropom&#233;tricos:</p>
              <p>Peso:&#8230;&#8230;. Kg Estatura:&#8230;&#8230;. m SC:&#8230;&#8230;. m<sup>2</sup>IMC:&#8230;&#8230;.</p>
            </list-item>
            <list-item>
              <p>Sinais vitais:</p>
              <p>FC: bpm PA: X mmHg FR: ipm Temp.: &#176;</p>
            </list-item>
            <list-item>
              <p>Condi&#231;&#245;es de volemia:</p>
              <list list-type="simple">
                <list-item>
                  <label>&#9633;</label>
                  <p>Hipervolemia</p>
                </list-item>
                <list-item>
                  <label>&#9633;</label>
                  <p>Desidrata&#231;&#227;o</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>&#8211; <bold>Medidas ecocardiogr&#225;ficas bidimensionais convencionais: (&#8230;.)</bold></p>
            </list-item>
            <list-item>
              <p>
                <bold>Volume VEd:mLVolume VEs:mL</bold>
              </p>
            </list-item>
            <list-item>
              <p>
                <bold>Massa VE:g&#205;ndice de massa do VE:g/m2</bold>
              </p>
            </list-item>
            <list-item>
              <p>
                <bold>Anatomia card&#237;aca: (descri&#231;&#227;o sequencial)</bold>
              </p>
            </list-item>
            <list-item>
              <p>
                <bold>Aparelhos valvares: (descri&#231;&#227;o estrutural, mobilidade, Doppler&#8230;)</bold>
              </p>
            </list-item>
            <list-item>
              <p>
                <bold>Estimativa da press&#227;o sist&#243;lica arterial pulmonar:mmHg</bold>
              </p>
            </list-item>
            <list-item>
              <p>
                <bold>Par&#226;metros de avalia&#231;&#227;oda fun&#231;&#227;o diast&#243;lica:</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>E/A:</p>
                </list-item>
                <list-item>
                  <p>E/e&#8217; septal:cm/s</p>
                </list-item>
                <list-item>
                  <p>E/e&#8217;lateral:cm/s</p>
                </list-item>
                <list-item>
                  <p>S:cm/s</p>
                </list-item>
                <list-item>
                  <p>Volume AEi:mL/m<sup>2</sup></p>
                </list-item>
                <list-item>
                  <p>SLG AE:</p>
                </list-item>
                <list-item>
                  <p>Outros?</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>
                <bold>Par&#226;metros de avalia&#231;&#227;o da fun&#231;&#227;o sist&#243;lica:</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>FEVE (Simpson biplanar):</p>
                </list-item>
                <list-item>
                  <p>Fra&#231;&#227;o de eje&#231;&#227;o pelo m&#233;todo 3D:</p>
                </list-item>
                <list-item>
                  <p><italic>Strain</italic> longitudinal global do VE (SLGVE):</p>
                </list-item>
                <list-item>
                  <p>Altera&#231;&#245;es na contratilidade segmentar:</p>
                </list-item>
                <list-item>
                  <p>Contratilidade global do VD (an&#225;lise qualitativa):</p>
                </list-item>
                <list-item>
                  <p>FEVD (Simpson):</p>
                </list-item>
                <list-item>
                  <p><italic>Strain</italic> longitudinal global do VD (SLGVD):</p>
                </list-item>
                <list-item>
                  <p>Outros?</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>
                <bold>Peric&#225;rdio:</bold>
              </p>
            </list-item>
            <list-item>
              <p>
                <bold>Conclus&#245;es:</bold>
              </p>
            </list-item>
            <list-item>
              <p>
                <bold>An&#225;lise comparativa funcional:</bold>
              </p>
              <p>Queda da FEVE em compara&#231;&#227;o com o exame basal:%</p>
              <p>Queda do SLG em compara&#231;&#227;o com o exame basal:</p>
            </list-item>
            <list-item>
              <p>
                <bold>Observa&#231;&#245;es:</bold>
              </p>
            </list-item>
          </list>
        </sec>
      </app>
      <app id="app2">
        <label>ANEXO 2</label>
        <sec>
          <title>CONSIDERA&#199;&#213;ES IMPORTANTES NA AVALIA&#199;&#195;O DO LAUDO DO ECOCARDIOGRAMA NA CARDIO-ONCOLOGIA</title>
          <list list-type="order">
            <list-item>
              <p>A ecocardiografia deve sempre ser realizada antes de qualquer tratamento onco-hematol&#243;gico para registro do estado funcional inicial do paciente e identifica&#231;&#227;o de cardiopatia preexistente. Esses dados servir&#227;o como base comparativa para os exames subsequentes.</p>
            </list-item>
            <list-item>
              <p>O tempo ideal para avalia&#231;&#227;o ecocardiogr&#225;fica antes do pr&#243;ximo ciclo quimioter&#225;pico &#233; usualmente de 3 semanas ap&#243;s a &#250;ltima infus&#227;o, ou o mais pr&#243;ximo poss&#237;vel da pr&#243;xima.</p>
            </list-item>
            <list-item>
              <p>Os exames intermedi&#225;rios s&#227;o indicados de acordo com o protocolo terap&#234;utico (potencial cardiot&#243;xico dos quimioter&#225;picos utilizados) ou pela estratifica&#231;&#227;o do risco cardiovascular individual.</p>
            </list-item>
            <list-item>
              <p>Atentar quanto ao estado vol&#234;mico do paciente (condi&#231;&#245;es de pr&#233; e p&#243;s-carga) que poder&#227;o influenciar nos valores reais do <italic>strain</italic> .</p>
            </list-item>
            <list-item>
              <p>Avalia&#231;&#245;es em vig&#234;ncia de intercorr&#234;ncias que comprometam o estado hemodin&#226;mico do paciente servir&#227;o de informa&#231;&#227;o pontual. O exame dever&#225; ser repetido ap&#243;s a melhora cl&#237;nica do paciente.</p>
            </list-item>
            <list-item>
              <p>Em caso de disfun&#231;&#227;o detectada (queda da FEVE e/ou do SLG, ou altera&#231;&#227;o de fun&#231;&#227;o diast&#243;lica), repetir o exame ap&#243;s 3 semanas para confirma&#231;&#227;o da suspeita ou interpreta&#231;&#227;o como condi&#231;&#227;o transit&#243;ria que merecer&#225; aten&#231;&#227;o evolutiva.</p>
            </list-item>
            <list-item>
              <p>Em situa&#231;&#245;es de queda da FEVE e/ou do SLG em uso de f&#225;rmacossabidamente n&#227;o cardiot&#243;xicos, considerar outras causas para a disfun&#231;&#227;o mioc&#225;rdica (p. ex., infec&#231;&#227;o, DAC).</p>
            </list-item>
            <list-item>
              <p>Obter um bom tra&#231;ado de ECG para adequada quantifica&#231;&#227;o do <italic>strain</italic> .</p>
            </list-item>
            <list-item>
              <p>Usar janelas ecocardiogr&#225;ficas o mais adequadas poss&#237;veis, evitando o encurtamento da imagem que induz &#224; supervaloriza&#231;&#227;o dos &#237;ndices de deforma&#231;&#227;o mioc&#225;rdica.</p>
            </list-item>
            <list-item>
              <p>Preferencialmente, ser um mesmo examinador para o mesmo paciente durante todo o acompanhamento.</p>
            </list-item>
            <list-item>
              <p>Considerar o uso da mesma marca de equipamento na avalia&#231;&#227;o do mesmo paciente.</p>
            </list-item>
            <list-item>
              <p>N&#227;o realizar SLG em pacientes com arritmia card&#237;aca (fibrila&#231;&#227;o atrial, taquicardia intensa e bloqueio AV).</p>
            </list-item>
          </list>
        </sec>
      </app>
      <app id="app3">
        <label>ANEXO 3</label>
        <sec>
          <title>SINAIS DE ALERTA DURANTE A AVALIA&#199;&#195;O DO ECOCARDIOGRAMA NA CARDIO-ONCOLOGIA:</title>
          <table-wrap id="t11">
            <table frame="box" rules="none">
              <colgroup width="25%">
                <col/>
                <col/>
                <col/>
                <col/>
              </colgroup>
              <tbody style="border-bottom: thin solid; border-color: #000000">
                <tr>
                  <td align="center" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Favor&#225;vel</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="center" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Aten&#231;&#227;o</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="center" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Cuidado</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="center" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Desfavor&#225;vel</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
              </tbody>
            </table>
          </table-wrap>
          <list list-type="bullet">
            <list-item>
              <p>FEVE normal + SLG normal + Troponina (-)</p>
            </list-item>
            <list-item>
              <p>FEVE normal + SLG normal + disfun&#231;&#227;o diast&#243;lica tipo I</p>
              <list list-type="simple">
                <list-item>
                  <p>= altera&#231;&#227;o transit&#243;ria? Reavaliar a situa&#231;&#227;o no pr&#243;ximo exame eletivo.</p>
                </list-item>
                <list-item>
                  <p>Altera&#231;&#245;es da contratilidade segmentar + FEVE normal + SLG normal</p>
                </list-item>
                <list-item>
                  <p>= Disfun&#231;&#227;o subcl&#237;nica? Altera&#231;&#227;o transit&#243;ria?</p>
                </list-item>
                <list-item>
                  <p>= Reavaliar a situa&#231;&#227;o no pr&#243;ximo exame eletivo.</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>FEVE nos limites inferiores da normalidade em paciente taquic&#225;rdico.</p>
            </list-item>
            <list-item>
              <p>FEVE normal + SLG &lt;16% ou queda SLG &gt; 15% do valor basal</p>
              <list list-type="simple">
                <list-item>
                  <p>= Disfun&#231;&#227;o subcl&#237;nica? Considerar medidas cardioprotetoras.</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>FEVE anormal + SLG &lt;16% ou queda SLG &gt;15% do valor basal + troponina (+)</p>
              <list list-type="simple">
                <list-item>
                  <p>= Discutir risco/benef&#237;cio do esquema QT + tratamento cardiol&#243;gico.</p>
                </list-item>
                <list-item>
                  <p>= Repetir ecocardiograma em curto prazo.</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>FEVE anormal (&lt;40%)</p>
              <list list-type="simple">
                <list-item>
                  <p>= Discutir suspens&#227;o tempor&#225;ria do esquema QT + tratamento cardiol&#243;gico.</p>
                </list-item>
                <list-item>
                  <p>= Repetir ecocardiograma em curto prazo.</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>Hipertens&#227;o pulmonar com repercuss&#227;o de ventr&#237;culo direito.</p>
            </list-item>
            <list-item>
              <p>Tamponamento card&#237;aco.</p>
            </list-item>
          </list>
        </sec>
      </app>
    </app-group>
  </back>
  <sub-article article-type="translation" id="S01" xml:lang="en">
    <front-stub>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Statement</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Brazilian Position Statement on the Use Of Multimodality Imaging in Cardio-Oncology &#8211; 2021</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-8809-8783</contrib-id>
          <name>
            <surname>Melo</surname>
            <given-names>Marcelo Dantas Tavares de</given-names>
          </name>
          <xref ref-type="aff" rid="aff81">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Paiva</surname>
            <given-names>Marcelo Goulart</given-names>
          </name>
          <xref ref-type="aff" rid="aff82">
            <sup>2</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Santos</surname>
            <given-names>Maria Ver&#244;nica C&#226;mara</given-names>
          </name>
          <xref ref-type="aff" rid="aff83">
            <sup>3</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-4505-3344</contrib-id>
          <name>
            <surname>Rochitte</surname>
            <given-names>Carlos Eduardo</given-names>
          </name>
          <xref ref-type="aff" rid="aff84">
            <sup>4</sup>
          </xref>
          <xref ref-type="aff" rid="aff85">
            <sup>5</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Moreira</surname>
            <given-names>Val&#233;ria de Melo</given-names>
          </name>
          <xref ref-type="aff" rid="aff85">
            <sup>5</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Saleh</surname>
            <given-names>Mohamed Hassan</given-names>
          </name>
          <xref ref-type="aff" rid="aff84">
            <sup>4</sup>
          </xref>
          <xref ref-type="aff" rid="aff86">
            <sup>6</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Brand&#227;o</surname>
            <given-names>Simone Cristina Soares</given-names>
          </name>
          <xref ref-type="aff" rid="aff87">
            <sup>7</sup>
          </xref>
          <xref ref-type="aff" rid="aff88">
            <sup>8</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-6684-5952</contrib-id>
          <name>
            <surname>Gallafrio</surname>
            <given-names>Claudia Cosentino</given-names>
          </name>
          <xref ref-type="aff" rid="aff89">
            <sup>9</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Goldwasser</surname>
            <given-names>Daniel</given-names>
          </name>
          <xref ref-type="aff" rid="aff90">
            <sup>10</sup>
          </xref>
          <xref ref-type="aff" rid="aff91">
            <sup>11</sup>
          </xref>
          <xref ref-type="aff" rid="aff92">
            <sup>12</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-0477-480X</contrib-id>
          <name>
            <surname>Gripp</surname>
            <given-names>Eliza de Almeida</given-names>
          </name>
          <xref ref-type="aff" rid="aff93">
            <sup>13</sup>
          </xref>
          <xref ref-type="aff" rid="aff94">
            <sup>14</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-4154-3197</contrib-id>
          <name>
            <surname>Piveta</surname>
            <given-names>Rafael Bonafim</given-names>
          </name>
          <xref ref-type="aff" rid="aff95">
            <sup>15</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-9983-6438</contrib-id>
          <name>
            <surname>Silva</surname>
            <given-names>Tonnison Oliveira</given-names>
          </name>
          <xref ref-type="aff" rid="aff96">
            <sup>16</sup>
          </xref>
          <xref ref-type="aff" rid="aff97">
            <sup>17</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Santo</surname>
            <given-names>Thais Harada Campos Espirito</given-names>
          </name>
          <xref ref-type="aff" rid="aff98">
            <sup>18</sup>
          </xref>
          <xref ref-type="aff" rid="aff99">
            <sup>19</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-9748-1784</contrib-id>
          <name>
            <surname>Ferreira</surname>
            <given-names>Waldinai Pereira</given-names>
          </name>
          <xref ref-type="aff" rid="aff100">
            <sup>20</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-7152-1810</contrib-id>
          <name>
            <surname>Salemi</surname>
            <given-names>Vera Maria Cury</given-names>
          </name>
          <xref ref-type="aff" rid="aff84">
            <sup>4</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Cauduro</surname>
            <given-names>Sanderson A.</given-names>
          </name>
          <xref ref-type="aff" rid="aff101">
            <sup>21</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-0711-7995</contrib-id>
          <name>
            <surname>Barberato</surname>
            <given-names>Silvio Henrique</given-names>
          </name>
          <xref ref-type="aff" rid="aff102">
            <sup>22</sup>
          </xref>
          <xref ref-type="aff" rid="aff103">
            <sup>23</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Lopes</surname>
            <given-names>Helo&#237;sa M. Christovam</given-names>
          </name>
          <xref ref-type="aff" rid="aff104">
            <sup>24</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Pena</surname>
            <given-names>Jos&#233; Luiz Barros</given-names>
          </name>
          <xref ref-type="aff" rid="aff105">
            <sup>25</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-4207-4484</contrib-id>
          <name>
            <surname>Rached</surname>
            <given-names>Heron Rhydan Saad</given-names>
          </name>
          <xref ref-type="aff" rid="aff106">
            <sup>26</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-3314-9712</contrib-id>
          <name>
            <surname>Miglioranza</surname>
            <given-names>Marcelo Haertel</given-names>
          </name>
          <xref ref-type="aff" rid="aff107">
            <sup>27</sup>
          </xref>
          <xref ref-type="aff" rid="aff108">
            <sup>28</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Pinheiro</surname>
            <given-names>Aur&#233;lio Carvalho</given-names>
          </name>
          <xref ref-type="aff" rid="aff109">
            <sup>29</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-5611-4002</contrib-id>
          <name>
            <surname>Vrandecic</surname>
            <given-names>B&#225;rbara Athayde Linhares Martins</given-names>
          </name>
          <xref ref-type="aff" rid="aff110">
            <sup>30</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Cruz</surname>
            <given-names>Cecilia Beatriz Bittencourt Viana</given-names>
          </name>
          <xref ref-type="aff" rid="aff84">
            <sup>4</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-7131-6614</contrib-id>
          <name>
            <surname>Nomura</surname>
            <given-names>C&#233;sar Higa</given-names>
          </name>
          <xref ref-type="aff" rid="aff84">
            <sup>4</sup>
          </xref>
          <xref ref-type="aff" rid="aff111">
            <sup>31</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Cerbino</surname>
            <given-names>Fernanda Mello Erthal</given-names>
          </name>
          <xref ref-type="aff" rid="aff112">
            <sup>32</sup>
          </xref>
          <xref ref-type="aff" rid="aff113">
            <sup>33</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-1418-9361</contrib-id>
          <name>
            <surname>Costa</surname>
            <given-names>Isabela Bispo Santos da Silva</given-names>
          </name>
          <xref ref-type="aff" rid="aff114">
            <sup>34</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-4428-5186</contrib-id>
          <name>
            <surname>Coelho</surname>
            <given-names>Otavio Rizzi</given-names>
            <suffix>Filho</suffix>
          </name>
          <xref ref-type="aff" rid="aff115">
            <sup>35</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Carneiro</surname>
            <given-names>Adriano Camargo de Castro</given-names>
          </name>
          <xref ref-type="aff" rid="aff85">
            <sup>5</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-7234-4046</contrib-id>
          <name>
            <surname>Burgos</surname>
            <given-names>Ursula Maria Moreira Costa</given-names>
          </name>
          <xref ref-type="aff" rid="aff116">
            <sup>36</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-6726-5324</contrib-id>
          <name>
            <surname>Fernandes</surname>
            <given-names>Juliano Lara</given-names>
          </name>
          <xref ref-type="aff" rid="aff117">
            <sup>37</sup>
          </xref>
          <xref ref-type="aff" rid="aff118">
            <sup>38</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-7302-7448</contrib-id>
          <name>
            <surname>Uellendahl</surname>
            <given-names>Marly</given-names>
          </name>
          <xref ref-type="aff" rid="aff113">
            <sup>33</sup>
          </xref>
          <xref ref-type="aff" rid="aff119">
            <sup>39</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-7079-2600</contrib-id>
          <name>
            <surname>Calado</surname>
            <given-names>Eveline Barros</given-names>
          </name>
          <xref ref-type="aff" rid="aff120">
            <sup>40</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-6728-3565</contrib-id>
          <name>
            <surname>Senra</surname>
            <given-names>Tiago</given-names>
          </name>
          <xref ref-type="aff" rid="aff86">
            <sup>6</sup>
          </xref>
          <xref ref-type="aff" rid="aff111">
            <sup>31</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Assun&#231;&#227;o</surname>
            <given-names>Bruna Leal</given-names>
          </name>
          <xref ref-type="aff" rid="aff114">
            <sup>34</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Freire</surname>
            <given-names>Claudia Maria Vilas</given-names>
          </name>
          <xref ref-type="aff" rid="aff121">
            <sup>41</sup>
          </xref>
          <xref ref-type="aff" rid="aff122">
            <sup>42</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Martins</surname>
            <given-names>Cristiane Nunes</given-names>
          </name>
          <xref ref-type="aff" rid="aff110">
            <sup>30</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-6418-1424</contrib-id>
          <name>
            <surname>Sawamura</surname>
            <given-names>Karen Saori Shiraishi</given-names>
          </name>
          <xref ref-type="aff" rid="aff85">
            <sup>5</sup>
          </xref>
          <xref ref-type="aff" rid="aff94">
            <sup>14</sup>
          </xref>
          <xref ref-type="aff" rid="aff123">
            <sup>43</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Brito</surname>
            <given-names>M&#225;rcio Miranda</given-names>
          </name>
          <xref ref-type="aff" rid="aff124">
            <sup>44</sup>
          </xref>
          <xref ref-type="aff" rid="aff125">
            <sup>45</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Jardim</surname>
            <given-names>Maria Fernanda Silva</given-names>
          </name>
          <xref ref-type="aff" rid="aff126">
            <sup>46</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Bernardes</surname>
            <given-names>Renata Junqueira Moll</given-names>
          </name>
          <xref ref-type="aff" rid="aff127">
            <sup>47</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Di&#243;genes</surname>
            <given-names>Tereza Cristina</given-names>
          </name>
          <xref ref-type="aff" rid="aff128">
            <sup>48</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Vieira</surname>
            <given-names>Lucas de Oliveira</given-names>
          </name>
          <xref ref-type="aff" rid="aff129">
            <sup>49</sup>
          </xref>
          <xref ref-type="aff" rid="aff130">
            <sup>50</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-1466-9413</contrib-id>
          <name>
            <surname>Mesquita</surname>
            <given-names>Claudio Tinoco</given-names>
          </name>
          <xref ref-type="aff" rid="aff93">
            <sup>13</sup>
          </xref>
          <xref ref-type="aff" rid="aff131">
            <sup>51</sup>
          </xref>
          <xref ref-type="aff" rid="aff132">
            <sup>52</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Lopes</surname>
            <given-names>Rafael Willain</given-names>
          </name>
          <xref ref-type="aff" rid="aff85">
            <sup>5</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Segundo</surname>
            <given-names>Elry Medeiros Vieira</given-names>
            <suffix>Neto</suffix>
          </name>
          <xref ref-type="aff" rid="aff86">
            <sup>6</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Rigo</surname>
            <given-names>Let&#237;cia</given-names>
          </name>
          <xref ref-type="aff" rid="aff133">
            <sup>53</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Marin</surname>
            <given-names>Valeska Leite Siqueira</given-names>
          </name>
          <xref ref-type="aff" rid="aff134">
            <sup>54</sup>
          </xref>
          <xref ref-type="aff" rid="aff135">
            <sup>55</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Santos</surname>
            <given-names>Marcelo Jos&#233;</given-names>
          </name>
          <xref ref-type="aff" rid="aff136">
            <sup>56</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-6485-4900</contrib-id>
          <name>
            <surname>Grossman</surname>
            <given-names>Gabriel Blacher</given-names>
          </name>
          <xref ref-type="aff" rid="aff137">
            <sup>57</sup>
          </xref>
          <xref ref-type="aff" rid="aff138">
            <sup>58</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Quagliato</surname>
            <given-names>Priscila Cestari</given-names>
          </name>
          <xref ref-type="aff" rid="aff86">
            <sup>6</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Alcantara</surname>
            <given-names>Monica Luiza de</given-names>
          </name>
          <xref ref-type="aff" rid="aff139">
            <sup>59</sup>
          </xref>
          <xref ref-type="aff" rid="aff140">
            <sup>60</sup>
          </xref>
          <xref ref-type="aff" rid="aff141">
            <sup>61</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Teodoro</surname>
            <given-names>Jos&#233; Aldo Ribeiro</given-names>
          </name>
          <xref ref-type="aff" rid="aff142">
            <sup>62</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Albricker</surname>
            <given-names>Ana Cristina Lopes</given-names>
          </name>
          <xref ref-type="aff" rid="aff143">
            <sup>63</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Barros</surname>
            <given-names>Fanilda Souto</given-names>
          </name>
          <xref ref-type="aff" rid="aff144">
            <sup>64</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Amaral</surname>
            <given-names>Salomon Israel do</given-names>
          </name>
          <xref ref-type="aff" rid="aff145">
            <sup>65</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Porto</surname>
            <given-names>Carmen L&#250;cia Lascasas</given-names>
          </name>
          <xref ref-type="aff" rid="aff146">
            <sup>66</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Barros</surname>
            <given-names>Marcio Vin&#237;cius Lins</given-names>
          </name>
          <xref ref-type="aff" rid="aff147">
            <sup>67</sup>
          </xref>
          <xref ref-type="aff" rid="aff148">
            <sup>68</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Santos</surname>
            <given-names>Simone Nascimento dos</given-names>
          </name>
          <xref ref-type="aff" rid="aff149">
            <sup>69</sup>
          </xref>
          <xref ref-type="aff" rid="aff150">
            <sup>70</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Cantisano</surname>
            <given-names>Armando Lu&#237;s</given-names>
          </name>
          <xref ref-type="aff" rid="aff151">
            <sup>71</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-6186-1531</contrib-id>
          <name>
            <surname>Petisco</surname>
            <given-names>Ana Cl&#225;udia Gomes Pereira</given-names>
          </name>
          <xref ref-type="aff" rid="aff86">
            <sup>6</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Barbosa</surname>
            <given-names>Jos&#233; Eduardo Martins</given-names>
          </name>
          <xref ref-type="aff" rid="aff86">
            <sup>6</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Veloso</surname>
            <given-names>Orlando Carlos Gl&#243;ria</given-names>
          </name>
          <xref ref-type="aff" rid="aff152">
            <sup>72</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-4884-0223</contrib-id>
          <name>
            <surname>Spina</surname>
            <given-names>Salvador</given-names>
          </name>
          <xref ref-type="aff" rid="aff153">
            <sup>73</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Pignatelli</surname>
            <given-names>Ricardo</given-names>
          </name>
          <xref ref-type="aff" rid="aff154">
            <sup>74</sup>
          </xref>
          <xref ref-type="aff" rid="aff155">
            <sup>75</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-5645-2055</contrib-id>
          <name>
            <surname>Hajjar</surname>
            <given-names>Ludhmilla Abrah&#227;o</given-names>
          </name>
          <xref ref-type="aff" rid="aff84">
            <sup>4</sup>
          </xref>
          <xref ref-type="aff" rid="aff114">
            <sup>34</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-1033-3672</contrib-id>
          <name>
            <surname>Kalil</surname>
            <given-names>Roberto</given-names>
            <suffix>Filho</suffix>
          </name>
          <xref ref-type="aff" rid="aff84">
            <sup>4</sup>
          </xref>
          <xref ref-type="aff" rid="aff114">
            <sup>34</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-1253-1514</contrib-id>
          <name>
            <surname>Lopes</surname>
            <given-names>Marcelo Ant&#244;nio Cartaxo Queiroga</given-names>
          </name>
          <xref ref-type="aff" rid="aff156">
            <sup>76</sup>
          </xref>
          <xref ref-type="aff" rid="aff157">
            <sup>77</sup>
          </xref>
          <xref ref-type="aff" rid="aff158">
            <sup>78</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Vieira</surname>
            <given-names>Marcelo Luiz Campos</given-names>
          </name>
          <xref ref-type="aff" rid="aff84">
            <sup>4</sup>
          </xref>
          <xref ref-type="aff" rid="aff95">
            <sup>15</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-1777-477X</contrib-id>
          <name>
            <surname>Almeida</surname>
            <given-names>Andr&#233; Luiz Cerqueira</given-names>
          </name>
          <xref ref-type="aff" rid="aff159">
            <sup>79</sup>
          </xref>
          <xref ref-type="aff" rid="aff160">
            <sup>80</sup>
          </xref>
        </contrib>
        <aff id="aff81">
          <label>1</label>
          <addr-line>
            <named-content content-type="city">Jo&#227;o Pessoa</named-content>
            <named-content content-type="state">PB</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Universidade Federal da Para&#237;ba, Jo&#227;o Pessoa, PB &#8211; Brazil</institution>
        </aff>
        <aff id="aff82">
          <label>2</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">S&#227;o Paulo</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital 9 de Julho, Cardiologia, S&#227;o Paulo, S&#227;o Paulo &#8211; Brazil</institution>
        </aff>
        <aff id="aff83">
          <label>3</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Sociedade Brasileira de Oncologia Pedi&#225;trica, S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff84">
          <label>4</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Instituto do Cora&#231;&#227;o (Incor) do Hospital das Cl&#237;nicas da Faculdade de Medicina da Universidade de S&#227;o Paulo (HCFMUSP), S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff85">
          <label>5</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital do Cora&#231;&#227;o (HCOR), S&#227;o Paulo, SP &#8211; Brasil.</institution>
        </aff>
        <aff id="aff86">
          <label>6</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Instituto Dante Pazzanese de Cardiologia, S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff87">
          <label>7</label>
          <addr-line>
            <named-content content-type="city">Recife</named-content>
            <named-content content-type="state">PE</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital das Cl&#237;nicas, Universidade Federal de Pernambuco, Recife, PE - Brazil</institution>
        </aff>
        <aff id="aff88">
          <label>8</label>
          <addr-line>
            <named-content content-type="city">Jo&#227;o Pessoa</named-content>
            <named-content content-type="state">PB</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Cl&#237;nica Diagson, Jo&#227;o Pessoa, PB &#8211; Brazil</institution>
        </aff>
        <aff id="aff89">
          <label>9</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Instituto de Oncologia Pedi&#225;trica, S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff90">
          <label>10</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Federal de Ipanema, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff91">
          <label>11</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Copa D'Or, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff92">
          <label>12</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Casa de Sa&#250;de S&#227;o Jos&#233;, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff93">
          <label>13</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Pr&#243;-Card&#237;aco, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff94">
          <label>14</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Universit&#225;rio Ant&#244;nio Pedro, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff95">
          <label>15</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Israelita Albert Einstein, S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff96">
          <label>16</label>
          <addr-line>
            <named-content content-type="city">Salvador</named-content>
            <named-content content-type="state">BA</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Cardio Pulmonar &#8211; Centro de Estudos em Cardiologia, Salvador, BA &#8211; Brazil</institution>
        </aff>
        <aff id="aff97">
          <label>17</label>
          <addr-line>
            <named-content content-type="city">Salvador</named-content>
            <named-content content-type="state">BA</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Escola Bahiana de Medicina e Sa&#250;de P&#250;blica, Salvador, BA &#8211; Brazil</institution>
        </aff>
        <aff id="aff98">
          <label>18</label>
          <addr-line>
            <named-content content-type="city">Salvador</named-content>
            <named-content content-type="state">BA</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Ana Nery, Salvador, BA &#8211; Brazil</institution>
        </aff>
        <aff id="aff99">
          <label>19</label>
          <addr-line>
            <named-content content-type="city">Salvador</named-content>
            <named-content content-type="state">BA</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Diagnoson/Fleury, Salvador, BA &#8211; Brazil</institution>
        </aff>
        <aff id="aff100">
          <label>20</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">ACCamargoCancer Center &#8211; IMAGE, S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff101">
          <label>21</label>
          <addr-line>
            <named-content content-type="city">Curitiba</named-content>
            <named-content content-type="state">PR</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Erasto Gaertner, Curitiba, PR &#8211; Brazil</institution>
        </aff>
        <aff id="aff102">
          <label>22</label>
          <addr-line>
            <named-content content-type="city">Curitiba</named-content>
            <named-content content-type="state">PR</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">CardioEco Centro de Diagn&#243;stico Cardiovascular, Curitiba, PR &#8211; Brazil</institution>
        </aff>
        <aff id="aff103">
          <label>23</label>
          <addr-line>
            <named-content content-type="city">Curitiba</named-content>
            <named-content content-type="state">PR</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Quanta Diagn&#243;stico, Curitiba, PR &#8211; Brazil</institution>
        </aff>
        <aff id="aff104">
          <label>24</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital de Amor, Barretos, S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff105">
          <label>25</label>
          <addr-line>
            <named-content content-type="city">Belo Horizonte</named-content>
            <named-content content-type="state">MG</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Faculdade de Ci&#234;ncias M&#233;dicas de Minas Gerais, Belo Horizonte, MG &#8211; Brazil</institution>
        </aff>
        <aff id="aff106">
          <label>26</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Leforte Liberdade, S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff107">
          <label>27</label>
          <addr-line>
            <named-content content-type="city">Porto Alegre</named-content>
            <named-content content-type="state">RS</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Instituto de Cardiologia do Rio Grande do Sul &#8211; Laborat&#243;rio de Pesquisa e Inova&#231;&#227;o em Imagem Cardiovascular, Porto Alegre, RS &#8211; Brazil</institution>
        </aff>
        <aff id="aff108">
          <label>28</label>
          <addr-line>
            <named-content content-type="city">Porto Alegre</named-content>
            <named-content content-type="state">RS</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital M&#227;e de Deus, Porto Alegre, RS &#8211; Brazil</institution>
        </aff>
        <aff id="aff109">
          <label>29</label>
          <addr-line>
            <named-content content-type="city">Manaus</named-content>
            <named-content content-type="state">AM</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Adventista de Manaus, Manaus, AM &#8211; Brazil</institution>
        </aff>
        <aff id="aff110">
          <label>30</label>
          <addr-line>
            <named-content content-type="city">Nova Lima</named-content>
            <named-content content-type="state">MG</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Biocor Instituto, Nova Lima, MG &#8211; Brazil</institution>
        </aff>
        <aff id="aff111">
          <label>31</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital S&#237;rio-Liban&#234;s, S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff112">
          <label>32</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Cl&#237;nica de Diagn&#243;stico por Imagem, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff113">
          <label>33</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Diagn&#243;sticos da Am&#233;rica AS, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff114">
          <label>34</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Universidade de S&#227;o Paulo Instituto do C&#226;ncer do Estado de S&#227;o Paulo, S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff115">
          <label>35</label>
          <addr-line>
            <named-content content-type="city">Campinas</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Universidade Estadual de Campinas (UNICAMP), Campinas, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff116">
          <label>36</label>
          <addr-line>
            <named-content content-type="city">Aracaju</named-content>
            <named-content content-type="state">SE</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Universidade Tiradentes, Aracaju, SE &#8211; Brazil</institution>
        </aff>
        <aff id="aff117">
          <label>37</label>
          <addr-line>
            <named-content content-type="city">Campinas</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Radiologia Cl&#237;nica de Campinas, Campinas, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff118">
          <label>38</label>
          <addr-line>
            <named-content content-type="city">Campinas</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Instituto de Ensino e Pesquisa Jos&#233; Michel Kalaf, Campinas, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff119">
          <label>39</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Universidade Federal de S&#227;o Paulo (UNIFESP), S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff120">
          <label>40</label>
          <addr-line>
            <named-content content-type="city">Recife</named-content>
            <named-content content-type="state">PE</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital das Cl&#237;nicas da Universidade Federal de Pernambuco, Recife, PE &#8211; Brazil</institution>
        </aff>
        <aff id="aff121">
          <label>41</label>
          <addr-line>
            <named-content content-type="city">Belo Horizonte</named-content>
            <named-content content-type="state">MG</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG &#8211; Brazil</institution>
        </aff>
        <aff id="aff122">
          <label>42</label>
          <addr-line>
            <named-content content-type="city">Belo Horizonte</named-content>
            <named-content content-type="state">MG</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">ECOCENTER, Belo Horizonte, MG &#8211; Brazil</institution>
        </aff>
        <aff id="aff123">
          <label>43</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Instituto da Crian&#231;a da Universidade de S&#227;o Paulo (USP), S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff124">
          <label>44</label>
          <addr-line>
            <named-content content-type="city">Araguaina</named-content>
            <named-content content-type="state">TO</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Universidade Federal do Tocantins &#8211; Campus de Araguaina, Araguaina, TO &#8211; Brazil</institution>
        </aff>
        <aff id="aff125">
          <label>45</label>
          <addr-line>
            <named-content content-type="city">Araguaina</named-content>
            <named-content content-type="state">TO</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Municipal de Araguaina, Araguaina, TO &#8211; Brazil</institution>
        </aff>
        <aff id="aff126">
          <label>46</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Samaritano de S&#227;o Paulo, S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff127">
          <label>47</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Instituto D'Or de Pesquisa e Ensino, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff128">
          <label>48</label>
          <addr-line>
            <named-content content-type="city">Fortaleza</named-content>
            <named-content content-type="state">CE</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Infantil Albert Sabin, Fortaleza, CE &#8211; Brazil</institution>
        </aff>
        <aff id="aff129">
          <label>49</label>
          <addr-line>
            <named-content content-type="city">Salvador</named-content>
            <named-content content-type="state">BA</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital S&#227;o Rafael, Salvador, BA &#8211; Brazil</institution>
        </aff>
        <aff id="aff130">
          <label>50</label>
          <addr-line>
            <named-content content-type="city">Salvador</named-content>
            <named-content content-type="state">BA</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Rede D'Or, Salvador, BA &#8211; Brazil</institution>
        </aff>
        <aff id="aff131">
          <label>51</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <institution content-type="original">Universidade Federal Fluminense (UFF), Rio de Janeiro, RJ - Brazil</institution>
        </aff>
        <aff id="aff132">
          <label>52</label>
          <addr-line/>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Vit&#243;ria, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff133">
          <label>53</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Benefic&#234;ncia Portuguesa, S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff134">
          <label>54</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Samaritano, S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff135">
          <label>55</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Santa Casa de Miseric&#243;rdia, S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff136">
          <label>56</label>
          <addr-line>
            <named-content content-type="city">Barretos</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital de C&#226;ncer de Barretos, Barretos, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff137">
          <label>57</label>
          <addr-line>
            <named-content content-type="city">Porto Alegre</named-content>
            <named-content content-type="state">RS</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Cl&#237;nica Cardionuclear, Porto Alegre, RS &#8211; Brazil</institution>
        </aff>
        <aff id="aff138">
          <label>58</label>
          <addr-line>
            <named-content content-type="city">Porto Alegre</named-content>
            <named-content content-type="state">RS</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Moinhos de Vento, Porto Alegre, RS &#8211; Brazil</institution>
        </aff>
        <aff id="aff139">
          <label>59</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">Rio</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Americas Medical City, Rio de Janeiro, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff140">
          <label>60</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Americas Servi&#231;os M&#233;dicos, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff141">
          <label>61</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Rede D'Or, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff142">
          <label>62</label>
          <addr-line>
            <named-content content-type="city">Ribeir&#227;o Preto</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Prenoto Medicina Diagn&#243;stica, Ribeir&#227;o Preto, SP &#8211; Brazil</institution>
        </aff>
        <aff id="aff143">
          <label>63</label>
          <addr-line>
            <named-content content-type="city">Belo Horizonte</named-content>
            <named-content content-type="state">MG</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Centro Universit&#225;rio Unihorizontes, Belo Horizonte, MG &#8211; Brazil</institution>
        </aff>
        <aff id="aff144">
          <label>64</label>
          <addr-line>
            <named-content content-type="city">Vit&#243;ria</named-content>
            <named-content content-type="state">ES</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Angiolab Vit&#243;ria &#8211; Diagn&#243;stico Vascular, Vit&#243;ria, ES &#8211; Brazil</institution>
        </aff>
        <aff id="aff145">
          <label>65</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Casa de Sa&#250;de Nossa Senhora do Carmo, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff146">
          <label>66</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Universidade do Estado do Rio de Janeiro Faculdade de Ci&#234;ncias M&#233;dicas, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff147">
          <label>67</label>
          <addr-line>
            <named-content content-type="city">Belo Horizonte</named-content>
            <named-content content-type="state">MG</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Mater Dei Rede de Sa&#250;de, Belo Horizonte, MG &#8211; Brazil</institution>
        </aff>
        <aff id="aff148">
          <label>68</label>
          <addr-line>
            <named-content content-type="city">Belo Horizonte</named-content>
            <named-content content-type="state">MG</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Vera Cruz, Belo Horizonte, MG &#8211; Brazil</institution>
        </aff>
        <aff id="aff149">
          <label>69</label>
          <addr-line>
            <named-content content-type="city">Bras&#237;lia</named-content>
            <named-content content-type="state">DF</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Bras&#237;lia &#8211; Ecocardiografia, Bras&#237;lia, DF &#8211; Brazil</institution>
        </aff>
        <aff id="aff150">
          <label>70</label>
          <addr-line>
            <named-content content-type="city">Bras&#237;lia</named-content>
            <named-content content-type="state">DF</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Eccos Diagn&#243;stico Cardiovascular Avan&#231;ado, Bras&#237;lia, DF &#8211; Brazil</institution>
        </aff>
        <aff id="aff151">
          <label>71</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Barra D'Or, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff152">
          <label>72</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Rede UHG, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff153">
          <label>73</label>
          <addr-line>
            <named-content content-type="city">Buenos Aires</named-content>
          </addr-line>
          <country country="AR">Argentina</country>
          <institution content-type="original">Hospital Aeron&#225;utico Central, Buenos Aires &#8211; Argentina</institution>
        </aff>
        <aff id="aff154">
          <label>74</label>
          <addr-line>
            <named-content content-type="city">Houston</named-content>
            <named-content content-type="state">Texas</named-content>
          </addr-line>
          <country country="US">USA</country>
          <institution content-type="original">Texas Children's Hospital, Houston, Texas &#8211; USA</institution>
        </aff>
        <aff id="aff155">
          <label>75</label>
          <addr-line>
            <named-content content-type="city">Houston</named-content>
            <named-content content-type="state">Texas</named-content>
          </addr-line>
          <country country="US">USA</country>
          <institution content-type="original">Baylor College of Medicine, Houston, Texas &#8211; USA</institution>
        </aff>
        <aff id="aff156">
          <label>76</label>
          <addr-line>
            <named-content content-type="city">Jo&#227;o Pessoa</named-content>
            <named-content content-type="state">PB</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Alberto Urquiza Wanderley &#8211; Hemodin&#226;mica e Cardiologia Intervencionista, Jo&#227;o Pessoa, PB &#8211; Brazil</institution>
        </aff>
        <aff id="aff157">
          <label>77</label>
          <addr-line>
            <named-content content-type="city">Jo&#227;o Pessoa</named-content>
            <named-content content-type="state">PB</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Hospital Metropolitano Dom Jos&#233; Maria Pires, Jo&#227;o Pessoa, PB &#8211; Brazil</institution>
        </aff>
        <aff id="aff158">
          <label>78</label>
          <addr-line>
            <named-content content-type="city">Rio de Janeiro</named-content>
            <named-content content-type="state">RJ</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Sociedade Brasileira de Cardiologia, Rio de Janeiro, RJ &#8211; Brazil</institution>
        </aff>
        <aff id="aff159">
          <label>79</label>
          <addr-line>
            <named-content content-type="city">Feira de Santana</named-content>
            <named-content content-type="state">BA</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Santa Casa de Miseric&#243;rdia de Feira de Santana &#8211; Cardiologia, Feira de Santana, BA &#8211; Brazil</institution>
        </aff>
        <aff id="aff160">
          <label>80</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Departamento de Imagem Cardiovascular da Sociedade Brasileira de Cardiologia, S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
      </contrib-group>
      <author-notes>
        <corresp id="c2"><bold>Correspondence:</bold> Sociedade Brasileira de Cardiologia &#8211; Av. Marechal C&#226;mara, 360/330 &#8211; Centro &#8211; Rio de Janeiro &#8211; Postal Code: <postal-code>20020-907</postal-code> . E-mail: <email>diretrizes@cardiol.br</email> </corresp>
      </author-notes>
    </front-stub>
    <body>
      <table-wrap id="t12">
        <table frame="hsides" rules="rows">
          <colgroup width="12%">
            <col/>
            <col/>
            <col/>
            <col/>
            <col/>
            <col/>
            <col/>
            <col/>
          </colgroup>
          <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
            <tr>
              <th align="center" colspan="8" valign="middle">Declaration of potential conflict of interests of authors/collaborators of the Brazilian Position Statement on the Use Of Multimodality Imaging in Cardio-Oncology &#8211; 2021</th>
            </tr>
            <tr>
              <th align="center" colspan="8" valign="middle">If, within the last 3 years, the author/collaborator of the statement:</th>
            </tr>
            <tr>
              <th align="left" valign="middle">Names of statement collaborators</th>
              <th align="center" valign="middle">Participated in clinical and/or experimental studies sponsored by pharmaceutical or equipment companies related to thxxxis statement</th>
              <th align="center" valign="middle">Spoke at events or activities sponsored by industry related to this statement</th>
              <th align="center" valign="middle">Was (is) a member of a board of advisors or a board of directors of a pharmaceutical or equipment industry</th>
              <th align="center" valign="middle">Participated in normative committees of scientific research sponsored by industry</th>
              <th align="center" valign="middle">Received personal or institutional funding from industry</th>
              <th align="center" valign="middle">Wrote scientific papers in journals sponsored by industry</th>
              <th align="center" valign="middle">Owns stocks in industry</th>
            </tr>
          </thead>
          <tbody style="border-bottom: thin solid; border-color: #000000">
            <tr>
              <td align="left" valign="middle">Adriano Camargo de Castro Carneiro</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Ana Cl&#225;udia Gomes Pereira Petisco</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Ana Cristina Lopes Albricker</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Andr&#233; Luiz Cerqueira de Almeida</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Armando Lu&#237;s Cantisano</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Aur&#233;lio Carvalho Pinheiro</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">B&#225;rbara Arhayde Lihares Martins Vrandecic</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Bruna Leal Assun&#231;&#227;o</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Carlos Eduardo Rochitte</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Carmen Lucia Lascasas Porto</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Cecilia Beatriz Bittencourt Viana Cruz</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">C&#233;sar Higa Nomura</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Cl&#225;udia Cosentino Gallafrio</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Cl&#225;udia Maria Vilas Freire</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Claudio Tinoco Mesquita</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Cristiane Nunes Martins</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Daniel Goldwasser</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Eliza de Almeida Gripp</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Elry Medeiros Vieira Segundo Neto</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Eveline Barros Calado</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Fanilda Souto Barros</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Fernanda Mello Erthal Cerbino</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Gabriel Blacher Grossman</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Helo&#237;sa Helena M. Christovam Lopes</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Heron Rhydan Saad Rached</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Isabela Bispo Santos da Silva Costa</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Jos&#233; Aldo Ribeiro Teodoro</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Jos&#233; Eduardo Martins Barbosa</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Jos&#233; Luiz Barros Pena</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Juliano Lara Fernandes</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Karen Saori Shiraishi Sawamura</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Let&#237;cia Rigo</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Lucas de Oliveira Vieira</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Ludhmila Abrah&#227;o Hajjar</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Marcelo Ant&#244;nio Cartaxo Queiroga Lopes</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Marcelo Dantas Tavares de Melo</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Marcelo Goulart Paiva</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Marcelo Haertel Miglioranza</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Marcelo Luiz Campos Vieira</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Marcelo Santos</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">M&#225;rcio Miranda Brito</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">M&#225;rcio Vin&#237;cius Lins Barros</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Maria Fernanda Silva Jardim</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Maria Ver&#244;nica C&#226;mara dos Santos</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Marly Uellendahl</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Mohamed Hassan Saleh</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">M&#244;nica Luiza de Alcantara</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Orlando Carlos Gl&#243;ria Veloso</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Ot&#225;vio Rizzi Coelho-Filho</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Priscila Cestari Quagliato</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Rafael Bonafim Piveta</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Rafael Willain Lopes</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Renata Junqueira Moll Bernardes</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Ricardo Pignatelli</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Roberto Kalil Filho</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Salomon Israel do Amaral</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Salvador Spina</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Sanderson A. Cauduro</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Silvio Henrique Barberato</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Simone Cristina Soares Brand&#227;o</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Simone Nascimento dos Santos</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Tereza Cristina Di&#243;genes</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Thais Harada Campos Espirito Santo</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Tiago Senra</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Tonnison de Oliveira Silva</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Ursula Maria Moreira Costa Burgos</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Val&#233;ria de Melo Moreira</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Valeska Leite</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Vera Maria Cury Salemi</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Waldinai P. Ferreira</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Vera Maria Cury Salemi</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
            <tr>
              <td align="left" valign="middle">Waldinai P. Ferreira</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
              <td align="center" valign="middle">No</td>
            </tr>
          </tbody>
        </table>
      </table-wrap>
      <sec>
        <title>1. General Aspects</title>
        <sec>
          <title>1.1. Current Situation of Cardio-Oncology in Brazil and Worldwide</title>
          <p>The estimated incidence of cancer in Brazil was 600 thousand cases per year in 2018 and 2019. <xref ref-type="bibr" rid="B1"><sup>1</sup></xref> Only as of 2005, the survival rate surpassed that of overall cancer mortality, leading to an increased number of survivors exposed to the risk of cardiotoxicity (CTX), which is currently the second leading cause of morbidity and mortality in this population. <xref ref-type="bibr" rid="B2"><sup>2</sup></xref> </p>
          <p>Cardiovascular complications resulting from cancer treatment, which are the focus of this consensus statement, may result in premature deaths, costly hospitalizations, and absence from work, leading to the need for early diagnosis and interventions. <xref ref-type="bibr" rid="B3"><sup>3</sup></xref> </p>
          <p>Age (children and older adults), previous myocardial or coronary heart disease, hypertension, diabetes mellitus (DM), smoking, alcohol consumption, and sedentary lifestyle are factors associated with increased risk of CTX. <xref ref-type="bibr" rid="B4"><sup>4</sup></xref> </p>
          <p>Recent studies suggest that genotypic variants may modify the susceptibility to CTX, turning genetic mapping into a promising field for identification of risk subgroups. <xref ref-type="bibr" rid="B5"><sup>5</sup></xref> </p>
          <p>It is recommended that patients at high-risk for development of CTX be considered those whose treatment includes: <xref ref-type="bibr" rid="B6"><sup>6</sup></xref> </p>
          <list list-type="bullet">
            <list-item>
              <p>High-dose anthracycline (doxorubicin &gt; 250 mg/m&#178; or epirubicin &gt; 600 mg/m&#178;);</p>
            </list-item>
            <list-item>
              <p>Radiotherapy at a dose &#8805; 30 Gy (involving the heart) or &gt; 2 Gy/session;</p>
            </list-item>
            <list-item>
              <p>Lower doses of combined anthracycline and radiotherapy;</p>
            </list-item>
          </list>
          <list list-type="simple">
            <list-item>
              <label>&#10146;</label>
              <p>Lower doses of anthracyclines or trastuzumab alone, but associated with:</p>
            </list-item>
            <list-item>
              <label>&#10146;</label>
              <p>More than two cardiovascular risk factors (smoking, hypertension, DM, dyslipidemia, obesity &#8211; during or after therapy);</p>
            </list-item>
            <list-item>
              <label>&#10146;</label>
              <p>Age &#8805; 60 years;</p>
            </list-item>
            <list-item>
              <label>&#10146;</label>
              <p>Structural heart disease before or during treatment (ejection fraction: 50% to 55%, acute myocardial infarction [AMI], moderate/important valve disease);</p>
            </list-item>
            <list-item>
              <label>&#10146;</label>
              <p>Combination of low doses of anthracycline and trastuzumab.</p>
            </list-item>
          </list>
        </sec>
        <sec>
          <title>1.2. Definition of Cardiotoxicity</title>
          <p>The definition of CTX based on the degree of left ventricular ejection fraction (LVEF) reduction ignores the changes that precede the fall in LVEF and all other toxic effects that occur in addition to this parameter. <xref ref-type="bibr" rid="B6"><sup>6</sup></xref><sup>-</sup><xref ref-type="bibr" rid="B8"><sup>8</sup></xref> Lack of a more comprehensive definition and, sometimes, clinical, laboratory, and imaging limitations to document some events in the initial stage make CTX an underdiagnosed clinical condition. The European Society of Cardiology revised in 2017 the definition of CTX to cover any structural or functional changes in the heart and circulation, both in the presence or in the immediate or late post-treatment of cancer, and considered chemotherapy, radiotherapy, or the disease itself as aggressive agents. <xref ref-type="bibr" rid="B4"><sup>4</sup></xref> </p>
        </sec>
        <sec>
          <title>1.3. Mechanisms of Cardiotoxicity</title>
          <p>Although we are aware of some CTX-related mechanisms, identifying the predominant mechanism remains a great challenge, as the combination of different drugs and treatment protocols as well as constitutional factors inherent to each patient account for a complex interaction that results in damage to the cardiovascular system ( <xref ref-type="table" rid="t13">Table 1</xref> ). Depending on the chemotherapy agent class, cell damage may occur directly or indirectly and with or without potential for reversibility. <xref ref-type="bibr" rid="B9"><sup>9</sup></xref> Ewer et al. <xref ref-type="bibr" rid="B10"><sup>10</sup></xref> proposed in 2005 a classification of CTX in types 1 and 2; despite being the subject of much criticism, it has helped divide CTX into irreversible cell damage (type 1), attributed to anthracyclines, and reversible dysfunctions (type 2), attributed to trastuzumab. With the development of new anticancer therapies, including Bruton tyrosine kinase inhibitors, proteasome inhibitors, checkpoint inhibitors, among others known to be potentially cardiotoxic, it seems that this classification proposal deserves to be revised and expanded.</p>
          <table-wrap id="t13">
            <label>Table 1</label>
            <caption>
              <title>Summary of the main suggested mechanisms of cardiotoxicity by group of drugs</title>
            </caption>
            <table frame="hsides" rules="rows">
              <colgroup width="50%">
                <col/>
                <col/>
              </colgroup>
              <tbody style="border-bottom: thin solid; border-color: #000000">
                <tr>
                  <td align="left" rowspan="6" valign="middle">Anthracyclines</td>
                  <td align="left" valign="middle">DNA double-strand break (topoisomerase IIB)</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Oxidative stress (reactive oxygen species)</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Cell membrane hyperpermeability (lipid peroxidation)</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Ultrastructural changes</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Cytoplasmic vacuolization</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Apoptosis</td>
                </tr>
                <tr>
                  <td align="left" rowspan="3" valign="middle">Trastuzumab</td>
                  <td align="left" valign="middle">Interruption of HER-2/ERBB2 receptor signaling &#8211; Neuregulin 1</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Inhibits cell repair</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Cell dysfunction</td>
                </tr>
                <tr>
                  <td align="left" rowspan="3" valign="middle">Cisplatin <break/> Cyclophosphamide</td>
                  <td align="left" valign="middle">Direct endothelial injury</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Platelet activation and aggregation</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Coronary thrombosis</td>
                </tr>
                <tr>
                  <td align="left" rowspan="2" valign="middle"><break/> 5-Fluorouracil</td>
                  <td align="left" valign="middle">Acts on the molecular signaling pathway that regulates smooth muscle tone</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Vasospasm &#8211; vasoconstriction</td>
                </tr>
                <tr>
                  <td align="left" rowspan="4" valign="middle"><break/> Vascular endothelial growth factor (VEGF) inhibitors</td>
                  <td align="left" valign="middle">Inhibit nitric oxide synthase activity</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Increase endothelin production</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Inhibit rho-kinase activation</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Vasospasm</td>
                </tr>
                <tr>
                  <td align="left" rowspan="2" valign="middle">Protease inhibitors</td>
                  <td align="left" valign="middle">Interference with the degradation of dysfunctional proteins</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Functional changes in the myocyte</td>
                </tr>
                <tr>
                  <td align="left" rowspan="2" valign="middle">Immune checkpoint inhibitors</td>
                  <td align="left" valign="middle">Increased T-cell activity</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Autoimmune activity in the heart muscle</td>
                </tr>
              </tbody>
            </table>
          </table-wrap>
        </sec>
        <sec>
          <title>1.4. Clinical Manifestations of Cardiotoxicity</title>
          <p>The cardiovascular clinical manifestations arising from cancer treatment are the tip of an iceberg whose base consists of structural and functional changes that precede signs and symptoms. For didactic purposes, we chose to divide CTX manifestations into three subgroups: clinical, laboratory, and imaging/tracing ( <xref ref-type="table" rid="t14">Table 2</xref> ). It should be noted that such proposal may be criticized at first, as routine genetic mapping is not yet feasible to determine more accurately the culpability of the phenotypic expression.</p>
          <table-wrap id="t14">
            <label>Tabble</label>
            <caption>
              <title>Cardiotoxicity phenotypes</title>
            </caption>
            <table frame="hsides" rules="rows">
              <colgroup width="50%">
                <col/>
                <col/>
              </colgroup>
              <tbody style="border-bottom: thin solid; border-color: #000000">
                <tr>
                  <td align="left" rowspan="9" valign="middle">Clinical status</td>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Hypertension</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Pulmonary hypertension</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Venous and arterial embolic events</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Carotid artery disease</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Heart failure/myocarditis</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Pericardial effusion/pericarditis</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Valve dysfunctions</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Myocardial ischemia/infarction</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Pericardial disease</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" rowspan="2" valign="middle">Laboratory</td>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Elevated troponins (T or I) and/or CK-MB</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Elevated natriuretic peptide (BNP/NT-proBNP)</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" rowspan="8" valign="middle">Imaging/Tracing</td>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Heart rhythm disorders (extrasystoles, blocks, supraventricular and ventricular tachycardias, bradyarrhythmias, increased corrected QT interval on electrocardiogram)</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Dilated cardiac chambers with preserved LVEF</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>LVEF reduction &gt; 10% (baseline) or &gt; 15% (global longitudinal strain)</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Left ventricular diastolic dysfunction</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Pericardial thickening and/or effusion</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Valve dysfunctions (stenosis, failures)</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Changes in imaging tests that indicate active inflammatory signs or necrosis (scintigraphy/cardiac MRI)</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Changes in coronary CT angiography or calcium score that were initiated or aggravated during or after cancer treatment (chemotherapy and/or radiotherapy)</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="TFN5">
                <p>BNP: brain natriuretic peptide; CT: computed tomography; LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging.</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
          <p>Anthracyclines and anti-HER2 monoclonal antibodies account for most documented cases of left ventricular (LV) dysfunction. Cardinale et al. <xref ref-type="bibr" rid="B11"><sup>11</sup></xref> demonstrated that the incidence of CTX for anthracycline use in a population of 2,625 patients was 9%, with 98% of cases occurring in the first year of treatment. <xref ref-type="bibr" rid="B11"><sup>11</sup></xref> Alkylating agents, proteasome inhibitors, and some tyrosine kinase inhibitors also cause dysfunction by means of several mechanisms. <xref ref-type="bibr" rid="B4"><sup>4</sup></xref> Severe inflammatory myocarditis may be associated with immune checkpoint inhibitors in 0.27% of patients in use of a combination of nivolumab and ipilimumab. <xref ref-type="bibr" rid="B12"><sup>12</sup></xref> </p>
          <p>Coronary artery disease (CAD), clinically manifested as stable or unstable angina or AMI, may be secondary to direct endothelial injury, acute arterial thrombosis, or vasospasm, depending on the therapeutic class that was used. Obstructive atherosclerosis, plaque rupture and coronary thrombosis, annular/valvular degenerations, and pericarditis are related to mediastinal radiotherapy and are dependent on the radiation dose that was used. Hypertension is closely linked to the use of endothelial growth factor inhibitors. Deep venous thrombosis (DVT), peripheral artery disease, and pulmonary hypertension are also within the range of clinical manifestations of CTX. <xref ref-type="bibr" rid="B4"><sup>4</sup></xref> </p>
        </sec>
      </sec>
      <sec>
        <title>2. Myocardial Cardiotoxicity</title>
        <sec>
          <title>2.1. Contribution from Echocardiography</title>
          <sec>
            <title>2.1.1. Myocardial Structural and Functional Assessment of the Left Ventricle</title>
            <sec>
              <title>2.1.1.1. Standard Doppler Echocardiography</title>
              <p>When myocardial dysfunction was recognized as a potential adverse effect of cancer treatment, several strategies were then tested to monitor myocardial function. Initially considered to be the most accurate method, endomyocardial biopsy quickly fell into disuse because of its invasive nature, being then replaced by serial monitoring of LV systolic function by noninvasive cardiovascular imaging tests.</p>
              <p>Echocardiography has become a consolidated method for monitoring CTX using LVEF, as it is widely available, cost-effective, and harmless, allowing for it to be repeated multiple times. Additionally, it provides several other anatomical and functional findings.</p>
              <p>Administration of the Simpson method improves the estimation of ventricular volumes, overcoming the limitations of fractional shortening and the Teichholz formula, obtained from linear measurements of M-mode or two-dimensional (2D) echocardiography. However, sensitivity to detect small longitudinal variations in systolic function remains low, mainly because of frequent preload and afterload variations during chemotherapy and intra- and inter-observer variability (one of the most accepted parameters for diagnosis of CTX), which may reach up to 10%. <xref ref-type="bibr" rid="B13"><sup>13</sup></xref> It is important to remember that, because of those variations, tests with results outside the expected parameters should be repeated and confirmed 2 to 3 weeks after the initial finding.</p>
              <p>The risk of CTX is considered to range from 3.6 to 11.8 times for use of cardiotoxic drugs (especially anthracyclines) if pre-treatment LVEF is between 50% and 55%. During monitoring and after cancer treatment, CTX identification should be based on a fall &gt; 10% in LVEF (compared to pre-treatment values) to less than 50. <xref ref-type="bibr" rid="B14"><sup>14</sup></xref> This situation is the subject of an important debate in medical teams regarding cardiological risk and cancer benefit. The discussed approaches include replacing it with lower cardiotoxic risk treatments, using cardioprotective measures, and even discontinuing treatment (if LVEF &lt; 45% for anthracyclines and &lt; 40% for the other classes), a decision always made together with the oncologist. <xref ref-type="bibr" rid="B14"><sup>14</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B15"><sup>15</sup></xref> </p>
              <p>The assessment of longitudinal systolic function, especially when advanced methods (three-dimensional [3D] echocardiography and myocardial deformation analysis) are unavailable, should be performed jointly. Although there are no reference ranges for diagnosis, a progressive decline in the measurement of mitral annular peak systolic velocity by tissue Doppler imaging (s' wave) and mitral annular plane systolic excursion (MAPSE) is significant. <xref ref-type="bibr" rid="B16"><sup>16</sup></xref> </p>
              <p>The number of times that echocardiographic imaging is required remains controversial in the literature, varying according to individual risk, therapeutic protocol (drugs used and total dosage), and identification of CTX signs and symptoms.</p>
              <p>It is important to remember that CTX, in the form of quantitative changes in conventional parameters for assessing systolic function, may not be evident until there is a substantial reduction in myocardial reserve. Thus, cardiac damage may not become apparent for years or even decades after the end of cardiotoxic treatment, a fact that is particularly applicable to adult survivors of tumors during childhood.</p>
            </sec>
            <sec>
              <title>2.1.1.2. Myocardial Strain</title>
              <p>Strain, or deformation, is defined as the amount of deformation or the fractional change in the length of a myocardial segment from initial length. Such parameter is expressed as a percentage (%) and with the negative sign. <xref ref-type="bibr" rid="B17"><sup>17</sup></xref> </p>
              <p>Two-dimensional strain imaging, deriving from speckle tracking, is not dependent on the angle (a limiting factor when tissue Doppler imaging is used), which makes it more reproducible and more commonly used in general clinical practice to detect early changes in myocardial mechanics. <xref ref-type="bibr" rid="B17"><sup>17</sup></xref> Three-dimensional strain imaging represents an improvement of the technique. In this modality, an entire pyramidal volume is obtained from the apical view and then analyzed, being much faster than the other modalities but having lower spatial and temporal resolution.</p>
              <p>The fall in LVEF is a late marker of myocardial damage and translates into a poor prognosis, with reduced chance of ventricular function recovery in 58% of patients, despite any intervention with cardioprotective drugs. Cardiac dysfunction only becomes evident when myocardial damage is significant; therefore, absence of LVEF reduction does not exclude CTX. <xref ref-type="bibr" rid="B18"><sup>18</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B19"><sup>19</sup></xref> </p>
              <p>Thus, administration of speckle-tracking strain imaging to analyze ventricular mechanics is gradually extending to all heart diseases, especially those associated with the use of anticancer agents, such as anthracyclines and trastuzumab. <xref ref-type="bibr" rid="B20"><sup>20</sup></xref> The possibility of detecting subclinical lesions has been one of the great advantages. Overall, although early change detection is conceptually important, the value of actual changes must be proven to correlate with the outcomes.</p>
              <p>A review of several studies demonstrated the ability of strain imaging to detect myocardial deformation changes earlier than the fall in LVEF, either immediately after therapy infusion or in later stages. <xref ref-type="bibr" rid="B21"><sup>21</sup></xref> </p>
              <p>Ganame et al. <xref ref-type="bibr" rid="B22"><sup>22</sup></xref> demonstrated the acute effects of anthracyclines, which are able to induce systolic dysfunction. <xref ref-type="bibr" rid="B22"><sup>22</sup></xref> The same group of investigators studied 56 patients without any risk factors for cardiovascular disease (CVD), diagnosed with lymphoma, leukemia, and other malignant tumors, treated only with anthracyclines (dose lower than 300 mg/m<sup>2</sup>), and compared them with a control group. <xref ref-type="bibr" rid="B23"><sup>23</sup></xref> After a mean follow-up of 5.2 years, a significant reduction in global longitudinal strain (GLS) was demonstrated at a time point when LVEF was still normal, showing that new diagnostic tools are able to predict this decline early in time.</p>
              <p>Sawaya et al. <xref ref-type="bibr" rid="B24"><sup>24</sup></xref> used 2D speckle tracking to demonstrate that GLS and troponin were predictors of systolic dysfunction in patients with breast cancer treated with anthracyclines and trastuzumab. <xref ref-type="bibr" rid="B24"><sup>24</sup></xref> Forty-three patients underwent echocardiography at baseline and at three and six months of treatment. LVEF using the Simpson biplane method, GLS, radial and circumferential strain, and biomarkers were assessed. In that study, GLS was able to predict CTX in seven out of nine patients, with a sensitivity of 78% and a specificity of 79%. The event occurred at three months of follow-up in one of the patients and at six months in the others.</p>
              <p>Tan et al. <xref ref-type="bibr" rid="B25"><sup>25</sup></xref> examined LVEF and GLS in 19 patients with breast cancer using trastuzumab and followed-up for 34 months (mean 24.7 months). They observed that changes in ventricular function persisted for a long period, with increased LV chamber dimensions and reduced GLS throughout the entire follow-up, questioning the reversibility of the damage caused by trastuzumab. <xref ref-type="bibr" rid="B25"><sup>25</sup></xref> </p>
              <p>Almeida et al. evaluated 40 patients with breast cancer who had used doxorubicin two years prior to undergoing an echocardiogram and compared them with 41 healthy women. The authors demonstrated that GLS and S&#8217; wave of the mitral annulus were reduced in patients who underwent chemotherapy, but LVEF remained normal, suggesting the presence of subclinical ventricular dysfunction. The authors also showed that age and previous use of doxorubicin were independent markers of GLS reduction. <xref ref-type="bibr" rid="B26"><sup>26</sup></xref> </p>
              <p>Recently, Piveta et al. <xref ref-type="bibr" rid="B27"><sup>27</sup></xref> evaluated the role of 3D strain in patients with breast cancer treated with anthracyclines. After exposure to a low anthracycline dose (120 mg/m<sup>2</sup>), only 3D circumferential strain and 3D area strain showed changes, while 2D strain parameters remained unchanged. <xref ref-type="bibr" rid="B27"><sup>27</sup></xref> </p>
              <p>A systematic review of 1,504 patients showed that a relative reduction of 10% to 15% in GLS from baseline was an important predictor for a decline in LVEF. Radial and circumferential strain measurements also show changes, but such variables are not yet routinely used. When pre-chemotherapy values are not available for comparison, GLS values greater than -19% are suggestive of CTX, and the association with biomarkers, especially ultrasensitive troponin, increases the sensitivity for diagnosis of CTX. It is worth noting that reference ranges may vary depending on the software used in the devices and age and sex of the patients, hence the recommendation to repeat the tests using always the same device and, preferably, the same examiner. <xref ref-type="bibr" rid="B21"><sup>21</sup></xref> </p>
              <p>An expert consensus of the American and European Cardiovascular Imaging Societies suggests that changes in deformation precede ventricular dysfunction. <xref ref-type="bibr" rid="B28"><sup>28</sup></xref> A reduction &gt; 15% in GLS immediately after or during anthracycline therapy is the most useful parameter in predicting CTX, while a reduction &gt; 8% will probably exclude the diagnosis of CTX ( <xref ref-type="fig" rid="f31">Figure 1</xref> ).</p>
              <fig id="f31">
                <label>Figure 1</label>
                <caption>
                  <title>Clinical monitoring and management during cardiotoxic therapy.</title>
                </caption>
                <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf01-en.tif"/></fig>
              <p>Liu et al. <xref ref-type="bibr" rid="B29"><sup>29</sup></xref> described in 2018 an algorithm to follow-up patients treated with anticancer agents that used LVEF and GLS as echocardiographic measures. In patients with LVEF &gt; 60%, the recommendation was to optimize the control of existing cardiovascular risk factors. Those with LVEF between 50% and 59% and with GLS lower than -16% or at the lower limit of normal were classified as preserved myocardial function; those with GLS greater than -16% or a 15% reduction from baseline were considered to have subclinical dysfunction. Patients with LVEF between 40% and 49% were considered to have myocardial dysfunction; thus, this specific group was indicated for initiation of cardioprotective therapy and a joint evaluation with the oncologist on the risks and benefits of anticancer therapy, with an occasional dose reduction or medication change. In patients with LVEF &lt; 40%, it is recommended that cardioprotective therapy is initiated and the use of a noncardiotoxic alternative therapy is discussed with the oncologist.</p>
              <p>There is no consensus on systolic function indices to be monitored during treatment. <xref ref-type="bibr" rid="B14"><sup>14</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B15"><sup>15</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B29"><sup>29</sup></xref> However, recently, the SUCCOUR (Strain sUrveillance of Chemotherapy for improving Cardiovascular Outcomes) study was published. It showed that treatment guided by a greater than 12% drop in the LV global longitudinal strain in patients treated with anthracyclines is able to prevent the drop in ejection fraction and cardiotoxicity in 1 year. <xref ref-type="bibr" rid="B30"><sup>30</sup></xref> In addition to the diagnosis of CTX, the identification of GLS reduction has prognostic value, as it has been associated with higher late mortality in a retrospective study involving 120 patients followed-up for 21.6 &#177; 13.9 months. <xref ref-type="bibr" rid="B31"><sup>31</sup></xref> </p>
            </sec>
            <sec>
              <title>2.1.1.3. Left Ventricular Ejection Fraction by 3D Imaging</title>
              <p>Three-dimensional echocardiographic imaging is the method of choice for calculating LVEF during cancer treatment ( <xref ref-type="fig" rid="f32">Figure 2</xref> ). <xref ref-type="bibr" rid="B32"><sup>32</sup></xref> By providing greater resemblance to cardiac anatomy, it is much consistent with cardiac magnetic resonance imaging (MRI) in the calculation of volumes, mass, and LVEF. <xref ref-type="bibr" rid="B33"><sup>33</sup></xref> The 3D analysis is not dependent on geometric assumptions, as is the case of 2D analysis, in addition to minimizing limitations related to that technique such as &#8220;apical shortening.&#8221;</p>
              <fig id="f32">
                <label>Figure 2</label>
                <caption>
                  <title>Example of a tree-dimensional echocardiogram with full volume analysis and estimated volumes and left ventricular ejection fraction.</title>
                </caption>
                <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf02-en.tif"/></fig>
              <p>The predominant CTX change for a consequent decrease in LVEF is an increase in LV end-systolic volume. <xref ref-type="bibr" rid="B15"><sup>15</sup></xref> In the oncology population, studies suggest that 3D imaging is preferable to 2D imaging mainly because the former has demonstrated greater reproducibility and greater accuracy in the recognition of borderline or slightly reduced LVEF. In survivors of cancer treated with anthracyclines, Armstrong et al. <xref ref-type="bibr" rid="B34"><sup>34</sup></xref> demonstrated that 3D imaging had greater ability to identify patients with LVEF &lt; 50% than 2D imaging, with an accuracy very similar to that of cardiac MRI, allowing for earlier identification of subclinical CTX. <xref ref-type="bibr" rid="B34"><sup>34</sup></xref> The SUCCOUR study used two criteria of cardiotoxicity by preferentially 3D echocardiography: a fall of more than 5% in patients with symptoms of heart failure, or greater than 10% in asymptomatic patients, compared with the baseline test for values of ejection fraction lower than 55%. <xref ref-type="bibr" rid="B30"><sup>30</sup></xref> </p>
              <p>In patients undergoing chemotherapy, Thavendiranathan et al. <xref ref-type="bibr" rid="B13"><sup>13</sup></xref> compared different echocardiographic techniques for sequential assessment of LVEF over 1 year and demonstrated that 3D imaging had the lowest intra- and inter-observer temporal variability (5.6%). <xref ref-type="bibr" rid="B13"><sup>13</sup></xref> This finding suggests that, in addition to being reliable, 3D imaging is a consistent and reproducible method for evaluation of patients with cancer. <xref ref-type="bibr" rid="B32"><sup>32</sup></xref> Other papers also highlight the greater reproducibility of 3D imaging in the calculation of LVEF, mainly because, as a semiautomatic technique for endocardial tracing, it is less affected by variability in image acquisition. <xref ref-type="bibr" rid="B35"><sup>35</sup></xref> </p>
            </sec>
            <sec>
              <title>2.1.1.4. Contrast Echocardiography</title>
              <p>Inadequate visualization of LV endocardial borders often occurs in patients undergoing chemotherapy for breast cancer, particularly when following mastectomy and radiotherapy. Consequently, underestimated volumes and inaccurate LVEF determination may occur. According to international guidelines, an ultrasound contrast agent should be used to improve the definition of endocardial borders and the analysis of LV function when endocardial visualization is limited in two or more segments. <xref ref-type="bibr" rid="B36"><sup>36</sup></xref> Conversely, contrast agents are not recommended when LVEF is estimated on 3D echocardiogram, as they lead to less reproducibility and greater temporal variability in LVEF compared to 3D imaging alone. <xref ref-type="bibr" rid="B13"><sup>13</sup></xref> </p>
            </sec>
            <sec>
              <title>2.1.1.5. Stress Echocardiography</title>
              <p>Exercise or pharmacological stress echocardiography is an established method for detecting obstructive CAD and subclinical changes in myocardial function. Patients with cancer often have a decrease in global cardiovascular reserve, attributed to the direct effects of adjuvant cancer therapy and/or the indirect effects of lifestyle changes associated with treatment. <xref ref-type="bibr" rid="B37"><sup>37</sup></xref> Thus, the potential uses for stress echocardiography in patients undergoing cancer therapy include the following: (a) initial investigation of presence of obstructive CAD in patients with intermediate-to-high pre-test probability, noninterpretable ECG (exercise) or unable to exercise (dobutamine), especially if receiving chemotherapy associated with ischemia or after long-term radiotherapy; (b) determination of left ventricular contractile reserve (LVCR) as a predictor of CTX in patients with normal rest LVEF and GLS; (c) determination of LVCR in established CTX, as transient recovery of LV function during stress could indicate a better prognosis. <xref ref-type="bibr" rid="B28"><sup>28</sup></xref> Despite those potentialities, stress echocardiography has been scarcely used in the field of cardio-oncology.</p>
              <p>Using exercise stress echocardiography in 57 asymptomatic women with normal LVEF treated for breast cancer with anthracyclines, Khouri et al. <xref ref-type="bibr" rid="B38"><sup>38</sup></xref> found a 12% reduction in stroke volume and a 24% reduction in cardiac index from rest when compared to controls, suggesting impaired LVCR. <xref ref-type="bibr" rid="B38"><sup>38</sup></xref> </p>
              <p>Civelli et al. <xref ref-type="bibr" rid="B39"><sup>39</sup></xref> prospectively measured LVCR (defined as the difference between peak and rest LVEF) using low-dose dobutamine stress echocardiography during and after high-dose chemotherapy in 49 women with advanced breast cancer. An asymptomatic decline &#8805; 5% in LVCR from baseline was able to predict a fall in LVEF to &lt; 50%. <xref ref-type="bibr" rid="B39"><sup>39</sup></xref> </p>
              <p>The only published systematic review on the utility of cardiac stress methods for detecting CVD in survivors of breast cancer concluded that there seems to be evidence that stress echocardiography is beneficial to early prognostic evaluation and late follow-up after anthracycline therapy. <xref ref-type="bibr" rid="B40"><sup>40</sup></xref> </p>
              <p>Before stress echocardiography can be routinely added to clinical practice in cardio-oncology, further studies are needed to determine the best stressor, which parameters should be measured during the test, the best time to perform the test according to the different types of treatment, cost-benefit and feasibility in the oncology population, and, finally, the presence of incremental prognostic value over traditional parameters measured at rest (LVEF and GLS).</p>
            </sec>
            <sec>
              <title>2.1.1.6. Diastolic Function</title>
              <p>Abnormal parameters related to diastolic function, such as E and A waves, E/A ratio, isovolumic relaxation time, and myocardial performance index, have been described early after chemotherapy. <xref ref-type="bibr" rid="B41"><sup>41</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B42"><sup>42</sup></xref> However, longitudinal studies have not been able to reproduce the prognostic value of those findings and there is insufficient evidence to recommend such assessment in the diagnosis of chemotherapy-induced CTX. <xref ref-type="bibr" rid="B43"><sup>43</sup></xref> </p>
              <p>Studies have demonstrated the utility of tissue Doppler-derived measurements in the assessment of diastolic function in patients undergoing cancer treatment. Some papers have shown a reduction in tissue Doppler-derived early diastolic velocity (e&#8217; wave) of the mitral annulus in patients treated with anthracyclines, which remained reduced during treatment and years later, but no predictive value for CTX was demonstrated. <xref ref-type="bibr" rid="B16"><sup>16</sup></xref> Negishi et al. <xref ref-type="bibr" rid="B44"><sup>44</sup></xref> revealed that a 10% reduction in e&#8217; wave velocity was observed in patients who developed CTX after treatment with higher cumulative doses of doxorubicin, but this parameter was not shown to have a predictive role for LVEF fall. <xref ref-type="bibr" rid="B44"><sup>44</sup></xref> </p>
              <p>The use of diastolic dysfunction as a specific CTX marker has been questioned. Abnormalities may occur due to preload changes resulting from volume replacements associated with cancer treatment or volume depletion associated with side effects of chemotherapy, such as nausea, vomiting, and diarrhea. In such cases, they may not represent an actual change in LV diastolic performance.</p>
            </sec>
          </sec>
          <sec>
            <title>2.1.2. Myocardial Structural and Functional Assessment of the Right Ventricle</title>
            <p>The prevalence and prognostic value of right ventricular (RV) involvement have not yet been properly studied. Data on the influence of chemotherapy on RV remodeling, function, and mechanics are scarce and, at times, conflicting.</p>
            <p>The difficulty inherent to RV assessment and hemodynamic variations suggests that parameters such as tricuspid annular plane systolic excursion (TAPSE), tissue velocity of the basal segment of the RV free wall (S&#8217; wave), RV fractional area change (FAC), as well as myocardial strain are ideally measured by echocardiography, while the assessment of right ventricular ejection fraction (RVEF) is left to MRI or 3D echocardiography.</p>
            <p>The drugs most frequently related to RV dysfunction and changes in pulmonary circulation are anthracyclines, trastuzumab, cyclophosphamide, and dasatinib. <xref ref-type="bibr" rid="B45"><sup>45</sup></xref> Boczar et al. assessed RV longitudinal strain in patients with breast cancer treated with anthracycline. After 3 months, they observed that strain reduced from -16.2% to -13.81%. <xref ref-type="bibr" rid="B46"><sup>46</sup></xref> The difference in RV longitudinal strain is more pronounced when the septum is excluded, suggesting a greater sensitivity of the RV myocardium. <xref ref-type="bibr" rid="B47"><sup>47</sup></xref> </p>
          </sec>
          <sec>
            <title>2.1.3. Late Echocardiographic Follow-up</title>
            <p>Recommendations regarding patient follow-up after completion of chemotherapy will vary according to the clinical characteristics of the study population, the protocol used in chemotherapy (with or without radiotherapy), and the cumulative dose of drugs (especially trastuzumab and anthracyclines). Because of the increased risk of developing CTX within 12 months of anthracycline use, the fall in LVEF during trastuzumab use, and the appearance of late complications following radiotherapy, we suggest performing late follow-up as shown in <xref ref-type="fig" rid="f33">Figure 3</xref> .</p>
            <fig id="f33">
              <label>Figure 3</label>
              <caption>
                <title>Recommendations for late echocardiographic follow-up.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf03-en.tif"/></fig>
          </sec>
        </sec>
        <sec>
          <title>2.2. Contribution from Nuclear Medicine</title>
          <sec>
            <title>2.2.1. Radionuclide Ventriculography</title>
            <p>Radionuclide ventriculography, often referred to as a multigated acquisition (MUGA) scan, is a scintigraphic test performed using a gamma chamber in the nuclear medicine (NM) department. This is a noninvasive method that produces low radiation exposure and does not cause severe side effects, with excellent reproducibility and low inter- and intra-observer variability in assessing ventricular function. <xref ref-type="bibr" rid="B48"><sup>48</sup></xref> </p>
            <p>Together with echocardiography, radionuclide ventriculography is the most widely accepted method for assessing LVEF in patients before and during cancer treatment and identifying the risk for chronic HF (90% sensitivity and 72% specificity). <xref ref-type="bibr" rid="B49"><sup>49</sup></xref> </p>
            <p>With a normal baseline LVEF, the next measurements should be made at cumulative doses of 250 to 300 and 400 to 450 mg/m<sup>2</sup>. For patients with abnormal baseline LVEF (&lt; 50%), serial studies are recommended before each subsequent dose of doxorubicin. <xref ref-type="fig" rid="f34">Figure 4</xref> shows examples of LVEF behavior assessed by radionuclide ventriculography in patients undergoing chemotherapy.</p>
            <fig id="f34">
              <label>Figure 4</label>
              <caption>
                <title>Examples of two patients who underwent radionuclide ventriculography to measure left ventricular ejection fraction (LVEF) before and after anthracycline chemotherapy. The upper left image shows the baseline LVEF of the first patient, which was 71% (normal) and then decreased to 50% after the end of chemotherapy and start of trastuzumab therapy (upper right). The lower left image shows the baseline LVEF (52%) of a patient with breast cancer before the start of chemotherapy, which decreased to 46% during follow-up (lower right), leading to the use of cardioprotective medication. The images were kindly provided by Dr. M&#225;rcia Modesto (Nuclear Medicine Department of the Instituto Brasileiro de Controle do C&#226;ncer, S&#227;o Paulo, Brazil).</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf04-en.tif"/></fig>
          </sec>
          <sec>
            <title>2.2.2. Assessment of Cardiac Sympathetic Activity with mIBG</title>
            <p>Meta-iodobenzylguanidine (mIBG) is a molecule with a structure similar to that of norepinephrine and selectively acts on sympathetic nerves without, however, being metabolized by monoamine oxidase or catechol-O-methyltransferase, and not having a stimulatory effect as norepinephrine does. Cardiac <xref ref-type="bibr" rid="B123"><sup>123</sup></xref> I-mIBG scintigraphy directly assesses the global and regional sympathetic function of the heart, including uptake, reuptake, storage, and release processes of norepinephrine at presynaptic nerve terminals. <xref ref-type="bibr" rid="B50"><sup>50</sup></xref> </p>
            <p>Guimar&#227;es et al. <xref ref-type="bibr" rid="B51"><sup>51</sup></xref> performed cardiac <xref ref-type="bibr" rid="B123"><sup>123</sup></xref> I-mIBG scintigraphy in 20 women with breast cancer and normal LVEF who had been treated with anthracycline derivatives combined with trastuzumab or alone. The authors observed that the combined use of anthracycline and trastuzumab provided a higher frequency and intensity of cardiac adrenergic hyperactivity. <xref ref-type="bibr" rid="B51"><sup>51</sup></xref> Another study identified abnormal <xref ref-type="bibr" rid="B123"><sup>123</sup></xref> I-mIBG uptake in patients who used anthracycline. Additionally, <xref ref-type="bibr" rid="B123"><sup>123</sup></xref> I-mIBG uptake from heart-to-mediastinum ratio decreased as the cumulative dose of the drug increased. <xref ref-type="bibr" rid="B52"><sup>52</sup></xref> Those results support the hypothesis that early cardioprotection with beta-blockers may be beneficial for those patients.</p>
          </sec>
          <sec>
            <title>2.2.3. Myocardial Metabolism &#8211; <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG PET-CT</title>
            <p>Recently, Borde et al. <xref ref-type="bibr" rid="B53"><sup>53</sup></xref> retrospectively analyzed myocardial uptake of <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-fluorodeoxyglucose (FDG) in patients with lymphoma treated with adriamycin-based chemotherapy. <xref ref-type="bibr" rid="B53"><sup>53</sup></xref> The authors demonstrated that increased myocardial metabolic activity may be a potential marker of cell alteration preceding the CTX cascade. In that study, the increase in glucose metabolism in the heart muscle was directly proportional to the cumulative dose of doxorubicin (in mg/m<sup>2</sup>). Similar findings have also been suggested in patients with radiation-induced cardiac damage. <xref ref-type="bibr" rid="B54"><sup>54</sup></xref> Toubert et al. <xref ref-type="bibr" rid="B55"><sup>55</sup></xref> demonstrated a change in myocardial <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG uptake in a patient treated with a combination of tyrosine kinase inhibitors (imatinib and sorafenib) who subsequently developed fatal HF ( <xref ref-type="table" rid="t15">Table 3</xref> ). <xref ref-type="bibr" rid="B55"><sup>55</sup></xref> </p>
            <table-wrap id="t15">
              <label>Table 3</label>
              <caption>
                <title>PET-CT studies that assessed the relationship of 18F-FDG myocardial uptake in patients undergoing chemotherapy or radiotherapy <xref ref-type="bibr" rid="B55"><sup>55</sup></xref> </title>
              </caption>
              <table frame="hsides" rules="rows">
                <colgroup width="50%">
                  <col/>
                  <col/>
                </colgroup>
                <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
                  <tr>
                    <th align="left" colspan="2" valign="middle">Myocardial <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG PET-CT vs. drugs: what do the studies show?</th>
                  </tr>
                </thead>
                <tbody style="border-bottom: thin solid; border-color: #000000">
                  <tr>
                    <td align="left" valign="middle">Borde et al. <xref ref-type="bibr" rid="B53"><sup>53</sup></xref> </td>
                    <td align="left" valign="middle">Adriamycin: increased <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG uptake in the myocardium may precede a reduction in left ventricular function, and the degree of cardiotoxicity is proportional to the received dose.</td>
                  </tr>
                  <tr>
                    <td align="left" valign="middle">Toubert et al. <xref ref-type="bibr" rid="B55"><sup>55</sup></xref> </td>
                    <td align="left" valign="middle">Tyrosine kinase inhibitors (imatinib and sorafenib): a case report showed a change in <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG myocardial uptake prior to a fatal cardiac event.</td>
                  </tr>
                  <tr>
                    <td align="left" valign="middle">Evans et al. <xref ref-type="bibr" rid="B58"><sup>58</sup></xref> </td>
                    <td align="left" valign="middle">Increased <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG uptake in patients who received thoracic radiotherapy of &gt; 20 Gy to &gt; 5 cm<sup>2</sup>of the heart: indicator of myocardial injury.</td>
                  </tr>
                </tbody>
              </table>
              <table-wrap-foot>
                <fn id="TFN6">
                  <p><xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG: <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-fluorodeoxyglucose; PET-CT: positron emission tomography&#8211;computed tomography.</p>
                </fn>
              </table-wrap-foot>
            </table-wrap>
            <p>Positron emission tomography with computed tomography (PET-CT) scans using <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG, as well as those obtained by MRI, may be useful in the diagnosis of CTX induced by immune checkpoint inhibitors, as they allow detecting, evaluating the extent, and even quantifying the inflammatory process of several CVDs, such as myocarditis, pericarditis, and vasculitis. <xref ref-type="bibr" rid="B56"><sup>56</sup></xref><sup>-</sup><xref ref-type="bibr" rid="B58"><sup>58</sup></xref> </p>
          </sec>
        </sec>
        <sec>
          <title>2.3. Contribution from Cardiac Magnetic Resonance Imaging</title>
          <sec>
            <title>2.3.1. Assessment of Cardiotoxicity during Antineoplastic Treatment</title>
            <p>Cardiac MRI is considered the gold standard for measuring LVEF and ventricular mass and volume, making it a valuable tool to assess chemotherapy-induced CTX. <xref ref-type="bibr" rid="B34"><sup>34</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B59"><sup>59</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B60"><sup>60</sup></xref> LVEF may be reduced by changing one or both volumes. In general, reduced diastolic volume is related to preload status that undergoes dynamic, constant changes in a patient with cancer due to vomiting, bleeding, diarrhea, or dehydration. These are readily reversible with blood volume restoration. However, a progressive increase in stroke volume is considered a marker of chemotherapy-related myocardial injury. Another important parameter that should be monitored during chemotherapy is ventricular mass. CTX causes an initial increase in ventricular mass, probably due to induction of inflammatory response by chemotherapy, leading to an increased volume of the interstitium and cardiomyocytes. However, in later stages, usually after 6 months, there is a process of ventricular mass reduction (apoptosis, fibrosis, cardiomyocyte hypotrophy, etc.). Thus, when we are facing an increase in stroke volume and a reduction in ventricular mass, this combination is very suggestive of CTX, even if ejection fraction is preserved.</p>
            <p>More recently, myocardial strain analysis by cardiac MRI has been gaining prominence. In the population undergoing chemotherapy, the literature highlights the potential of the test to diagnose subclinical changes. <xref ref-type="bibr" rid="B61"><sup>61</sup></xref><sup>-</sup><xref ref-type="bibr" rid="B63"><sup>63</sup></xref> Jolly et al. <xref ref-type="bibr" rid="B61"><sup>61</sup></xref> studied 72 patients undergoing chemotherapy for breast cancer, sarcoma, or lymphoma with serial cardiac MRI. <xref ref-type="bibr" rid="B61"><sup>61</sup></xref> There was a significant impairment in global circumferential strain 3 months after treatment compared to baseline. Moreover, global circumferential strain strongly correlated with a subclinical fall in LVEF. In a different study of 41 patients with breast cancer treated with trastuzumab, both GLS and global circumferential strain decreased during treatment and correlated with a fall in LVEF. <xref ref-type="bibr" rid="B62"><sup>62</sup></xref> Cardiac MRI strain is not yet widely used in clinical practice, but studies have demonstrated that the method is potentially applicable to cardio-oncology patients.</p>
          </sec>
          <sec>
            <title>2.3.2. Cardiac Magnetic Resonance Imaging in Late Follow-up</title>
            <p>Late evaluation with cardiac MRI provides important diagnostic and prognostic findings when complemented with tissue analysis. It is important to understand that early changes during treatment are markers of some late changes, such as presence of delayed enhancement. Myocardial edema is suggestive of an inflammatory process in the myocardium, and the greater the water content, the greater the local signal intensity. <xref ref-type="bibr" rid="B64"><sup>64</sup></xref> A useful sequence in this context is triple inversion recovery, which is obtained by adding a third saturation pulse, to eliminate any adipose tissue signal (fat saturation) from the image. <xref ref-type="bibr" rid="B64"><sup>64</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B65"><sup>65</sup></xref> Some studies have shown myocardial edema in cardiac MRI soon after anthracycline therapy using T2-weighted sequences. <xref ref-type="bibr" rid="B66"><sup>66</sup></xref> Early increase in edema and subacute increase in fibrosis seen in mice that received anthracyclines were strongly related and are both indicators of late mortality. <xref ref-type="bibr" rid="B67"><sup>67</sup></xref> </p>
            <p>Delayed enhancement imaging is a widely validated noninvasive technique to identify and quantify myocardial fibrosis using gadolinium, a paramagnetic contrast agent. Different delayed enhancement patterns are recognized in cardiac MRI, which allows for identification of different types of myocardial involvement, thus distinguishing between ischemic and nonischemic cardiomyopathies. <xref ref-type="bibr" rid="B68"><sup>68</sup></xref> This is of particular importance when assessing chemotherapy-induced cardiomyopathy in individuals with preexisting cardiac conditions, such as CAD.</p>
            <p>The prevalence of delayed enhancement in CTX is low. <xref ref-type="bibr" rid="B59"><sup>59</sup></xref> Despite being the gold standard for identifying focal areas of myocardial fibrosis, delayed enhancement imaging is not suitable for assessing diffuse interstitial fibrosis, which is generally found in cardiomyopathy caused by CTX. There is no typical pattern of delayed enhancement for CTX related to anthracyclines and trastuzumab, and LVEF may fall even without delayed enhancement. <xref ref-type="bibr" rid="B60"><sup>60</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B69"><sup>69</sup></xref> If present, its characteristics resemble the known patterns of nonischemic cardiomyopathies (epicardial, mesocardial, focal, and/or junctional) ( <xref ref-type="fig" rid="f35">Figure 5</xref> ). <xref ref-type="bibr" rid="B68"><sup>68</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B70"><sup>70</sup></xref> </p>
            <fig id="f35">
              <label>Figure 5</label>
              <caption>
                <title>Focal delayed enhancement in the left ventricular inferolateral wall of a patient with breast cancer treated with anthracycline and trastuzumab.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf05-en.tif"/></fig>
            <p>Myocarditis is a severe, potentially fatal complication in patients undergoing immunotherapy, with a mortality rate of approximately 40%. <xref ref-type="bibr" rid="B71"><sup>71</sup></xref> It may have a higher incidence and even manifest as a fulminant condition in patients using immune checkpoint inhibitors, especially if they are in combination therapy and on average 34 days after therapy is initiated. <xref ref-type="bibr" rid="B72"><sup>72</sup></xref> </p>
          </sec>
          <sec>
            <title>2.3.3. Tissue Characterization by Cardiac Magnetic Resonance Imaging</title>
            <sec>
              <title>2.3.3.1. T2 Mapping</title>
              <p>Cardiac MRI has the advantage of providing detailed information on cardiac remodeling, which is complementary to the traditional morphological and functional assessment of the myocardium. Consistent data suggest that edema, inflammation, expansion of connective tissue matrix, and change in regional myocardial deformation occur before myocardial dysfunction in patients undergoing cardiotoxic treatment, reinforcing the potential applicability of that imaging modality in individuals exposed to cardiotoxic therapies.</p>
              <p>Clinical studies have recently shown that the use of cardiac MRI protocols that incorporate multiparametric T1 and T2 mapping sequences led to the detection of preclinical and early changes in CTX. <xref ref-type="bibr" rid="B73"><sup>73</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B74"><sup>74</sup></xref> The detection of myocardial edema, which is usually based on increased signal intensity on T2-weighted images in the myocardium normalized to skeletal muscle values, has been successfully used for ischemic and nonischemic heart muscle disease. <xref ref-type="bibr" rid="B75"><sup>75</sup></xref><sup>-</sup><xref ref-type="bibr" rid="B77"><sup>77</sup></xref> </p>
              <p>Using sequences widely available and simpler than T2 mapping, Ferreira de Souza et al. documented a significant increase in T2 signal intensity in women treated with moderate doses of doxorubicin (240 mg/m<sup>2</sup>). <xref ref-type="bibr" rid="B74"><sup>74</sup></xref> Several groups are currently investigating whether T2 mapping is applicable to the assessment of myocardial edema in survivors of cancer treated with antineoplastic therapies, but, to date, limited clinical data are available to warrant their use in everyday practice.</p>
            </sec>
            <sec>
              <title>2.3.3.2. T1 Mapping</title>
              <p>Although delayed enhancement imaging accurately demonstrates the presence of scarring and replacement fibrosis, this technique is not able to provide complete and definitive data on the total amount of fibrosis in the myocardium, especially on interstitial fibrosis. <xref ref-type="bibr" rid="B78"><sup>78</sup></xref> Because delayed enhancement imaging is based on relative differences in T1 signal intensity after administration of gadolinium-based contrast agents, visualization of diffuse interstitial fibrosis may be incomplete or limited by this technique.</p>
              <p>In both retrospective and prospective studies, delayed enhancement has not been uniformly detected in patients treated with anthracycline-based chemotherapy. <xref ref-type="bibr" rid="B79"><sup>79</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B80"><sup>80</sup></xref> In fact, a cardiac MRI scan with negative delayed enhancement or without areas of fibrosis does not necessarily exclude the presence of myocardial fibrosis, thus reinforcing the limitation of this method in this context. Although Fallah-Rad et al. have demonstrated the presence of subepicardial delayed enhancement in all patients who had LV dysfunction induced by trastuzumab, <xref ref-type="bibr" rid="B79"><sup>79</sup></xref> other studies have found conflicting results. Lawley et al. <xref ref-type="bibr" rid="B81"><sup>81</sup></xref> showed that &lt; 10% of women treated with trastuzumab had positive delayed enhancement. <xref ref-type="bibr" rid="B81"><sup>81</sup></xref> </p>
              <p>New techniques based on sequential T1 measurements performed before and after the administration of gadolinium-based contrast agents provide a more accurate assessment of myocardial extracellular volume (ECV), a marker of connective tissue matrix in the myocardium and interstitial fibrosis. Even before the introduction of T1 mapping, authors had already shown that T1 measurements were able to detect increased distribution of gadolinium in the myocardium in survivors of cancer treated with chemotherapy. <xref ref-type="bibr" rid="B79"><sup>79</sup></xref> These findings suggest that the expansion of connective tissue matrix assessed by T1 mapping emerges as an early marker of CTX and is able to predict impaired functional status.</p>
              <p>Patients previously exposed to anthracyclines have significantly higher ECV values when compared to healthy controls matched for age and sex. Jordan et al. investigated patients with and without cancer, including some treated and not treated with anthracycline as well as some treated with other chemotherapy agents. <xref ref-type="bibr" rid="B82"><sup>82</sup></xref> Native T1 values (prior to contrast administration) were consistently higher before and after treatment in those with cancer compared to those without cancer. The study also demonstrated that ECV increased significantly after anthracycline therapy (30.4 &#177; 0.7% vs. 27.8 &#177; 0.7%; P &lt; 0.01). Moreover, in multivariate statistical models, both native T1 and ECV values remained consistently higher in patients with cancer regardless of adjusting for other variables.</p>
              <p>As recently demonstrated, quantifying intracellular water lifetime (T1) in the myocardium emerges as an innovative approach to detect myocardial remodeling following cancer treatment, providing additional information to the assessment of ECV alone. <xref ref-type="bibr" rid="B15"><sup>15</sup></xref> A recent study evaluated 27 women with breast cancer before and after a cumulative doxorubicin dose of 240 mg/m<sup>2</sup>, including the measurement of biomarkers. From 1 to 2 years following doxorubicin use, there was a decrease in LVEF and indexed LV mass. Conversely, there was an increase in ECV and a reduction in intracellular water lifetime. <xref ref-type="bibr" rid="B74"><sup>74</sup></xref> </p>
            </sec>
          </sec>
        </sec>
      </sec>
      <sec>
        <title>3. Vascular Toxicity</title>
        <sec>
          <title>3.1. Contribution from Vascular Ultrasonography</title>
          <sec>
            <title>3.1.1. Venous Thromboembolism and Cancer</title>
            <sec>
              <title>3.1.1.1. Introduction</title>
              <p>The association between cancer and superficial venous thrombosis or DVT was first reported by Armand Trousseau in 1865. <xref ref-type="bibr" rid="B83"><sup>83</sup></xref> The relative risk of venous thromboembolism (VTE) is approximately seven times higher in patients with active cancer, and VTE may be the first manifestation of occult cancer (7% to 12% of cases), consisting of a &#8220;paraneoplastic phenomenon.&#8221; <xref ref-type="bibr" rid="B84"><sup>84</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B85"><sup>85</sup></xref> </p>
              <p>Occurrence of thrombosis complicates the management of patients with cancer because of the need for anticoagulant therapy and the potential risk of bleeding. Patients with cancer and acute VTE are at a higher risk of recurrent thrombosis than those without cancer. Finally, an episode of VTE increases the mortality of patients with cancer and this may be the result of massive pulmonary embolism or tumor progression. <xref ref-type="bibr" rid="B86"><sup>86</sup></xref> </p>
            </sec>
            <sec>
              <title>3.1.1.2. Epidemiology</title>
              <p>There are several associated factors that may increase the risk of thrombosis in patients with cancer, such as treatment (radiotherapy and/or chemotherapy), postoperative period, and intravascular devices. <xref ref-type="bibr" rid="B87"><sup>87</sup></xref> The incidence of DVT in patients with cancer is 4.7-fold higher than in those without cancer after adjusting for comorbidities, as demonstrated in a general population in Denmark. <xref ref-type="bibr" rid="B88"><sup>88</sup></xref> Two-year incidence rate ranges from 0.8% to 8.0% and is associated with high rates of recurrence and mortality. A higher incidence of VTE within 1 year of diagnosis occurs in those with advanced neoplastic disease of the brain, lung, uterus, bladder, pancreas, stomach, and kidney (4- to 13-fold higher in metastatic disease than in localized disease). Chemotherapy increases the risk of VTE by 7 times in patients with cancer.</p>
            </sec>
            <sec>
              <title>3.1.1.3. Diagnosis of Deep Venous Thrombosis</title>
              <p>Venous ultrasonography is the standard imaging test for patients with suspected (deep and/or superficial) venous thrombosis in central vessels, abdominal vessels, or extremities (cervical spine, upper and lower limbs). In addition to confirming or discarding the presence of thrombi, it allows for a differential diagnosis against other diseases.</p>
              <p>In clinical practice, the definition of the body segment to be examined depends on the signs and symptoms presented by the patient. In cases of suspected pulmonary embolism and no evidence of the location of the thrombi, venous ultrasound screening should prioritize the vessels in the lower limbs (site of 85% of DVT cases). If the result is negative for that site, the investigation will then include the iliac veins and the inferior vena cava, and, finally, cervical and upper limb vessels.</p>
            </sec>
            <sec>
              <title>3.1.1.4. Venous Ultrasound Protocols</title>
              <p>It is recommended that patients with a Wells score &#8805; 2 undergo venous ultrasonography (involving the compression of the entire lower limb every 2 cm from the inguinal ligament to the ankle, including the posterior tibial and peroneal veins as well as the gastrocnemius and soleus muscle veins in the calf; and color images with a spectral analysis of at least the common femoral and popliteal veins) because if only the femoropopliteal segment is examined and doubt remains, a complete examination should be repeated within 5 to 7 days to discard DVT (delaying diagnosis and increasing risks and costs). If there are symptomatic areas not included in the protocol, these must be assessed (e.g., anterior tibial veins, plantar veins, etc.). <xref ref-type="bibr" rid="B89"><sup>89</sup></xref> </p>
              <p>If a complete examination cannot be promptly conducted, a two-point compression ultrasound should be initially performed until a new test with complete protocol can be carried out. It is known that the availability of this diagnostic modality is limited in smaller medical centers and outpatient clinics as well as in the evenings and weekends.</p>
              <p>Specific examinations of the iliac veins and the inferior vena cava should be reserved for doubtful cases; rhizomelic thrombosis initiating in the upper thigh ( <xref ref-type="fig" rid="f36">Figure 6 A-B</xref> ); or when spectral flow curves (pulsed-wave Doppler) in the common femoral vein have a continuous pattern (loss of phasicity), suggesting proximal involvement.</p>
              <fig id="f36">
                <label>Figure 6</label>
                <caption>
                  <title>A and B &#8211; Rhizomelic edema in an adolescent with cancer and thrombotic occlusion of the right iliac vein (RIV).</title>
                </caption>
                <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf06-en.tif"/></fig>
            </sec>
            <sec>
              <title>3.1.1.5. Differential Diagnosis of Deep Venous Thrombosis</title>
              <p>Patients with cancer (occult or active, bedridden or not, undergoing chemotherapy or radiotherapy, using anticoagulants, with a venous catheter for drug infusion) and other comorbidities may have complications that require a differential diagnosis against venous thrombosis. The most frequent complications are unilateral or bilateral edema at any site and calf pain.</p>
              <p>Ultrasonography, in addition to discarding the presence of thrombi in the lumen of vessels in edematous segments, allows for diagnosis of tumor masses compressing the iliac veins and causing unilateral or bilateral edema; May-Thurner syndrome and left lower limb edema; extensive cellulite; and mediastinal masses compressing the superior vena cava and causing upper limb and neck edema. As bilateral edema is rarely caused by thrombosis, systemic conditions (heart failure [HF], liver failure, kidney failure, hypothyroidism) or medication use should be discarded.</p>
              <p>Another advantage of ultrasonography in cases of significant increase in limb volume due to tumor mass compression, extensive DVT, or large hematomas is the rapid assessment of possible impairment associated with regional arterial flow (i.e., compartment syndrome), which may lead to severe ischemia.</p>
            </sec>
          </sec>
          <sec>
            <title>3.1.2. Catheter-Related Thrombosis in Patients with Cancer</title>
            <sec>
              <title>3.1.2.1. Introduction</title>
              <p>Long-term catheter use is frequent in patients with cancer because of the need for infusion of chemotherapy agents and intravenous administration of supportive therapies. Catheter-related thrombosis (CRT) is defined as a mural thrombus that extends from the catheter to the lumen of the vessel, leading to partial obstruction or occlusion of the catheter, with or without clinical symptoms. <xref ref-type="bibr" rid="B90"><sup>90</sup></xref> </p>
              <p>Most cases of CRT occur within 100 days of catheter insertion. CRT rate is between 14% and 18% when venography or vascular ultrasound screening is performed. Of those, less than 5% of patients are symptomatic. <xref ref-type="bibr" rid="B91"><sup>91</sup></xref> </p>
              <p>CRT may cause pulmonary embolism and loss of vascular access in 15% and 10% of patients, respectively, which significantly increases the costs related to treatment and management. <xref ref-type="bibr" rid="B92"><sup>92</sup></xref> </p>
            </sec>
            <sec>
              <title>3.1.2.2. Risk Factors</title>
              <p>A meta-analysis that included five randomized studies of individuals with and without cancer prospectively evaluated CRT-related variables and found that the following were significant: <xref ref-type="bibr" rid="B93"><sup>93</sup></xref> </p>
              <list list-type="alpha-lower">
                <list-item>
                  <p>Subclavian vein &#215; upper limb insertion (odds ratio [OR] 2.16; 95% confidence interval [CI] 1.07-4.34);</p>
                </list-item>
                <list-item>
                  <p>Previous history of DVT (OR 2.03; 95% CI 1.05-3.92);</p>
                </list-item>
                <list-item>
                  <p>Improper catheter tip position (OR 1.92; 95% CI 1.22-3.02).</p>
                </list-item>
              </list>
              <p>In multivariate analysis, implanted ports showed a 57% reduction in the risk of CRT when compared to peripherally implanted central venous catheters. <xref ref-type="bibr" rid="B93"><sup>93</sup></xref> </p>
            </sec>
            <sec>
              <title>3.1.2.3. Diagnosis and Complications</title>
              <p>In thrombosis involving veins of the arm, axillary vein, distal subclavian vein, or jugular vein, sensitivity and specificity are very high (&gt; 95%) ( <xref ref-type="fig" rid="f37">Figure 7</xref> ). These values, however, fall to about 55% in thrombosis involving the proximal subclavian vein, the brachiocephalic veins, and the superior vena cava. This is due to a naturally difficult approach imposed by the anatomical barrier of bone and lung in this region. An alternative approach is the use of probes with a smaller contact surface area such as pediatric and/or adult sector probes and microconvex probes. The most frequent complications of thrombi are secondary infection (bacterial colonization), pulmonary embolism, and postthrombotic syndrome. <xref ref-type="bibr" rid="B94"><sup>94</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B95"><sup>95</sup></xref> </p>
              <fig id="f37">
                <label>Figure 7</label>
                <caption>
                  <title>Vascular ultrasound of the proximal supraclavicular region showing thrombus in the proximal right internal jugular vein (RIJV), brachiocephalic venous trunk (BCVT), and proximal right subclavian vein (RSCV). A central venous catheter (CATH) is observed in the RSCV directed towards the BCVT.</title>
                </caption>
                <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf07-en.tif"/></fig>
            </sec>
          </sec>
          <sec>
            <title>3.1.3. Pulmonary Hypertension in Patients with Cancer</title>
            <p>Pulmonary hypertension is defined as an increase in mean arterial pressure greater than 20 mm Hg detected through an invasive procedure of right heart catheterization. The most common form is due to LV involvement (World Health Organization group II).</p>
            <p>Echocardiogram remains the first-line test in the diagnostic investigation of pulmonary hypertension; however, it is important to reinforce that etiological diagnosis of pulmonary hypertension in patients with cancer is clinically complex, as we may find:</p>
            <list list-type="simple">
              <list-item>
                <label>&#8211;</label>
                <p>Masses or tumors in the left atrium (LA) causing obstruction and thereby leading to increased capillary pressure;</p>
              </list-item>
              <list-item>
                <label>&#8211;</label>
                <p>Extrinsic tumor compression, as seen in cases of large thymomas, lymphomas, or fibrosing mediastinitis;</p>
              </list-item>
              <list-item>
                <label>&#8211;</label>
                <p>Pulmonary thromboembolism secondary to the use of tyrosine kinase inhibitors such as dasatinib or to LV involvement (CTX, preexisting heart disease, valve diseases, etc.). <xref ref-type="bibr" rid="B96"><sup>96</sup></xref> </p>
              </list-item>
            </list>
            <p>In patients with pulmonary hypertension, computed tomography (CT) has a special value for assessing pulmonary vascularization and pulmonary parenchyma, providing information on possible mechanisms and consequences of pulmonary hypertension. Pulmonary parenchymal findings on CT scans of patients with pulmonary hypertension may vary and depend on the etiology. <xref ref-type="bibr" rid="B97"><sup>97</sup></xref> </p>
            <p>Noncontrast CT allows for detection of abnormalities related to pulmonary hypertension, such as enlarged pulmonary artery and dilated right chambers, and identifies conditions secondary to pulmonary disease, thus being sufficient for assessing most lung diseases. The test is indicated for assessing pulmonary parenchyma in diffuse lung diseases, such as interstitial lung diseases and chronic obstructive pulmonary disease, for detecting arteriovenous malformations, and for diagnosing veno-occlusive disease or pulmonary capillary hemangiomatosis.</p>
            <p>Contrast CT can define the pulmonary vascular anatomy and structure, obtaining accurate angiographic images from the pulmonary artery down to the subsegmental vessels. The technique is widely available, easy to perform, and more sensitive than invasive angiography in the detection of pulmonary emboli and thus has become the standard modality for noninvasive diagnosis of acute pulmonary embolism.</p>
            <p>In pulmonary hypertension, the RV will reflect pressure overload with hypertrophy and dilation, and may show ventricular dysfunction. Significant distortion of ventricular geometry may be present, with the RV taking on a globose shape, leading to LV compression in more advanced stages. Patients with pulmonary hypertension with RV dilation and reduced RV ejection fraction have a poorer prognosis. <xref ref-type="bibr" rid="B98"><sup>98</sup></xref> </p>
            <p>Cine imaging provides an accurate assessment of ventricular morphology and function with images acquired in short-axis orientation, obtaining complete volumetric coverage of the RV, although images acquired in transaxial orientation may also be used. Several data are obtained, such as end-systolic and end-diastolic volumes, ejection fraction, cardiac output, and myocardial mass. <xref ref-type="bibr" rid="B99"><sup>99</sup></xref> RV mass is measured by tracing the epicardial and endocardial borders, and ventricular mass index is usually calculated as the ratio between RV mass and LV mass.</p>
            <p>Interventricular septal geometry is also assessed by MRI, and projection to the left during systole indicates increased pressure in the right chambers. As the pressure in the lungs increases, systolic pressure of the RV may exceed that of the LV and lead to impaired LV stroke volume. In cases of more severe pulmonary hypertension, progressive RV failure affects LV diastolic function because the interventricular septum projects also during diastole, thus compromising LV diastolic filling and further reducing cardiac output. Interventricular septal curvature is an effective measure of geometric deformation involving the ventricles, with a strong correlation between paradoxical interventricular septal curvature and severity of pulmonary hypertension. <xref ref-type="bibr" rid="B100"><sup>100</sup></xref> </p>
            <p>New techniques are being implemented, such as myocardial strain analysis, phase-contrast imaging, and delayed enhancement imaging, with potential application in cases of patients with pulmonary hypertension, allowing for analysis of regional myocardial function, hemodynamic repercussions, and extent of RV impairment. <xref ref-type="bibr" rid="B101"><sup>101</sup></xref> </p>
          </sec>
        </sec>
      </sec>
      <sec>
        <title>4. Radiotherapy-Induced Cardiotoxicity</title>
        <sec>
          <title>4.1. Role of Echocardiography</title>
          <sec>
            <title>4.1.1. Epidemiology</title>
            <p>Radiotherapy holds an important place in cancer treatment. In the United States (US), over 3 million survivors of cancer underwent radiotherapy in 2016, accounting for 29% of all survivors 5 years after the initial diagnosis. The proportion of patients with cancer undergoing thoracic radiotherapy reaches 45.6% if those with breast cancer and lymphoma are included. Several studies have demonstrated an increased incidence of CAD, AMI, and sudden cardiac death in patients undergoing radiotherapy, especially those with Hodgkin lymphoma or breast cancer, reinforcing the potential side effects of the treatment. <xref ref-type="bibr" rid="B102"><sup>102</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B103"><sup>103</sup></xref> </p>
            <p>Radiation-induced heart disease (RIHD) is known as the multiple deleterious effects generated by the total cumulative dose of radiotherapy and enhanced by adjuvant chemotherapy on the cardiovascular system. The spectrum is highly variable and includes the involvement of any cardiovascular system structure, and late manifestation is much more frequent. Acute complications, usually more subtle and clinically less important, consist of myopericarditis and pericarditis. Late findings, which appear years or decades after exposure, tend to be clinically relevant and include cases of chronic pericarditis, valve diseases, medium- and large-vessel diseases (porcelain aorta and carotid stenosis), cardiomyopathies (dilated and restrictive types), conduction disorders, and CAD. <xref ref-type="bibr" rid="B104"><sup>104</sup></xref> There is abundant literature demonstrating that exposure to radiation, especially of the left chest, is associated with increased cardiovascular mortality, attributed mainly to CAD and a higher risk of developing HF. <xref ref-type="bibr" rid="B105"><sup>105</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B106"><sup>106</sup></xref> The most relevant risk factors for developing RIHD are shown in <xref ref-type="table" rid="t16">Table 4</xref> .</p>
            <table-wrap id="t16">
              <label>Table 4</label>
              <caption>
                <title>Risk factors for radiation-induced heart disease (RIHD)</title>
              </caption>
              <table frame="hsides" rules="rows">
                <colgroup width="99%">
                  <col width="1%"/>
                  <col/>
                </colgroup>
                <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
                  <tr>
                    <th align="left" colspan="2" valign="middle">RISK FACTORS FOR RIHD</th>
                  </tr>
                </thead>
                <tbody style="border-bottom: thin solid; border-color: #000000">
                  <tr>
                    <td align="left" valign="middle"/>
                    <td align="left" valign="middle">&lt; 50 years of age</td>
                  </tr>
                  <tr>
                    <td align="left" valign="middle"/>
                    <td align="left" valign="middle">Cumulative radiation dose &gt; 30 Gy</td>
                  </tr>
                  <tr>
                    <td align="left" valign="middle"/>
                    <td align="left" valign="middle">High fractional doses of radiation &gt; 2 Gy/day</td>
                  </tr>
                  <tr>
                    <td align="left" valign="middle"/>
                    <td align="left" valign="middle">Presence and extent of a tumor close to the heart</td>
                  </tr>
                  <tr>
                    <td align="left" valign="middle"/>
                    <td align="left" valign="middle">Concomitant use of chemotherapy agents (mainly anthracyclines)</td>
                  </tr>
                  <tr>
                    <td align="left" valign="middle"/>
                    <td align="left" valign="middle">Risk factors for cardiovascular disease (hypertension, DM, dyslipidemia, smoking)</td>
                  </tr>
                  <tr>
                    <td align="left" valign="middle"/>
                    <td align="left" valign="middle">Preexisting cardiovascular disease</td>
                  </tr>
                  <tr>
                    <td align="left" valign="middle"/>
                    <td align="left" valign="middle">Inadequate cardiac protection</td>
                  </tr>
                  <tr>
                    <td align="left" valign="middle"/>
                    <td align="left" valign="middle">Irradiation in the anterior region or left hemithorax</td>
                  </tr>
                  <tr>
                    <td align="left" colspan="2" valign="middle">
                      <bold>Definition of high risk: exposure to thoracic radiotherapy in the anterior or left chest region in addition to at least one of the listed factors</bold>
                    </td>
                  </tr>
                </tbody>
              </table>
              <table-wrap-foot>
                <fn id="TFN7">
                  <p>DM: diabetes mellitus.</p>
                </fn>
              </table-wrap-foot>
            </table-wrap>
          </sec>
          <sec>
            <title>4.1.2. Pathophysiology</title>
            <p>Cardiomyocytes are relatively resistant to radiation damage because of their postmitotic state. However, endothelial cells remain sensitive to radiation, and the pathophysiology of most forms of RIHD seems to be related to these cells. Other mechanisms that perpetuate cellular injury also seem to be implicated, such as ischemia and tissue hypoxia, in addition to the direct injury manifested by accelerated atherosclerosis, thrombosis, oxidative stress induction, myocytolysis, and activation of neurohumoral mechanisms leading to atherosclerosis and, finally, fibrosis. <xref ref-type="bibr" rid="B107"><sup>107</sup></xref> </p>
          </sec>
          <sec>
            <title>4.1.3. Initial Evaluation and Follow-Up</title>
            <p>In patients with cancer, complementary cardiovascular evaluation is classically dictated by symptom status or by suggestive findings on physical examination. Echocardiography plays a key role in the assessment of heart morphology and function and is considered the first imaging modality in most cases.</p>
            <p>Regarding post-radiotherapy follow-up, annual clinical evaluations are recommended, including targeted history taking, clinical examination, and resting electrocardiogram. In the presence of symptoms and/or new suggestive findings on physical examination, a new transthoracic echocardiogram (TTE) is suggested. In asymptomatic patients classified as low risk for developing RIHD, TTE surveillance is recommended after 10 years of exposure with subsequent reassessments every 5 years. In asymptomatic individuals classified as high risk, however, evaluation should be anticipated, including the investigation of myocardial ischemia using a noninvasive functional test, as shown in <xref ref-type="fig" rid="f38">Figure 8</xref> . <xref ref-type="bibr" rid="B104"><sup>104</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B108"><sup>108</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B109"><sup>109</sup></xref> </p>
            <fig id="f38">
              <label>Figure 8</label>
              <caption>
                <title>Algorithm for echocardiographic monitoring following thoracic radiotherapy. <xref ref-type="bibr" rid="B104"><sup>104</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B108"><sup>108</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B109"><sup>109</sup></xref> CAD: coronary artery disease; ECG: electrocardiogram; echo: echocardiogram; RF: risk factor; RIHD: radiation-induced heart disease; TTE: transthoracic echocardiogram.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf08-en.tif"/></fig>
          </sec>
          <sec>
            <title>4.1.4. Radiation-Induced Heart Disease and Role of Echocardiogram</title>
            <sec>
              <title>4.1.4.1. Radiation-Induced Pericardial and Myocardial Disease</title>
              <p>Pericardial disease is described as the most common side effect of thoracic radiotherapy, usually appearing a few weeks after treatment. New protocols including lower doses and implementation of cardioprotective techniques decreased the incidence from 20% to 2.5%, with a correlation proportional to the dose and volume exposed during treatment. <xref ref-type="bibr" rid="B103"><sup>103</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B104"><sup>104</sup></xref> Pericarditis is typically self-limiting. However, 10% to 20% of patients develop chronic or constrictive pericarditis 5 to 10 years after treatment, which is indicative of a more reserved prognosis. <xref ref-type="bibr" rid="B109"><sup>109</sup></xref> TTE provides diagnosis, allows for quantification of pericardial effusions, and serves as a guide to pericardiocentesis. A great advantage of the method is allowing for analysis of constrictive physiology, characterized by echocardiographic findings such as pericardial thickening, septal bounce, restrictive diastolic filling pattern, significant inspiratory variation in mitral inflow (&gt; 25%), inferior vena cava plethora, reduced circumferential strain, and hepatic vein diastolic expiratory flow reversal. The impact on survival has been attributed to the concomitant finding of other radiation-associated cardiac injuries, being commonly accompanied by myocardial fibrosis, premature coronary artery stenosis, and important valve injuries.</p>
            </sec>
            <sec>
              <title>4.1.4.2. Radiation-Induced Coronary Artery Disease</title>
              <p>Treatment of Hodgkin lymphoma and breast cancer typically includes thoracic radiotherapy, resulting in cardiac tissue exposure to radiation. The cumulative incidence of radiation-induced coronary artery disease (RICAD) is estimated to reach almost 60% in survivors of Hodgkin lymphoma, with a relative risk 3.2 times greater than that of the general population. <xref ref-type="bibr" rid="B109"><sup>109</sup></xref> Regarding breast cancer, which is the most frequent cancer among women, meta-analyses showed that the relative risk of developing RICAD is higher in patients undergoing left thoracic radiotherapy. <xref ref-type="bibr" rid="B110"><sup>110</sup></xref> </p>
              <p>Therefore, patients with thoracic neoplasms are at a considerably higher risk of developing RICAD compared to the general population, especially in the presence of risk factors such as the cumulative dose used (in general &gt; 30 Gy), early age at exposure, affected tissue volume, lack of cardiac protection, and presence of preexisting traditional cardiovascular risk factors. <xref ref-type="bibr" rid="B104"><sup>104</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B105"><sup>105</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B109"><sup>109</sup></xref> </p>
              <p>Although RIHD manifests late, CAD, in particular, may appear earlier, as of the fifth year after exposure. <xref ref-type="bibr" rid="B105"><sup>105</sup></xref> RICAD is known to mostly exhibit ostial and proximal involvement, typically affecting the left main coronary artery, the left anterior descending artery, or the right coronary artery. <xref ref-type="bibr" rid="B107"><sup>107</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B111"><sup>111</sup></xref> Radiotherapy predisposes to or accelerates atherosclerosis, even in those without classic cardiovascular risk factors, and may have sudden death as the first clinical presentation. Because of high morbidity and mortality rates and heterogeneous and sometimes atypical clinical presentation, we thus recommend performing stress TTE screening using exercise or pharmacological (dobutamine) stress whenever relevant. This noninvasive functional method offers advantages such as satisfactory accuracy, no radiation, relatively low cost, and high availability.</p>
            </sec>
            <sec>
              <title>4.1.4.3. Radiation-Induced Valve Disease</title>
              <p>A higher prevalence of radiation-induced valve disease (RIVD) is reported in the subgroups of patients with Hodgkin lymphoma (17%) and breast cancer (4.2%). Similar to RICAD, the risk is related to total radiation dose and radiation field.</p>
              <p>Valve involvement with hemodynamic repercussions usually occurs after 10 years of radiotherapy and most commonly affects left heart valves. The aortic valve is more frequently affected than the mitral valve. Valve regurgitation manifests earlier than stenosis, which usually appears about 20 years after radiotherapy. Echocardiographic findings are variable and may range from minimal changes without any associated valve dysfunction to diffuse fibrosis, thickening, and calcification. The involvement of any component of the valve apparatus is typical, but the commissures are spared, thus allowing for differentiation from a rheumatic etiology. Aortomitral curtain impairment (i.e., thickening and calcification) is a typical post-radiotherapy finding associated with poor long-term survival. <xref ref-type="bibr" rid="B103"><sup>103</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B108"><sup>108</sup></xref> </p>
              <p>With the progression of symptoms and severity of the lesions, surgical intervention or percutaneous management may be required. Specific echocardiographic techniques such as 3D echocardiography and transesophageal echocardiography (TEE) contribute to improved anatomical and functional assessment, especially in valve lesions with greater hemodynamic and structural repercussions. However, caution is recommended when performing TEE in patients undergoing thoracic radiotherapy, given the possibility of associated esophageal impairment.</p>
            </sec>
          </sec>
        </sec>
        <sec>
          <title>4.2. Radiation-Induced Arteritis &#8211; Actinic Arteritis</title>
          <p>Radiation-induced arteritis, also known as actinic arteritis, is the result of changes in the arterial wall leading to stenosis or occlusion. These phenomena may lead to an accelerated atherosclerotic process of inflammatory etiology, secondary to endothelial cell injury, which can occur in medium- or large-sized arteries. In cases of radiotherapy for head and neck tumors, the affected arteries may be both intracranial and extracranial.</p>
          <p>Radiation-induced carotid artery stenosis had its course investigated by Cheng et al. <xref ref-type="bibr" rid="B112"><sup>112</sup></xref> The authors demonstrated that there was an annual progression of the degree of stenosis from less than 50% to more than 50% in 15.4% of irradiated patients versus 4.8% of nonirradiated patients. There was no difference in symptom onset or mortality between the study groups. However, such changes may lead to the onset of cerebrovascular symptoms, and symptomatic patients with carotid artery lesions following radiotherapy have been shown to exhibit reduced cerebral flow. <xref ref-type="bibr" rid="B113"><sup>113</sup></xref> </p>
          <p>Peripheral artery disease, although rare, has also been reported following radiotherapy for the treatment of cervical cancer, with involvement of the iliac and femoral arteries. Symptoms may be those of chronic ischemia, although cases of acute arterial occlusion have been observed. <xref ref-type="bibr" rid="B114"><sup>114</sup></xref> </p>
          <p>Peripheral artery disease, although comparatively rare, has also been reported following radiotherapy, e.g., for the treatment of cervical cancer, with involvement of the iliac and femoral arteries. Symptoms may be those of chronic ischemia, although cases of acute arterial occlusion have been observed. <xref ref-type="bibr" rid="B114"><sup>114</sup></xref> </p>
          <sec>
            <title>4.2.1. Diagnosis</title>
            <p>The diagnosis of carotid artery stenosis may be clinically inferred by neck auscultation for a bruit in the irradiated region. Imaging modalities such as vascular ultrasonography, CT angiography, MRI, or conventional contrast angiography are able to detect and quantify a stenotic lesion. <xref ref-type="bibr" rid="B115"><sup>115</sup></xref> </p>
            <p>Vascular ultrasonography has the advantages of being noninvasive and low-cost, using no nephrotoxic contrast, and thus being safe for medium- and long-term follow-up.</p>
          </sec>
          <sec>
            <title>4.2.2. Ultrasonographic Features</title>
            <p>Arterial injuries induced by ionizing radiation may occur in the various arteries of the body, and have been described especially in the supraaortic vessels (i.e., the carotid and subclavian arteries). In the first year after treatment of localized head and neck cancers with radiotherapy, a process of accelerated and progressive intima-media thickening occurs in both carotid arteries, which may lead to significant luminal narrowing. <xref ref-type="bibr" rid="B116"><sup>116</sup></xref> Wilbers et al. found similar results 7 years after radiotherapy was used in this region. <xref ref-type="bibr" rid="B117"><sup>117</sup></xref> A 20-year follow-up study of young adults who underwent radiotherapy showed the following findings: a higher prevalence of atherosclerotic plaques in the irradiated vessels than the nonirradiated vessels (18% vs. 2%), greater intima-media thickness (IMT) in treated patients than controls, and a linear increase in IMT over time after radiotherapy <xref ref-type="bibr" rid="B118"><sup>118</sup></xref> ( <xref ref-type="fig" rid="f39">Figures 9</xref> and <xref ref-type="fig" rid="f40">10</xref> ).</p>
            <fig id="f39">
              <label>Figure 9</label>
              <caption>
                <title>Transverse plane of the right common carotid artery showing significant intima-media thickening with consequent luminal narrowing.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf09-en.tif"/></fig>
            <fig id="f40">
              <label>Figure 10</label>
              <caption>
                <title>Patient with actinic arteritis 6 years after radiotherapy. A. Stenosis &gt; 70% of the right common carotid artery on color Doppler image &#8211; significant luminal narrowing and turbulent flow are observed. B. Large increase in intima-media thickness of the right common carotid artery on B-mode image causing luminal narrowing. C. Pulsed-wave Doppler image showing increased flow velocity. D. Occluded left common carotid artery.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf10-en.tif"/></fig>
            <p>This accelerated atherosclerotic process often affects the common carotid artery, although the internal carotid artery may also be involved. Differential diagnosis using ultrasound imaging alone is not always possible, and a history of radiotherapy in the affected region is crucial for the diagnosis to be established. Chronic atherosclerotic disease and Takayasu arteritis are the main differential diagnoses. In chronic atherosclerotic disease, involvement is more common in the carotid bifurcation and the internal carotid artery. The common carotid artery may also be affected ( <xref ref-type="fig" rid="f41">Figure 11</xref> ). In actinic arteritis, involvement of the common carotid artery is more evident, with more diffuse, pronounced, and progressive atherosclerosis <xref ref-type="bibr" rid="B112"><sup>112</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B115"><sup>115</sup></xref> .</p>
            <fig id="f41">
              <label>Figure 11</label>
              <caption>
                <title>Atherosclerotic plaque in the carotid bifurcation.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf11-en.tif"/></fig>
            <p>In Takayasu arteritis, there is a homogeneous and concentric thickening that may lead to significant stenosis and occlusion of the vessel, and there may also be dilations (aneurysms). It typically affects the common carotid artery up to the bifurcation, but spares the internal carotid <xref ref-type="bibr" rid="B119"><sup>119</sup></xref> ( <xref ref-type="fig" rid="f42">Figure 12 A-B</xref> ).</p>
            <fig id="f42">
              <label>Figure 12</label>
              <caption>
                <title>Takayasu arteritis in a 17-year-old female patient. A. Longitudinal plane of the left common carotid artery (LCCA) showing a significant concentric wall thickening. <xref ref-type="bibr" rid="B119"><sup>119</sup></xref> B. Power Doppler image showing great luminal narrowing of the common carotid artery with preserved lumen from the carotid bifurcation.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf12-en.tif"/></fig>
          </sec>
          <sec>
            <title>4.2.3. Arterial Stenosis Follow-Up</title>
            <p>Because of the progressive nature of radiation-induced arterial stenoses, a more rigorous follow-up using imaging methods is suggested to detect significant but still treatable stenoses. Initially, vascular ultrasonography may be performed annually and then individualized, with shorter intervals in case of rapid disease progression as well as after treatment. <xref ref-type="bibr" rid="B120"><sup>120</sup></xref> </p>
            <p>Carotid endarterectomy (ECA) and endovascular approaches (carotid angioplasty and stenting) have proven effective in the treatment of radiotherapy-induced stenosis. <xref ref-type="bibr" rid="B121"><sup>121</sup></xref> The extent of the disease and a large arterial area affected may facilitate the development of embolic phenomena during stenting, with consequent cerebrovascular events. Moreover, stenting may favor intimal hyperplasia with restenosis ( <xref ref-type="fig" rid="f43">Figure 13</xref> ). The mechanism that leads to the emergence of intrastent intimal hyperplasia in those patients seems to be related to the proliferation of smooth muscle cells <xref ref-type="bibr" rid="B122"><sup>122</sup></xref> Restenosis has been shown to be a problem following endovascular treatment, appearing to be greater in previously irradiated patients compared to controls. The rate of restenosis &gt;50% is higher in patients treated with stenting compared to those treated with carotid endarterectomy. <xref ref-type="bibr" rid="B123"><sup>123</sup></xref> </p>
            <fig id="f43">
              <label>Figure 13</label>
              <caption>
                <title>Patient after 10 years of radiotherapy with a stent in the left common carotid artery; longitudinal color Doppler image showing intimal hyperplasia and intrastent flow; pulsed-wave Doppler image showing increased local velocity.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf13-en.tif"/></fig>
            <p>The treatment of involved arteries other than cervical arteries should be individualized. There are case reports of patients treated with surgery and endovascularly, with angioplasty and stenting. <xref ref-type="bibr" rid="B114"><sup>114</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B124"><sup>124</sup></xref> </p>
          </sec>
        </sec>
        <sec>
          <title>4.3. Cardiovascular Evaluation after Radiotherapy and Role of Nuclear Medicine</title>
          <sec>
            <title>4.3.1. Coronary Artery Disease Evaluation and Follow-Up after Radiotherapy</title>
            <p>Lind et al. <xref ref-type="bibr" rid="B125"><sup>125</sup></xref> evaluated 69 women undergoing thoracic radiotherapy at doses of 46 to 50 Gy, with fractions of up to 2 Gy per session, using proper cardiac shielding. They underwent rest myocardial perfusion imaging with technetium-99m (<sup>99m</sup>Tc) sestamibi or<sup>99m</sup>Tc tetrofosmin before and at 6, 12, and 18 months following radiotherapy. Myocardial perfusion changes were observed at 6 months, especially in the left anterior descending artery. <xref ref-type="bibr" rid="B125"><sup>125</sup></xref> This finding is consistent with that of Hardenbergh et al., <xref ref-type="bibr" rid="B126"><sup>126</sup></xref> who showed myocardial perfusion changes in about 60% of patients 6 months after thoracic radiotherapy. <xref ref-type="bibr" rid="B126"><sup>126</sup></xref> Ventricular function analysis on echocardiography showed that only one of the patients had a reduction of over 10% in LVEF. Although an association with microcirculation damage was found, the authors highlighted the importance of those changes, which may subsequently lead to diastolic and systolic dysfunction.</p>
            <p>Both microvascular and macrovascular changes in the coronary arteries are recognized late sequelae of thoracic radiotherapy. The importance of regular coronary artery screening for effects of radiotherapy is known. However, specific screening regimens for this population are still lacking, despite a large arsenal of noninvasive methods available. <xref ref-type="bibr" rid="B127"><sup>127</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B128"><sup>128</sup></xref> </p>
          </sec>
        </sec>
        <sec>
          <title>4.4. Coronary Artery Disease Evaluation after Radiotherapy &#8211; Role of Computed Tomography</title>
          <p>Radiotherapy-induced cardiotoxicity involves several pathophysiological mechanisms that trigger various forms of harm to the cardiovascular system. In the coronary arteries, there may be a direct vasospastic effect, endothelial damage or changes in lipid metabolism and consequent premature atherosclerosis. The risk of subsequent coronary events is proportional to the radiation dose.</p>
          <p>The high accuracy of coronary CT angiography for detection of CAD gives this method the potential to provide accurate information on suspected CAD in cancer patients, especially in those presenting with chest pain and symptoms of heart failure of potentially ischemic etiology.</p>
          <p>Several studies have reported an increased incidence of CAD, acute myocardial infarction, and sudden cardiac death in patients undergoing radiotherapy, especially in patients with Hodgkin lymphoma or breast cancer, which highlights the potential of this treatment modality to cause harm. Current guidelines suggest screening for CAD within 5 to 10 years after irradiation of the chest to screen for late cardiotoxicity. <xref ref-type="bibr" rid="B129"><sup>129</sup></xref> Multiple studies, including CT studies, have confirmed these clinical and epidemiological findings in patients with Hodgkin lymphoma. Mulrooney et al. <xref ref-type="bibr" rid="B130"><sup>130</sup></xref> identified plaque on CT angiography in 39% of survivors. In a prospective study of 179 patients with a mean follow-up of 9.5 years, Girinsky et al. <xref ref-type="bibr" rid="B131"><sup>131</sup></xref> found plaque in 26% of those who had undergone radiotherapy. On multivariate analysis, the radiation dose applied to the origin of the coronary arteries was associated with subsequent detection of plaque. Van Rosendael et al. <xref ref-type="bibr" rid="B132"><sup>132</sup></xref> compared 71 patients undergoing radiotherapy versus 237 nonirradiated controls, matched for multiple CAD risk factors, and found a higher prevalence of plaques, more proximal disease, greater degree of stenosis, and a greater number of vessels with significant lesions in the group undergoing radiotherapy.</p>
        </sec>
        <sec>
          <title>4.5. Coronary Artery Disease Evaluation after Radiotherapy &#8211; Role of Magnetic Resonance Imaging</title>
          <p>CMR has excellent accuracy for the diagnosis of myocardial ischemia when combined with pharmacological stress testing, and is considered the gold standard for assessment of infarction areas, myocardial viability, and ventricular function, with prognostic value in predicting cardiovascular events.</p>
          <p>The CE-MARC study compared investigation of ischemia by stress myocardial perfusion CMR versus scintigraphy in 628 patients undergoing cine coronary angiography as the gold-standard reference, in a population with a 39% baseline prevalence of obstructive CAD. <xref ref-type="bibr" rid="B133"><sup>133</sup></xref> Both methods had similar specificities (CMR, 83.4%; SPECT, 82.6%, p = 0.916), but CMR was significantly more sensitive for the diagnosis of myocardial ischemia (86.5%) than SPECT (66.5%) (p &lt; 0.0001).</p>
          <p>The late gadolinium enhancement (LGE) technique, in which images are acquired after infusion of gadolinium contrast without the need for stressors, is considered the leading noninvasive method for detection of myocardial fibrosis. Analysis of the extent of myocardial infarction predicts myocardial viability in the segment under investigation. Assessment of the presence and extent of infarction by CMR has established prognostic value; detection of previously unknown infarcts in patients undergoing CMR is associated with worse cardiovascular prognosis and mortality. <xref ref-type="bibr" rid="B134"><sup>134</sup></xref> </p>
        </sec>
      </sec>
      <sec>
        <title>5. Cardiac Tumors and Masses</title>
        <sec>
          <title>5.1. Contribution from Echocardiography</title>
          <p>Cardiac masses are often challenging to echocardiographic diagnosis. Thrombi, vegetations, and pseudotumors account for 75% of cases. Primary cardiac tumors (PCTs), in turn, are extremely rare with an estimated frequency of 0.02%. They may be benign or malignant in terms of histology. Cardiac metastases are up to 100 times more frequent. The World Health Organization recently updated the classification of cardiac and pericardial tumors. <xref ref-type="bibr" rid="B135"><sup>135</sup></xref> </p>
          <p>Transthoracic echocardiography (TTE) assesses location, morphology, dimensions, echogenicity, mobility, extent, calcifications, type of insertion, and presence or absence of pericardial effusion. <xref ref-type="bibr" rid="B136"><sup>136</sup></xref> Different Doppler imaging modalities allow for assessment of blood flow and consequent hemodynamic repercussions, such as flow obstruction or valve dysfunction. Color flow mapping reveals the presence of vascularization in some types of tumors, and the use of contrast perfusion allows for identification and differentiation of thrombi from tumors. In general, thrombi do not enhance and are well delineated in the contrasted chamber. Contrast agents also assist in the differentiation of benign from malignant tumors. <xref ref-type="bibr" rid="B137"><sup>137</sup></xref> Malignant tumors tend to be completely enhanced, while benign tumors are only partially enhanced. Perfusion imaging analysis of post-impulse contrast replenishment may be qualitative using visual inspection or quantitative using time-signal intensity curves and parametric maps (color-coded signal intensity). The difference in post-impulse ( <italic>A</italic> ) maximal steady-state pixel intensity between the mass and the adjacent myocardium (Delta <italic>A</italic> <sub>mass-myocardium</sub>) is calculated. Reported sensitivity and specificity of Delta <italic>A</italic> <sub>mass-myocardium</sub>in differentiating thrombi from benign and malignant tumors were 93% and 100%, respectively, with a cutoff value of 23.2 dB, and were 100% and 97%, with a cutoff value of 0.45 dB. <xref ref-type="bibr" rid="B138"><sup>138</sup></xref> Estimated volume, velocity, and microvascular blood flow of the masses may also be obtained. Strain imaging can differentiate the nature and contractile pattern of some types of tumors, such as fibroma and rhabdomyoma. In rhabdomyomas, deformation is opposite to that of the myocardium, while fibromas have no deformation. <xref ref-type="bibr" rid="B139"><sup>139</sup></xref> TEE has greater sensitivity (&gt; 95%) and acoustic resolution than TTE, providing a better characterization of tumors and masses in terms of location, insertion, and relationship with the vena cava, especially in atrial and valvular lesions. TEE plays an important role in cases of systemic embolization, in intraoperative assessment of tumor resection, as well as in ventricular lesions in patients with limited thoracic acoustic window. Real-time 3D echocardiogram is the latest technique for assessing cardiac masses, providing more accurate data on volume, morphology, and relationship with adjacent structures, as well as aspects such as location and type of insertion, homogeneity, vascularization, calcification, and areas of necrosis. <xref ref-type="bibr" rid="B140"><sup>140</sup></xref> </p>
          <p>Any cardiac mass detected on echocardiography must be analyzed within the respective clinical and epidemiological context. Age, sex, symptoms, and concomitant oncology disease are important inputs for diagnosis. Artifacts should be excluded by analyzing multiple cut planes and adjusting the imaging parameters. Eustachian valve and prominent crista terminalis, Chiari network, and coumadin ridge are anatomic variants that may be misinterpreted as masses. Lambl excrescences are filiform structures ranging from 3 to 5 mm found at sites of valve closure, downstream of valve. They do not cause valve dysfunction but may embolize. Lipomatous hypertrophy of the interatrial septum is characterized by infiltration of mature fat, which spares the fossa ovalis resulting in a typical dumbbell shape. Calcified amorphous tumors are heterogeneous, hyperechoic, nonneoplastic masses with hypoechoic or isoechoic areas, of variable mobility, often associated with mitral annular calcification and considered to be potential sources of embolism. <xref ref-type="bibr" rid="B141"><sup>141</sup></xref> Pericardial cysts are hypoechoic, usually loculated masses with varying dimensions that are adjacent to the cardiac border. Thrombi may be found in any chamber and vary in size, morphology, and mobility but do not usually occur outside predisposing conditions. When inside the LA, they are present mainly in patients who have spontaneous echo contrast, atrial fibrillation, stenosis, or mitral prosthesis. In the right atrium (RA), they are relatively common in oncology patients with a long-term catheter and a hypercoagulable state. Migrating thrombi are seen on the right side of the heart in patients with DVT and pulmonary embolism. LV thrombus is associated with changes in segmental contractility and dilated cardiomyopathy. Vegetations mainly affect the left heart valves, have great mobility, and move independently. They are found on the atrial surface of the atrioventricular valves and on the ventricular surface of the semilunar valves, often causing valve dysfunction in endocarditis.</p>
          <sec>
            <title>5.1.1. Benign Primary Cardiac Tumors</title>
            <p>From 85% to 90% of all PCTs are benign. Of these, nearly 50% are myxomas. <xref ref-type="bibr" rid="B136"><sup>136</sup></xref> Rhabdomyoma is the most common type in children, accounting for approximately 50% of cases, followed by fibroma and myxoma. <xref ref-type="bibr" rid="B142"><sup>142</sup></xref> </p>
            <sec>
              <title>5.1.1.1. Cardiac Myxomas</title>
              <p>These are more frequent in patients aged from 30 to 60 years, presenting with constitutional, obstructive, or embolic symptoms. They are in the LA in 75% of cases, in the RA in 20%, and in the ventricles in 5%. Typically, they are described as oscillating polypoid masses attached to the interatrial septum through a narrow pedicle. They are heterogeneous tumors with echogenic nuclei, cystic areas, and smooth surfaces. Depending on their size, they may obstruct the flow of the atrioventricular valve. Papillary myxomas are smaller and have a stretched appearance, irregular surface, greater mobility, and greater risk of embolization. Both 2D and 3D TEE and the use of contrast perfusion assist in the characterization of those tumors. Cardiac myxomas may be recurrent when associated with Carney complex. In such cases, TTE is the optimal imaging technique for follow-up. <xref ref-type="bibr" rid="B143"><sup>143</sup></xref> </p>
            </sec>
            <sec>
              <title>5.1.1.2. Papillary Fibroelastomas</title>
              <p>These are small (usually &lt; 10mm) sessile or pedunculated, rounded, gelatinous, avascular tumors with multiple narrow, elongated, branched papillary projections. They resemble sea anemones when placed under water. These characteristics provide them with friability and predispose them to adherent thrombi. <xref ref-type="bibr" rid="B144"><sup>144</sup></xref> Embolization is more common in tumors larger than 10 mm and may be due to adherent thrombi or fragmented papillae. They are usually single, mobile, and attached to any endocardial surface by a short pedicle. They affect the endocardial surface of valve in 77% of cases and occur mainly in older adults. They are commonly seen in the middle section of the left heart valve leaflets. They usually project into the arterial lumen in the aortic valve and into the atrial surface in the mitral valve. <xref ref-type="bibr" rid="B144"><sup>144</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B145"><sup>145</sup></xref> On echocardiogram, they exhibit independent mobility, stippled and sparkling edges, and a narrow central pedicle. They usually cause no valve dysfunction. TEE plays an important role in the assessment of those tumors.</p>
            </sec>
            <sec>
              <title>5.1.1.3. Rhabdomyomas</title>
              <p>These are usually diagnosed in the first year of life or during fetal life. They are associated with tuberous sclerosis, are usually multiple, and tend to regress spontaneously. <xref ref-type="bibr" rid="B146"><sup>146</sup></xref> They mainly affect the interventricular septum, ventricular walls, and atrioventricular valves. They appear as multiple nodular or pedunculated, lobulated, well-defined, homogeneous masses that are hyperechogenic to the surrounding myocardium. They show deformation opposite to that of the myocardium on strain imaging. <xref ref-type="bibr" rid="B139"><sup>139</sup></xref> </p>
            </sec>
            <sec>
              <title>5.1.1.4. Cardiac Fibromas</title>
              <p>These rarely occur in adults. Approximately 3% to 5% of cases are associated with Gorlin syndrome (also called nevoid basal cell carcinoma syndrome). <xref ref-type="bibr" rid="B147"><sup>147</sup></xref> They are characterized as a single intramural, hyperechogenic, well-defined, noncontractile solid mass with calcifications that extend into the LV chamber. They may cause arrhythmia, ventricular dysfunction, and flow obstruction. They show no deformation on strain imaging. <xref ref-type="bibr" rid="B139"><sup>139</sup></xref> </p>
            </sec>
            <sec>
              <title>5.1.1.5. Cardiac Lipomas</title>
              <p>These are masses of encapsulated adipose tissue that are found mainly in the LV subendocardium but also occur in other chambers, the pericardium, and cardiac valves, reaching several centimeters in size. They are broad-based, homogeneous, immobile tumors without calcification. They are hyperechoic in the chamber and hypoechoic in the pericardium. <xref ref-type="bibr" rid="B148"><sup>148</sup></xref> </p>
            </sec>
            <sec>
              <title>5.1.1.6. Teratomas</title>
              <p>These are germ cell tumors found in infants, children, and fetuses. <xref ref-type="bibr" rid="B147"><sup>147</sup></xref> They may be mature or immature and rarely occur in adults. They are preferably located in the pericardial space and may cause cardiac tamponade or compression of adjacent structures. <xref ref-type="bibr" rid="B149"><sup>149</sup></xref> They are characterized as heterogeneous masses containing solid, cystic areas and calcifications, often accompanied by pericardial effusion.</p>
            </sec>
            <sec>
              <title>5.1.1.7. Cardiac Hemangiomas</title>
              <p>These vascular tumors are rarely found and may occur at any age, including fetal life. They are located mainly in the LV and RA, measuring between 2 and 10 cm in most cases. They are pedunculated and mobile in half of the cases. They appear as well circumscribed masses that may be cystic or solid, unilobulated or multilobulated, depending on their type, i.e., cavernous, capillary, or arteriovenous. <xref ref-type="bibr" rid="B150"><sup>150</sup></xref> </p>
            </sec>
            <sec>
              <title>5.1.1.8. Cardiac Paragangliomas</title>
              <p>These are very rare neuroendocrine tumors. They are associated with several syndromes, such as Von Hippel-Lindau disease, neurofibromatosis type I, and Carney complex. They may be benign or malignant and hormonally active or inactive. They are extremely vascularized and nonencapsulated. They occur most often between the 4<sup>th</sup>and 5<sup>th</sup>decades of life and are located mainly in the pericardial space, next to the atrioventricular groove, at the root of the great vessels, and in the LA. They are characterized as broad-based, usually ovoid, well-demarcated echogenic masses with an average size of 5cm, surrounding the coronary artery and possibly compressing adjacent structures. <xref ref-type="bibr" rid="B151"><sup>151</sup></xref> </p>
            </sec>
            <sec>
              <title>5.1.1.9. Cardiac Schwannomas</title>
              <p>These are extremely rare slow-growing tumors with only 25 cases reported in the English literature (18 intracardiac and 7 intrapericardial tumors). They arise from the cardiac plexus or branches of the vagus nerve and involve the right side of the heart more often. They are benign but may exhibit malignant behavior. They are echogenic, hypodense, nonpedunculated, demarcated masses that may reach several centimeters in size and cause signs and symptoms related to the compression of adjacent structures. <xref ref-type="bibr" rid="B152"><sup>152</sup></xref> </p>
            </sec>
          </sec>
          <sec>
            <title>5.1.2. Malignant Primary Cardiac Tumors</title>
            <p>These are extremely rare tumors whose frequency is 0.008%. From 10% to 15% of all PCTs are malignant. They are represented by different types of sarcomas, lymphomas, and mesotheliomas. They mainly affect adults in the fifth decade of life. Sarcomas account for 65% to 95% of cases in adults and 70% in children and adolescents (&lt; 18 years). <xref ref-type="bibr" rid="B143"><sup>143</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B154"><sup>154</sup></xref> Angiosarcoma is the most common type. Usually it produces symptoms such as dyspnea and pleuritic chest pain. <xref ref-type="bibr" rid="B155"><sup>155</sup></xref> </p>
            <sec>
              <title>5.1.2.1. Angiosarcomas</title>
              <p>These exhibit an aggressive behavior and may metastasize. They are preferably located in the RA. They present as voluminous, homogeneous, immobile, nonpedunculated, stalkless, lobulated, echogenic masses with a broad base of endocardial insertion and smooth intracardiac borders. Because they are located next to the atrioventricular groove, angiosarcomas usually cause obstructions in the tricuspid valve and, in most cases, affect the pericardium causing hemorrhagic effusions. Partly because of their slender vascular channels, they do not significantly enhance with the use of contrast perfusion. The sensitivity of TTE for identification is 75%. <xref ref-type="bibr" rid="B155"><sup>155</sup></xref> </p>
              <sec>
                <title>5.1.2.1.1. Undifferentiated Sarcomas</title>
                <p>These are typically located in the LA and may mimic myxomas. They tend to involve the mitral valve causing flow obstruction. They have a broad base, some mobility, and a smooth and homogeneous appearance. <xref ref-type="bibr" rid="B156"><sup>156</sup></xref> </p>
              </sec>
              <sec>
                <title>5.1.2.1.2. Rhabdomyosarcomas</title>
                <p>These are the most common type in children. They usually arise from the ventricular walls and often interfere with valve function because of intracavitary growth. <xref ref-type="bibr" rid="B148"><sup>148</sup></xref> They tend to occur in more than one location causing obstruction at multiple levels. They grow rapidly and usually invade the pericardium. <xref ref-type="bibr" rid="B136"><sup>136</sup></xref> </p>
              </sec>
              <sec>
                <title>5.1.2.1.3. Leiomyosarcomas</title>
                <p>These arise most commonly from vessels such as the inferior vena cava and pulmonary artery but may also occur in the LA.</p>
              </sec>
            </sec>
            <sec>
              <title>5.1.2.2. Primary Cardiac Lymphomas</title>
              <p>These account for approximately 27% of malignant PCTs, and diffuse large B-cell lymphoma is the most common type. <xref ref-type="bibr" rid="B153"><sup>153</sup></xref> They predominate in the 6th decade of life but also occur between the 1st and 9th decades, and are frequently seen in immunocompromised patients. They are located mainly on the right side of the heart and in the pericardium. They involve the superior vena cava and the interatrial septum in 25% and 48% of cases, respectively. They appear as infiltrating or nodular masses. Infiltrating forms are homogeneous and lead to wall thickening and restrictive hemodynamics. Nodular forms intrude into the chambers and may compromise the atrioventricular node, right coronary artery, and pericardium. <xref ref-type="bibr" rid="B136"><sup>136</sup></xref> More than one chamber is involved in 75% of cases. Depending on the location and dimensions, they may cause inflow obstruction, superior vena cava syndrome, arrhythmias, atrioventricular block, restrictive or constrictive syndromes, pericardial effusion, and embolic phenomena. Both 2D and 3D TEE and the use of contrast perfusion are useful for the characterization of those tumors. <xref ref-type="bibr" rid="B157"><sup>157</sup></xref> </p>
            </sec>
            <sec>
              <title>5.1.2.3. Primary Malignant Pericardial Mesotheliomas</title>
              <p>These account for 8% of malignant PCTs and approximately 50% of primary pericardial tumors. <xref ref-type="bibr" rid="B153"><sup>153</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B158"><sup>158</sup></xref> They are more frequent between the 5th and 7th decades of life and show low survival. In many cases, they are associated with exposure to asbestos and radiation. <xref ref-type="bibr" rid="B159"><sup>159</sup></xref> Symptoms are vague and include constrictive pericarditis and pericardial effusion with cardiac tamponade. Myocardial infiltration may occur and lead to conduction abnormalities. TTE has low sensitivity for detection. <xref ref-type="bibr" rid="B158"><sup>158</sup></xref> </p>
            </sec>
          </sec>
          <sec>
            <title>5.1.3. Metastatic Cardiac Tumors</title>
            <p>These are by definition malignant, and their incidence has increased in recent decades, reaching 18.35% in patients with advanced cancer. <xref ref-type="bibr" rid="B159"><sup>159</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B160"><sup>160</sup></xref> They predominate between the 6<sup>th</sup>and 7<sup>th</sup>decade of life. Cardiac metastases may occur by direct extension of the tumor, hematogenous spread, lymphatic spread, or intracavitary extension from the inferior vena cava or pulmonary veins. With the exception of central nervous system tumors, any malignant tumor may spread to the heart, but carcinomas of the lung, breast, and esophagus, melanoma, and hematologic neoplasms (leukemia and lymphoma) are responsible for most cases. <xref ref-type="bibr" rid="B159"><sup>159</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B161"><sup>161</sup></xref> Malignant melanomas are the most likely tumors to affect the heart. Pericardium, epicardium, myocardium, and endocardium are, in descending order of frequency, the most affected sites. If intracavitary, they are preferably located in the right chambers. Pericardial effusions are frequent and may be asymptomatic. Cardiac involvement should be suspected in all patients with cancer who develop new cardiovascular symptoms. <xref ref-type="bibr" rid="B162"><sup>162</sup></xref> TTE is the initial assessment method for detecting tumor thrombi in the inferior vena cava and cardiac chambers as well as pericardial effusion. Other imaging modalities are required to better characterize the lesions, including their extent and relationship with adjacent structures, as well as to reveal the primary tumor site. <xref ref-type="bibr" rid="B161"><sup>161</sup></xref> </p>
          </sec>
        </sec>
        <sec>
          <title>5.2. Contribution from Cardiac Magnetic Resonance Imaging</title>
          <p>Cardiac MRI, mainly because of the property of tissue characterization, has been established as a robust method in the assessment of cardiac masses, especially in differentiating benign from malignant tumors. In addition to tissue characterization, cardiac MRI will provide important information regarding location, dimensions, extent, and signs of compression or obstruction of cardiac structures. <xref ref-type="bibr" rid="B163"><sup>163</sup></xref> </p>
          <p>Steady-state free precession MRI sequences are used to assess the morphology and mobility of the mass and its relationship with the myocardium, as well as whether the mass is causing hemodynamic obstruction to the valve structures. Pre-contrast T1- and T2-weighted black-blood sequences assist in defining the relationship with the adjacent anatomy, size, extent, and characterization of the mass. Signal intensity of the mass on MRI depends on T1 and T2 relaxation time. The signal intensity should be evaluated in relation to that of the myocardium, i.e., whether the mass signal is isointense, hypointense, or hyperintense to the myocardial signal. <xref ref-type="bibr" rid="B164"><sup>164</sup></xref> </p>
          <p>Fat saturation allows for identification of a fat signal in the composition of the mass, as this is hyperintense on T1- and T2-weighted sequences; saturation of the signal suggests a fatty component in the mass. This technique can detect benign structures such as lipomatous infiltration of the interatrial septum, benign tumors such as lipoma, and the presence of fat as a component of a liposarcoma.</p>
          <p>Vascularization of the tumor may be assessed using first-pass perfusion imaging for presence or absence of perfusion and whether this is isoperfused, hypoperfused, or hyperperfused in relation to the LV myocardium, while delayed enhancement detects the presence of fibrosis in the mass composition. <xref ref-type="bibr" rid="B165"><sup>165</sup></xref> </p>
          <p>The cardiac MRI protocol for assessing a cardiac or pericardial mass should be initiated with high-resolution axial slices, followed by cine sequences for location and analysis of cardiac function and hemodynamic repercussions. Then, according to the diagnostic suspicion, slices are made over the mass for proper tissue characterization. T1- and T2-weighted sequences may be used, as well as fat suppression sequences to assess the lipid component of the suspected mass, first-pass perfusion with gadolinium to assess vascularization, and delayed enhancement sequences to assess fibrosis.</p>
          <p>If a thrombus is suspected, delayed enhancement sequences with a long inversion time may also be used to confirm the diagnosis. Cardiac MRI allows for differentiation of thrombus from tumor, as there is no perfusion in the thrombus by the paramagnetic contrast agent. The thrombus appears very dark on delayed enhancement sequences, even with a prolonged inversion time of up to 600 ms, and an adjacent hyperintense area may be observed by the surrounding blood. A slight delayed enhancement may be present in very organized, old thrombi.</p>
          <sec>
            <title>5.2.1. Benign Primary Tumors</title>
            <sec>
              <title>5.2.1.1. Myxomas</title>
              <p>Pre-contrast findings may be explained by their histology: high signal intensity on T2-weighted sequences is related to the myxoid matrix with a high content of water and polysaccharides, while low signal intensity is related to areas of hemorrhage, hemosiderin (degradation of hemoglobin), calcifications, and surface thrombi. Myxomas are isointense on T1-weighted images and hyperintense on T2-weighted images ( <xref ref-type="fig" rid="f44">Figure 14</xref> ). A slight enhancement on first-pass perfusion imaging was observed in 16% to 66% of cases. Delayed enhancement has a variable and heterogeneous pattern, with a more diffuse distribution (&gt; 50% of the tumor &#8211; more frequent) and a less intense pattern (&lt; 50% of the tumor). <xref ref-type="bibr" rid="B166"><sup>166</sup></xref> From 10% to 20% of myxomas have calcifications and some may have thrombi on their surface.</p>
              <fig id="f44">
                <label>Figure 14</label>
                <caption>
                  <title>Myxoma in the left atrium.</title>
                </caption>
                <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf14-en.tif"/></fig>
            </sec>
            <sec>
              <title>5.2.1.2. Lipomas</title>
              <p>These arise from the subendocardial layer in 50% of cases and from the mesocardial or epicardial layers in the other 50%. They may determine hemodynamic changes, depending on their size. They show a homogeneous signal similar to that of fatty tissue: hyperintense on T1-weighted images and with signal dropout on fat saturation sequences and isointense or hyperintense on T2-weighted images. <xref ref-type="bibr" rid="B167"><sup>167</sup></xref> There is no first-pass perfusion or delayed enhancement on contrasted sequences <xref ref-type="bibr" rid="B168"><sup>168</sup></xref> ( <xref ref-type="fig" rid="f45">Figure 15</xref> ).</p>
              <fig id="f45">
                <label>Figure 15</label>
                <caption>
                  <title>Lipoma in the right atrium. A. Four-chamber cine image of a large lipoma in the right atrium. B. T1-weighted image showing that the lipoma is hyperintense. C. No local delayed enhancement.</title>
                </caption>
                <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf15-en.tif"/></fig>
            </sec>
            <sec>
              <title>5.2.1.3. Papillary Fibroelastomas</title>
              <p>On cine imaging, they present as a hypointense and extremely mobile mass, without necessarily causing a functional impact on the valve. Assessing tissue characteristics of those tumors is difficult because of their small size and great mobility, but intermediate signal intensity on T1- and high signal intensity on T2-weighted images can be observed, with no first-pass perfusion or high signal intensity on delayed enhancement images <xref ref-type="bibr" rid="B167"><sup>167</sup></xref> ( <xref ref-type="fig" rid="f46">Figure 16</xref> ).</p>
              <fig id="f46">
                <label>Figure 16</label>
                <caption>
                  <title>Papillary fibroelastoma in the mitral valve. A. Four-chamber cine image of a hypointense mass. B. T1-weighted image showing intermediate signal intensity. C. Early late gadolinium enhancement sequence showing a slight local enhancement.</title>
                </caption>
                <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf16-en.tif"/></fig>
            </sec>
            <sec>
              <title>5.2.1.4. Rhabdomyomas</title>
              <p>These are slightly hyperintense on T1-weighted images and hyperintense on T2-weighted images. They show minimal or even no enhancement with gadolinium ( <xref ref-type="fig" rid="f47">Figure 17</xref> ).</p>
              <fig id="f47">
                <label>Figure 17</label>
                <caption>
                  <title>Rhabdomyoma in the left ventricle: A. Short-axis cine image of an intramural mass in the interventricular septum. B. T2-weighted image showing high signal intensity. C. Delayed enhancement sequence showing a slight local enhancement.</title>
                </caption>
                <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf17-en.tif"/></fig>
            </sec>
            <sec>
              <title>5.2.1.5. Fibromas</title>
              <p>These are usually isointense or hypointense on T1-weighted images and homogeneously hypointense on T2-weighted images. In general, they do not appear on first-pass perfusion imaging because of their low vascularity. On delayed enhancement imaging, fibromas are intensely and homogeneously enhanced, although sometimes the lesions may have a central component of low signal intensity that may be associated with local calcification <xref ref-type="bibr" rid="B169"><sup>169</sup></xref> ( <xref ref-type="fig" rid="f48">Figure 18</xref> ).</p>
              <fig id="f48">
                <label>Figure 18</label>
                <caption>
                  <title>Intramural fibroma. A. Four-chamber cine image of an intramural tumor on the lateral wall. B. T2-weighted image of a hypointense mass in relation to the myocardium. C and D. Short- and long-axis delayed enhancement image showing homogeneously high signal intensity of the tumor compatible with fibrous tissue.</title>
                </caption>
                <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf18-en.tif"/></fig>
            </sec>
            <sec>
              <title>5.2.1.6. Hemangiomas</title>
              <p>These are heterogeneously isointense or hyperintense on T1- weighted images and usually hyperintense on T2-weighted images, and heterogeneous areas of low signal intensity may also occur. The delayed enhancement pattern is typically heterogeneous and hyperintense with a marked first-pass perfusion. <xref ref-type="bibr" rid="B168"><sup>168</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B169"><sup>169</sup></xref> </p>
            </sec>
          </sec>
          <sec>
            <title>5.2.2. Malignant Tumors</title>
            <p>Malignant tumors tend to be larger, are more frequently perfused with gadolinium, and have a higher prevalence of delayed enhancement. <xref ref-type="bibr" rid="B170"><sup>170</sup></xref> </p>
            <sec>
              <title>5.2.2.1. Sarcomas</title>
              <p>Most sarcomas have characteristics suggestive of malignancy, such as a heterogeneous signal due to necrosis and internal hemorrhage, nodular or irregular shape, ill-defined borders, infiltration of the myocardium and adjacent structures, extension to the pericardium, and associated pericardial effusion. Angiosarcoma accounts for 40% of cardiac sarcomas and is mostly located in the RA with infiltration of the atrial wall and the pericardium associated with pericardial effusion ( <xref ref-type="fig" rid="f49">Figure 19</xref> ). On cardiac MRI, it is shown as a large heterogeneous lobular mass that is isointense or hyperintense on T1-weighted images, hyperintense on T2-weighted images, perfused with gadolinium on first-pass images, and heterogeneously hyperintense on delayed enhancement images ( <xref ref-type="fig" rid="f50">Figure 20</xref> ). <xref ref-type="bibr" rid="B147"><sup>147</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B169"><sup>169</sup></xref> </p>
              <fig id="f49">
                <label>Figure 19</label>
                <caption>
                  <title>Angiosarcoma in the right atrium. A. Four-chamber cine image of a sarcoma arising from the posterior wall of the right atrium and invading the walls, the basal portion of the right ventricle, and the pericardium. B. Delayed enhancement image of a heterogeneously hyperintense mass on upper axial plane.</title>
                </caption>
                <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf19-en.tif"/></fig>
              <fig id="f50">
                <label>Figure 20</label>
                <caption>
                  <title>Rhabdomyosarcoma in the right ventricle. A. Four-chamber cine image of a large multilobulated intracavitary mass in the right ventricle. B. Delayed enhancement image showing a heterogeneously hyperintense mass.</title>
                </caption>
                <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf20-en.tif"/></fig>
            </sec>
            <sec>
              <title>5.2.2.2. Lymphomas</title>
              <p>These are isointense or hypointense on T1-weighted images, isointense or hyperintense on T2-weighted images, and heterogeneously enhanced on delayed enhancement images.</p>
            </sec>
          </sec>
        </sec>
        <sec>
          <title>5.3. Contribution from Nuclear Medicine</title>
          <sec>
            <title>5.3.1. <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG PET-CT</title>
            <p>Scanning with <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG PET-CT remains seldom used in cardiac tumors, especially malignant PCTs. In secondary malignant cardiac tumors (metastases), which are most frequent, <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG PET-CT is an established technique. <xref ref-type="bibr" rid="B171"><sup>171</sup></xref> </p>
            <p>A case series conducted by Rahbar et al. <xref ref-type="bibr" rid="B172"><sup>172</sup></xref> evaluated 24 consecutive patients with cardiac tumors using <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG PET-CT scanning before treatment. <xref ref-type="bibr" rid="B172"><sup>172</sup></xref> The patients were divided according to histological subtype of the tumors, obtained by surgical resection or biopsy, into: benign (n = 7), primary malignant (n = 8), or secondary malignant (n = 9). Tumor <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG uptake was observed between groups. Then, to assess sensitivity and specificity of the method in differentiating benign from malignant tumors, they were divided into malignant (n = 17) or benign (n = 7) only. <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG uptake was quantified according to the maximum standardized uptake value (SUV<sub>max</sub>) of 3D volumes covering the tumor mass. In case of low tumor <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG uptake, CT images were used to identify and obtain tumor volumes. Additionally, because of physiological myocardial <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG uptake, uptake in the normal myocardium and blood pool were measured and compared with SUV<sub>max</sub>of the tumors. They found that <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG uptake was low in the blood pool and normal myocardium, and significantly high in the primary malignant tumors compared to the benign ones. Secondary malignant tumors showed an uptake comparable to that of primary malignant tumors but with a considerably higher SUV<sub>max</sub>variation. The mean SUV<sub>max</sub>was 2.8 &#177; 0.6 in the benign cardiac tumor group. Such tumors usually show no positive contrast to the normal myocardium and are only seen on morphologic CT images. In contrast, SUV<sub>max</sub>of primary malignant tumors is 2.5 times greater than that of benign tumors. Among metastatic cardiac tumors, SUV<sub>max</sub>was 10.8 &#177; 4.9 with a significant variation in <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG uptake from 3.4 to 16.7. In primary malignant tumors, <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG uptake was greater than that of benign tumors and similar to that of secondary malignant tumors. <xref ref-type="bibr" rid="B172"><sup>172</sup></xref> </p>
            <sec>
              <title>5.3.1.1. Cutoff SUV<sub>max</sub>value for <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG to better differentiate benign from malignant cardiac tumors</title>
              <p>Different cutoff SUV<sub>max</sub>values have been suggested for determination of malignancy using <xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG PET-CT scanning. Rahbar et al. <xref ref-type="bibr" rid="B172"><sup>172</sup></xref> demonstrated that a value of 3.5 reached a sensitivity of 100%, a specificity of 86%, a positive predictive value of 94%, and a negative predictive value of 100%. <xref ref-type="bibr" rid="B172"><sup>172</sup></xref> When they increased this value to 4.6, they found a specificity of 100%, a sensitivity of 94%, and a positive predictive value of 100% for malignancy. The main limitations of that study were the retrospective nature, the lack of a diagnostic pattern for cardiac tumors, and the heterogeneity of the results. Also, several myxomas were not included in the analysis because they were diagnosed on echocardiogram and cardiac MRI.</p>
            </sec>
          </sec>
        </sec>
      </sec>
      <sec>
        <title>6. Special Situations</title>
        <sec>
          <title>6.1. Carcinoid Heart Disease</title>
          <p>Neuroendocrine tumors are rare neoplasms (2.5 to 5 cases per 100,000 population) that may occur anywhere but often involve the gastrointestinal tract (carcinoid tumors). <xref ref-type="bibr" rid="B173"><sup>173</sup></xref> In about 30% to 40% of cases, mostly in the small intestine and proximal colon, patients experience vasomotor changes (hypotension, hypertension, flushing), diarrhea, and bronchospasm. This is called carcinoid syndrome, and it is usually associated with hepatic metastasis. <xref ref-type="bibr" rid="B174"><sup>174</sup></xref> The presence of biomarkers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP), chromogranin A (CgA), and 5-hydroxyindoleacetic acid (5-HIAA) is useful both in diagnosis and prognosis of carcinoid disease. <xref ref-type="bibr" rid="B175"><sup>175</sup></xref> </p>
          <p>Carcinoid heart disease (CHD), manifested by plaque formation, thickening, and endocardial fibrosis, is probably related to chronic exposure to 5-HIAA and preferably affects the right chambers and the tricuspid and pulmonary valves. Impairment of left chambers (15% of cases) and mitral and aortic valves is seen in the presence of a right-to-left shunt (e.g., patent foramen ovale) or a bronchial carcinoid tumor. <xref ref-type="bibr" rid="B176"><sup>176</sup></xref> Early diagnosis and monitoring of disease progression have a dramatic impact on prognosis and long-term survival (mean survival of 1.6 years vs. 4.6 years in patients without CHD), as early surgical intervention is essential for a successful management.</p>
          <p>Echocardiography is considered the gold standard for the diagnosis and monitoring of CHD. <xref ref-type="bibr" rid="B173"><sup>173</sup></xref> The assessment of right heart chambers (atrium and ventricle), RV function, thickening, leaflet mobility, and presence of valve regurgitation or stenosis (individually analyzed) should be performed on initial clinical suspicion, in case of a new bruit, new symptoms, or every 3 to 6 months according to CHD severity ( <xref ref-type="fig" rid="f51">Figure 21</xref> ).</p>
          <fig id="f51">
            <label>Figure 21</label>
            <caption>
              <title>Patient with a carcinoid tumor, liver metastasis, and clinical status of right heart failure. RV: right ventricle, RA: right atrium, TR: tricuspid regurgitation, IVC: inferior vena cava.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf21-en.tif"/></fig>
          <p>Tricuspid valve involvement leading to regurgitation is the most frequent alteration, followed by pulmonary regurgitation, tricuspid stenosis and, finally, pulmonary stenosis. In the tricuspid valve, there is main involvement of the anterior and septal leaflets, and the posterior leaflet is relatively preserved. RV dilation and dysfunction are consequences of the severity of the valve lesions. Cardiac metastases (4% of cases) may be identified on echocardiography but are more visible on MRI. <xref ref-type="bibr" rid="B173"><sup>173</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B176"><sup>176</sup></xref> </p>
          <p>Several echocardiographic scores have been proposed for CHD assessment. Among the simplest ones, Westberg et al. <xref ref-type="bibr" rid="B177"><sup>177</sup></xref> ( <xref ref-type="table" rid="t17">Table 5</xref> ) evaluates only tricuspid valve regurgitation and anatomy. A score &gt; 1 is considered pathological (87% accuracy). A score &gt; 4 has a 3-year survival rate &lt; 45% vs. 75% for a score of 0. <xref ref-type="bibr" rid="B177"><sup>177</sup></xref> </p>
          <table-wrap id="t17">
            <label>Table 5</label>
            <caption>
              <title>Westberg score <xref ref-type="bibr" rid="B171"><sup>171</sup></xref> </title>
            </caption>
            <table frame="hsides" rules="rows">
              <colgroup width="16%">
                <col/>
                <col/>
                <col/>
                <col/>
                <col/>
                <col/>
              </colgroup>
              <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
                <tr>
                  <th align="left" valign="middle">Characteristics</th>
                  <th align="center" colspan="5" valign="middle">Severity and scoring</th>
                </tr>
              </thead>
              <tbody style="border-bottom: thin solid; border-color: #000000">
                <tr>
                  <td align="left" valign="middle">Valve thickening</td>
                  <td align="center" valign="middle">Normal <break/> 0</td>
                  <td align="center" valign="middle">Mild <break/> 1</td>
                  <td align="center" valign="middle">Moderate <break/> 2</td>
                  <td align="center" valign="middle">Severe <break/> 3</td>
                  <td align="center" valign="middle">Severe with valve retraction <break/> 4</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Regurgitation</td>
                  <td align="center" valign="middle">Normal <break/> 0</td>
                  <td align="center" valign="middle">Mild <break/> 1</td>
                  <td align="center" valign="middle">Moderate <break/> 2</td>
                  <td align="center" valign="middle">Significant <break/> 3</td>
                  <td align="center" valign="middle">Extreme <break/> 4</td>
                </tr>
              </tbody>
            </table>
          </table-wrap>
          <p>More complex scores provide a greater amount of information and are useful for surgical monitoring and planning. In Bhattacharyya et al. <xref ref-type="bibr" rid="B173"><sup>173</sup></xref> ( <xref ref-type="table" rid="t18">Table 6</xref> ), a score &gt; 8 has a diagnostic accuracy of 96% for CHD, and a 5-point increase in the score is an independent predictor of CHD progression (RR 2.95) and mortality (RR 2.66), according to Dobson et al. <xref ref-type="bibr" rid="B176"><sup>176</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B178"><sup>178</sup></xref> </p>
          <table-wrap id="t18">
            <label>Table 6</label>
            <caption>
              <title>Bhattacharyya score <xref ref-type="bibr" rid="B167"><sup>167</sup></xref> </title>
            </caption>
            <table frame="hsides" rules="rows">
              <colgroup width="20%">
                <col/>
                <col/>
                <col/>
                <col/>
                <col/>
              </colgroup>
              <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
                <tr>
                  <th align="left" valign="middle">Characteristics</th>
                  <th align="center" colspan="4" valign="middle">Severity and scoring</th>
                </tr>
              </thead>
              <tbody style="border-bottom: thin solid; border-color: #000000">
                <tr>
                  <td align="left" valign="middle">Valve thickening</td>
                  <td align="center" valign="middle">&lt; 3 mm <break/> 0</td>
                  <td align="center" valign="middle">&#8805; 3 and &lt; 4 mm <break/> 1</td>
                  <td align="center" valign="middle">&#8805; 4 and &lt; 5 mm <break/> 2</td>
                  <td align="center" valign="middle">&#8805; 5 mm <break/> 3</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Valve mobility</td>
                  <td align="center" valign="middle">Normal <break/> 0</td>
                  <td align="center" valign="middle">Mild <break/> 1</td>
                  <td align="center" valign="middle">Moderate <break/> 2</td>
                  <td align="center" valign="middle">Severe/fixed <break/> 3</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Valve morphology</td>
                  <td align="center" valign="middle">Normal <break/> 0</td>
                  <td align="center" valign="middle">Rectified <break/> 1</td>
                  <td align="center" valign="middle">Slight retraction <break/> 2</td>
                  <td align="center" valign="middle">Moderate/severe retraction <break/> 3</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Valve stenosis</td>
                  <td align="center" valign="middle">Normal <break/> 0</td>
                  <td align="center" valign="middle">Mild <break/> 1</td>
                  <td align="center" valign="middle">Moderate <break/> 2</td>
                  <td align="center" valign="middle">Significant <break/> 3</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Valve regurgitation</td>
                  <td align="center" valign="middle">Normal <break/> 0</td>
                  <td align="center" valign="middle">Mild <break/> 1</td>
                  <td align="center" valign="middle">Moderate <break/> 2</td>
                  <td align="center" valign="middle">Significant <break/> 3</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Right ventricle diameter</td>
                  <td align="center" valign="middle">Normal <break/> 0</td>
                  <td align="center" valign="middle">Slight increase <break/> 1</td>
                  <td align="center" valign="middle">Moderate increase <break/> 2</td>
                  <td align="center" valign="middle">Significant increase <break/> 3</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">Right ventricle function</td>
                  <td align="center" valign="middle">Normal <break/> 0</td>
                  <td align="center" valign="middle">Slight reduction <break/> 1</td>
                  <td align="center" valign="middle">Moderate reduction <break/> 2</td>
                  <td align="center" valign="middle">Significant reduction <break/> 3</td>
                </tr>
              </tbody>
            </table>
          </table-wrap>
          <p>Surgical cardiac intervention is indicated in case of RV dilation and dysfunction and signs of HF refractory to drug treatment. Closure of the patent foramen ovale, aiming to reduce right-to-left shunt, and removal of metastases are recommended during the approach. <xref ref-type="bibr" rid="B175"><sup>175</sup></xref> </p>
        </sec>
        <sec>
          <title>6.2. Cardiac Amyloidosis</title>
          <sec>
            <title>6.2.1. Introduction</title>
            <p>Amyloidosis is a multisystemic disease arising from the deposition of compound proteinaceous material in the extracellular space that is difficult to diagnose and, once cardiac involvement is proven, has a poor prognosis. According to the type of precursor protein, it can be classified as light-chain (AL) amyloidosis (when the deposits originate from light-chain proteins) and transthyretin (ATTR) amyloidosis (when the protein carries thyroxine and retinol). <xref ref-type="bibr" rid="B179"><sup>179</sup></xref> </p>
          </sec>
          <sec>
            <title>6.2.2. Clinical Types and Cardiac Involvement</title>
            <p>Besides the heart, AL amyloidosis may affect several organs such as the kidneys, the gastrointestinal tract, and the autonomic nervous system. It is caused by the deposition of proteins deriving from immunoglobulin light chains produced by plasma cells in cases of plasma dyscrasia, such as in multiple myeloma. Approximately 10% of patients with multiple myeloma may develop AL amyloidosis, and more than half of them may have cardiac amyloidosis. Cardiac involvement is second to kidney involvement in AL amyloidosis. <xref ref-type="bibr" rid="B180"><sup>180</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B181"><sup>181</sup></xref> </p>
            <p>The pathological mechanism of ATTR amyloidosis is the deposition of transthyretin derivatives produced by the liver. It is further divided into two subtypes: a) wild-type ATTR (ATTRwt), with predominant involvement of the heart and often causing carpal tunnel syndrome, biceps tendon rupture, and spinal stenosis; and b) mutant ATTR (ATTRm), associated with specific substitutions of transthyretin-coding genes that may affect, besides the heart, the autonomic and peripheral nervous systems. <xref ref-type="bibr" rid="B182"><sup>182</sup></xref> </p>
          </sec>
          <sec>
            <title>6.2.3. Contribution from Echocardiography</title>
            <p>TTE is the most widely used diagnostic option when cardiac amyloidosis is suspected, being also used to screen for cases in family members. It is highly available in medical services of variable complexity, has a relatively low cost, and allows for serial repetition with good reproducibility and consistent findings. Cardiac involvement has the poorest prognosis in this group of patients.</p>
            <sec>
              <title>6.2.3.1. Increased Myocardial Thickness</title>
              <p>The myocardium has a bright or speckled granular appearance, which is more visible on conventional imaging without harmonics. The increase in myocardial thickness is often concentric and symmetrical, unlike that of hypertrophic cardiomyopathy, which tends to show greater asymmetry in distribution ( <xref ref-type="fig" rid="f52">Figure 22</xref> ). The presence of increased myocardial thickness and low-voltage waves on electrocardiogram is a finding that leads to suspected cardiac amyloidosis. <xref ref-type="bibr" rid="B183"><sup>183</sup></xref> The term "increased myocardial thickness" must be distinguished from secondary myocardial hypertrophy: there is myocellular hypertrophy in the latter, while in the former it is the extracellular space that is increased by the deposition of amyloid protein material. <xref ref-type="bibr" rid="B184"><sup>184</sup></xref> The increase in myocardial thickness is diffuse and may include all LV walls, RV free wall, interatrial septum, and valves with or without associated regurgitation. Myocardial thickness &#8805; 12 mm may be used as a cutoff value for suspected cardiac amyloidosis. <xref ref-type="bibr" rid="B185"><sup>185</sup></xref> The clinical value and prognosis of increased myocardial thickness are already known: the more exuberant, the greater the occurrence of congestive HF and the poorer the survival.</p>
              <fig id="f52">
                <label>Figure 22</label>
                <caption>
                  <title>Patient with left ventricular hypertrophy with no determined cause. Echocardiogram showing shiny or granular scintillating aspect of the myocardium suggestive of cardiac amyloidosis. PE: pericardial effusion; LA: left atrium; LV: left ventricle; RV: right ventricle; RA: right atrium.</title>
                </caption>
                <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf22-en.tif"/></fig>
            </sec>
            <sec>
              <title>6.2.3.2. Left Atrium</title>
              <p>There may also be changes in the LA, and the increase in LA volume may be due not only to high degrees of diastolic dysfunction but also to the deposition of amyloid fibrils.</p>
              <p>Changes in atrial myocardial deformation (strain and strain rate) and in atrial systolic function parameters are frequently observed in patients with few echocardiographic characteristics related to cardiac amyloidosis and in those with congestive HF symptoms, which are associated with a poor prognosis. <xref ref-type="bibr" rid="B186"><sup>186</sup></xref> </p>
            </sec>
            <sec>
              <title>6.2.3.3. Diastolic Function</title>
              <p>In more advanced stages, the assessment of diastolic function usually reveals increased E/e' ratio compatible with increased LV filling pressures. However, diastolic function parameters are abnormal even in the early stages of cardiac amyloidosis. The presence of diastolic dysfunction is associated with poor clinical outcomes, as already demonstrated, and suggests greater risk of thromboembolism. <xref ref-type="bibr" rid="B187"><sup>187</sup></xref><sup>-</sup><xref ref-type="bibr" rid="B189"><sup>189</sup></xref> </p>
            </sec>
            <sec>
              <title>6.3.3.4. Left Ventricular Systolic Function</title>
              <p>LVEF may still be within normal limits, and this feature allows for cardiac amyloidosis to be included as a cause of HF with preserved ejection fraction. Deteriorated systolic function occurs in later stages and is associated with poor clinical outcomes and prognosis. <xref ref-type="bibr" rid="B187"><sup>187</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B189"><sup>189</sup></xref> </p>
              <p>Regarding myocardial deformation measurements, cardiac amyloidosis exhibits a reduction in myocardial GLS mainly in the basal and middle segments of the LV with preserved values in the apical segment (i.e., apical sparing). <xref ref-type="bibr" rid="B188"><sup>188</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B190"><sup>190</sup></xref> It is useful to calculate the ratio of the mean apical GLS values by the sum of mean GLS values in the basal and middle LV segments. A ratio &gt; 1 means a high specificity for diagnosis of cardiac amyloidosis. <xref ref-type="bibr" rid="B190"><sup>190</sup></xref> When considering the relationship between LVEF measurements and myocardial strain values (referred to as ejection fraction-to-strain ratio [EFSR]), there is an inversion of the ratio with lower values of myocardial deformation and preserved LVEF, regardless of clear congestive HF symptoms. An EFSR &#8805; 4 is useful in differentiating cardiac amyloidosis from hypertrophic cardiomyopathy, with 89.7% sensitivity and 91.7% specificity. <xref ref-type="bibr" rid="B187"><sup>187</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B188"><sup>188</sup></xref> </p>
              <p>In cardiac amyloidosis, isolated myocardial GLS values &gt; -15% have been associated with greater severity and increased mortality. <xref ref-type="bibr" rid="B191"><sup>191</sup></xref> In another study, a strain value &gt; -17% managed to separate groups of patients with unfavorable clinical response after autologous bone marrow transplantation (BMT). An apical sparing index &#8805; 1.19 was associated with higher mortality and need for heart transplantation at 5 years of follow-up. This index also showed a predictive value in the survival curves and the need for heart transplantation when associated with a lower LVEF value. <xref ref-type="bibr" rid="B192"><sup>192</sup></xref> </p>
              <p>Liu et al. <xref ref-type="bibr" rid="B193"><sup>193</sup></xref> analyzed the value of the diastolic wave peak of the strain rate curve alone (rapid diastolic filling phase) in 41 patients with cardiac amyloidosis, demonstrating that the global value of the diastolic strain rate (global LSR<sub>dias</sub>&gt; - 0.85 S<sup>&#8722;1</sup>) was predictive of a 4-fold increase in mortality in patients with cardiac amyloidosis with preserved LVEF (LVEF &gt; 50%). <xref ref-type="bibr" rid="B193"><sup>193</sup></xref> </p>
              <p>Strain measurements are highly sensitive and exhibit good specificity in cases of cardiac amyloidosis; however, it should be noted that conventional echocardiographic measurements of systolic function are still important and demonstrate excellent prognostic correlation in such cases. Thus, stroke volume index (SVi) and the measure that associates stroke volume with total myocardial mass volume (referred to as myocardial contraction fraction [MCF]) showed a good prognostic value in patients with cardiac amyloidosis, regardless of type and comparable to that of strain measurements. Therefore, in this group of patients, SVi &lt; 33 mL/min and MCF &lt; 34% with cardiac index &lt; 2.4 L/min/m<sup>2</sup>were the best predictors of overall survival with an accuracy comparable to that of strain measurements <xref ref-type="bibr" rid="B194"><sup>194</sup></xref> ( <xref ref-type="fig" rid="f53">Figure 23</xref> ).</p>
              <fig id="f53">
                <label>Figure 23</label>
                <caption>
                  <title>Global longitudinal strain of the left ventricle in a patient with transthyretin amyloidosis, demonstrating a peculiar pattern that preserves the apex and majorly affects the middle and basal segments.</title>
                </caption>
                <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf23-en.tif"/></fig>
            </sec>
            <sec>
              <title>6.2.3.5. Other Findings</title>
              <p>Despite not having a notable incidence in cases of cardiac amyloidosis, the presence of intracardiac thrombi has been reported and, of note, is not necessarily associated with the presence of atrial fibrillation. <xref ref-type="bibr" rid="B195"><sup>195</sup></xref> Some authors have demonstrated that AL amyloidosis and diastolic dysfunction are independent risk factors for intracardiac thrombi. <xref ref-type="bibr" rid="B196"><sup>196</sup></xref> The search for thrombi should always be considered in patients who have criteria for severe cardiac amyloidosis (e.g., high degrees of increased myocardial thickness, decreased LVEF, and advanced stages of diastolic dysfunction). Several mechanisms have already been proposed to explain the occurrence of thrombi in addition to the presence of atrial fibrillation, such as: amyloid deposits in the subendocardial region that produce damage and greater parietal stiffness; hemodynamic stasis as a consequence of important diastolic dysfunction, usually of the restrictive type; and plasma hypercoagulability as a systemic mechanism resulting from various conditions.</p>
              <p>Cardiac tamponade due to major pericardial effusion is rare, and diagnosis is predominantly clinical, as the high pressures in the right chambers decrease the chances of classic echocardiographic collapse. Less intense pericardial effusion is more common. Heart valves may also be infiltrated but rarely exhibit severe valve regurgitation. <xref ref-type="bibr" rid="B187"><sup>187</sup></xref> </p>
            </sec>
            <sec>
              <title>6.2.3.6. Diagnostic Approach</title>
              <p>In several clinical situations, the diagnosis of cardiac amyloidosis is initiated with an echocardiographic examination but very often occurs in one out of two contexts of cardiac evaluation.</p>
              <p>The first situation concerns the need for cardiac evaluation in patients with multiple myeloma. In such cases, confirmation of cardiac involvement is imperative, as the survival rate in AL amyloidosis may be extremely unfavorable. Even if the classic echocardiographic findings are absent in the first examination, it is recommended that the examination is repeated in a follow-up visit.</p>
              <p>In the second situation, patients undergo cardiac evaluation because they have either clinical manifestations of HF with preserved ejection fraction or &#8220;hypertrophy&#8221; on echocardiogram (often associated with low-voltage complexes on electrocardiogram).</p>
              <p>In such cases, in addition to the echocardiographic findings described above, investigation should continue with other imaging tests (MRI and NM imaging) and laboratory tests such as protein electrophoresis and light-chain protein testing.</p>
              <p>In centers where myocardial deformation analysis is available, the presence of apical sparing is typical but not exclusive. Other causes of LV hypertrophy may exhibit the same pattern, such as hypertrophy secondary to hypertension and aortic stenosis.</p>
            </sec>
          </sec>
          <sec>
            <title>6.2.4. Contribution from Cardiac Magnetic Resonance Imaging</title>
            <p>Cardiac MRI allows for diagnosis of cardiac amyloidosis by morphological and functional changes on cine sequences, as is the case with TTE, and more accurately through delayed enhancement and T1 map sequences.</p>
            <p>A delayed enhancement sequence usually detects the deposition of amyloid protein in the myocardial interstitial space through the presence of hyperenhancement (white color) against the usually black muscle on the images. <xref ref-type="bibr" rid="B197"><sup>197</sup></xref> Syed et al. <xref ref-type="bibr" rid="B198"><sup>198</sup></xref> analyzed cardiac MRIs of 120 patients with amyloidosis, <xref ref-type="bibr" rid="B198"><sup>198</sup></xref> of which 35 had confirmed cardiac involvement by histology. The other 85 patients were divided into those with or without echocardiographic evidence of cardiac amyloidosis. In the 35 patients with histological diagnosis, 97% showed delayed enhancement and 91% had increased wall thickness on echocardiography. Transmural or subendocardial delayed enhancement was the most common pattern (83%), associated with greater interstitial amyloid deposition; focal delayed enhancement (6%) and difficulty in canceling the myocardial signal (8%) were other patterns associated with cardiac involvement. In the 85 patients without histological diagnosis, delayed enhancement was present in 86% of those with echocardiographic abnormalities and in 47% of those without evidence of cardiac amyloidosis on TTE. The presence and pattern of delayed enhancement were associated with the New York Heart Association (NYHA) functional class, low voltage on electrocardiogram, LV mass index, RV wall thickness, and serum troponin and type B natriuretic peptide (BNP) values. <xref ref-type="bibr" rid="B198"><sup>198</sup></xref> </p>
            <p>Austin et al. <xref ref-type="bibr" rid="B199"><sup>199</sup></xref> evaluated 47 patients with suspected cardiac amyloidosis who underwent cardiac MRI, electrocardiogram, TTE, and biopsy. <xref ref-type="bibr" rid="B199"><sup>199</sup></xref> Compared to biopsy, delayed enhancement had a sensitivity of 88%, a specificity of 90%, a positive predictive value of 88%, and a negative predictive value of 90%, thus being the only parameter with significant diagnostic accuracy in multivariate analysis. One year after biopsy, 19% of patients died, and delayed enhancement was the only significant predictor of mortality in this period, showing the prognostic role of this parameter in amyloidosis.</p>
            <p>Regarding the differentiation of types of cardiac amyloidosis, cardiac MRI is useful in predicting AL and ATTR amyloidosis. Dungu et al. <xref ref-type="bibr" rid="B200"><sup>200</sup></xref> showed a greater increase in myocardial thickness (228 g vs. 167 g) and a greater extent of delayed enhancement in patients with ATTR amyloidosis, although mortality in patients with AL amyloidosis was higher. In that study, 90% of patients with ATTR amyloidosis had some segment with transmural delayed enhancement compared to 37% of patients with AL amyloidosis. In addition, 100% of patients had delayed RV enhancement in ATTR amyloidosis compared to 72% in AL amyloidosis. The authors created a score called Query Amyloid Late Enhancement (QALE) with values ranging from 0 to 18. Values &#8805; 13 can predict ATTR instead of AL amyloidosis, with a sensitivity of 82% and a specificity of 76%.</p>
            <p>T1 mapping sequence, the most recent MRI technique, is useful in the diagnosis and prognosis of patients with cardiac amyloidosis. It may also be used to monitor the treatment of new therapeutic agents in this disease. Pre-contrast T1 values are increased in patients with cardiac amyloidosis; this is a diagnostic option for patients without delayed enhancement or those who do not undergo the delayed enhancement sequence because of contraindication to gadolinium injection. In addition, the gadolinium injection makes it possible to calculate myocardial ECV, which is expanded in cardiac amyloidosis by the deposition of amyloid fibrils in the interstitium, showing a good correlation with biopsy, with proven prognostic value. <xref ref-type="bibr" rid="B201"><sup>201</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B202"><sup>202</sup></xref> </p>
          </sec>
          <sec>
            <title>6.2.5. Contribution from Nuclear Medicine</title>
            <p>NM has gained new relevance in the diagnosis of cardiac amyloidosis, with studies showing that radiotracers with affinity for bone, such as 3,3-diphosphono-1,2-propanedicarboxylic acid (DPD) and pyrophosphate, both labeled with technetium-99m [<sup>99m</sup>Tc], have very high sensitivity for the detection of ATTR. Scintigraphy with those tracers allows for noninvasive differentiation of amyloid protein subtypes based on the concentration levels of the tracer in the cardiac area. This differentiation has prognostic and therapeutic implications. <xref ref-type="bibr" rid="B203"><sup>203</sup></xref> Gilmore et al. <xref ref-type="bibr" rid="B204"><sup>204</sup></xref> have conducted the most important study on the subject to date. They evaluated the results of scintigraphy with bone-affine radiotracers in 1,217 patients with suspected cardiac amyloidosis referred for evaluation in specialty centers, and obtained sensitivity values of up to 99% when AL amyloidosis had already been ruled out by biochemical testing. <xref ref-type="bibr" rid="B204"><sup>204</sup></xref> The examination technique consists of injecting the tracer into a peripheral vein and then acquiring planar images of the chest in the anterior projection 1 hour post radiopharmaceutical administration ( <xref ref-type="fig" rid="f54">Figure 24</xref> ). This allows for a quantitative analysis to be performed in which two mirrored regions of interest (ROIs) are drawn, one over the cardiac area in the left hemithorax and another in the right hemithorax. A ratio between left and right hemithorax counts (representing the amount of tracer present in each area) &gt; 1.5 has a high diagnostic sensitivity (95% sensitivity and 79% specificity), <xref ref-type="bibr" rid="B203"><sup>203</sup></xref> as well as prognostic value; ratios &gt; 1.6 are associated with poor prognosis on 5-year follow-up. After 3 hours, whole-body images are acquired in the anterior, posterior, oblique, and left lateral projections. The level of concentration of the tracer in the cardiac area is compared to that of the ribcage and graded on a scale of 0 to 3, in which grade 0 denotes no cardiac concentration; grade 1, slight cardiac concentration, lower than that of the ribcage; grade 2, equal to that of the ribcage; and grade 3, greater than that of the ribcage. Grades 2 and 3 are strongly associated with ATTR amyloidosis (&gt; 99% sensitivity and 86% specificity) ( <xref ref-type="fig" rid="f55">Figure 25</xref> ) if AL disease has already been ruled out. Grades 0 and 1 may be related to AL amyloidosis ( <xref ref-type="fig" rid="f56">Figure 26</xref> ) or early-stage familial ATTR amyloidosis. Three-hour imaging has greater diagnostic specificity for ATTR amyloidosis (58% sensitivity and 100% specificity). <xref ref-type="bibr" rid="B205"><sup>205</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B206"><sup>206</sup></xref> Three-hour single-photon emission computed tomography (SPECT) of the chest has been frequently used because it improves the ability to distinguish the presence of activity in the LV (blood pool) and assess the interventricular septum, which is the usual site of myocardial biopsy if this procedure is necessary. This additional scan also allows for a more accurate quantitative comparison of the myocardial concentration of radiotracer to that of the ribcage. <xref ref-type="fig" rid="f57">Figure 27</xref> shows RV involvement by familial ATTR amyloidosis, best evaluated on SPECT images. Technetium-99m-labeled methylene diphosphonate (<sup>99m</sup>Tc MDP) is the most widely available bone-affine radiotracer in Brazil, but its use for assessment of cardiac amyloidosis is discouraged. A study compared<sup>99m</sup>Tc MDP and DPD in a group of patients with familial amyloidosis and found that MDP performed suboptimally, with occasional false-negative findings. <xref ref-type="bibr" rid="B207"><sup>207</sup></xref> </p>
            <fig id="f54">
              <label>Figure 24</label>
              <caption>
                <title>Anterior image of the chest 1 hour after intravenous administration of technetium-99m-labeled pyrophosphate. Each of the circles represents a region of interest (ROI) and allows for quantification of tracer concentration. The ratio between left and right hemithorax counts, in this case, was 1.75, therefore positive for transthyretin amyloidosis.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf24-en.tif"/></fig>
            <fig id="f55">
              <label>Figure 25</label>
              <caption>
                <title>Whole-body scintigraphy and planar chest images with technetium-99m-labeled pyrophosphate show abnormal radiopharmaceutical accumulation projecting from the heart (arrows) of a patient with advanced heart failure with preserved ejection fraction. Serum light-chain measurements were negative, and abdominal fat biopsy was positive for amyloidosis. The definitive diagnosis was transthyretin amyloidosis.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf25-en.tif"/></fig>
            <fig id="f56">
              <label>Figure 26</label>
              <caption>
                <title>Whole-body scintigraphy and planar chest images with technetium-99m-labeled pyrophosphate showing light-intensity accumulation (grade 1) projecting from the heart (arrow) of a patient with subsequent confirmation of light-chain amyloidosis due to a monoclonal spike in serum and urine electrophoresis, increased serum free light-chain antibodies, and bone marrow aspirate showing plasma cell infiltrate &lt; 10%. Final confirmation was performed by abdominal fat biopsy, which was positive for amyloidosis.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf26-en.tif"/></fig>
            <fig id="f57">
              <label>Figure 27</label>
              <caption>
                <title>Reconstructed single-photon emission computed tomography scans of the axial, coronal, and sagittal axes showing accumulation of technetium-99m-labeled pyrophosphate in the left ventricle and simultaneous involvement of the right ventricle (arrows) in a patient with suspected mutant transthyretin amyloidosis, confirmed by a genetic test.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf27-en.tif"/></fig>
            <p><xref ref-type="fig" rid="f58">Figure 28</xref> shows an algorithm for NM diagnosis of suspected cases of cardiac amyloidosis.</p>
            <fig id="f58">
              <label>Figure 28</label>
              <caption>
                <title>Proposed nuclear medicine diagnostic sequence for suspected cases of cardiac amyloidosis (CA). TTE: transthoracic echocardiogram; MRI: magnetic resonance imaging; TTR: transthyretin amyloidosis (TTRm: mutant TTR; TTRwt: wild-type TTR); AL: light-chain amyloidosis; PYP: pyrophosphate; DPD: 3,3-diphosphono-1,2-propanodicarboxylic acid;<sup>99m</sup>Tc: technetium-99m.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf28-en.tif"/></fig>
          </sec>
        </sec>
        <sec>
          <title>6.3. Takotsubo Syndrome</title>
          <p>Takotsubo syndrome (TTS) is characterized by acute and reversible LV dysfunction with a behavior similar to that of acute coronary syndrome, usually with abrupt onset of precordial pain and dyspnea. It is a stress-induced cardiac syndrome without any evidence of obstructive CAD that usually resolves spontaneously within days or weeks.</p>
          <p>In recent years, there has been a growing interest in studying the relationship between cancer and TTS. This happened especially after some published studies showed a strong association between the two conditions. <xref ref-type="bibr" rid="B208"><sup>208</sup></xref> </p>
          <p>The prevalence of neoplasms seems to be higher in patients with TTS when compared to individuals of the same age and sex, both at the time of diagnosis and at follow-up. While the diagnosis of TTS is around 1% to 2% in the general population, it reaches 10% in individuals with malignancies. <xref ref-type="bibr" rid="B209"><sup>209</sup></xref> </p>
          <p>In most cases, TTS involves apical and middle LV segments, which are akinetic or dyskinetic (apical ballooning pattern), as opposed to basal segments, which are generally hyperkinetic. Some forms with a variant pattern have been described such as the midventricular and inverted variants. The midventricular variant is characterized by akinesia of the midventricular segments, with hypokinesia or normal contraction of the apical segments and hypercontractility of the base. The inverted variant has two different forms: the first is characterized by apical sparing, presenting with hypokinesia of the remaining walls, and the second by hypokinesia limited to the basal segments.</p>
          <p>Speckle tracking echocardiography allows for the assessment of multidirectional LV deformation. In typical cases (apical ballooning pattern), there is a compromise of apical and midventricular longitudinal deformation, with a base-to-apex strain gradient. In this phase, all components of the LV torsion mechanics involving the systolic and diastolic phases are compromised. Given its greater sensitivity in detecting subtle abnormalities compared to that of more traditional parameters, such as LVEF and wall motility index, speckle tracking echocardiography is useful in the diagnosis of TTS. <xref ref-type="bibr" rid="B210"><sup>210</sup></xref> </p>
          <p>Three-dimensional echocardiography enabled a more accurate demonstration of LV volumes and LVEF compared to 2D echocardiography and angiography. However, further studies using this technology during the course of TTS are still required to establish its role in clinical practice.</p>
          <p>The most prevalent tumors among patients with TTS are colorectal, breast, and bronchial malignancies and melanoma. <xref ref-type="bibr" rid="B208"><sup>208</sup></xref> Hematologic neoplasms are less prevalent. Regarding potential triggering factors, a relationship with cancer treatment was identified in 57% of cases, including surgical stress (33%), chemotherapy (17%), and radiotherapy (7%); the others were emotional stress (30%) and the presence of another acute illness (13%). <xref ref-type="bibr" rid="B209"><sup>209</sup></xref> </p>
          <p>Patients with malignancies have a reduced tolerance threshold for stressors and an increased sensitivity of cardiac adrenergic receptors. In this context, the addition of physical (pain secondary to cancer, diagnostic procedures, cancer surgery) and emotional (fear of illness or death, changes in family dynamics) stressors, which are common to the disease, contributes to a greater predisposition to TTS. Some malignancies, such as pheochromocytoma and paraganglioma, cause hypercatecholaminemia and may be a trigger of TTS. <xref ref-type="bibr" rid="B211"><sup>211</sup></xref> </p>
        </sec>
        <sec>
          <title>6.4. Siderotic Cardiomyopathy (Iron Overload)</title>
          <p>The prevalence of anemia in patients with cancer is high, and the condition is found in more than half of patients during the course of the disease, especially in those with hematologic neoplasms. Moderate-to-severe anemia occurs in approximately 40% of patients, and the cause is multifactorial; it may be secondary to treatment-related myelosuppression, occult bleeding, functional iron deficiency, erythropoietin deficiency due to kidney disease, and/or marrow involvement with tumor. <xref ref-type="bibr" rid="B212"><sup>212</sup></xref> The main oncologic disease leading to iron overload is myelodysplastic syndrome, due to both increased absorption and regular transfusions. Consequently, patients or survivors of cancer may experience iron overload in the liver, heart, and adrenal gland. Patients with cardiac iron overload usually have poorer cardiovascular prognosis compared to the general population, with outcomes present in 73.2% versus 54.5% over a 3-year period. <xref ref-type="bibr" rid="B213"><sup>213</sup></xref> </p>
          <p>Iron overload cardiomyopathy in early stages commonly presents with normal ventricular function. Echocardiographic diagnosis is often challenging, but some findings may suggest a diagnosis compatible with clinical history. Ventricular diastolic dysfunction may progress to restrictive physiology, leading to dilated heart disease with reduced LVEF. It may manifest as pericardial constriction due to iron deposition in the pericardium. Speckle tracking still has a conflicting role in this context, but increased cardiac iron overload may be associated with a reduced absolute GLS value. There is no description in the literature of a strain pattern that is specific to myocardial iron overload. The results of studies that attempted to correlate circumferential and radial strain with iron deposits were conflicting. Three-dimensional speckle tracking echocardiography also has no established role in these patients but has been showing favorable results for the detection of early subclinical dysfunction. <xref ref-type="bibr" rid="B214"><sup>214</sup></xref><sup>-</sup><xref ref-type="bibr" rid="B216"><sup>216</sup></xref> </p>
          <p>Although echocardiography may be used to screen for iron overload, the method is not able to accurately predict myocardial iron content, unlike cardiac MRI ( <xref ref-type="table" rid="t19">Table 7</xref> ).</p>
          <table-wrap id="t19">
            <label>Table 7</label>
            <caption>
              <title>Classification of myocardial and hepatic iron overload (MIO/HIO) by magnetic resonance imaging</title>
            </caption>
            <table frame="hsides" rules="rows">
              <colgroup width="16%">
                <col/>
                <col/>
                <col/>
                <col/>
                <col/>
                <col/>
              </colgroup>
              <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
                <tr>
                  <th align="left" valign="middle">T2* (ms) 1.5 T</th>
                  <th align="center" valign="middle">R2* (Hz) 1.5 T</th>
                  <th align="center" valign="middle">T2* (ms) 3.0 T</th>
                  <th align="center" valign="middle">R2* (Hz) 3.0 T</th>
                  <th align="center" valign="middle">MIO/HIO (mg/g DW)</th>
                  <th align="center" valign="middle">Classification</th>
                </tr>
              </thead>
              <tbody style="border-bottom: thin solid; border-color: #000000">
                <tr>
                  <td align="center" colspan="6" valign="middle">Heart</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">&gt; 20</td>
                  <td align="center" valign="middle">&#8804; 50</td>
                  <td align="center" valign="middle">&gt; 12.6</td>
                  <td align="center" valign="middle">&#8804; 79</td>
                  <td align="center" valign="middle">&#8804; 1.16</td>
                  <td align="center" valign="middle">Normal</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">10 to 20</td>
                  <td align="center" valign="middle">50 to 100</td>
                  <td align="center" valign="middle">5.8 to 12.6</td>
                  <td align="center" valign="middle">79 to 172</td>
                  <td align="center" valign="middle">1.16 to 2.71</td>
                  <td align="center" valign="middle">Slight/moderate overload</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">&lt; 10</td>
                  <td align="center" valign="middle">&gt; 100</td>
                  <td align="center" valign="middle">&lt; 5.8</td>
                  <td align="center" valign="middle">&gt; 172</td>
                  <td align="center" valign="middle">&gt; 2.71</td>
                  <td align="center" valign="middle">Severe overload</td>
                </tr>
                <tr>
                  <td align="center" colspan="6" valign="middle">Liver</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">&gt; 15.4</td>
                  <td align="center" valign="middle">&#8804; 65</td>
                  <td align="center" valign="middle">&gt; 8.4</td>
                  <td align="center" valign="middle">&#8804; 119</td>
                  <td align="center" valign="middle">&#8804; 2.0</td>
                  <td align="center" valign="middle">Normal</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">4.5 to 15.4</td>
                  <td align="center" valign="middle">66 to 224</td>
                  <td align="center" valign="middle">2.3 to 8.4</td>
                  <td align="center" valign="middle">120 to 435</td>
                  <td align="center" valign="middle">2.0 to 7.0</td>
                  <td align="center" valign="middle">Mild</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">2.1 to 4.5</td>
                  <td align="center" valign="middle">225 to 475</td>
                  <td align="center" valign="middle">1.05 to 2.3</td>
                  <td align="center" valign="middle">436 to 952</td>
                  <td align="center" valign="middle">7.0 to 15</td>
                  <td align="center" valign="middle">Moderate</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">&lt; 2.1</td>
                  <td align="center" valign="middle">&gt; 475</td>
                  <td align="center" valign="middle">&lt; 1.05</td>
                  <td align="center" valign="middle">&gt; 952</td>
                  <td align="center" valign="middle">&gt; 15</td>
                  <td align="center" valign="middle">Severe</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="TFN8">
                <p>DW: dry weight.</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
          <p>Because of this limitation, current guidelines of several international societies for different diseases recommend routine use of MRI to determine and monitor the level of iron overload in different organs. MRI is recommended for patients with cancer with detected serum ferritin levels &gt; 1,000 ng/mL or for patients with a life expectancy &gt; 12 months who received &gt; 10 transfusion bags. <xref ref-type="bibr" rid="B217"><sup>217</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B218"><sup>218</sup></xref> </p>
          <p>The MRI scan should evaluate both liver and heart, and be repeated annually or according to therapeutic changes in the iron chelator or transfusion load. The quantification is made by the indirect effect that the iron molecules exert on the local magnetic field in the tissue under analysis. Therefore, the higher the concentration of tissue iron, the lower the signal of the measured tissue (darker); thus, iron quantification in proportion to signal intensity is obtained from several images with consecutive modifications of echo time ( <xref ref-type="fig" rid="f59">Figure 29</xref> ).</p>
          <fig id="f59">
            <label>Figure 29</label>
            <caption>
              <title>Example of patients with cancer with normal myocardial iron levels (A) and significant iron overload (B). T2* in patient A was 22.8 ms with a myocardial iron concentration (MIC) of 0.98 mg/g; in patient B, T2* was 11.9 ms with an MIC of 2.2 mg/g. More myocardial darkening is observed in patient B with increased echo time values, visually determining the highest degree of myocardial overload. Patient B was initiated on oral iron chelation therapy after myocardial overload was determined by magnetic resonance imaging.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf29-en.tif"/></fig>
          <p>Currently, the MRI scan has no specific substitute, being the only test capable of quantitatively determining the levels of iron overload in different organs simultaneously, noninvasively, and without any contrast or ionizing radiation.</p>
        </sec>
      </sec>
      <sec>
        <title>7. Pericardial Diseases</title>
        <sec>
          <title>7.1. Pericardial Tumors</title>
          <p>Although usually asymptomatic, pericardial malignancy may manifest as nonspecific symptoms such as dyspnea and tachycardia, which are often related to pericarditis, pericardial constriction, myocardial invasion, or, more commonly, pericardial effusion (with or without tamponade). Tamponade occurs in patients with major effusion and no previous symptoms in up to one third of cases. <xref ref-type="bibr" rid="B219"><sup>219</sup></xref> </p>
          <p>In 20% to 50% of patients with cancer and pericardial effusion, the latter is caused by neoplastic involvement; in 30%, it may be due to lymphatic impairment secondary to radiotherapy or viral infection. In 10% to 25% of cases, pericardial effusion is the first sign of cancer. <xref ref-type="bibr" rid="B220"><sup>220</sup></xref> </p>
          <p>The tumors may be either primary pericardial neoplasms or metastases involving the pericardium (secondary pericardial neoplasm). The dissemination may occur through hematogenic spread, lymphatic spread, or direct invasion of the lung and mediastinum. The most common metastatic tumors involving the pericardium are lymphomas, melanomas, and lung, breast, and renal cell carcinomas; adenocarcinoma is the most common histological pattern. <xref ref-type="bibr" rid="B221"><sup>221</sup></xref> </p>
          <p>A recent study showed that the presence of occult hematologic, colorectal, ovarian, kidney, pancreas, breast, and bladder neoplasms should be suspected in older adults, obese patients, and/or smokers who present with acute pericarditis and need for hospitalization. The cancer diagnosis was usually made 3 to 12 months following the episode of pericarditis. <xref ref-type="bibr" rid="B222"><sup>222</sup></xref> </p>
          <sec>
            <title>7.1.1. Echocardiogram in Patients with Pericardial Neoplasm</title>
            <p>Pericardial effusion may be assessed semiquantitatively by TTE. Rapid volume increase and presence of spontaneous contrast on TTE, with or without identification of pericardial mass, are suggestive of pericardial neoplasm. It usually has a solid appearance, increased echogenicity, and may infiltrate the myocardium. <xref ref-type="bibr" rid="B220"><sup>220</sup></xref> As a differential diagnosis, pericardial fat has low echogenicity and may be seen adjacent to the RV free wall and atrioventricular junction.</p>
            <p>Among the primary tumors, mesothelioma, arising from the mesothelial cells of visceral or parietal pericardium, presents with pericardial effusion, tamponade, or constriction, and the nodules in the pericardium may invade the myocardium. A retrospective study of 64 patients with primary malignant pericardial mesothelioma showed that echocardiographic presentations were nonspecific, with pericardial effusion in 86% of cases (of which 67% were massive and 95% were bloody), pericardial masses in 36%, and thickening in 17%. Tamponade and constrictive pericarditis occurred in 37% and 27% of cases, respectively. Tamponade may be associated with the proliferation of diffuse mesothelial cells and myocardial infiltration, which may cause decreased relaxation and complacency. Reaccumulation of effusion following pericardiocentesis occurred in 73% of cases. <xref ref-type="bibr" rid="B223"><sup>223</sup></xref> </p>
            <p>The measurement of pericardial thickness is limited on echocardiography, except when the measures are greater than 5 mm. In general, the measurement of pericardial thickness is best performed by CT or cardiac MRI, which allow for a better evaluation of the implant and tumor extent. Thus, the use of multimodality imaging shows incremental value. Speckle tracking, in turn, can detect subclinical myocardial dysfunction because of early myocardial infiltration.</p>
            <p>Usually, pericardial fluid should only be seen on systole, but accumulation makes it present during the entire cardiac cycle. Pericardial effusion is considered significant in the presence of at least 2cm of pericardial fluid around the heart. In cardiac tamponade, the heart is compressed by the accumulation of fluid in the pericardial space, which leads to increased intrapericardial pressure that exceeds the intracavitary pressure. Such accumulation may occur rapidly or gradually. The consequent collapse of the right heart chambers, secondary to increased intrapericardial pressure, is more prominent on expiration, when RA and RV filling is reduced. However, in the presence of pulmonary hypertension, RA collapse is delayed, resisting until the intrapericardial pressure exceeds the high pressures in the right chambers. In cases of massive effusions, the heart tends to &#8220;swing&#8221; inside the pericardial fluid at each heartbeat and may have an electrical alternation on the electrocardiographic record. There are also respiratory changes in cardiac flows. The pressure increase inside the RV during inspiration leads to a deviation of the interventricular septum to the left and a consequent increase in the flow and volume of the right chambers, in addition to dilation of the inferior vena cava ( <xref ref-type="fig" rid="f60">Figure 30 A-B</xref> ).</p>
            <fig id="f60">
              <label>Figure 30</label>
              <caption>
                <title>A. Tricuspid valve flow variation &gt; 40%. B. Dilated inferior vena cava (IVC) with no caliber variation with respiratory maneuvers (patient with breast cancer).</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-117-04-0845-00266-gf30-en.tif"/></fig>
            <p>Subxiphoid incision is the gold standard for surgical approach in biopsy or pericardial drainage. However, pericardiocentesis is routinely guided by fluoroscopy or echocardiography, with a complication rate of 4% to 10%. During echocardiography-guided pericardiocentesis, agitated saline is useful to assess the position of the needle before inserting the catheter and then to assess the position of the catheter. <xref ref-type="bibr" rid="B224"><sup>224</sup></xref> Pericardial effusion is considered to be recurrent if reaccumulation of fluid occurs within 3 months of drainage.</p>
          </sec>
        </sec>
      </sec>
      <sec>
        <title>8. Cardio-Oncology in Children and Adolescents</title>
        <sec>
          <title>8.1. General Considerations</title>
          <p>The number of new cases of childhood and adolescent cancer expected in Brazil, for each year of the 2020-2022 triennium, is of 4,310 new cases in males and 4,150 in females. These figures correspond to an estimated risk of 137 new cases per million in males and 139 per million in females. Childhood and adolescent cancer consists of a set of diseases with their own characteristics in relation to histopathology and clinical behavior. The predominant types of pediatric cancer (aged 0 to 19 years) are leukemia (28%), central nervous system neoplasms (26%), and lymphomas (8%), followed by tumors of the peripheral nervous system (neuroblastomas), Wilms&#8217; tumor, retinoblastoma, germ cell tumors (ovaries and testes), soft tissue sarcomas, and osteosarcoma. <xref ref-type="bibr" rid="B225"><sup>225</sup></xref> </p>
          <p>The prospects for childhood and adolescent cancer cure are promising, with current survival rates approaching 80% in high-quality institutions if diagnosed early. <xref ref-type="bibr" rid="B226"><sup>226</sup></xref> Despite successful treatment, complications inherent to chemotherapy drugs and/or radiotherapy compromise several organ systems in the short, medium, or long term. There is clear evidence that survivors of cancer treated during childhood with anthracyclines and/or radiotherapy are significantly more likely to develop cardiovascular complications during their lifetime, estimated at 5% to 30%, especially considering the protocol used and certain risk factors. The cumulative incidence of severe chronic problems may reach 40% in the 30-year follow-up period for survivors. <xref ref-type="bibr" rid="B227"><sup>227</sup></xref> </p>
          <p>Cancer is the second most common cause of death among children aged 1 to 14 years in the US, second only to accidents and violent deaths. In Brazil, cancer accounted for 8% of the total deaths among children and adolescents aged 1 to 19 years and 12% of deaths in the age range of 1 to 14 years between 2009 and 2013. In 2014, 2,724 deaths from childhood and adolescent cancer occurred in Brazil. <xref ref-type="bibr" rid="B225"><sup>225</sup></xref> This reality demonstrates how important the interaction between hematologist-oncologists and cardiologists is for safety in the treatment of this type of cancer.</p>
          <p>Cardiovascular complications are the main causes of morbidity and mortality in survivors of cancer treated during childhood, second only to disease recurrences and secondary neoplasms. The mechanisms of action of the various chemotherapy agents as well as the physical injuries caused by radiotherapy are comparable among adults, children, and adolescents. However, the younger age group is particularly more vulnerable in view of the ongoing process of growth and physical development. In addition, cardiomyocytes have a limited regeneration capacity, and the drug metabolism in this population behaves differently from that of adults. <xref ref-type="bibr" rid="B228"><sup>228</sup></xref> Therefore, injuries considered to be minor at the time of treatment may progressively compromise myocardial function over time, leading to decompensation in adulthood. Inadequate gain in LV mass, decreased contractile function, and possible development of progressive restrictive cardiomyopathy over the years lead to cardiovascular sequelae that are often irreversible in some of these patients.</p>
          <p>In addition to ventricular myocardial dysfunction, other complications can result from the use of chemotherapy agents: arterial endothelial injuries (related to the effects of systemic and pulmonary hypertension), impaired coronary blood flow, venous endothelial injuries (related to thrombotic effects), valve dysfunction, arrhythmias, and pericardial diseases. <xref ref-type="bibr" rid="B229"><sup>229</sup></xref> </p>
          <p>Pericardial impairment may be directly related to the neoplasm, may result from the action of some chemotherapy agents, or may be secondary to cardiac metastasis. Pericarditis, with or without stroke, may or may not be associated with myocarditis. Constrictive pericarditis is more commonly associated with radiotherapy-induced CTX, and it is necessary to differentiate it from restrictive myocarditis. Cardiovascular imaging examinations are essential to elucidate these changes, especially in subclinical stages.</p>
          <p>Anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin, and mitoxantrone) are extremely potent chemotherapy agents widely used in most childhood cancer treatment protocols. There is a strong relationship between the cumulative dose of anthracyclines and the risk of HF, and in some cases there may be a long latency period between exposure to chemotherapy and the onset of cardiovascular symptoms. <xref ref-type="bibr" rid="B227"><sup>227</sup></xref> Myocardial injury is progressive and usually irreversible, culminating in severe cardiac dysfunction. There are several mechanisms by which the cardiotoxic action of anthracyclines may occur. The most common ones are the formation of cytoplasmic free radicals, resulting in oxidative stress in myocytes, and a direct action on the nucleus, in which anthracyclines act on topoisomerase 2 (Top2) by preventing the replication of DNA that induces cell death. Although the Top2&#945; fraction, which is the focus of anticancer treatment, is expressed in tumor cells, the Top2&#946; fraction is expressed in cardiomyocytes, thus allowing a similar toxic action. <xref ref-type="bibr" rid="B230"><sup>230</sup></xref> Current hematology-oncology treatment protocols follow a trend toward the use of lower doses of anthracyclines. However, even at doses that are considered low, some pediatric patients have cardiotoxic reactions during the course of treatment and/or late follow-up, so that some authors believe that there is no safe dose. <xref ref-type="bibr" rid="B231"><sup>231</sup></xref> Individual susceptibility is not yet fully elucidated, but there are hypotheses that some genetic characteristics increase vulnerability and early occurrence of myocardial dysfunction. Some preventive actions are recommended, especially in patients stratified as being at high risk of developing cardiovascular complications. The primary strategy, specifically against the cardiotoxic effects of anthracyclines, is given by infusion of dexrazoxane or by using liposomal doxorubicin (not commonly used in young patients). The secondary strategy, represented by the administration of drugs with hemodynamic effects, such as beta-blockers (in particular carvedilol), angiotensin-converting enzyme inhibitors, and spironolactone, has been considered an adjuvant in the prevention or treatment of established lesions, whose prospective studies in children are still ongoing. <xref ref-type="bibr" rid="B228"><sup>228</sup></xref> </p>
          <p>Other potentially cardiotoxic substances are used to treat neoplasms in children and adolescents, often in combination with anthracyclines. CTX is not uncommon with the use of alkylating agents, such as cyclophosphamide, cisplatin, and ifosfamide, with the most frequent presentations being myocarditis, arrhythmias, and HF. The most common cardiovascular complication of antimetabolites, such as 5-fluorouracil, is myocardial ischemia, reported mainly in adults. Biological agents such as tyrosine kinase inhibitors can cause QT interval prolongation, HF, hypertension, and AMI. Etoposide is a synthetic podophyllotoxin approved for the treatment of some neoplasms such as Ewing's sarcoma and lymphomas. Cardiovascular complications are rare, but chest pain, angina, and AMI have been reported in adults receiving etoposide in combination with bleomycin, cisplatin, and ifosfamide. Biological agents such as interleukins and interferon may cause hypotension or arrhythmias. The main cardiovascular effect of vinca alkaloids, such as vincristine and vinblastine, is myocardial ischemia due to coronary vasospasm. Immunotherapy has also been important in the treatment of childhood and adolescent cancer, with the potential to trigger myocarditis, although rare (&lt; 1%), and pericarditis. <xref ref-type="bibr" rid="B232"><sup>232</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B233"><sup>233</sup></xref> </p>
          <p>Radiotherapy is a therapeutic method often used in pediatric cancer treatment (about 40% of protocols). Cardiac complications resulting from radiotherapy are due to inflammation and fibrosis of cardiac structures, which may involve the pericardium, myocardium, heart valves, and coronary arteries. The pericardium is the most frequently affected structure. Although the lesions may remain asymptomatic for 5 to 15 years, they are usually progressive. Lesion severity is proportional to the dose, irradiated volume, and the combination with chemotherapy agents, which confers greater risk. Advances in radiotherapy techniques in the past two decades have allowed a reduction in the volume and doses of radiation in the cardiac area. With the emergence of 3D planning techniques, the demarcation of adjacent structures, dose adjustments, and field modifications have allowed a significant reduction in the doses applied to organs at risk, such as the heart. <xref ref-type="bibr" rid="B227"><sup>227</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B234"><sup>234</sup></xref> </p>
        </sec>
        <sec>
          <title>8.2. Main Risk Factors for the Development of Cardiotoxicity in Children and Adolescents</title>
          <p><bold>Cumulative dose</bold>: even at relatively low doses, anthracyclines have been reported to trigger CTX. The concept of a safe anthracycline dose has been disregarded by some authors, as observed in a study that showed a 30% increase in subclinical echocardiographic abnormalities 13 years after leukemia treatment, even with cumulative doses of anthracyclines ranging from 180 to 240mg/m<sup>2</sup>. <xref ref-type="bibr" rid="B234"><sup>234</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B235"><sup>235</sup></xref></p>
          <p><bold>Combination of chemotherapy agents</bold>: concomitant administration of more than one chemotherapy agent known to be cardiotoxic not only facilitates but also potentiates adverse cardiovascular effects.</p>
          <p><bold>Age at treatment</bold>: children treated before 5 years of age are more likely to have cardiovascular complications in the short or long term, especially due to progressive myocardial functional limitation resulting from the demands of physical growth.</p>
          <p><bold>Sex</bold>: girls have a 2-fold higher incidence of CTX than boys, probably due to a higher percentage of body fat that allows longer exposure time and body concentration of anthracyclines.</p>
          <p><bold>Infusion rate</bold>: some studies in adults suggested a reduction in the prevalence of CTX by continuous infusion of anthracyclines, compared to bolus administration. This mode of infusion, however, was not cardioprotective in the long term in the pediatric population. <xref ref-type="bibr" rid="B231"><sup>231</sup></xref></p>
          <p><bold>Mediastinal and neuroaxis radiotherapy</bold>: radiotherapy doses &#8805; 30 Gy or the combination of anthracycline with radiotherapy, even at low doses, may also aggravate the risk of developing cardiovascular complications. Exposure to radiation at a young age is also an important factor. These patients may progress with valve complications, pericardial complications, restrictive cardiomyopathy, CAD, and arrhythmias that can induce sudden cardiac death. <xref ref-type="bibr" rid="B227"><sup>227</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B234"><sup>234</sup></xref> </p>
          <p><bold>Radiotherapy of the central nervous system</bold>: in the long term, children who received cranial irradiation showed greater loss of ventricular mass, a fact attributed to the impairment of the pituitary gland with consequent secondary deficiency in the production of insulin-like growth factor 1, a precursor of growth hormone. <xref ref-type="bibr" rid="B236"><sup>236</sup></xref></p>
          <p><bold>Comorbidities</bold>: the presence of two or more comorbidities increases cardiovascular risk in adults surviving cancer treatment in the pediatric age. The development of hypertension, DM, dyslipidemia, and CAD, especially in association with obesity and smoking, increases the risk of early onset of complications when compared to their siblings. The presence of liver dysfunction, renal dysfunction, and electrolyte disturbances compromises drug clearance, slows down its elimination, and increases drug exposure time.</p>
          <p><bold>Genetic variants</bold>: individual predisposition to CTX has been reported in several studies. Some genetic variants, such as RARG and UGT1A6, increase Top2 or slow down drug metabolism. The incidence of myocardial dysfunction is increased 9-fold in patients with C282Y mutation for hereditary hemochromatosis. People with trisomy 21 are more likely to develop acute myeloid leukemia and more sensitive to the toxic effects of chemotherapy agents. Familial (hypertrophic, arrhythmogenic) cardiomyopathies and patients with congenital heart defects may have a more vulnerable myocardium. <xref ref-type="bibr" rid="B237"><sup>237</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B238"><sup>238</sup></xref></p>
        </sec>
        <sec>
          <title>8.3. Cardiac Monitoring during Treatment</title>
          <p>The method of cardiovascular imaging tests, definitions, and parameters used in the evaluation of children and adolescents or survivors of cancer treatment at pediatric age is the same method that is used in the adult population.</p>
          <p>Echocardiography is the main imaging test indicated for monitoring those patients, as it provides information on the main parameters of diastolic and systolic function of both ventricles, anatomical and functional status of the valve structures and the pericardium, in addition to investigating masses, thrombi, and vegetations. The ventricular myocardial function is quantified using several parameters and methods. The most recommended ones are LVEF using the Simpson biplane method and myocardial strain analysis using the speckle tracking technique. Myocardial deformation measurements are obtained using 2D and 3D echocardiography and then analyzed on longitudinal, radial, or circumferential modes, as they do not depend on the angle of ultrasound incidence. This method has been the subject of several studies that seek to detect early subclinical changes that may be predictors of CTX in children and adolescents. <xref ref-type="bibr" rid="B239"><sup>239</sup></xref> The longitudinal mode has been the one with best reproducibility used in the vast majority of studies. Despite its advantages (availability, accessibility, and low cost), echocardiography has some limitations, especially interobserver variability and compromised quality of the images obtained because of inadequate acoustic windows. Another limitation is related to ejection fraction, which has been proven to be of low sensitivity in the context of early detection of myocardial functional changes. In contrast, myocardial strain analysis using speckle tracking allows for the identification of subclinical lesions that precede the decrease in LVEF. <xref ref-type="bibr" rid="B239"><sup>239</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B240"><sup>240</sup></xref> </p>
          <p>Cardiac MRI is another important diagnostic test in childhood and adolescent cardio-oncology. In addition to being the gold standard for LVEF quantification, it can detect early interstitial edema and myocardial fibrosis using contemporary methods associated with the use of gadolinium contrast by T1 mapping and delayed enhancement identification. Also, it plays an important role in the characterization of intracardiac and extracardiac masses. However, because of intrinsic characteristics, it has limitations for routine use.</p>
          <p>The use of NM imaging in the pediatric area requires, in addition to technical knowledge, a joint assessment with the pediatric team on risk versus benefit of the exposure of children and adolescents to radiation doses (although low, based on radiation safety principles). <xref ref-type="bibr" rid="B241"><sup>241</sup></xref> Radionuclide ventriculography, a noninvasive technique that uses<sup>99m</sup>Tc-labeled red blood cells as a radiopharmaceutical, allows for analysis of several ventricular function parameters (time activity curve, phase analysis, and amplitude), providing a refined assessment of the regions with better contractile performance (amplitude) and the time point when this contraction occurred (phase analysis), detecting the presence of interventricular and left intraventricular contractile dyssynchrony. However, information on diastolic function is limited. The timing for performing radionuclide ventriculography during cancer treatment to minimize the confounding variables is debatable. The suggestion is to perform it at least 3 weeks after anthracycline therapy, when patients have no fever and hemoglobin above 9 g/dL. <xref ref-type="bibr" rid="B242"><sup>242</sup></xref> Regarding other NM imaging methods used to detect CTX such as myocardial uptake of <xref ref-type="bibr" rid="B123"><sup>123</sup></xref> I-mIBG and PET-CT, there are still no robust data for indication in the pediatric population.</p>
          <p>The diagnosis of CTX using cardiovascular imaging methods is based on the changes detected in the baseline examination. Thus, it is recommended that the functional assessment is conducted before the start of cancer treatment and then during the course of treatment for comparison purposes, making an effort to always use the same equipment, the same methods, and the same variables used in previous assessments.</p>
          <p><xref ref-type="table" rid="t20">Table 8</xref> shows the international recommendations for echocardiographic monitoring of patients during and after treatment with anthracyclines (main representatives of CTX in children and adolescents).</p>
          <table-wrap id="t20">
            <label>Table 8</label>
            <caption>
              <title>Echocardiographic monitoring of patients treated with anthracyclines in childhood</title>
            </caption>
            <table frame="hsides" rules="rows">
              <colgroup width="20%">
                <col/>
                <col/>
                <col/>
                <col/>
                <col/>
              </colgroup>
              <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
                <tr>
                  <th align="left" rowspan="2" valign="middle">CD (kg/m<sup>2</sup>)</th>
                  <th align="center" colspan="2" valign="middle">During treatment</th>
                  <th align="center" colspan="2" valign="middle">After treatment</th>
                </tr>
                <tr>
                  <th align="center" valign="middle">No PRF</th>
                  <th align="center" valign="middle">At least 1 PRF</th>
                  <th align="center" valign="middle">No PRF</th>
                  <th align="center" valign="middle">At least 1 PRF</th>
                </tr>
              </thead>
              <tbody style="border-bottom: thin solid; border-color: #000000">
                <tr>
                  <td align="left" valign="middle">Baseline</td>
                  <td align="center" valign="middle">Yes</td>
                  <td align="center" valign="middle">Yes</td>
                  <td align="center" valign="middle">N/A</td>
                  <td align="center" valign="middle">N/A</td>
                </tr>
                <tr>
                  <td align="left" valign="middle">&lt; 200</td>
                  <td align="center" valign="middle">
                    <list list-type="simple">
                      <list-item>
                        <label>&#8211;</label>
                        <p>Clinical criterion</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="center" valign="middle">
                    <list list-type="simple">
                      <list-item>
                        <label>&#8211;</label>
                        <p>Every 2/3 cycles</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="center" valign="middle">
                    <list list-type="simple">
                      <list-item>
                        <label>&#8211;</label>
                        <p>1 month after treatment</p>
                      </list-item>
                      <list-item>
                        <label>&#8211;</label>
                        <p>Evaluate in 1, 2, and 5 years</p>
                      </list-item>
                      <list-item>
                        <label>&#8211;</label>
                        <p>Individualize if required</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="center" valign="middle">
                    <list list-type="simple">
                      <list-item>
                        <label>&#8211;</label>
                        <p>1 month after treatment</p>
                      </list-item>
                      <list-item>
                        <label>&#8211;</label>
                        <p>Evaluate in 1, 2, and 5 years</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">200 to 300</td>
                  <td align="center" valign="middle">
                    <list list-type="simple">
                      <list-item>
                        <label>&#8211;</label>
                        <p>Clinical criterion</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="center" valign="middle">
                    <list list-type="simple">
                      <list-item>
                        <label>&#8211;</label>
                        <p>Every 2/3 cycles</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="center" valign="middle">
                    <list list-type="simple">
                      <list-item>
                        <label>&#8211;</label>
                        <p>1, 6, and 12 months after treatment</p>
                      </list-item>
                      <list-item>
                        <label>&#8211;</label>
                        <p>Then every 2 years (asymptomatic)</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="center" valign="middle">
                    <list list-type="simple">
                      <list-item>
                        <label>&#8211;</label>
                        <p>1, 6, and 12 months after treatment</p>
                      </list-item>
                      <list-item>
                        <label>&#8211;</label>
                        <p>Then annually</p>
                      </list-item>
                      <list-item>
                        <label>&#8211;</label>
                        <p>Individualize</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">300 to 450</td>
                  <td align="center" valign="middle">
                    <list list-type="simple">
                      <list-item>
                        <label>&#8211;</label>
                        <p>Clinical criterion</p>
                      </list-item>
                      <list-item>
                        <label>&#8211;</label>
                        <p>Individualize if required</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="center" valign="middle">
                    <list list-type="simple">
                      <list-item>
                        <label>&#8211;</label>
                        <p>Every 2 cycles</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="center" valign="middle">
                    <list list-type="simple">
                      <list-item>
                        <label>&#8211;</label>
                        <p>1, 6, and 12 months after treatment</p>
                      </list-item>
                      <list-item>
                        <label>&#8211;</label>
                        <p>Then annually</p>
                      </list-item>
                      <list-item>
                        <label>&#8211;</label>
                        <p>Individualize</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="center" valign="middle">
                    <list list-type="simple">
                      <list-item>
                        <label>&#8211;</label>
                        <p>1 month after treatment</p>
                      </list-item>
                      <list-item>
                        <label>&#8211;</label>
                        <p>Then every 6 months</p>
                      </list-item>
                      <list-item>
                        <label>&#8211;</label>
                        <p>Individualize if required</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
                <tr>
                  <td align="left" valign="middle">&gt; 450</td>
                  <td align="center" valign="middle">
                    <list list-type="simple">
                      <list-item>
                        <label>&#8211;</label>
                        <p>Halfway through treatment</p>
                      </list-item>
                      <list-item>
                        <label>&#8211;</label>
                        <p>Individualize if required</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="center" valign="middle">
                    <list list-type="simple">
                      <list-item>
                        <label>&#8211;</label>
                        <p>Every 2 cycles</p>
                      </list-item>
                      <list-item>
                        <label>&#8211;</label>
                        <p>Individualize if required</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="center" colspan="2" valign="middle">
                    <list list-type="simple">
                      <list-item>
                        <label>&#8211;</label>
                        <p>1 month after treatment</p>
                      </list-item>
                      <list-item>
                        <label>&#8211;</label>
                        <p>Then every 6 months</p>
                      </list-item>
                      <list-item>
                        <label>&#8211;</label>
                        <p>Individualize if required</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="TFN9">
                <p>CD: cumulative dose; PRF: preexisting risk factor; N/A: not applicable.</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
          <p>Each patient's hemodynamic status must be considered at the time of assessment. Whenever possible, the status should be stable. The frailty of the pediatric patient in the face of certain situations, such as changes in blood volume (dehydration, hyperhydration), anemia, fever, hypothermia, shock, sepsis, abnormal heart rate, and changes in rhythm, may occasionally influence the interpretation of results. These conditions affect preload and afterload and can promote a variation of 5% to 10% in stroke volume per cardiac cycle, influencing the ejection fraction. Changes in global and segmental contractility during chemotherapy may be related to secondary cardiomyopathy induced by transient stress (idiopathic cause, sepsis, neurological injury, catecholamine release). <xref ref-type="bibr" rid="B243"><sup>243</sup></xref> Functional changes due to clinical complications may be transient or definitive. The recommendation is to reevaluate the patient soon after compensation.</p>
          <p>The definition of subclinical CTX remains challenging for children and adolescents. Some studies have reported segmental changes even before the fall in GLS, which has suggested the greater accuracy of this method for early detection of myocardial dysfunction. Current international recommendations consider a 15% fall in GLS from baseline as indicative of subclinical dysfunction, provided that hemodynamic conditions are comparatively similar. <xref ref-type="bibr" rid="B239"><sup>239</sup></xref> </p>
        </sec>
        <sec>
          <title>8.4. Long Term Follow-up of Survivors</title>
          <p>The risk of developing cardiovascular complications and the severity of lesions increase over time. Studies have shown that, among survivors of cancer treated during childhood and followed-up for 30 years, 8% had HF. The early detection of CTX induced by antineoplastic therapy seems to have a significant effect on the control of outcomes and on the hemodynamic effects resulting from myocardial injury. The identification of the best method for early detection of CTX in those patients is extremely important. Echocardiography and cardiac MRI are the most recommended tests by the main international guidelines and studies. <xref ref-type="bibr" rid="B28"><sup>28</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B227"><sup>227</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B239"><sup>239</sup></xref> </p>
          <p>Despite the lack of randomized controlled studies in children and adolescents, early detection of subclinical lesions is of fundamental importance to stop their progression, which will then allow for prevention or reversal of LV pathological remodeling. <xref ref-type="bibr" rid="B228"><sup>228</sup></xref> </p>
          <p>The American Society of Clinical Oncology (ASCO) proposes five clinical questions that will guide management planning and cardiovascular monitoring of survivors: <xref ref-type="bibr" rid="B6"><sup>6</sup></xref> </p>
          <list list-type="order">
            <list-item>
              <p>Which patients are at increased risk for developing cardiac dysfunction?</p>
            </list-item>
            <list-item>
              <p>Which preventative strategies will minimize risk BEFORE initiation of therapy?</p>
            </list-item>
            <list-item>
              <p>Which preventive strategies will minimize risk DURING potentially cardiotoxic therapy?</p>
            </list-item>
            <list-item>
              <p>What are the preferred surveillance and monitoring approaches DURING treatment?</p>
            </list-item>
            <list-item>
              <p>What are the preferred surveillance and monitoring approaches AFTER treatment?</p>
            </list-item>
          </list>
          <p>Late follow-up planning based on risk stratification contributes to the choice of the best method for monitoring myocardial function (biomarkers and imaging tests). The aim is to detect subclinical dysfunction early, with consequent use of drugs that can prevent or reverse cardiac remodeling.</p>
          <p>With regard to late follow-up after radiotherapy&#8212;which is one of the pillars of pediatric cancer treatment and about 40% of children, adolescents, and young adults undergo at some stage of the treatment&#8212; incidence and severity are directly proportional to the dose and irradiated volume and inversely proportional to age. Occurrence also increases with elapsed radiotherapy time and associated use of cardiotoxic agents, in particular anthracyclines, in addition to possible previous heart disease. <xref ref-type="bibr" rid="B34"><sup>34</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B234"><sup>234</sup></xref> Radiation leads to diffuse interstitial myocardial fibrosis related to the irradiated area, especially of the LV anterior wall, and clinical manifestation will consist of restrictive cardiomyopathy. In view of the difficulty in assessing diastolic function in children, each patient&#8217;s follow-up values must be compared to baseline values. Endothelial damage favors early development of atherosclerotic plaques complicated by hemorrhage and inflammation with risk of rupture and thrombosis. The pericardium is the main target of injury usually initiated by fibrinous pericarditis and pericardial effusion, followed by fibrous thickening, preferably in the parietal pericardium and RV, and may extend to the mediastinum. Valve involvement is less frequent and, unlike pericardial involvement, affects the left side of the heart more often. The cusps become thickened and may calcify and lead to insufficiency and stenosis, especially of the mitral and aortic valves, sparing the tips of the cusps and the valve commissures. <xref ref-type="bibr" rid="B244"><sup>244</sup></xref> </p>
          <p>Survivors of cancer treatment in childhood and adolescence are more vulnerable to the development of premature CAD, including in subclinical stages, with a risk of myocardial infarction 2 to 8 times greater than that of the general population. As coronary events are rare in younger patients, even in those at increased risk, pharmacological stress echocardiography and NM imaging tests to assess myocardial perfusion and viability are recommended. <xref ref-type="bibr" rid="B245"><sup>245</sup></xref> </p>
          <p>Late follow-up of individuals without ventricular dysfunction should be performed routinely after 6 months to 1 year and then periodically, given that the incidence of HF related to the use of anthracycline and radiotherapy increases with late monitoring; the condition may appear after 15 years or more. Although the ideal frequency for assessing LV structure and function in survivors exposed to cardiac radiation is not yet well established in consensus statements, the greater the number of risk factors, the greater the frequency that assessments should be conducted. <xref ref-type="bibr" rid="B246"><sup>246</sup></xref> </p>
        </sec>
        <sec>
          <title>8.5. Pregnancy in Survivors of Childhood and Adolescent Cancer</title>
          <p>With advances in cancer treatment and the remarkable number of survivors of childhood and adolescent cancer, more women reach the childbearing age, and many will choose to become pregnant. Some have undiagnosed subclinical lesions and others are undergoing treatment for HF or other late complications of antineoplastic treatment. Pregnancy is associated with substantial changes in the cardiovascular system, as there is an increased metabolic demand in the pregnant woman's heart. Marked increases in circulating blood volume contribute to an additional 30% to 40% in cardiac output in a relatively early period of pregnancy (20 to 24 weeks), and these changes will influence the interpretation of cardiovascular status. The consequences are tachycardia, relative anemia, and hypercoagulability phenomena. The risk of developing cardiac events during pregnancy in women previously exposed to anthracyclines and/or thoracic radiotherapy in childhood is not clearly known, with limited data available in the literature. <xref ref-type="bibr" rid="B247"><sup>247</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B248"><sup>248</sup></xref> </p>
          <p>Physiological multivalve regurgitations, especially in the right heart chambers, due to chamber enlargement, annular dilation, as well as mild pericardial effusion, are frequent in late pregnancy and postpartum, and seem to be caused by hypervolemia resulting from this period.</p>
          <p><xref ref-type="table" rid="t21">Table 9</xref> lists maternal physiological cardiovascular changes according to each trimester of pregnancy.</p>
          <table-wrap id="t21">
            <label>Table 9</label>
            <caption>
              <title>Physiological echocardiographic changes during pregnancy</title>
            </caption>
            <table frame="hsides" rules="rows">
              <colgroup width="12%">
                <col/>
                <col/>
                <col/>
                <col/>
                <col/>
                <col/>
                <col/>
                <col/>
              </colgroup>
              <thead style="border-top: thin solid; border-bottom: thin solid; border-color: #000000">
                <tr>
                  <th align="center" colspan="2" style="border-right: thin solid; border-color: #000000" valign="middle">1<sup>st</sup>trimester</th>
                  <th align="center" colspan="2" style="border-right: thin solid; border-color: #000000" valign="middle">2<sup>nd</sup>trimester</th>
                  <th align="center" colspan="2" style="border-right: thin solid; border-color: #000000" valign="middle">2<sup>nd</sup>trimester</th>
                  <th align="center" colspan="2" valign="middle">Postpartum</th>
                </tr>
              </thead>
              <tbody style="border-bottom: thin solid; border-color: #000000">
                <tr>
                  <td align="center" valign="middle">&#8595;</td>
                  <td align="center" style="border-right: thin solid; border-color: #000000" valign="middle">SVR</td>
                  <td align="center" valign="middle">&#8595;</td>
                  <td align="center" style="border-right: thin solid; border-color: #000000" valign="middle">SVR</td>
                  <td align="center" valign="middle">&#8595;</td>
                  <td align="center" style="border-right: thin solid; border-color: #000000" valign="middle">SVR <break/> GLS</td>
                  <td align="center" valign="middle">&#8595;</td>
                  <td align="center" valign="middle">HR <break/> LV end-diastolic diameter <break/> LV mass <break/> CO</td>
                </tr>
                <tr>
                  <td align="center" valign="middle">&#8593;</td>
                  <td align="center" style="border-right: thin solid; border-color: #000000" valign="middle">HR <break/> LV end-diastolic diameter <break/> LV mass <break/> CO</td>
                  <td align="center" valign="middle">&#8593;</td>
                  <td align="center" style="border-right: thin solid; border-color: #000000" valign="middle">HR <break/> LV end-diastolic diameter <break/> LV mass <break/> CO</td>
                  <td align="center" valign="middle">&#8593;</td>
                  <td align="center" style="border-right: thin solid; border-color: #000000" valign="middle">HR <break/> LV end-diastolic diameter <break/> LV mass <break/> CO</td>
                  <td align="center" valign="middle">&#8593;</td>
                  <td align="center" valign="middle">SVR <break/> GLS</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="TFN10">
                <p>SVR: systemic vascular resistance; HR: heart rate; LV: left ventricle; GLS: global longitudinal strain; CO: cardiac output; &#8593; = increases; &#8595; = decreases.</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
          <sec>
            <title>8.5.1. Cardiac Outcomes in Pregnant Survivors of Childhood and Adolescent Cancer</title>
            <p>Some clinical studies have evaluated cardiac outcomes in pregnant women previously exposed to cardiotoxic cancer therapy.</p>
            <p>Van Dalen et al. <xref ref-type="bibr" rid="B247"><sup>247</sup></xref> retrospectively evaluated 53 female survivors of childhood and adolescent cancer who had one or more children. Data on LV systolic function and other echocardiographic parameters were not available for analysis. HF diagnosis was defined based on signs and symptoms. No patient developed HF during pregnancy or within 5 months of delivery. <xref ref-type="bibr" rid="B247"><sup>247</sup></xref> </p>
            <p>Hines et al. <xref ref-type="bibr" rid="B248"><sup>248</sup></xref> administered a questionnaire to 847 female survivors of childhood and adolescent cancer who had at least one complete pregnancy. The authors found that most female survivors of childhood and adolescent cancer did not experience cardiac complications during or after delivery; however, pregnant women with a history of cardiotoxic therapy should be followed-up carefully during pregnancy, especially those with a history of anthracycline exposure and who have been diagnosed with previous or current subclinical or symptomatic cardiomyopathy. <xref ref-type="bibr" rid="B248"><sup>248</sup></xref> </p>
            <p>In another study, 37 women who received doxorubicin as part of a chemotherapy protocol for a childhood neoplastic disorder were followed-up at the same center during pregnancy (72 gestations) and after delivery. The authors concluded that the pregnancy outcome in women who received doxorubicin for childhood malignancy is generally favorable. However, those with LV dysfunction before pregnancy should be considered at increased risk of a poor pregnancy outcome and further deterioration of myocardial function. <xref ref-type="bibr" rid="B249"><sup>249</sup></xref> </p>
            <p>Thompson et al. <xref ref-type="bibr" rid="B250"><sup>250</sup></xref> evaluated a cohort of 58 women who were treated with anthracyclines and/or thoracic radiotherapy before the age of 20 at the MD Anderson Cancer Center. The incidence of adverse cardiac events (defined as LVEF &lt; 50% on at least two echocardiograms or CAD) was significantly higher in women who had at least one pregnancy (29%) compared to nulliparous controls matched for anthracycline dose and follow-up period (15%), with p &lt; 0.05. Among the 58 pregnant women, nine were diagnosed with CVD during pregnancy and five were diagnosed after pregnancy. In this small cohort, the time from exposure to anthracyclines to the first pregnancy and the total anthracycline dose were associated with an increased risk of adverse cardiac events. In addition, pregnancy was associated with a 2.4-fold increase in the risk of developing adverse cardiac events (95% CI: 1.02-5.41, p = 0.045). <xref ref-type="bibr" rid="B250"><sup>250</sup></xref> </p>
          </sec>
          <sec>
            <title>8.5.2. Cardiovascular Monitoring Recommendation in Survivors of Childhood and Adolescent Cancer Wishing to Become Pregnant</title>
            <p>Studies of non-cancer populations with preexisting cardiomyopathies have reported a high risk of cardiac decompensation due to changes in cardiac physiology during pregnancy. Pregnancy is not recommended in patients with cardiomyopathies with LVEF &lt; 40%. <xref ref-type="bibr" rid="B251"><sup>251</sup></xref> </p>
            <p>In survivors of childhood and adolescent cancer, there is limited evidence on cardiac monitoring during pregnancy. International guidelines recommend a cardiovascular evaluation before pregnancy and in the first trimester for all women who were treated during childhood with anthracyclines and/or thoracic radiotherapy. The Children's Oncology Group recommends performing an echocardiogram before and then periodically during pregnancy (especially during the third trimester), in addition to cardiac monitoring during labor and delivery in patients receiving anthracycline doses &gt; 300 mg/m<sup>2</sup>, thoracic radiation doses &gt; 30 Gy, and those who received both cancer treatments, i.e., anthracyclines and thoracic radiotherapy. <xref ref-type="bibr" rid="B246"><sup>246</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B251"><sup>251</sup></xref> </p>
            <p>Recommendations are as follows:</p>
            <list list-type="bullet">
              <list-item>
                <p>Echocardiographic assessment of cardiac function before pregnancy and then periodically, every trimester, in women who were treated with anthracyclines (especially at doses &gt; 300 mg/m<sup>2</sup>) and/or thoracic radiotherapy (especially at doses &gt; 30 Gy) with previous LVEF &#8805; 50%.</p>
              </list-item>
              <list-item>
                <p>Echocardiographic assessment of cardiac function before pregnancy and in the last trimester of pregnancy, or when clinically indicated, in women who were treated with anthracyclines (doses &lt; 300 mg/m<sup>2</sup>) and/or thoracic radiotherapy (doses &lt; 30 Gy) with previous LVEF &#8805; 50%.</p>
              </list-item>
              <list-item>
                <p>Echocardiographic assessment of cardiac function before pregnancy and then periodically, every trimester, or when clinically indicated, in addition to cardiac monitoring during labor and delivery in women with LVEF between 40% and 50%. Consider repeating the echocardiogram 1 month after delivery.</p>
              </list-item>
              <list-item>
                <p>Pregnancy is not recommended for patients with LVEF &lt; 40%.</p>
              </list-item>
            </list>
          </sec>
        </sec>
        <sec>
          <title>8.6. Predisposing Situations to Thrombotic Events Related to Childhood and Adolescent Cancer Treatment</title>
          <sec>
            <title>8.6.1. Intracardiac thrombus</title>
            <p>Much of the chemotherapy treatment of patients with childhood and adolescent cancer is performed intravenously using long-term catheters, which increase the risk of thrombus or vegetation formation. In Also, the procoagulant properties of tumor cells favor tumor invasion and metastasis. <xref ref-type="bibr" rid="B252"><sup>252</sup></xref> </p>
            <p>In the pediatric population, the mean incidence of cancer-associated thrombotic events is 8%, most frequently in acute leukemias, followed by sarcomas, lymphomas, acute myeloid leukemia, Wilms' tumor, neuroblastomas, and central nervous system tumors. Occurrence may reach 36.7% among leukemias and 16% among lymphomas (due to extrinsic mass compression in the mediastinum), solid tumors and central nervous system tumors. Among sarcomas, Ewing's is the one at most risk for thrombotic events, followed by rhabdomyosarcoma and osteosarcoma. <xref ref-type="bibr" rid="B253"><sup>253</sup></xref> </p>
            <p>Several clinical conditions are related to the etiology of thrombotic events in children and adolescents, such as recent surgery, congenital heart disease, immobilization, trauma, nephrotic syndrome, use of oral contraceptives, congenital thrombophilia, and presence of a central venous catheter, which is the most important predisposing factor alone. <xref ref-type="bibr" rid="B252"><sup>252</sup></xref> L-asparaginase, used in acute lymphoblastic leukemia protocols, may suppress natural anticoagulants, particularly antithrombin and plasminogen. Corticosteroid use may lead to activation of both factor VIII-von Willebrand factor complex and plasminogen activator inhibitor-1. The combination of L-asparaginase and corticosteroids is a high-risk factor for the development of thrombotic events, especially in the induction phase, when there is reduced ability to inhibit thrombin. <xref ref-type="bibr" rid="B253"><sup>253</sup></xref> </p>
            <p>Pulmonary thromboembolism is much less reported among children and adolescents compared to adults. In a Canadian study, an incidence of 0.86 per 10,000 hospital admissions was demonstrated; however, there are limited data on long-term follow-up. <xref ref-type="bibr" rid="B254"><sup>254</sup></xref> </p>
            <p>The genetic characteristics of the host also contribute to a greater vulnerability to thrombotic events. A deficiency in natural anticoagulants such as antithrombin, protein C, and protein S is the genetic factor most often related to thrombotic events in the pediatric population. <xref ref-type="bibr" rid="B252"><sup>252</sup></xref> </p>
            <p>TTE is an important tool for the investigation of intracardiac thrombi and vegetations, being complemented by TEE, which is more sensitive. The use of microbubble contrast agents helps detect thrombi and differentiate avascular thrombus from vascularized tumors. Intracardiac thrombi are characterized by their hyperechogenic appearance and generally regular borders. MRI and CT angiography may be adjuvant for diagnostic clarification; however, it may remain difficult to differentiate thrombi from other cardiac tumors. A diagnosis of intracardiac thrombus results from a combination of image presentation, location, and clinical status. In uncertain cases, diagnosis is often made after a anticoagulation cycle and imaging reassessment. <xref ref-type="bibr" rid="B255"><sup>255</sup></xref> </p>
          </sec>
          <sec>
            <title>8.6.2. Central Venous Catheter</title>
            <p>According to estimates, more than 5 million central venous catheters are implanted annually in the US. Children with cancer require intravenous administration of chemotherapy for a considerable amount of time. The use of central venous catheters after the 1980s improved the quality of life of these patients, but use is associated with mechanical, infectious, and thrombotic complications. The incidence of CRT in pediatric patients with cancer reported in recent years has ranged from 4.6% to 7%. <xref ref-type="bibr" rid="B252"><sup>252</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B256"><sup>256</sup></xref> </p>
            <p>Echocardiogram has a key role in the evaluation of this device. The tip of the catheter should ideally be in the superior vena cava close to the junction with the RA to prevent arrhythmias and thrombus formation. The entire visible venous path should be evaluated, as well as the flow behavior close to the device, in the cardiac chambers, and in the valves. <xref ref-type="bibr" rid="B256"><sup>256</sup></xref> </p>
          </sec>
          <sec>
            <title>8.6.3. Differential Diagnosis of Intracardiac Mass</title>
            <sec>
              <title>8.6.3.1. Prominent Crista Terminalis</title>
              <p>The crista terminalis is a fibromuscular tissue that demarcates the limits of the embryological venous sinus and the RA muscular wall. When prominent, it can be mistakenly diagnosed as an intracardiac mass. On echocardiography, it appears as a hyperechogenic image in the posterolateral portion of the RA. Identification avoids incorrect diagnosis of intracardiac thrombus.</p>
            </sec>
            <sec>
              <title>8.6.3.2. Mitral Annular Calcification</title>
              <p>Mitral annular calcification is the deposition of calcium and fat throughout the fibrous annulus, most commonly in the posterior portion of the mitral annulus, with a hyperechogenic appearance. It may be the basis for the formation of thrombi or vegetations and exhibits mobile calcified components with potential for embolization.</p>
            </sec>
            <sec>
              <title>8.6.3.3. Infective Endocarditis</title>
              <p>In patients undergoing cancer treatment with positive blood culture, infective endocarditis (IE) should be suspected, as these individuals are at high risk for hospital infections because of the number of hospitalizations and immunosuppression. TTE is mandatory in such cases. The investigation includes cardiac valves in search of signs of vegetation, abscess, or cardiac fistula, presence of new valve regurgitation, as well as the appearance of long-term intravenous devices. The specificity for diagnosis of endocardial vegetation using TTE is greater than 90%, but the sensitivity ranges from 62 to 79%, as images smaller than 2 to 3 mm may not be visible. TEE also has a specificity greater than 90%; however, it has a higher sensitivity for diagnosis of IE (&gt; 80% to 90%).</p>
              <p>Endocardial vegetations are characterized by very irregular shapes and chaotic movement that is independent from valve movement. They are usually located on the atrial side of atrioventricular valves and on the ventricular side of semilunar valves and are associated with the destruction of the valve apparatus, leading to valve regurgitation or abscess. Valve abscesses most commonly affect the aortic valve and may fistulate to the LV or the atrium. There is an increased risk for stroke and AMI in patients diagnosed with IE. The main agents responsible for stroke are endocardial vegetations with dimensions greater than 10 to 15 mm that affect more than one valve, have excessive mobility, and show positive blood culture for fungus, <italic>Staphylococcus aureus</italic> , and <italic>Streptococcus bovis</italic> .</p>
            </sec>
            <sec>
              <title>8.6.3.4. Nonbacterial Thrombotic Endocarditis</title>
              <p><bold>Libman-Sacks endocarditis:</bold> this consists of granular material with immune complexes and platelets, without bacteria; it usually has small dimensions (1 to 4 mm), is found at the same sites as endocarditis, but is usually less irregular and better defined and is not associated with valve destruction. These lesions are usually asymptomatic and are more common in patients diagnosed with lupus.</p>
              <p><bold>Marantic endocarditis:</bold> this is a type of noninfectious endocarditis associated with malignancy, especially solid metastatic carcinomas and adenocarcinomas of the lung, pancreas, stomach, and other adenocarcinomas. There are descriptions of association with myelodysplastic syndromes. Marantic vegetations are composed of fibrin and platelets and rarely lead to valve dysfunction; classically, they affect the atrial face of the mitral valve and the ventricular face of the aortic valve. They may embolize in more than 50% of cases. Echotexture, dimensions, and location are no different from those of IE. However, significant diffuse valve thickening is frequently observed, which may help in the diagnosis.</p>
            </sec>
            <sec>
              <title>8.6.3.5. Lambl Excrescences</title>
              <p>Lambl excrescences are defined as filiform structures, less than 2 mm wide and 3 to 10 mm long, with undulating motion, located on the atrial face of the mitral valve and on the ventricular face of the aortic valve. They are not associated with thromboembolic events.</p>
            </sec>
          </sec>
        </sec>
        <sec>
          <title>8.6. Cardiovascular Evaluation in Case of Bone Marrow Transplantation in Children and Adolescents</title>
          <p>BMT, or hematopoietic stem cell transplantation, either autologous or allogeneic, plays an important role in the treatment of various neoplasms during childhood and adolescence. The most frequent ones are leukemias, some solid tumors, bone marrow aplasia, immunodeficiencies, and some inherited diseases that affect the hematopoietic system.</p>
          <p>Autologous transplants are, in general, less susceptible to cardiovascular complications compared to allogeneic transplants. The incidence of cardiovascular complications increases according to the time of cure of these patients, reaching up to 17% after 15 years of treatment. BMT survivors are at a 13-fold higher risk for cardiovascular complications compared to their siblings. <xref ref-type="bibr" rid="B257"><sup>257</sup></xref> The following factors favor CTX after BMT:</p>
          <list list-type="bullet">
            <list-item>
              <p>Age at BMT;</p>
            </list-item>
            <list-item>
              <p>Anterior cardiotoxic chemotherapy (e.g., anthracyclines);</p>
            </list-item>
            <list-item>
              <p>Myeloablative conditioning regimen (e.g., cyclophosphamide);</p>
            </list-item>
            <list-item>
              <p>Prior chest irradiation;</p>
            </list-item>
            <list-item>
              <p>Total body irradiation;</p>
            </list-item>
            <list-item>
              <p>Type of transplant;</p>
            </list-item>
            <list-item>
              <p>Presence of graft-versus-host disease (GvHD);</p>
            </list-item>
            <list-item>
              <p>Comorbidities (e.g., hypertension, DM, dyslipidemia, smoking, obesity).</p>
            </list-item>
          </list>
          <p>GvHD is the most common complication in allogeneic BMT and requires regular assessments using cardiovascular imaging methods. It triggers immune responses that lead to endothelial damage and chronic inflammatory processes, affects several organs, including the lungs, and may simulate pulmonary arterial hypertension. It favors the development of vasculitis, early atherosclerosis, hypertension, cerebrovascular diseases, angina, and AMI. <xref ref-type="bibr" rid="B258"><sup>258</sup></xref> Prolonged use of corticosteroids and other immunosuppressants in GvHD treatment accelerates those events, and presence of conventional cardiovascular risk factors contributes to the appearance of these complications. Cardiac involvement alone in GvHD is rare and may manifest as pericarditis, arrhythmias, and CAD. <xref ref-type="bibr" rid="B257"><sup>257</sup></xref> </p>
          <p>Another factor to be considered is the deposition of iron in the myocardium resulting from multiple blood transfusions, which may persist for years after BMT and is usually assessed by means of cardiac and liver MRI. <xref ref-type="bibr" rid="B259"><sup>259</sup></xref> </p>
          <p>Survivors of BMT treated with anthracyclines and/or chest irradiation should be examined annually for signs of cardiovascular complications. Both systolic and diastolic cardiac function should be assessed using echocardiography, either annually or every 5 years, depending on dosage and age of exposure. They must be preventively advised regarding modifiable cardiovascular risk factors (hypertension, DM, dyslipidemia, smoking).</p>
        </sec>
      </sec>
    </body>
    <back>
      <fn-group>
        <fn fn-type="other" id="fn5">
          <p><bold>Development:</bold> Cardiovascular Imaging Department (Departamento de Imagem Cardiovascular &#8211; DIC) of the Brazilian Society of Cardiology (Sociedade Brasileira de Cardiologia &#8211; SBC) endorsed by the Sociedad Interamericana de Im&#225;genes Cardiovasculares (SiSIAC) of the Sociedad Interamericana de Cardiolog&#237;a (SIAC)</p>
        </fn>
        <fn fn-type="other" id="fn6">
          <p><bold>Norms and Guidelines Council (2020-2021):</bold> Brivaldo Markman Filho, Antonio Carlos Sobral Sousa, Aurora Felice Castro Issa, Bruno Ramos Nascimento, Harry Correa Filho, Marcelo Luiz Campos Vieira</p>
        </fn>
        <fn fn-type="other" id="fn7">
          <p><bold>Norms and Guidelines Coordinator (2020-2021):</bold> Brivaldo Markman Filho</p>
        </fn>
        <fn fn-type="other" id="fn8">
          <p><bold>Note:</bold> These statements are for information purposes and should not replace the clinical judgment of a physician, who must ultimately determine the appropriate treatment for each patient.</p>
        </fn>
      </fn-group>
      <glossary>
        <title>List of Abbreviations</title>
        <def-list>
          <def-item>
            <term id="G59"><xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-FDG</term>
            <def>
              <p><xref ref-type="bibr" rid="B18"><sup>18</sup></xref> F-fluorodeoxyglucose</p>
            </def>
          </def-item>
          <def-item>
            <term id="G60">AMI</term>
            <def>
              <p>Acute myocardial infarction</p>
            </def>
          </def-item>
          <def-item>
            <term id="G61">BMT</term>
            <def>
              <p>Bone marrow transplantation</p>
            </def>
          </def-item>
          <def-item>
            <term id="G62">CHD</term>
            <def>
              <p>Carcinoid heart disease</p>
            </def>
          </def-item>
          <def-item>
            <term id="G63">CTX</term>
            <def>
              <p>Cardiotoxicity</p>
            </def>
          </def-item>
          <def-item>
            <term id="G64">CVD</term>
            <def>
              <p>Cardiovascular disease</p>
            </def>
          </def-item>
          <def-item>
            <term id="G65">CRT</term>
            <def>
              <p>Catheter-related thrombosis</p>
            </def>
          </def-item>
          <def-item>
            <term id="G66">CT</term>
            <def>
              <p>Computed tomography</p>
            </def>
          </def-item>
          <def-item>
            <term id="G67">CAD</term>
            <def>
              <p>Coronary artery disease</p>
            </def>
          </def-item>
          <def-item>
            <term id="G68">DVT</term>
            <def>
              <p>Deep venous thrombosis</p>
            </def>
          </def-item>
          <def-item>
            <term id="G69">DM</term>
            <def>
              <p>Diabetes mellitus</p>
            </def>
          </def-item>
          <def-item>
            <term id="G70">ECV</term>
            <def>
              <p>Extracellular volume</p>
            </def>
          </def-item>
          <def-item>
            <term id="G71">GLS</term>
            <def>
              <p>Global longitudinal strain</p>
            </def>
          </def-item>
          <def-item>
            <term id="G72">GvHD</term>
            <def>
              <p>Graft-versus-host disease</p>
            </def>
          </def-item>
          <def-item>
            <term id="G73">HF</term>
            <def>
              <p>Heart failure</p>
            </def>
          </def-item>
          <def-item>
            <term id="G74">IE</term>
            <def>
              <p>Infective endocarditis</p>
            </def>
          </def-item>
          <def-item>
            <term id="G75">IMT</term>
            <def>
              <p>Intima-media thickness</p>
            </def>
          </def-item>
          <def-item>
            <term id="G76">LA</term>
            <def>
              <p>Left atrium/atrial</p>
            </def>
          </def-item>
          <def-item>
            <term id="G77">LV</term>
            <def>
              <p>Left ventricle/ventricular</p>
            </def>
          </def-item>
          <def-item>
            <term id="G78">LVCR</term>
            <def>
              <p>Left ventricular contractile reserve</p>
            </def>
          </def-item>
          <def-item>
            <term id="G79">LVEF</term>
            <def>
              <p>Left ventricular ejection fraction</p>
            </def>
          </def-item>
          <def-item>
            <term id="G80">AL amyloidosis</term>
            <def>
              <p>Light-chain amyloidosis</p>
            </def>
          </def-item>
          <def-item>
            <term id="G81">MRI</term>
            <def>
              <p>Magnetic resonance imaging</p>
            </def>
          </def-item>
          <def-item>
            <term id="G82">SUV<sub>max</sub></term>
            <def>
              <p>Maximum standardized uptake value</p>
            </def>
          </def-item>
          <def-item>
            <term id="G83">NM</term>
            <def>
              <p>Nuclear medicine</p>
            </def>
          </def-item>
          <def-item>
            <term id="G84">PCT</term>
            <def>
              <p>Primary cardiac tumor</p>
            </def>
          </def-item>
          <def-item>
            <term id="G85">RICAD</term>
            <def>
              <p>Radiation-induced coronary artery disease</p>
            </def>
          </def-item>
          <def-item>
            <term id="G86">RIHD</term>
            <def>
              <p>Radiation-induced heart disease</p>
            </def>
          </def-item>
          <def-item>
            <term id="G87">RIVD</term>
            <def>
              <p>Radiation-induced valve disease</p>
            </def>
          </def-item>
          <def-item>
            <term id="G88">RA</term>
            <def>
              <p>Right atrium/atrial</p>
            </def>
          </def-item>
          <def-item>
            <term id="G89">RV</term>
            <def>
              <p>Right ventricle/ventricular</p>
            </def>
          </def-item>
          <def-item>
            <term id="G90">TTS</term>
            <def>
              <p>Takotsubo syndrome</p>
            </def>
          </def-item>
          <def-item>
            <term id="G91"><sup>99m</sup>Tc</term>
            <def>
              <p>Technetium-99m</p>
            </def>
          </def-item>
          <def-item>
            <term id="G92">TEE</term>
            <def>
              <p>Transesophageal echocardiography</p>
            </def>
          </def-item>
          <def-item>
            <term id="G93">TTE</term>
            <def>
              <p>Transthoracic echocardiography</p>
            </def>
          </def-item>
          <def-item>
            <term id="G94">ATTR amyloidosis</term>
            <def>
              <p>Transthyretin amyloidosis</p>
            </def>
          </def-item>
          <def-item>
            <term id="G95">Top2</term>
            <def>
              <p>Topoisomerase 2</p>
            </def>
          </def-item>
          <def-item>
            <term id="G96">VTE</term>
            <def>
              <p>Venous thromboembolism</p>
            </def>
          </def-item>
        </def-list>
      </glossary>
      <app-group>
        <app id="app4">
          <label>APPENDIX 1</label>
          <title>SUGGESTED ECHOCARDIOGRAM REPORT FOR CARDIO-ONCOLOGY</title>
          <list list-type="roman-upper">
            <list-item>
              <p>
                <bold>Patient identification:</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>Name:</p>
                </list-item>
                <list-item>
                  <p>Hospital registration/personal ID:</p>
                </list-item>
                <list-item>
                  <p>Sex:</p>
                </list-item>
                <list-item>
                  <p>Date of birth: // (&#8230; years old)</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>
                <bold>Cancer diagnosis:</bold>
              </p>
            </list-item>
            <list-item>
              <p>
                <bold>Comorbidities:</bold>
              </p>
            </list-item>
            <list-item>
              <p>
                <bold>Treatment:</bold>
              </p>
              <list list-type="simple">
                <list-item>
                  <p>Date of start of treatment: / /</p>
                </list-item>
                <list-item>
                  <p>Date of end of treatment: / /</p>
                </list-item>
                <list-item>
                  <p>Treatment protocol (drugs used):</p>
                </list-item>
                <list-item>
                  <p>Cumulative anthracycline dose: mg/m<sup>2</sup></p>
                </list-item>
                <list-item>
                  <p>Thoracic radiotherapy: Gy</p>
                </list-item>
                <list-item>
                  <p>Other medications being used:</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>
                <bold>Timing of examination:</bold>
              </p>
              <list list-type="simple">
                <list-item>
                  <label>&#9633;</label>
                  <p>Baseline examination</p>
                </list-item>
                <list-item>
                  <label>&#9633;</label>
                  <p>Intermediate examination (routine). Delta chemo: &#8230;&#8230;. days</p>
                </list-item>
                <list-item>
                  <label>&#9633;</label>
                  <p>Examination due to complications. Describe: &#8230;.</p>
                </list-item>
                <list-item>
                  <label>&#9633;</label>
                  <p>Examination at the end of treatment.</p>
                </list-item>
                <list-item>
                  <label>&#9633;</label>
                  <p>Examination after treatment: &#8230;.. months / &#8230; years</p>
                </list-item>
                <list-item>
                  <label>&#9633;</label>
                  <p>Date of last examination: / /</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>
                <bold>Anthropometric data:</bold>
              </p>
              <list list-type="simple">
                <list-item>
                  <p>Weight: kg Height: m BSA: m<sup>2</sup>BMI:</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>
                <bold>Vital signs:</bold>
              </p>
              <list list-type="simple">
                <list-item>
                  <p>HR: bpm BP: X mm Hg RR: bpm Temp.: &#176;</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>
                <bold>Blood volume status:</bold>
              </p>
              <list list-type="simple">
                <list-item>
                  <label>&#9633;</label>
                  <p>Hypervolemia</p>
                </list-item>
                <list-item>
                  <label>&#9633;</label>
                  <p>Dehydration</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p><bold>Conventional two-dimensional echocardiographic measurements:</bold> (&#8230;)</p>
            </list-item>
            <list-item>
              <p>
                <bold>LVd volume: mL LVs volume: mL</bold>
              </p>
            </list-item>
            <list-item>
              <p>
                <bold>LV mass: g LV mass index: g/m2</bold>
              </p>
            </list-item>
            <list-item>
              <p>Cardiac anatomy: (sequential description)</p>
            </list-item>
            <list-item>
              <p>
                <bold>Valve devices: (structural description, mobility, Doppler)</bold>
              </p>
            </list-item>
            <list-item>
              <p>
                <bold>Estimated pulmonary artery systolic pressure: (mm Hg)</bold>
              </p>
            </list-item>
            <list-item>
              <p>
                <bold>Parameters for diastolic function assessment:</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>E/A:</p>
                </list-item>
                <list-item>
                  <p>Septal E/e&#8217;: cm/s</p>
                </list-item>
                <list-item>
                  <p>Lateral E/e&#8217;: cm/s</p>
                </list-item>
                <list-item>
                  <p>S: cm/s</p>
                </list-item>
                <list-item>
                  <p>LAVI: mL/m<sup>2</sup></p>
                </list-item>
                <list-item>
                  <p>LA GLS:</p>
                </list-item>
                <list-item>
                  <p>Others?</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>
                <bold>Parameters for systolic function assessment:</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>LVEF (Simpson biplane method):</p>
                </list-item>
                <list-item>
                  <p>Ejection fraction by 3D imaging:</p>
                </list-item>
                <list-item>
                  <p>LV global longitudinal strain (GLS):</p>
                </list-item>
                <list-item>
                  <p>Changes in segmental contractility:</p>
                </list-item>
                <list-item>
                  <p>RV global contractility (qualitative analysis):</p>
                </list-item>
                <list-item>
                  <p>RVEF (Simpson):</p>
                </list-item>
                <list-item>
                  <p>RV global longitudinal strain (GLS)</p>
                </list-item>
                <list-item>
                  <p>Other?</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>
                <bold>Pericardium:</bold>
              </p>
            </list-item>
            <list-item>
              <p>
                <bold>Conclusions:</bold>
              </p>
            </list-item>
            <list-item>
              <p>
                <bold>Functional comparative analysis:</bold>
              </p>
              <list list-type="bullet">
                <list-item>
                  <p>Decrease in LVEF from baseline:</p>
                </list-item>
                <list-item>
                  <p>Decrease in GLS from baseline:</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>
                <bold>Observations:</bold>
              </p>
            </list-item>
          </list>
        </app>
        <app id="app5">
          <label>APPENDIX 2</label>
          <title>IMPORTANT CONSIDERATIONS IN THE EVALUATION OF ECHOCARDIOGRAM REPORT IN CARDIO-ONCOLOGY</title>
          <list list-type="order">
            <list-item>
              <p>Echocardiography should always be performed before any hematology-oncology treatment to record the patient's initial functional status and identify preexisting heart disease. These data will serve as a comparative basis for subsequent examinations.</p>
            </list-item>
            <list-item>
              <p>Before the next cycle of chemotherapy, echocardiographic tests should ideally be performed 3 weeks after the last infusion or as close as possible to the next.</p>
            </list-item>
            <list-item>
              <p>Intermediate examinations are recommended according to the treatment protocol (cardiotoxic potential of the chemotherapeutic drugs used) or stratification of individual cardiovascular risk.</p>
            </list-item>
            <list-item>
              <p>Consider the patient's blood volume status (preload and afterload) as it may influence the actual strain values.</p>
            </list-item>
            <list-item>
              <p>Evaluations in case of complications that compromise the patient's hemodynamic status will serve as isolated information. The examination must be repeated after improvement of the patient&#8217;s clinical symptoms.</p>
            </list-item>
            <list-item>
              <p>In case of detected dysfunctions (decreased LVEF and/or GLS or changes in diastolic function), the examination must be repeated after 3 weeks for confirmation of suspected condition or interpretation as a transient condition that will require future consideration.</p>
            </list-item>
            <list-item>
              <p>In case of decreased LVEF and/or GLS when using known noncardiotoxic drugs, other causes for myocardial dysfunction must be considered (e.g., infection, CAD).</p>
            </list-item>
            <list-item>
              <p>A good ECG tracing must be obtained for adequate strain quantification.</p>
            </list-item>
            <list-item>
              <p>Use adequate echocardiographic windows whenever possible, avoiding image shortening as it leads to overvalued myocardial deformation indices.</p>
            </list-item>
            <list-item>
              <p>Ideally, the same examiner should assess the patient during the entire follow-up.</p>
            </list-item>
            <list-item>
              <p>When assessing a patient, consider using equipment of the same manufacturer during the entire follow-up.</p>
            </list-item>
            <list-item>
              <p>GLS should not be performed in patients with cardiac arrhythmia (atrial fibrillation, severe tachycardia, and atrioventricular block).</p>
            </list-item>
          </list>
        </app>
        <app id="app6">
          <label>APPENDIX 3</label>
          <title>WARNING SIGNS DURING ECHOCARDIOGRAM EVALUATION IN CARDIO-ONCOLOGY</title>
          <table-wrap id="t22">
            <table frame="box" rules="none">
              <colgroup width="25%">
                <col/>
                <col/>
                <col/>
                <col/>
              </colgroup>
              <tbody style="border-bottom: thin solid; border-color: #000000">
                <tr>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Favorable</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Attention</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Caution</p>
                      </list-item>
                    </list>
                  </td>
                  <td align="left" valign="middle">
                    <list list-type="bullet">
                      <list-item>
                        <p>Unfavorable</p>
                      </list-item>
                    </list>
                  </td>
                </tr>
              </tbody>
            </table>
          </table-wrap>
          <list list-type="bullet">
            <list-item>
              <p>Normal LVEF + normal GLS + Troponin (-)</p>
            </list-item>
            <list-item>
              <p>Normal LVEF + normal GLS + type I diastolic dysfunction</p>
              <list list-type="simple">
                <list-item>
                  <p>= transient change? Reassess situation during the next elective examination.</p>
                </list-item>
                <list-item>
                  <p>Changes in segmental contractility + normal LVEF + normal GLS</p>
                </list-item>
                <list-item>
                  <p>= Subclinical dysfunction? Transient change?</p>
                </list-item>
                <list-item>
                  <p>= Reassess situation during the next elective examination.</p>
                </list-item>
              </list>
            </list-item>
          </list>
          <list list-type="bullet">
            <list-item>
              <p>LVEF in the lower limit of normal in tachycardic patient.</p>
            </list-item>
            <list-item>
              <p>Normal LVEF + GLS &lt; 16% or &gt; 15% decrease from baseline GLS</p>
              <list list-type="simple">
                <list-item>
                  <p>= Subclinical dysfunction? Consider cardioprotective measures.</p>
                </list-item>
              </list>
            </list-item>
          </list>
          <list list-type="bullet">
            <list-item>
              <p>Abnormal LVEF + GLS &lt; 16% or &gt; 15% decrease from baseline GLS + troponin (+)</p>
              <list list-type="simple">
                <list-item>
                  <p>= Discuss risks/benefits of chemotherapy regimen + cardiovascular treatment.</p>
                </list-item>
                <list-item>
                  <p>= Repeat echocardiogram soon.</p>
                </list-item>
              </list>
            </list-item>
          </list>
          <list list-type="bullet">
            <list-item>
              <p>Abnormal LVEF (&lt; 40%)</p>
              <list list-type="simple">
                <list-item>
                  <p>= Discuss temporary cessation of chemotherapy regimen + cardiovascular treatment.</p>
                </list-item>
                <list-item>
                  <p>= Repeat echocardiogram soon.</p>
                </list-item>
              </list>
            </list-item>
            <list-item>
              <p>Pulmonary hypertension with right ventricle involvement.</p>
            </list-item>
            <list-item>
              <p>Cardiac tamponade.</p>
            </list-item>
          </list>
        </app>
      </app-group>
    </back>
  </sub-article>
</article>
