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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 pub-id-type="publisher-id" specific-use="scielo-v3">sXkmjsDLxh9NPz3zTrrPZvJ</article-id>
      <article-id pub-id-type="other">00068</article-id>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v2">S0066-782X2021000100068</article-id>
      <article-id pub-id-type="publisher-id">abc.20190673</article-id>
      <article-id pub-id-type="doi">10.36660/abc.20190673</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Artigo Original</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Correla&#231;&#227;o entre Cardiomegalia pela Radiografia de T&#243;rax e Di&#226;metro do Ventr&#237;culo Esquerdo pela Ecocardiografia em Pacientes com Doen&#231;a de Chagas</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-9199-5995</contrib-id>
          <name>
            <surname>Ramos</surname>
            <given-names>Matheus Rassi Fernandes</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-4543-4684</contrib-id>
          <name>
            <surname>Moreira</surname>
            <given-names>Henrique Turin</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-4296-5460</contrib-id>
          <name>
            <surname>Volpe</surname>
            <given-names>Gustavo Jardim</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-2526-0656</contrib-id>
          <name>
            <surname>Romano</surname>
            <given-names>Minna</given-names>
          </name>
          <xref ref-type="aff" rid="aff2">
            <sup>2</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Maciel</surname>
            <given-names>Benedito Carlos</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-1090-8165</contrib-id>
          <name>
            <surname>Schmidt</surname>
            <given-names>Andr&#233;</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Rassi</surname>
            <given-names>Anis</given-names>
            <suffix>Junior</suffix>
          </name>
          <xref ref-type="aff" rid="aff3">
            <sup>3</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-8651-8833</contrib-id>
          <name>
            <surname>Marin</surname>
            <given-names>Jose Ant&#244;nio</given-names>
            <suffix>Neto</suffix>
          </name>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
        </contrib>
      </contrib-group>
      <aff id="aff1">
        <label>1</label>
        <institution content-type="orgname">Universidade de S&#227;o Paulo</institution>
        <institution content-type="orgdiv1">Faculdade de Medicina de Ribeir&#227;o Preto</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">Universidade de S&#227;o Paulo Faculdade de Medicina de Ribeir&#227;o Preto &#8211; Cardiologia, Ribeir&#227;o Preto, SP - Brasil</institution>
      </aff>
      <aff id="aff2">
        <label>2</label>
        <institution content-type="orgname">Universidade de S&#227;o Paulo</institution>
        <institution content-type="orgdiv1">Faculdade de Medicina de Ribeir&#227;o Preto</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">Universidade de S&#227;o Paulo Faculdade de Medicina de Ribeir&#227;o Preto &#8211; Medicina Interna, Ribeir&#227;o Preto, SP - Brasil</institution>
      </aff>
      <aff id="aff3">
        <label>3</label>
        <institution content-type="orgname">Hospital do Cora&#231;&#227;o Anis Rassi</institution>
        <addr-line>
          <named-content content-type="city">Goi&#226;nia</named-content>
          <named-content content-type="state">GO</named-content>
        </addr-line>
        <country country="BR">Brasil</country>
        <institution content-type="original">Hospital do Cora&#231;&#227;o Anis Rassi &#8211; Cardiologia, Goi&#226;nia, GO &#8211; Brasil</institution>
      </aff>
      <author-notes>
        <corresp id="c01"> Correspond&#234;ncia: Jose Ant&#244;nio Marin-Neto &#8226; Universidade de S&#227;o Paulo Faculdade de Medicina de Ribeir&#227;o Preto &#8211; Cardiologia - Hospital das Clinicas de Ribeir&#227;o Preto - Avenida Bandeirantes, 3900. CEP 14040-900, Ribeir&#227;o Preto, SP &#8211; Brasil E-mail: <email>jamarin@cardiol.br</email>, <email>marin_neto@yahoo.com</email>
				</corresp>
        <fn fn-type="con">
          <p>Contribui&#231;&#227;o dos Autores</p>
          <p>Concep&#231;&#227;o e desenho da pesquisa: Rassi Junior A, Marin-Neto JA; Obten&#231;&#227;o de dados: Ramos MRF, Moreira HT, Volpe GJ, Romano M; An&#225;lise e interpreta&#231;&#227;o dos dados: Ramos MRF, Moreira HT, Volpe GJ, Romano M, Maciel BC, Schmidt A, Marin-Neto JA; An&#225;lise estat&#237;stica: Moreira HT, Schmidt A; Obten&#231;&#227;o de financiamento: Marin-Neto JA; Reda&#231;&#227;o do manuscrito: Ramos MRF, Moreira HT, Maciel BC, Schmidt A, Marin-Neto JA; Revis&#227;o cr&#237;tica do manuscrito quanto ao conte&#250;do intelectual importante: Moreira HT, Volpe GJ, Romano M, Maciel BC, Schmidt A, Rassi Junior A, Marin-Neto J&#193;.</p>
        </fn>
        <fn fn-type="conflict">
          <p>Potencial Conflito de Interesses</p>
          <p>Declaro n&#227;o haver conflito de interesses pertinentes.</p>
        </fn>
      </author-notes>
      <pub-date date-type="pub" publication-format="electronic">
        <day>03</day>
        <month>02</month>
        <year>2021</year>
      </pub-date>
      <pub-date date-type="collection" publication-format="electronic">
        <month>01</month>
        <year>2021</year>
      </pub-date>
      <volume>116</volume>
      <issue>1</issue>
      <fpage>68</fpage>
      <lpage>74</lpage>
      <history>
        <date date-type="received">
          <day>08</day>
          <month>10</month>
          <year>2019</year>
        </date>
        <date date-type="rev-recd">
          <day>27</day>
          <month>12</month>
          <year>2019</year>
        </date>
        <date date-type="accepted">
          <day>27</day>
          <month>12</month>
          <year>2019</year>
        </date>
      </history>
      <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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. </license-p>
        </license>
      </permissions>
      <abstract>
        <title>Resumo</title>
        <sec>
          <title>Fundamento</title>
          <p> Cardiomegalia pela radiografia de t&#243;rax (RXT) &#233; preditor independente de morte em indiv&#237;duos com cardiomiopatia cr&#244;nica da doen&#231;a de Chagas (CCDC). Contudo, a correla&#231;&#227;o entre o aumento do &#237;ndice cardiotor&#225;cico (ICT) na RXT e do di&#226;metro telediast&#243;lico do ventr&#237;culo esquerdo (DDVE) pela ecocardiografia (ECO) nessa popula&#231;&#227;o n&#227;o est&#225; bem definida.</p>
        </sec>
        <sec>
          <title>Objetivos</title>
          <p> Analisar a rela&#231;&#227;o entre cardiomegalia pela RXT e DDVE pela ECO em pacientes com doen&#231;a de Chagas (DC) e sua aplicabilidade ao escore de Rassi.</p>
        </sec>
        <sec>
          <title>M&#233;todos</title>
          <p> Estudo retrospectivo incluiu 63 pacientes ambulatoriais com DC avaliados por RXT e ECO. Cardiomegalia na RXT foi definida como ICT &gt; 0,5. DDVE foi avaliado como vari&#225;vel cont&#237;nua. Curva ROC foi utilizada para avaliar o potencial do DDVE para identifica&#231;&#227;o de cardiomegalia pela RXT, com ponto de corte definido pela maior somat&#243;ria de sensibilidade e especificidade.</p>
        </sec>
        <sec>
          <title>Resultados</title>
          <p> Idade mediana = 61 anos [intervalo interquartil: 48-68], 56% mulheres. CCDC foi identificada em 58 pacientes; 5 tinham a forma indeterminada da DC. Cardiomegalia foi detectada em 28 indiv&#237;duos. A &#225;rea sob a curva ROC do DDVE para identifica&#231;&#227;o de cardiomegalia foi de 0,806 (IC 95%: 0,692-0,919). O ponto de corte &#243;timo para DDVE foi de 60 mm (sensibilidade = 64%, especificidade = 89%). O uso do DDVE pela ECO em substitui&#231;&#227;o ao ICT pela RXT alterou o escore de Rassi em 14 pacientes, e em 10 deles houve redu&#231;&#227;o do risco presumido.</p>
        </sec>
        <sec>
          <title>Conclus&#227;o</title>
          <p> DDVE pela ECO &#233; par&#226;metro adequado e com alta especificidade para distinguir entre presen&#231;a e aus&#234;ncia de cardiomegalia na RXT na DC. (Arq Bras Cardiol. 2021; 116(1):68-74)</p>
        </sec>
      </abstract>
      <kwd-group xml:lang="pt">
        <kwd>Doen&#231;a de Chagas/fisiopatologia</kwd>
        <kwd>Cardiomegalia</kwd>
        <kwd>RX/ T&#243;rax</kwd>
        <kwd>Cardiomiopatia Chag&#225;sica</kwd>
        <kwd>Bloqueio Card&#237;aco</kwd>
      </kwd-group>
      <funding-group>
        <award-group>
          <funding-source>FAPESP</funding-source>
          <award-id>2018/25403-9</award-id>
        </award-group>
        <funding-statement>Fontes de Financiamento.O presente estudo foi parcialmente financiado pela FAPESP - Projeto 2018/25403-9.</funding-statement>
      </funding-group>
      <counts>
        <fig-count count="6"/>
        <table-count count="2"/>
        <equation-count count="0"/>
        <ref-count count="13"/>
        <page-count count="7"/>
      </counts>
    </article-meta>
  </front>
  <body>
    <sec sec-type="intro">
      <title>Introdu&#231;&#227;o</title>
      <p>A doen&#231;a de Chagas (DC) resulta de infec&#231;&#227;o pelo protozo&#225;rio <italic>Trypanosoma cruzi</italic> (<italic>T. cruzi</italic>), cujo principal vetor de transmiss&#227;o ao ser humano s&#227;o insetos da subfam&#237;lia <italic>Triatominae,</italic> embora isso possa ocorrer por outros mecanismos, tais como transfus&#227;o sangu&#237;nea, transplante de medula &#243;ssea ou de &#243;rg&#227;os s&#243;lidos a partir de doadores contaminados, transmiss&#227;o vertical entre m&#227;e e filho e ingest&#227;o de alimentos contaminados.<sup><xref ref-type="bibr" rid="B1">1</xref></sup> Estimativas da Organiza&#231;&#227;o Mundial da Sa&#250;de (OMS) reportam que aproximadamente 7 milh&#245;es de indiv&#237;duos est&#227;o infectados mundialmente, proporcionando elevada morbimortalidade e impacto social.<sup><xref ref-type="bibr" rid="B2">2</xref></sup></p>
      <p>A cardiomiopatia &#233; a mais s&#233;ria e frequente forma cl&#237;nica da DC cr&#244;nica, que ocorre em 20% a 30% dos indiv&#237;duos cronicamente infectados.<sup><xref ref-type="bibr" rid="B3">3</xref>,<xref ref-type="bibr" rid="B4">4</xref></sup> O escore de Rassi &#233; estratificador do risco de morte validado em pacientes com cardiomiopatia cr&#244;nica da DC (CCDC). Dentre os fatores de risco que comp&#245;em esse escore, destaca-se a cardiomegalia na radiografia de t&#243;rax (RXT), que se associa a significativo risco de morte total e cardiovascular em pacientes com a CCDC.<sup><xref ref-type="bibr" rid="B5">5</xref></sup></p>
      <p>Embora o estudo de Rassi Jr et al.<sup><xref ref-type="bibr" rid="B5">5</xref></sup> tenha utilizado a ecocardiografia (ECO) para determinar o di&#226;metro telediast&#243;lico do ventr&#237;culo esquerdo (DDVE), esse par&#226;metro n&#227;o se mostrou marcador independente de mortalidade na CCDC. Entretanto, deve-se ressaltar que, naquele estudo, o DDVE foi avaliado de maneira categ&#243;rica, com pontos de corte convencionais que podem n&#227;o ser os mais adequados para pacientes com CCDC, devido ao t&#237;pico envolvimento mioc&#225;rdico segmentar nessa doen&#231;a. De outra parte, o c&#225;lculo do &#237;ndice cardiotor&#225;cico (ICT) pela RXT pode englobar, em muitos casos, a dilata&#231;&#227;o de &#225;trios e ventr&#237;culos, que se expressam linearmente na RXT. Embora o estudo radiol&#243;gico do cora&#231;&#227;o seja bastante dispon&#237;vel, implica radia&#231;&#227;o, enquanto a ECO tornou-se atualmente um m&#233;todo amplamente utilizado para avalia&#231;&#227;o cardiovascular. Dessa maneira, haveria indiscut&#237;vel interesse em, com um &#250;nico exame, avaliar fun&#231;&#227;o sist&#243;lica e dimens&#227;o do ventr&#237;culo esquerdo (VE), a fim de estimar o risco de morte com vari&#225;veis correlatas &#224;s aplicadas no escore de Rassi original.</p>
      <p>O presente estudo teve por objetivo analisar a rela&#231;&#227;o entre cardiomegalia definida pelo ICT na RXT e o DDVE avaliado com ECO em pacientes com DC.</p>
    </sec>
    <sec sec-type="methods">
      <title>M&#233;todos</title>
      <p>Neste estudo transversal retrospectivo, foram inclu&#237;dos pacientes de ambos os g&#234;neros, adultos (&gt; 18 anos de idade), com diagn&#243;stico de DC, caracterizados por positividade em dois exames sorol&#243;gicos para detec&#231;&#227;o de anticorpos contra o <italic>T. cruzi</italic>, embasados em t&#233;cnicas distintas, que se encontravam em seguimento ambulatorial no Hospital das Cl&#237;nicas da Faculdade de Medicina da Universidade de S&#227;o Paulo em Ribeir&#227;o Preto (HCFMRP-USP), hospital terci&#225;rio e centro de refer&#234;ncia em pesquisa de DC.</p>
      <p>A coleta de dados foi realizada por meio de revis&#227;o sistematizada de prontu&#225;rios cl&#237;nicos, a partir de um grupo de 158 pacientes com DC que participaram de estudo cl&#237;nico pr&#233;vio, cujos crit&#233;rios de inclus&#227;o e exclus&#227;o foram anteriormente reportados em detalhes por outra publica&#231;&#227;o.<sup><xref ref-type="bibr" rid="B6">6</xref></sup> Foram inclu&#237;dos neste estudo os pacientes que tivessem RXT e avalia&#231;&#227;o completa dos preditores independentes do escore de Rassi, mediante os exames essenciais de eletrocardiograma de 12 deriva&#231;&#245;es, em repouso, ECO, RXT e exame de monitoramento de 24 horas do ritmo card&#237;aco, al&#233;m de anamnese focada na grada&#231;&#227;o de dispneia conforme a New York Heart Association (NYHA). Para inclus&#227;o no estudo, o limite m&#225;ximo de tempo entre a realiza&#231;&#227;o da RXT, considerada como m&#233;todo comparativo de refer&#234;ncia, e a ECO foi de 1 ano, desde que o <italic>status</italic> cl&#237;nico do paciente tivesse se mantido est&#225;vel nesse per&#237;odo. Foram exclu&#237;dos da an&#225;lise os pacientes que apresentaram mudan&#231;a no quadro cl&#237;nico no decorrer do per&#237;odo entre a realiza&#231;&#227;o desses dois exames.</p>
      <sec>
        <title>Radiografia de T&#243;rax</title>
        <p>A cardiomegalia na RXT foi sempre avaliada na incid&#234;ncia posteroanterior e definida como a presen&#231;a de ICT &gt; 0,5. Foi envidado esfor&#231;o adicional para eventual caracteriza&#231;&#227;o de aumento ventricular direito, por compara&#231;&#227;o com a telerradiografia em perfil, nos casos em que essa incid&#234;ncia radiol&#243;gica estava dispon&#237;vel.</p>
      </sec>
      <sec>
        <title>Ecocardiografia</title>
        <p>Foram utilizados os dados de ECO transtor&#225;cica em repouso, realizada na data mais pr&#243;xima &#224; da RXT, desde que respeitado o per&#237;odo m&#225;ximo de 1 ano. O DDVE foi mensurado pelo m&#233;todo bidimensional, seguindo diretrizes ecocardiogr&#225;ficas recentes.<sup><xref ref-type="bibr" rid="B7">7</xref></sup> Outros par&#226;metros ecocardiogr&#225;ficos tamb&#233;m relacionados ao remodelamento do VE foram analisados, tais como o &#237;ndice de massa e a fra&#231;&#227;o de eje&#231;&#227;o (FE) do VE e o volume indexado do &#225;trio esquerdo.</p>
      </sec>
      <sec>
        <title>An&#225;lise Estat&#237;stica</title>
        <p>Vari&#225;veis cont&#237;nuas foram apresentadas como m&#233;dia e desvio padr&#227;o quando distribu&#237;das normalmente, e representadas como mediana e intervalo interquartil quando apresentavam distribui&#231;&#227;o n&#227;o normal. An&#225;lise de curva ROC (<italic>Receiver Operating Characteristic</italic>) foi realizada para verificar a capacidade de o DDVE, avaliado pela ECO, distinguir entre presen&#231;a e aus&#234;ncia de cardiomegalia pela RXT. Por fim, foi avaliado o impacto na reclassifica&#231;&#227;o dos pacientes com a forma card&#237;aca da DC pelo escore de Rassi, utilizando-se a ECO para a defini&#231;&#227;o de cardiomegalia, em substitui&#231;&#227;o ao tradicional ICT. Os indiv&#237;duos com a forma indeterminada da DC n&#227;o foram classificados pelo escore de Rassi neste estudo, pois pacientes com essa forma da doen&#231;a n&#227;o foram contemplados na investiga&#231;&#227;o original desse escore</p>
      </sec>
      <sec>
        <title>&#201;tica</title>
        <p>O presente estudo foi aprovado pelo Comit&#234; de &#201;tica em Pesquisa do HCRP-FMRP-USP (CAAE: 06415319.2.0000.5440; parecer 3.130.390) e conduzido sob os princ&#237;pios &#233;ticos da declara&#231;&#227;o de Helsinque e em conformidade com a resolu&#231;&#227;o do Conselho Nacional de Sa&#250;de n<sup>o</sup>466/2012.</p>
      </sec>
    </sec>
    <sec sec-type="results">
      <title>Resultados</title>
      <sec>
        <title>Descri&#231;&#227;o da Amostra Populacional Estudada</title>
        <p>Este estudo transversal retrospectivo incluiu 63 pacientes com DC que preencheram os crit&#233;rios de inclus&#227;o, correspondendo a 40% do total de 158 pacientes avaliados. As caracter&#237;sticas demogr&#225;ficas e cl&#237;nicas dos participantes est&#227;o descritas na <xref ref-type="table" rid="t1">Tabela 1</xref>. Os participantes apresentaram idade mediana de 61 anos (intervalo interquartil [IIQ]:48-68), na maioria mulheres (56%). Apenas 5 (8%) pacientes apresentavam a forma indeterminada da DC. A maioria dos participantes (68%) estava em classe funcional I pela NYHA, enquanto classes funcionais II e III foram encontradas em 21% e 11% dos indiv&#237;duos, respectivamente. O escore de Rassi calculado nos 58 pacientes com a CCDC foi de 9 &#177; 5 pontos.</p>
        <p>
          <table-wrap id="t1">
            <label>Tabela 1</label>
            <caption>
              <title>&#8211; Caracter&#237;sticas dos pacientes inclu&#237;dos no estudo</title>
            </caption>
            <table frame="hsides" rules="groups">
              <colgroup>
                <col/>
                <col/>
              </colgroup>
              <thead>
                <tr>
                  <th align="left" colspan="2">Demogr&#225;ficos e antropom&#233;tricos</th>
                </tr>
                <tr>
                  <th align="left" style="font-weight:normal">Idade (anos)</th>
                  <th style="font-weight:normal">61 [48-68]</th>
                </tr>
              </thead>
              <tbody>
                <tr>
                  <td>G&#234;nero feminino</td>
                  <td align="center">35 (56%)</td>
                </tr>
                <tr>
                  <td>IMC (kg/m<sup>2</sup>)</td>
                  <td align="center">26,6 &#177; 4,7</td>
                </tr>
                <tr>
                  <td colspan="2">
                    <bold>Cl&#237;nicos</bold>
                  </td>
                </tr>
                <tr>
                  <td>Classe funcional</td>
                  <td>
									</td>
                </tr>
                <tr>
                  <td>NYHA I</td>
                  <td align="center">37 (59%)</td>
                </tr>
                <tr>
                  <td>NYHA II</td>
                  <td align="center">17 (27%)</td>
                </tr>
                <tr>
                  <td>NYHA III</td>
                  <td align="center">9 (14%)</td>
                </tr>
                <tr>
                  <td>Edema de membros inferiores</td>
                  <td align="center">12 (19%)</td>
                </tr>
                <tr>
                  <td>Turg&#234;ncia jugular</td>
                  <td align="center">3 (5%)</td>
                </tr>
                <tr>
                  <td>IECA ou BRA</td>
                  <td align="center">48 (76%)</td>
                </tr>
                <tr>
                  <td>Betabloqueador</td>
                  <td align="center">34 (54%)</td>
                </tr>
                <tr>
                  <td>Espironolactona</td>
                  <td align="center">16 (25%)</td>
                </tr>
                <tr>
                  <td>Diur&#233;ticos</td>
                  <td align="center">29 (46%)</td>
                </tr>
                <tr>
                  <td>Amiodarona</td>
                  <td align="center">14 (22%)</td>
                </tr>
                <tr>
                  <td colspan="2">
                    <bold>Ecocardiogr&#225;ficos</bold>
                  </td>
                </tr>
                <tr>
                  <td>Di&#226;metro diast&#243;lico final do VE (mm)</td>
                  <td align="center">54 [47-61]</td>
                </tr>
                <tr>
                  <td>Volume indexado do &#225;trio esquerdo (mL/m<sup>2</sup>)</td>
                  <td align="center">42 [26-59]</td>
                </tr>
                <tr>
                  <td>&#205;ndice de massa ventricular (g/m<sup>2</sup>)</td>
                  <td align="center">123 [92-156]</td>
                </tr>
                <tr>
                  <td>Fra&#231;&#227;o de eje&#231;&#227;o do ventr&#237;culo esquerdo (%)</td>
                  <td align="center">51 [34-63]</td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="TFN1">
                <p>
                  <italic>Vari&#225;veis cont&#237;nuas param&#233;tricas e n&#227;o param&#233;tricas est&#227;o descritas como m&#233;dia &#177; desvio padr&#227;o e como mediana [intervalo interquartil], respectivamente. Vari&#225;veis categ&#243;ricas est&#227;o representadas como contagens absolutas e porcentagens. IMC: &#237;ndice de massa corporal; NYHA: New York Heart Association; IECA: inibidor da enzima de convers&#227;o da angiotensina; BRA: bloqueador do receptor da angiotensina II; VE: ventr&#237;culo esquerdo.</italic>
                </p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
        </p>
      </sec>
      <sec>
        <title>Compara&#231;&#227;o entre Radiografia de T&#243;rax e Ecocardiograma</title>
        <p>Cardiomegalia foi detectada pela RXT em 28 (44%) indiv&#237;duos. O tempo m&#233;dio entre a realiza&#231;&#227;o da RXT e da ECO foi de 5 &#177; 174 dias. O DDVE dos indiv&#237;duos no grupo com cardiomegalia (61 IIQ [53-70]) pela RXT mostrou-se maior do que no grupo sem cardiomegalia (49 IIQ [46-55]), p &lt; 0,001. A &#225;rea sob a curva ROC do DDVE para identifica&#231;&#227;o de cardiomegalia detectada pela RXT foi de 0,806 (intervalo de confian&#231;a de 95%: 0,692-0,919) (<xref ref-type="fig" rid="f01">Figura 1</xref>). Na amostra estudada, o DDVE de 60 mm apresentou-se como o ponto de maior acur&#225;cia, com sensibilidade de 64% e especificidade de 89%.</p>
        <p>
          <fig id="f01">
            <label>Figura 1</label>
            <caption>
              <title>&#8211; &#193;rea sob a curva ROC do di&#226;metro telediast&#243;lico do ventr&#237;culo esquerdo para a detec&#231;&#227;o de cardiomegalia em radiografia de t&#243;rax.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-116-01-0068-90673-gf01.jpg"/></fig>
        </p>
        <p>Os indiv&#237;duos com resultados discordantes para cardiomegalia definida pelos dois m&#233;todos de imagem n&#227;o mostraram diferen&#231;as estatisticamente significativas quanto a idade, g&#234;nero, &#237;ndice de massa ventricular esquerda e volume indexado do &#225;trio esquerdo em compara&#231;&#227;o aos indiv&#237;duos com resultados concordantes.</p>
      </sec>
      <sec>
        <title>Reclassifica&#231;&#227;o do Escore de Rassi</title>
        <p>Na presente amostra populacional, a propor&#231;&#227;o de indiv&#237;duos considerados de risco baixo, moderado e alto de morte pelo escore de Rassi, utilizando a RXT para identifica&#231;&#227;o de cardiomegalia, foi de 36% (n = 21), 33% (n = 19) e 31% (n = 18), respectivamente. Ao utilizar-se a ECO para identifica&#231;&#227;o de cardiomegalia, com o ponto de corte de maior acur&#225;cia, a propor&#231;&#227;o de pacientes com risco baixo, moderado e alto foi de 40% (n = 23), 28% (n = 16) e 32% (n = 19), respectivamente (<xref ref-type="fig" rid="f02">Figura 2</xref>). Em 44 (76%) participantes, o escore de Rassi com a utiliza&#231;&#227;o da ECO mostrou o mesmo valor num&#233;rico quando comparado com o escore estimado por utiliza&#231;&#227;o da RXT. Dentre os 14 participantes em que houve mudan&#231;a num&#233;rica do escore, 8 demonstraram redu&#231;&#227;o do mesmo, enquanto 6 demonstraram aumento. Quanto &#224;s categorias de risco (baixo, moderado, elevado), houve altera&#231;&#227;o com a utiliza&#231;&#227;o da ECO em 11 pacientes (19%), 5 deles com aumento e 6 deles com redu&#231;&#227;o do risco atribu&#237;do pelo escore assim constitu&#237;do (<xref ref-type="fig" rid="f03">Figura 3</xref>).</p>
        <p>
          <fig id="f02">
            <label>Figura 2</label>
            <caption>
              <title>&#8211; Classifica&#231;&#227;o de risco de acordo com o escore de Rassi utilizando a radiografia de t&#243;rax e a ecocardiografia para definir cardiomegalia nos indiv&#237;duos com a forma card&#237;aca da doen&#231;a de Chagas. DDVE: di&#226;metro diast&#243;lico final do ventr&#237;culo esquerdo pela ecocardiografia; ICT: &#237;ndice cardiotor&#225;cico pela radiografia de t&#243;rax.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-116-01-0068-90673-gf02.jpg"/></fig>
        </p>
        <p>
          <fig id="f03">
            <label>Figura 3</label>
            <caption>
              <title>&#8211; Classifica&#231;&#227;o de risco individual de acordo com o escore de Rassi utilizando a radiografia de t&#243;rax e a ecocardiografia para definir cardiomegalia nos indiv&#237;duos com a forma card&#237;aca da doen&#231;a de Chagas. Linhas tracejadas amarela e vermelha correspondem, respectivamente, a escore de Rassi = 7 (risco moderado) e a escore de Rassi = 12 (risco alto). DDVE: di&#226;metro diast&#243;lico final do ventr&#237;culo esquerdo pela ecocardiografia; ICT: &#237;ndice cardiotor&#225;cico pela radiografia de t&#243;rax.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-116-01-0068-90673-gf03.jpg"/></fig>
        </p>
      </sec>
    </sec>
    <sec sec-type="discussion">
      <title>Discuss&#227;o</title>
      <p>Este estudo demonstrou existir rela&#231;&#227;o bastante n&#237;tida e significativa entre a detec&#231;&#227;o de cardiomegalia pela RXT e a verifica&#231;&#227;o de dilata&#231;&#227;o ventricular esquerda, pela ECO, em amostra n&#227;o selecionada de pacientes ambulatoriais com diagn&#243;stico de CCDC. Esses resultados abrem a perspectiva para que o DDVE avaliado na ECO transtor&#225;cica em repouso possa substituir a aferi&#231;&#227;o do ICT na RXT, no sentido de se determinar o risco de morte em pacientes com a CCDC com o escore de Rassi, assim eventualmente modificado. Isso permitiria dispensar o exame radiol&#243;gico que requer irradia&#231;&#227;o do paciente, embora de pequena monta, e determinar com apenas um exame (tamb&#233;m n&#227;o invasivo, mas que, al&#233;m disso, ainda dispensa irradia&#231;&#227;o) tanto a fun&#231;&#227;o sist&#243;lica ventricular esquerda quanto a dimens&#227;o dessa c&#226;mara. Essa perspectiva torna-se atraente, uma vez que o DDVE, pela ECO, constituiu par&#226;metro adequado, com alta especificidade, para distinguir entre presen&#231;a e aus&#234;ncia de cardiomegalia em pacientes com DC cr&#244;nica.</p>
      <p>Os resultados da presente investiga&#231;&#227;o corroboram os de pesquisa anterior relatada em 1983 por Pereira-Barreto et al.,<sup><xref ref-type="bibr" rid="B8">8</xref></sup> com amostra bem menor, composta por 22 pacientes, que tamb&#233;m focalizou resultados da RXT e da ECO e concluiu por boa correla&#231;&#227;o entre os valores de ICT e de fun&#231;&#227;o ventricular esquerda.<sup><xref ref-type="bibr" rid="B8">8</xref></sup> Em contraposi&#231;&#227;o, outro estudo, por Perez et al. em 2003, relatou sobre an&#225;lise comparativa entre os resultados da RXT em incid&#234;ncia posteroanterior e os da ECO em repouso.<sup><xref ref-type="bibr" rid="B9">9</xref></sup> Diversamente dos resultados de nosso estudo, aqueles pesquisadores descreveram baixa correla&#231;&#227;o de valores de ICT pela RXT, tanto com o DDVE quanto com a FE do VE. Al&#233;m disso, o ICT naquela pesquisa n&#227;o demonstrou ter elevados &#237;ndices de sensibilidade ou valor preditivo positivo para detectar disfun&#231;&#227;o ventricular esquerda. Dessa maneira, concluiu-se que o ICT anormal (&gt; 0,5) apesar de elevada especificidade para detectar a disfun&#231;&#227;o sist&#243;lica do VE, n&#227;o seria exame &#250;til na avalia&#231;&#227;o dessa anormalidade na DC, em vista de sua baixa sensibilidade para detectar tanto a dilata&#231;&#227;o ventricular avaliada pela ECO transtor&#225;cica em repouso quanto a disfun&#231;&#227;o sist&#243;lica da c&#226;mara, medida pela FE do VE com o mesmo m&#233;todo.</p>
      <p>N&#227;o s&#227;o claros os poss&#237;veis motivos para a discrep&#226;ncia entre os resultados do presente estudo e aqueles relatados por Perez et al.<sup><xref ref-type="bibr" rid="B9">9</xref></sup> Ambos os estudos s&#227;o embasados em amostras populacionais de pacientes com CCDC que eram ambulatoriais, orbitando em ambientes de hospitais universit&#225;rios, mas h&#225; tamb&#233;m alguns aspectos diferenciais entre as amostras estudadas. Assim, n&#227;o houve praticamente crit&#233;rios de exclus&#227;o em nosso estudo, salvo os de conveni&#234;ncia log&#237;stica, decorrentes da disponibilidade dos dois exames comparativos em intervalo de tempo prefixado de 1 ano. Em contraste, os crit&#233;rios de exclus&#227;o na pesquisa de Perez et al.<sup><xref ref-type="bibr" rid="B9">9</xref></sup> foram bastante amplos e abrangentes, embora aplicados a pacientes sucessivos, e possivelmente resultaram em amostra relativamente selecionada e menos representativa da popula&#231;&#227;o de pacientes com DC. Assim, naquele estudo, apenas 28% e 29% dos pacientes apresentavam, respectivamente, aumento do ICT e disfun&#231;&#227;o ventricular esquerda. Em contraste, em nosso estudo, 44% dos pacientes exibiam aumento do ICT. Ademais, no estudo de Perez et al.,<sup><xref ref-type="bibr" rid="B9">9</xref></sup> o valor m&#233;dio de FE do VE foi de 61%; enquanto, na presente investiga&#231;&#227;o, esse par&#226;metro foi em m&#233;dia bem menor, de 51%. Em conjunto, tais aspectos configuram maior gravidade da CCDC em nossa amostra populacional estudada, incluindo o fato de apenas 8% de indiv&#237;duos estarem com a forma indeterminada da DC.</p>
      <p>Ainda comparando os resultados da presente pesquisa com a relatada por Perez et al.,<sup><xref ref-type="bibr" rid="B9">9</xref></sup> &#233; tamb&#233;m plaus&#237;vel inferir que a discrep&#226;ncia de conclus&#245;es quanto ao valor da RXT seja mais aparente do que real. De fato, quando aqueles autores dividiram sua amostra em dois grupos, com ICT normal e anormal (&gt; 0,5), seus resultados evidenciaram que o aumento de ICT associou-se significativamente (p &lt; 0,05) com queda da FE do VE, e com aumento da dimens&#227;o diast&#243;lica ventricular, bem como com a disfun&#231;&#227;o segmentar do VE, como avaliada por &#237;ndice de mobilidade parietal ventricular esquerda.</p>
      <p>&#201; relevante ressaltar que os resultados da presente pesquisa indicam que a aus&#234;ncia da cardiomegalia ao RXT n&#227;o descarta comprometimento card&#237;aco quando pacientes s&#227;o avaliados por m&#233;todos capazes de prover mais detalhes anat&#244;micos e funcionais como a ECO transtor&#225;cica em repouso. Portanto, embora espec&#237;fica, a RXT apresenta baixa sensibilidade para detectar acometimento card&#237;aco em pacientes com DC, e pode ser questionado seu uso como exame de rastreio e como crit&#233;rio para diagn&#243;stico de forma indeterminada da DC. Nesse contexto, deve-se observar que, embora a forma indeterminada da DC continue a ser definida em consensos recentes com base no conceito de uma RXT evidenciando ICT normal,<sup><xref ref-type="bibr" rid="B3">3</xref>,<xref ref-type="bibr" rid="B10">10</xref>,<xref ref-type="bibr" rid="B11">11</xref></sup> uma proposta de substitui&#231;&#227;o desse crit&#233;rio por ecocardiograma em repouso dentro da normalidade j&#225; foi publicada em 2002.<sup><xref ref-type="bibr" rid="B12">12</xref></sup></p>
      <p>O escore de Rassi &#233; universalmente entendido nos dias atuais como a ferramenta mais valiosa no estabelecimento do progn&#243;stico vital de pacientes com a CCDC. Trata-se de escore robusto, desenvolvido por an&#225;lise multivariada de v&#225;rios fatores simples de risco de morte na CCDC e validado externamente em outras coortes independentes. Entretanto, deve-se observar que o estudo em quest&#227;o abordou vari&#225;veis de maneira dicotomizada e n&#227;o cont&#237;nua, o que abre margem para complementa&#231;&#245;es. Dentre as vari&#225;veis abordadas de maneira n&#227;o cont&#237;nua est&#225; o DDVE, mensurado padronizadamente com a ECO. Entretanto, o DDVE, quando avaliado em categorias dicotomizadas de aumento <italic>versus</italic> n&#227;o aumento, pode n&#227;o ser apropriado &#224; avalia&#231;&#227;o de pacientes com a CCDC devido ao t&#237;pico envolvimento mioc&#225;rdico segmentar nessa doen&#231;a.<sup><xref ref-type="bibr" rid="B1">1</xref></sup></p>
      <p>Os resultados do presente estudo est&#227;o alinhados com a &#234;nfase na ECO como instrumento fundamental para o seguimento cl&#237;nico do paciente com DC cr&#244;nica, mormente quando j&#225; se configura o aparecimento da CCDC.<sup><xref ref-type="bibr" rid="B10">10</xref></sup> Al&#233;m de possibilitar a confirma&#231;&#227;o (ou n&#227;o) de cardiomegalia por RXT duvidosas, a ECO torna-se previsivelmente essencial para an&#225;lise de uma cardiomiopatia em que altera&#231;&#245;es regionais da contratilidade ventricular s&#227;o dist&#250;rbios precoces e proeminentes na hist&#243;ria natural da doen&#231;a de base.<sup><xref ref-type="bibr" rid="B13">13</xref></sup> Ademais, a detec&#231;&#227;o dessas anormalidades regionais, em fases precoces da evolu&#231;&#227;o da CCDC, passa a ter implica&#231;&#227;o progn&#243;stica e terap&#234;utica eventual, face aos resultados recentes de pesquisas evidenciando que um escore de mobilidade segmentar mesmo minimamente alterado &#8211; e ainda que a fun&#231;&#227;o ventricular sist&#243;lica global fosse preservada &#8211; &#233; determinante para desfechos graves, incluindo mortalidade.<sup><xref ref-type="bibr" rid="B13">13</xref></sup></p>
      <p>No estudo seminal de Rassi et al.,<sup><xref ref-type="bibr" rid="B5">5</xref></sup> coorte inclu&#237;da para an&#225;lise multivariada e elabora&#231;&#227;o do escore foi constitu&#237;da de 424 indiv&#237;duos, com a maioria deles de baixo risco (61%), enquanto aqueles com risco moderado e alto representaram 19% e 20% da amostra, respectivamente. J&#225; no presente estudo, obteve-se distribui&#231;&#227;o mais equilibrada entre os grupos de risco, com a propor&#231;&#227;o de indiv&#237;duos de risco baixo, intermedi&#225;rio e alto igual a 36%, 33% e 31%, respectivamente. De forma an&#225;loga, quando se substituiu o ICT pelo DDVE para composi&#231;&#227;o do escore, registrou-se pequeno aumento da propor&#231;&#227;o de baixo risco (40%) &#224;s custas de discreta redu&#231;&#227;o na de risco intermedi&#225;rio (28%). Dessa forma, torna-se imperativo conduzir estudos futuros (de seguimento cl&#237;nico) para eventual valida&#231;&#227;o de um escore de Rassi modificado pela substitui&#231;&#227;o do ICT como par&#226;metro radiol&#243;gico de dilata&#231;&#227;o card&#237;aca pelo mais espec&#237;fico par&#226;metro ecocardiogr&#225;fico de dilata&#231;&#227;o do VE, para se determinar. o impacto progn&#243;stico dessa modifica&#231;&#227;o.</p>
      <sec>
        <title>Limita&#231;&#245;es</title>
        <p>O presente estudo tem algumas limita&#231;&#245;es. Os exames utilizados de maneira comparativa (RXT e ECO) n&#227;o foram realizados no mesmo dia. Os outros exames e avalia&#231;&#245;es pertencentes ao escore de Rassi tamb&#233;m diferem em data. De toda maneira, objetivou-se diminuir ao m&#225;ximo fatores de confus&#227;o ou associados a altera&#231;&#245;es cl&#237;nicas, de forma a destacar-se que, no per&#237;odo entre os exames, n&#227;o houve altera&#231;&#227;o no quadro cl&#237;nico dos pacientes ou medicamentosa nos tratamentos dos mesmos. N&#227;o houve mensura&#231;&#227;o das dimens&#245;es do &#225;trio direito pela ECO, limitando assim a avalia&#231;&#227;o da dilata&#231;&#227;o dessa c&#226;mara card&#237;aca como fator de discord&#226;ncia entre a ECO e a RXT para defini&#231;&#227;o de cardiomegalia. Os pacientes n&#227;o foram avaliados de maneira longitudinal para an&#225;lise progn&#243;stica do DDVE pela ECO, mas est&#227;o em seguimento ambulatorial e, em ocasi&#227;o prop&#237;cia futura, ser&#227;o reavaliados quanto a isso.</p>
      </sec>
    </sec>
    <sec sec-type="conclusions">
      <title>Conclus&#245;es</title>
      <p>O DDVE pela ECO &#233; par&#226;metro adequado para distinguir entre presen&#231;a e aus&#234;ncia de cardiomegalia na RXT, com alta especificidade em pacientes com DC cr&#244;nica. A substitui&#231;&#227;o do ICT radiol&#243;gico pela DDVE ecocardiogr&#225;fica na composi&#231;&#227;o do escore de Rassi revelou-se poss&#237;vel e n&#227;o alterou substancialmente os valores do escore assim obtidos. Dessa maneira, abre-se relevante perspectiva de evitar um teste que implique radia&#231;&#227;o e, com um &#250;nico exame &#8211; ECO &#8211; obter mensura&#231;&#227;o de dois constituintes do escore de Rassi (dimens&#227;o card&#237;aca e fun&#231;&#227;o sist&#243;lica ventricular). O potencial papel progn&#243;stico do escore assim modificado passa a ser alvo preferencial de estudos futuros.</p>
    </sec>
  </body>
  <back>
    <ack>
      <title>Agradecimentos</title>
      <p>Estudo parcialmente subvencionado pela FAPESP e realizado durante inicia&#231;&#227;o cient&#237;fica pelo Acad&#234;mico MRFR, em 2018-2019.</p>
    </ack>
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    <fn-group>
      <fn fn-type="other">
        <p>Vincula&#231;&#227;o Acad&#234;mica</p>
        <p>Este artigo &#233; parte de Inicia&#231;&#227;o cient&#237;fica de Matheus Rassi Fernandes Ramos pela Universidade de S&#227;o Paulo Faculdade de Medicina de Ribeir&#227;o Preto.</p>
      </fn>
    </fn-group>
    <fn-group>
      <fn fn-type="financial-disclosure">
        <p><bold>Fontes de Financiamento</bold>.O presente estudo foi parcialmente financiado pela FAPESP - Projeto 2018/25403-9.</p>
      </fn>
    </fn-group>
  </back>
  <sub-article article-type="translation" id="TRen" xml:lang="en">
    <front-stub>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original Article</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Correlation between Cardiomegaly on Chest X-Ray and Left Ventricular Diameter on Echocardiography in Patients with Chagas Disease</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0001-9199-5995</contrib-id>
          <name>
            <surname>Ramos</surname>
            <given-names>Matheus Rassi Fernandes</given-names>
          </name>
          <xref ref-type="aff" rid="aff1001">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-4543-4684</contrib-id>
          <name>
            <surname>Moreira</surname>
            <given-names>Henrique Turin</given-names>
          </name>
          <xref ref-type="aff" rid="aff1001">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-4296-5460</contrib-id>
          <name>
            <surname>Volpe</surname>
            <given-names>Gustavo Jardim</given-names>
          </name>
          <xref ref-type="aff" rid="aff1001">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-2526-0656</contrib-id>
          <name>
            <surname>Romano</surname>
            <given-names>Minna</given-names>
          </name>
          <xref ref-type="aff" rid="aff2001">
            <sup>2</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Maciel</surname>
            <given-names>Benedito Carlos</given-names>
          </name>
          <xref ref-type="aff" rid="aff1001">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-1090-8165</contrib-id>
          <name>
            <surname>Schmidt</surname>
            <given-names>Andr&#233;</given-names>
          </name>
          <xref ref-type="aff" rid="aff1001">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Rassi</surname>
            <given-names>Anis</given-names>
            <suffix>Junior</suffix>
          </name>
          <xref ref-type="aff" rid="aff3001">
            <sup>3</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0002-8651-8833</contrib-id>
          <name>
            <surname>Marin</surname>
            <given-names>Jose Ant&#244;nio</given-names>
            <suffix>Neto</suffix>
          </name>
          <xref ref-type="aff" rid="aff1001">
            <sup>1</sup>
          </xref>
        </contrib>
      </contrib-group>
      <aff id="aff1001">
        <label>1</label>
        <country country="BR">Brazil</country>
        <institution content-type="original">Universidade de S&#227;o Paulo Faculdade de Medicina de Ribeir&#227;o Preto &#8211; Cardiologia, Ribeir&#227;o Preto, SP - Brazil</institution>
      </aff>
      <aff id="aff2001">
        <label>2</label>
        <country country="BR">Brazil</country>
        <institution content-type="original">Universidade de S&#227;o Paulo Faculdade de Medicina de Ribeir&#227;o Preto &#8211; Medicina Interna, Ribeir&#227;o Preto, SP - Brazil</institution>
      </aff>
      <aff id="aff3001">
        <label>3</label>
        <country country="BR">Brazil</country>
        <institution content-type="original">Hospital do Cora&#231;&#227;o Anis Rassi &#8211; Cardiologia, Goi&#226;nia, GO &#8211; Brazil</institution>
      </aff>
      <author-notes>
        <corresp id="c01001"><bold>Mailing Address: Jose Ant&#244;nio Marin-Neto &#8226;</bold> Universidade de S&#227;o Paulo Faculdade de Medicina de Ribeir&#227;o Preto &#8211; Cardiologia - Hospital das Clinicas de Ribeir&#227;o Preto - Avenida Bandeirantes, 3900. Postal Code 14040-900, Ribeir&#227;o Preto, SP &#8211; Brazil E-mail: jamarin@cardiol.br, marin_neto@yahoo.com </corresp>
        <fn fn-type="con">
          <p>Author Contributions</p>
          <p>Conception and design of the research: Rassi Junior A, Marin-Neto JA; Acquisition of data: Ramos MRF, Moreira HT, Volpe GJ, Romano M; Analysis and interpretation of the data: Ramos MRF, Moreira HT, Volpe GJ, Romano M, Maciel BC, Schmidt A, Marin-Neto JA; Statistical analysis: Moreira HT, Schmidt A; Obtaining financing: Marin-Neto JA; Writing of the manuscript: Ramos MRF, Moreira HT, Maciel BC, Schmidt A, Marin-Neto JA; Critical revision of the manuscript for intellectual content: Moreira HT, Volpe GJ, Romano M, Romano M, Maciel BC, Schmidt A, Rassi Junior A, Marin-Neto JA</p>
        </fn>
        <fn fn-type="conflict">
          <p>Potential Conflict of Interest</p>
          <p>No potential conflict of interest relevant to this article was reported.</p>
        </fn>
      </author-notes>
      <abstract>
        <title>Abstract</title>
        <sec>
          <title>Background</title>
          <p> Cardiomegaly on chest X-ray is an independent predictor of death in individuals with chronic Chagas cardiomyopathy (CCC). However, the correlation between increased cardiothoracic ratio (CTR) on chest X-ray and left ventricular end-diastolic diameter (LVEDD) on echocardiography is not well established in this population.</p>
        </sec>
        <sec>
          <title>Objectives</title>
          <p> To assess the relationship between chest X-ray and LVEDD on echocardiography in patients with Chagas disease and its applicability to the Rassi score.</p>
        </sec>
        <sec>
          <title>Methods</title>
          <p> Retrospective study on 63 Chagas disease outpatients who underwent chest X-ray and echocardiography. Cardiomegaly on chest X-ray was defined as a CTR&gt;0.5. LVEDD was analyzed as a continuous variable. ROC curve was used to evaluate the ability of LVEDD in detecting cardiomegaly by chest X-ray, with a cut-off point defined by the highest sum of sensitivity and specificity.</p>
        </sec>
        <sec>
          <title>Results</title>
          <p> Median age 61 years [interquartile range 48-68], 56% were women. CCC was detected in 58 patients, five patients had the indeterminate form of Chagas disease. Cardiomegaly was detected in 28 patients. The area under the ROC curve for LVEDD was 0.806 (95%CI: 0.692-0.919). The optimal cut-off for LVEDD was 60 mm (sensitivity = 64%, specificity = 89%). The use of LVEDD on echocardiography as a surrogate for CTR on chest X-ray changed the Rassi score values of 14 patients, with a reduction in the presumed risk in 10 of them.</p>
        </sec>
        <sec>
          <title>Conclusion</title>
          <p> LVEDD on echocardiography is an appropriate, highly specific parameter to distinguish between the presence and absence of cardiomegaly on chest X-ray in Chagas disease. (Arq Bras Cardiol. 2021; 116(1):68-74)</p>
        </sec>
      </abstract>
      <kwd-group xml:lang="en">
        <kwd>Chagas Disease/physiopathology</kwd>
        <kwd>Cardiomegaly</kwd>
        <kwd>X-Rays</kwd>
        <kwd>Chagasic, Cardiomyopathy</kwd>
        <kwd>Heart Block</kwd>
      </kwd-group>
    </front-stub>
    <body>
      <sec sec-type="intro">
        <title>Introduction</title>
        <p>Chagas disease (CD) is caused by infection with the protozoan parasite <italic>Trypanosoma cruzi</italic> (<italic>T.cruzi</italic>), which is mainly transmitted to humans by insects in the subfamily Triatominae. Other modes of transmission include blood transfusion, bone marrow or solid organ transplantation from infected donors, vertical transmission from mother to fetus and oral ingestion of contaminated food.<sup><xref ref-type="bibr" rid="B1">1</xref></sup> The World Health Organization estimates that CD affects approximately 7 million individuals in the world, causing high morbidity and mortality, and significant social impact.<sup><xref ref-type="bibr" rid="B2">2</xref></sup></p>
        <p>Chagas cardiomyopathy is the most common and serious clinical form of CD, affecting 20-30% of chronically infected individuals.<sup><xref ref-type="bibr" rid="B3">3</xref>,<xref ref-type="bibr" rid="B4">4</xref></sup> The Rassi score is a validated score for mortality risk stratification of patients with chronic Chagas cardiomyopathy (CCC). Among the risk factors assessed by the score, cardiomegaly on chest X-ray stands out for its strong association with overall and cardiovascular mortality risk in patients with CCC.<sup><xref ref-type="bibr" rid="B5">5</xref></sup></p>
        <p>In the study by Rassi Jr. et al.,<sup><xref ref-type="bibr" rid="B5">5</xref></sup> although echocardiography was used to assess left ventricular end-diastolic diameter (LVEDD), this parameter was not shown to be an independent marker of mortality in CCC. However, in their study, LVEDD was analyzed in a categorical manner, using conventional cut-off points, which may not be the most appropriate for CCC patients, due to the segmental myocardial dysfunction, characteristic of this condition. Besides, calculation of the cardiothoracic ratio (CTR) by chest X-ray, in many cases, may encompass both atrial and ventricular dilatation, that are expressed linearly in this method. Despite widely available, the radiological study of the heart involves radiation, and echocardiography has become the most used method for cardiovascular evaluation. Therefore, there is a genuine interest in assessing left ventricular size and systolic function to estimate the risk of death using a single imaging test and the variables used in the original Rassi score.</p>
        <p>The present study aimed to evaluate the relationship between cardiomegaly defined by the CTR on chest X-ray and the LVEDD determined by echocardiography in patients with CD.</p>
      </sec>
      <sec sec-type="methods">
        <title>Methods</title>
        <p>In this retrospective cross-sectional study, we studied patients of both sexes, adults (&gt;18 years old), with diagnosis of CD, attending the outpatient clinic of the General Hospital of the University of Sao Paulo Medical School in Ribeirao Preto (HCRP-FMRP-USO), a tertiary referral hospital for CD. The diagnosis of CD was confirmed by two positive serological tests for detection of antibodies against <italic>T. cruzi</italic>, using different techniques.</p>
        <p>Data were obtained by a systematic review of medical records of 158 patients who had participated in a previous clinical study,<sup><xref ref-type="bibr" rid="B6">6</xref></sup> which describes in detail the inclusion and exclusion criteria applied. Patients with CTR and complete evaluation of the independent predictors of the Rassi score by resting 12-lead electrocardiogram, echocardiography, CTR and 24-hour heart rhythm monitoring, and of the degree of dyspnea according to the New York Heart Association (NYHA) criteria were included. The maximum interval between the CTR (considered the reference method for comparison) and the echocardiography was of one year, and patients were clinically stable in this period. Patients who had changes in the clinical status in this period between the two tests were excluded from the study.</p>
        <sec>
          <title>Chest x-ray</title>
          <p>Cardiomegaly on chest X-ray was always evaluated in an anteroposterior view and defined as a CTR &gt; 0.5. Eventual enlargement of the right ventricle was also evaluated by comparison with profile teleradiography, when this technique was available.</p>
        </sec>
        <sec>
          <title>Echocardiography</title>
          <p>Data of resting transthoracic echocardiography (the last before the chest X-ray) were used for analysis, considering the maximum interval of one year between the tests. The LVEDD was measured by the two-dimensional test, following recent echocardiography guidelines.<sup><xref ref-type="bibr" rid="B7">7</xref></sup> Other echocardiographic parameters related to left ventricular remodeling were assessed, including the left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF), and the left atrial volume index (LAVI).</p>
        </sec>
      </sec>
      <sec>
        <title>Statistical Analysis</title>
        <p>Continuous variables with normal distribution were expressed as mean and standard deviation, and those without normal distribution were expressed as median and interquartile range (IQR). Analysis of the ROC (Receiver Operating Characteristic) was conducted to verify the ability of LVEDD, determined by echocardiography, to differ between presence and absence of cardiomegaly by the CTR. Finally, the impact of using cardiomegaly assessed by echocardiography, rather than the traditional CTR, on reclassification of patients with the cardiac form of CD by the Rassi score was evaluated. Individuals with the indeterminate form of CD were not classified by the Rassi score in the study, since patients with this form of the disease were not included in the original investigation of this instrument.</p>
        <sec>
          <title>Ethics</title>
          <p>The present study was approved by the research ethics committee (CAAE number 06415319.2.0000.5440; approval number 3.130.390) and conducted according to the Helsinki declaration and the Brazilian National Health Council resolution number 466/2012.</p>
        </sec>
      </sec>
      <sec sec-type="results">
        <title>Results</title>
        <sec>
          <title>Description of the Study Population Sample</title>
          <p>Of the 158 patients with CD evaluated, 63 (40%) patients met the inclusion criteria and were included in this retrospective cross-sectional study. Demographic and clinical characteristics of participants are described in <xref ref-type="table" rid="t1001">Table 1</xref>. Median age of participants was 61 (IQR 48-68) years, and many were women (56%). Only five (8%) patients had the indeterminate form of CD. Most patients (68%) had NYHA functional class I, followed by NYHA class II (21%) and III (115). The Rassi score of the 58 patients with CCC was 9 &#177; 5 points.</p>
          <p>
            <table-wrap id="t1001">
              <label>Table 1</label>
              <caption>
                <title>&#8211; Characteristics of patients included in the study (n=63)</title>
              </caption>
              <table frame="hsides" rules="groups">
                <colgroup>
                  <col/>
                  <col/>
                </colgroup>
                <thead>
                  <tr>
                    <th align="left" colspan="2">Demographic and anthropometric data</th>
                  </tr>
                  <tr>
                    <th align="left" style="font-weight:normal">Age (years)</th>
                    <th style="font-weight:normal">61 [48-68]</th>
                  </tr>
                </thead>
                <tbody>
                  <tr>
                    <td>Female sex</td>
                    <td align="center">35 (56%)</td>
                  </tr>
                  <tr>
                    <td>Body mass index (Kg/m<sup>2</sup>)</td>
                    <td align="center">26.6 &#177; 4.7</td>
                  </tr>
                  <tr>
                    <td colspan="2">
                      <bold>Clinical data</bold>
                    </td>
                  </tr>
                  <tr>
                    <td>
                      <bold>Functional class</bold>
                    </td>
                    <td>
										</td>
                  </tr>
                  <tr>
                    <td>NYHA I</td>
                    <td align="center">37 (59%)</td>
                  </tr>
                  <tr>
                    <td>NYHA II</td>
                    <td align="center">17 (27%)</td>
                  </tr>
                  <tr>
                    <td>NYHA III</td>
                    <td align="center">9 (14%)</td>
                  </tr>
                  <tr>
                    <td>Edema of lower limbs</td>
                    <td align="center">12 (19%)</td>
                  </tr>
                  <tr>
                    <td>Swollen jugular vein</td>
                    <td align="center">3 (5%)</td>
                  </tr>
                  <tr>
                    <td>ACEI or ARB</td>
                    <td align="center">48 (76%)</td>
                  </tr>
                  <tr>
                    <td>Betablocker</td>
                    <td align="center">34 (54%)</td>
                  </tr>
                  <tr>
                    <td>Spironolactone</td>
                    <td align="center">16 (25%)</td>
                  </tr>
                  <tr>
                    <td>Diuretics</td>
                    <td align="center">29 (46%)</td>
                  </tr>
                  <tr>
                    <td>Amiodarone</td>
                    <td align="center">14 (22%)</td>
                  </tr>
                  <tr>
                    <td colspan="2">
                      <bold>Echocardiographic data</bold>
                    </td>
                  </tr>
                  <tr>
                    <td>Left ventricular end-diastolic diameter (mm)</td>
                    <td align="center">54 [47-61]</td>
                  </tr>
                  <tr>
                    <td>Left atrial volume index (mL/m<sup>2</sup>)</td>
                    <td align="center">42 [26-59]</td>
                  </tr>
                  <tr>
                    <td>Left ventricular mass index (g/m<sup>2</sup>)</td>
                    <td align="center">123 [92-156]</td>
                  </tr>
                  <tr>
                    <td>Left ventricular ejection fraction (%)</td>
                    <td align="center">51 [34-63]</td>
                  </tr>
                </tbody>
              </table>
              <table-wrap-foot>
                <fn id="TFN1001">
                  <p>
                    <italic>Parametric and non-parametric continuous variables described as mean &#177; standard deviation and median [interquartile range], respectively. Categorical variables presented as absolute numbers and percentages NYHA: New York Heart Association; ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blocker</italic>
                  </p>
                </fn>
              </table-wrap-foot>
            </table-wrap>
          </p>
        </sec>
        <sec>
          <title>Comparison between Chest Radiography and Echocardiogram</title>
          <p>Cardiomegaly, assessed using the CTR, was detected in 28 (44%) patient. The mean interval between chest X-ray and echocardiography was 5 &#177; 174 days. LVEDD on chest X-ray was larger in the group of patients with cardiomegaly (61 IQR [53-70]) than in patients without cardiomegaly (49 IQR [46-55]), p &lt; 0.001. The area under the ROC curve for LVEDD for detection of cardiomegaly on chest X-ray was 0.806 (95% confidence interval 0.692 &#8211; 0.919) (<xref ref-type="fig" rid="f01001">Figure 1</xref>). A LVEDD of 60 mm was defined as the cut-off with the highest accuracy, with sensitivity of 64% and specificity of 89%.</p>
          <p>
            <fig id="f01001">
              <label>Figure 1</label>
              <caption>
                <title>&#8211; Area under the ROC curve of the left ventricular end-diastolic diameter for detection of cardiomegaly on chest radiography.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-116-01-0068-90673-gf01-en.jpg"/></fig>
          </p>
          <p>Patients with discordant test results regarding the detection of cardiomegaly did not show statistically significant differences in age, sex, LVMI, and LAVI compared with those patients with concordant test results.</p>
        </sec>
        <sec>
          <title>Reclassification of the Rassi Score</title>
          <p>In our study, the proportion of individuals at low, moderate and high risk by the Rassi score, using the CTR for detection of cardiomegaly was 36% (n = 21), 33% (n = 19) and 31% (n = 18), respectively. These proportions were 40% (n = 23), 28% (n = 16) and 32% (n = 19), respectively when cardiomegaly was detected by echocardiography using the most accurate cut-off point (<xref ref-type="fig" rid="f02001">Figure 2</xref>). In 44 (76%) patients, the Rassi score with echocardiography was the same as that estimated by the CTR. Among the 14 patients who showed a numerical change in the Rassi score, eight showed a reduction in the score and six showed an increase. Considering the risk categories (low, moderate, high), there was a change in category in 11 patients (19%); six showed a reduction and five showed an increase in the score (<xref ref-type="fig" rid="f03001">Figure 3</xref>).</p>
          <p>
            <fig id="f02001">
              <label>Figure 2</label>
              <caption>
                <title>&#8211; Risk of death according to the Rassi score on chest X-ray and echocardiography for definition of cardiomegaly in individuals with the cardiac form of Chagas disease; LVEDD: left ventricular end-diastolic diameter; CTR: cardiothoracic ratio.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-116-01-0068-90673-gf02-en.jpg"/></fig>
          </p>
          <p>
            <fig id="f03001">
              <label>Figure 3</label>
              <caption>
                <title>&#8211; Individual risk of death according to the Rassi score on chest X-ray and echocardiography for definition of cardiomegaly in individuals with the cardiac form of Chagas disease; red dashed line and yellow dashed line correspond to a Rassi score of 12 (high risk) and 7 (moderate risk); LVEDD: left ventricular end-diastolic diameter; CTR: cardiothoracic ratio.</title>
              </caption>
              <graphic xlink:href="1678-4170-abc-116-01-0068-90673-gf03-en.jpg"/></fig>
          </p>
        </sec>
      </sec>
      <sec sec-type="discussion">
        <title>Discussion</title>
        <p>The present study demonstrated that there is a clear and significative relationship between detection of cardiomegaly by CTR and detection of left ventricular dilatation by echocardiography in a non-selected group of outpatients with diagnosis of CCC. These results open new perspectives to the use of LVEDD determined by resting transthoracic echocardiography in substitution for the estimation of CTR by chest X-ray, to determine the risk of death in patients with CCC using the Rassi score, whose results were eventually modified. This would prevent the use of radiological test, which requires radiation, despite low, and allow determining both left ventricular size and left ventricular systolic function by a single, non-invasive test that does not involve radiation. This perspective seems attractive, since the LVEDD determined by echocardiography was shown to be a highly specific parameter to distinguish between the presence and absence of cardiomegaly in patients with chronic CD.</p>
        <p>Our findings corroborate previous observations reported by Pereira-Barreto et al.<sup><xref ref-type="bibr" rid="B8">8</xref></sup> in 1983, of chest X-ray and echocardiographic results of a smaller sample (n=22), showing a good correlation between CTR values and left ventricular function.<sup><xref ref-type="bibr" rid="B8">8</xref></sup> On the other hand, in a study published in 2003, Perez et al.,<sup><xref ref-type="bibr" rid="B9">9</xref></sup> conducted a comparative analysis between posteroanterior chest X-ray and resting echocardiographic results, and showed a poor correlation between the tests for LVEDD and LVEF results. Also, in this study,<sup><xref ref-type="bibr" rid="B9">9</xref></sup> CTR did not show high sensitivity or positive predictive value in detecting left ventricular dysfunction. Therefore, despite its high specificity in detecting left ventricular systolic dysfunction, a CTR &gt; 0.5 would not be useful in assessing this condition in CD, due to its low sensitivity in detecting, on resting transthoracic echocardiography, left ventricular dilatation or left ventricular systolic dysfunction by altered LVEF.</p>
        <p>The reasons of the discrepancies between these studies are not clear. In the study by Perez et al.<sup><xref ref-type="bibr" rid="B9">9</xref></sup> and in our study, although the population sample consisted of outpatients with CCC attending university hospital, there were differences between them. In our study, there were almost no exclusion criteria, except for those related to the availability of CTR and echocardiographic results within a one-year period. In contrast, the broad exclusion criteria used in consecutive patients in the study by Perez et al.<sup><xref ref-type="bibr" rid="B9">9</xref></sup> may have resulted in a highly selected sample that may not be representative of CD patients. Thus, in their study,<sup><xref ref-type="bibr" rid="B9">9</xref></sup> only 28% and 29% of patients had increased CTR and left ventricular dysfunction, respectively, and the mean LVEF was 61% (vs. 51% in our study). These aspects indicate that our population with CCC were more severely ill, especially considering that only 8% of them had the indeterminate form of CD. In addition, it is plausible that differences in the chest X-ray results regarding CTR values between the two studies are more apparent than real. In fact, in the study by Perez et al.,<sup><xref ref-type="bibr" rid="B9">9</xref></sup> patients were divided into two groups by CTR values (normal vs. abnormal, p&lt;0.05), and results showed a significant association (p&lt;0.05) of LVEF reduction with increase in ventricular diastolic dimension and left ventricular segmental dysfunction, as evidenced by the left ventricular wall motion index.</p>
        <p>It is worth pointing out that the results of the present study indicate that the absence of cardiomegaly on chest X-ray does not discard cardiac involvement when patients are assessed by methods able to provide better anatomic and functional details, comparable with resting transthoracic echocardiography. Thus, despite specific, chest X-ray has low sensitivity in detecting cardiac involvement in CD patients, and its use as screening method or diagnostic criterion for the indeterminate form of CD may be questionable. In this context, although the indeterminate form of CD is still defined in current guidelines based on a normal CTR on chest X-ray,<sup><xref ref-type="bibr" rid="B3">3</xref>,<xref ref-type="bibr" rid="B10">10</xref>,<xref ref-type="bibr" rid="B11">11</xref></sup> substitution of this criterion with normal resting echocardiogram was already proposed in 2002.<sup><xref ref-type="bibr" rid="B12">12</xref></sup></p>
        <p>The Rassi score is universally regarded as the most valuable instrument for the establishment of the vital prognosis of patients with CCC. This is a robust score, developed by a multivariate analysis of many risk factors of death in CCC, externally validated in other independent cohorts. However, in the study by Perez et al.,<sup><xref ref-type="bibr" rid="B9">9</xref></sup> variables were analyzed in a dichotomous rather than continuous manner, which gives room for complementation. Among the variables analyzed in a non-continuous manner, there was the LVEDD, conventionally measured by echocardiography. However, when LVEDD was assessed in dichotomized categories, <italic>i.e</italic>., presence or absence of increase, may be not appropriate for the evaluation of patients with CCC due to the typical segmental myocardial abnormality of the disease.<sup><xref ref-type="bibr" rid="B1">1</xref></sup></p>
        <p>Results of the present study are in line with the importance of echocardiography as an essential instrument for the follow-up of patients with chronic CD, especially of those with early myocardial deficits of CCC.<sup><xref ref-type="bibr" rid="B10">10</xref></sup> Echocardiography allows not only confirmation (or not) of cardiomegaly in case of questionable findings on chest X-ray, but also analysis of cardiomyopathy marked by regional changes of ventricular contractility that result from early and prominent disturbances in the natural course of the underlying disease.<sup><xref ref-type="bibr" rid="B13">13</xref></sup> Also, detection of these regional abnormalities at early stages of CCC has prognostic and therapeutic implications, in light of recent reports showing that even minimal changes in the left ventricular segmental wall motion index when left ventricular systolic function is preserved are determinant of severe outcomes including mortality.<sup><xref ref-type="bibr" rid="B13">13</xref></sup></p>
        <p>In the seminal study by Rassi Jr. et al.,<sup><xref ref-type="bibr" rid="B5">5</xref></sup> the cohort included in the multivariate analysis and development of the score consisted of 424 patients, most of them at low risk (61%), while 19% and 20% of the patients were at moderate and high risk, respectively. In the present study, we found a more balanced distribution of patients into the risk groups &#8211; 36%, 33% and 31% at low, intermediate, and high risk, respectively. Similarly, when LVEDD is substituted for CTR in the score, there was a small increase in the proportion of patients at low risk (40%) at the expense of a slight reduction in the percentage of patients at intermediate risk (28%). Therefore, further studies with clinical follow-up are warranted for validation of the Rassi score modified by substitution of the CTR as the radiological parameter of cardiac dilatation with the more specific echocardiographic parameter of left ventricular dilatation, and determination of the prognosis impact of such modification.</p>
        <sec>
          <title>Limitations</title>
          <p>The present study has some limitations. The tests compared (chest X-ray and echocardiography) were not conducted on the same day, similar to the other tests included in the Rassi score, which were performed on different days. In any case, efforts were made to minimize confounding factors and factors associated with clinical changes, to assure that no change in clinical status or in drug therapy of patients occurred in the interval between the tests. Right atrial dimensions were not measured, thereby limiting the assessment of dilation of this chamber as a discordant factor between echocardiography and chest X-ray. Finally, although patients were not followed longitudinally for the prognostic assessment of LEVDD by echocardiography, they have been followed-up at an outpatient clinic and will be reassessed for this parameter in the future.</p>
        </sec>
      </sec>
      <sec sec-type="conclusions">
        <title>Conclusions</title>
        <p>LVEDD measured by echocardiography is an appropriate parameter to distinguish between the presence and absence of cardiomegaly on chest X-ray, with high specificity in patients with chronic CD. Substitution of echocardiographic LVEDD for the radiological CTR in the Rassi score was shown to be feasible and did not cause substantial change in the scores obtained. These results open new perspectives to avoid the use of a test that involves radiation and, rather, use a single test (echocardiography) to measure two components of the Rassi score &#8211; cardiac dimension and ventricular systolic function. The potential prognostic role of this modified Rassi score is a worthy subject for future studies.</p>
      </sec>
    </body>
    <back>
      <ack>
        <title>Acknowledgments</title>
        <p>Study partially subsidized by FAPESP and carried out during scientific initiation by the Academic Matheus Rassi Fernandes Ramos, in 2018-2019.</p>
      </ack>
      <fn-group>
        <fn fn-type="other">
          <p>Study Association</p>
          <p>This article is part of the scientific research submitted by Matheus Rassi Fernandes Ramos, from Universidade de S&#227;o Paulo Faculdade de Medicina de Ribeir&#227;o Preto.</p>
        </fn>
      </fn-group>
      <fn-group>
        <fn fn-type="financial-disclosure">
          <p>Sources of Funding.This study was funded by FAPESP - Project 2018/25403-9.</p>
        </fn>
      </fn-group>
    </back>
  </sub-article>
</article>
