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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">F6788jcs6yRWnmMRTdjGwRq</article-id>
      <article-id specific-use="scielo-v2" pub-id-type="publisher-id">S0066-782X2024000100501</article-id>
      <article-id pub-id-type="other">00501</article-id>
      <article-id pub-id-type="doi">10.36660/abc.20230228</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Carta Cient&#237;fica</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Uma Apresenta&#231;&#227;o Invulgar de Cardite de Lyme e Bloqueio Atrioventricular Sens&#237;vel &#224; Adenosina</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-2465-2217</contrib-id>
          <name>
            <surname>Alexandre</surname>
            <given-names>Andr&#233;</given-names>
          </name>
          <role>Concep&#231;&#227;o e desenho da pesquisa</role>
          <role>Obten&#231;&#227;o de dados e Reda&#231;&#227;o do manuscrito</role>
          <role>An&#225;lise e interpreta&#231;&#227;o dos dados</role>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0009-0004-2422-0777</contrib-id>
          <name>
            <surname>Ribeiro</surname>
            <given-names>Diana</given-names>
          </name>
          <role>Obten&#231;&#227;o de dados e Reda&#231;&#227;o do manuscrito</role>
          <role>An&#225;lise e interpreta&#231;&#227;o dos dados</role>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Sousa</surname>
            <given-names>Maria Jo&#227;o</given-names>
          </name>
          <role>An&#225;lise e interpreta&#231;&#227;o dos dados</role>
          <role>Revis&#227;o cr&#237;tica do manuscrito quanto ao conte&#250;do intelectual importante</role>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Reis</surname>
            <given-names>Hip&#243;lito</given-names>
          </name>
          <role>Concep&#231;&#227;o e desenho da pesquisa</role>
          <role>An&#225;lise e interpreta&#231;&#227;o dos dados</role>
          <role>Revis&#227;o cr&#237;tica do manuscrito quanto ao conte&#250;do intelectual importante</role>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
          <xref ref-type="aff" rid="aff2">
            <sup>2</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Silveira</surname>
            <given-names>Jo&#227;o</given-names>
          </name>
          <role>Revis&#227;o cr&#237;tica do manuscrito quanto ao conte&#250;do intelectual importante</role>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
          <xref ref-type="aff" rid="aff2">
            <sup>2</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Torres</surname>
            <given-names>Severo</given-names>
          </name>
          <role>Revis&#227;o cr&#237;tica do manuscrito quanto ao conte&#250;do intelectual importante</role>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
          <xref ref-type="aff" rid="aff2">
            <sup>2</sup>
          </xref>
        </contrib>
      </contrib-group>
      <aff id="aff1">
        <label> 1 </label>
        <institution content-type="orgname">Centro Hospitalar Universit&#225;rio de Santo Ant&#243;nio</institution>
        <addr-line>
          <named-content content-type="city">Porto</named-content>
        </addr-line>
        <country country="PT">Portugal</country>
        <institution content-type="original"> Departamento de Cardiologia, Centro Hospitalar Universit&#225;rio de Santo Ant&#243;nio (CHUDSA), Porto &#8211; Portugal </institution>
      </aff>
      <aff id="aff2">
        <label> 2 </label>
        <institution content-type="orgdiv1">Faculdade de Medicina e Ci&#234;ncias Biom&#233;dicas</institution>
        <institution content-type="orgname">Universidade do Porto</institution>
        <addr-line>
          <named-content content-type="city">Porto</named-content>
        </addr-line>
        <country country="PT">Portugal</country>
        <institution content-type="original"> ICBAS &#8211; Faculdade de Medicina e Ci&#234;ncias Biom&#233;dicas , Universidade do Porto , Porto &#8211; Portugal </institution>
      </aff>
      <author-notes>
        <corresp id="c01">Correspond&#234;ncia: Andr&#233; Alexandre &#8226; Largo do Prof. Abel Salazar, 4099-001, Porto- Portugal E-mail: <email>andrealexandre_1@msn.com</email> </corresp>
        <fn fn-type="conflict">
          <p>Potencial conflito de interesse</p>
          <p>N&#227;o h&#225; conflito com o presente artigo</p>
        </fn>
        <fn fn-type="edited-by">
          <p>Editor respons&#225;vel pela revis&#227;o: Mauricio Scanavacca</p>
        </fn>
      </author-notes>
      <pub-date date-type="pub" publication-format="electronic">
        <day>05</day>
        <month>02</month>
        <year>2024</year>
      </pub-date>
      <pub-date date-type="collection" publication-format="electronic">
        <month>01</month>
        <year>2024</year>
      </pub-date>
      <volume>121</volume>
      <issue>1</issue>
      <elocation-id>e20230228</elocation-id>
      <history>
        <date date-type="received">
          <day>07</day>
          <month>04</month>
          <year>2023</year>
        </date>
        <date date-type="rev-recd">
          <day>23</day>
          <month>08</month>
          <year>2023</year>
        </date>
        <date date-type="accepted">
          <day>25</day>
          <month>10</month>
          <year>2023</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>
      <kwd-group xml:lang="pt">
        <kwd>Doen&#231;a de Lyme</kwd>
        <kwd>Bloqueio Atrioventricular</kwd>
        <kwd>Cardiomiopatia</kwd>
        <kwd>Adenosina</kwd>
        <kwd>Teofilina</kwd>
      </kwd-group>
      <counts>
        <fig-count count="2"/>
        <table-count count="0"/>
        <equation-count count="0"/>
        <ref-count count="11"/>
      </counts>
    </article-meta>
  </front>
  <body>
    <sec sec-type="intro">
      <title>Introdu&#231;&#227;o</title>
      <p>A cardite de Lyme (CL) &#233; uma manifesta&#231;&#227;o relativamente rara do est&#225;gio inicial disseminado da doen&#231;a de Lyme. <sup><xref rid="B1" ref-type="bibr">1</xref> , <xref rid="B2" ref-type="bibr">2</xref> </sup> A apresenta&#231;&#227;o mais frequente da CL &#233; o bloqueio atrioventricular (AV), caracterizado por r&#225;pidas flutua&#231;&#245;es no grau e que ocorre em aproximadamente 80-90% dos pacientes. <sup><xref rid="B1" ref-type="bibr">1</xref> , <xref rid="B3" ref-type="bibr">3</xref> </sup> Outras poss&#237;veis manifesta&#231;&#245;es cl&#237;nicas da CL s&#227;o miocardite, pericardite, cardiomiopatia dilatada e insufici&#234;ncia card&#237;aca. <sup><xref rid="B1" ref-type="bibr">1</xref> , <xref rid="B4" ref-type="bibr">4</xref> </sup> O curso cl&#237;nico &#233; geralmente leve, de curta dura&#231;&#227;o e, na maioria dos casos, completamente revers&#237;vel ap&#243;s tratamento antibi&#243;tico adequado. <sup><xref rid="B1" ref-type="bibr">1</xref></sup> Na verdade, o bloqueio AV de alto grau associado &#224; doen&#231;a de Lyme normalmente remite nos primeiros dez dias de terapia antibi&#243;tica. <sup><xref rid="B3" ref-type="bibr">3</xref></sup> Os autores apresentam o caso de uma jovem com diagn&#243;stico de doen&#231;a de Lyme precocemente disseminada e manifesta&#231;&#245;es card&#237;acas, na qual os dist&#250;rbios de condu&#231;&#227;o AV persistiram ap&#243;s quatro semanas de tratamento antibi&#243;tico adequado e levaram a um diagn&#243;stico alternativo.</p>
    </sec>
    <sec sec-type="cases">
      <title>Apresenta&#231;&#227;o do caso</title>
      <p>Paciente do sexo feminino, 20 anos, praticante de gin&#225;stica acrob&#225;tica de 12 a 18 anos, apresentou quadro de dor tor&#225;cica pleur&#237;tica aguda e dispneia. &#192; admiss&#227;o apresentava-se hemodinamicamente est&#225;vel, levemente taquic&#225;rdica (100/min), apir&#233;tica, com ausculta pulmonar e card&#237;aca normais e sem sinais congestivos.</p>
      <p>O paciente apresentou eletrocardiograma mostrando taquicardia sinusal (102/min) e invers&#227;o da onda T nas deriva&#231;&#245;es inferior e V3-V6 ( <xref rid="f01" ref-type="fig">Figura 1</xref> suplementar). A radiografia de t&#243;rax estava normal. A an&#225;lise sangu&#237;nea revelou eleva&#231;&#227;o dos biomarcadores card&#237;acos (troponina T de alta sensibilidade 0,085 ng/mL [valores de refer&#234;ncia 0,000&#8211;0,014]) e eleva&#231;&#227;o dos par&#226;metros inflamat&#243;rios (prote&#237;na C reativa 135 mg/L [0-5] e velocidade de hemossedimenta&#231;&#227;o 104 mm [0-19]). A ecocardiografia transtor&#225;cica mostrou hipocinesia do segmento basal do septo interventricular anterior, fun&#231;&#227;o sist&#243;lica biventricular preservada, sem disfun&#231;&#227;o valvar, nem derrame peric&#225;rdico. Considerando a suspeita de miocardite aguda, a paciente foi internada em unidade de terapia intensiva card&#237;aca. Durante a interna&#231;&#227;o, o monitoramento card&#237;aco cont&#237;nuo revelou v&#225;rios epis&#243;dios assintom&#225;ticos de bloqueio AV parox&#237;stico (Figura 2 suplementar), incluindo bloqueio AV Mobitz I de segundo grau, bloqueio AV 2:1 de segundo grau e bloqueio AV de alto grau (3:1 e 4). :1).</p>
      <p>
        <fig id="f01">
          <label>Figura 1</label>
          <caption>
            <title>&#8211; Monitoramento Holter demonstrando dois epis&#243;dios de bloqueio atrioventricular (AV) parox&#237;stico ap&#243;s o t&#233;rmino do tratamento com antibi&#243;ticos. O monitoramento cont&#237;nuo do Holter revelou que os dist&#250;rbios da condu&#231;&#227;o AV (incluindo bloqueio AV parox&#237;stico de alto grau) persistiram ap&#243;s quatro semanas de tratamento antibi&#243;tico apropriado. O painel A mostra um bloqueio AV 2:1 de segundo grau. O painel B mostra um bloqueio AV de alto grau com assistolia ventricular de 2,96 segundos.</title>
          </caption>
          <graphic xlink:href="1678-4170-abc-121-01-e20230228-30228-gf01.tif"/></fig>
      </p>
      <p>Apesar da aus&#234;ncia de um contexto de risco epidemiol&#243;gico espec&#237;fico para <italic>Borrelia spp</italic> . (como evid&#234;ncias de exposi&#231;&#227;o a carrapatos, les&#245;es articulares, diarreia ou les&#245;es cut&#226;neas), a paciente foi procurada para realiza&#231;&#227;o de testes sorol&#243;gicos para doen&#231;a de Lyme. As recomenda&#231;&#245;es atuais incluem o uso de um ensaio imunoenzim&#225;tico sens&#237;vel (ELISA), seguido por um ensaio de imunotransfer&#234;ncia Western para amostras que produzam resultados positivos ou equ&#237;vocos. <sup><xref rid="B5" ref-type="bibr">5</xref> , <xref rid="B6" ref-type="bibr">6</xref> </sup> No nosso caso, o exame sorol&#243;gico inicial com teste ELISA mostrou IgM lim&#237;trofe positivo (0,30 RU/mL [&lt;0,20]) com teste IgG ELISA negativo. Assim, foi realizado teste Western-Blot IgM, confirmando positividade e recente infec&#231;&#227;o por <italic>Borrelia spp</italic> .. Al&#233;m disso, testes ELISA IgM e IgG subsequentes foram realizados dois meses depois, o primeiro permanecendo claramente positivo (0,38 RU/mL [&lt; 0,20]) e o &#250;ltimo ainda negativo. Os resultados dos testes da doen&#231;a de Lyme de primeiro e segundo n&#237;veis relatados aqui apoiam a l&#243;gica combinada de sensibilidade e especificidade do algoritmo de dois n&#237;veis, em oposi&#231;&#227;o ao uso de apenas um teste. <sup><xref rid="B6" ref-type="bibr">6</xref></sup> Al&#233;m disso, os testes trepon&#234;micos e n&#227;o trepon&#234;micos (VDRL; FTA-ABS) foram negativos, excluindo s&#237;filis. Os testes de biologia molecular para um extenso painel de v&#237;rus respirat&#243;rios produziram resultados negativos (RSV, INF-A, INF-B, Parainfluenza 1, 2, 3, 4, Adenov&#237;rus, Metapneumov&#237;rus, Bocav&#237;rus, Rinov&#237;rus, Enterov&#237;rus, Coronav&#237;rus), assim como a sorologia testes para HIV, HBV e HCV. A paciente era imune a EBV, CMV, Parvov&#237;rus, Coxsackievirus e Enterov&#237;rus (IgM negativo; IgG positivo). Os testes de cultura para <italic>S. pyogenes</italic> e o t&#237;tulo de antiestreptolisina O foram negativos. Os testes imunol&#243;gicos foram normais. Portanto, &#233; improv&#225;vel que tenha ocorrido reatividade cruzada no nosso caso, o que permitiu a confirma&#231;&#227;o do diagn&#243;stico de doen&#231;a de Lyme. A resson&#226;ncia magn&#233;tica cardiovascular foi realizada uma semana ap&#243;s a admiss&#227;o e n&#227;o apresentou altera&#231;&#245;es dignas de nota. A tomografia por emiss&#227;o de p&#243;sitrons excluiu sarcoidose card&#237;aca.</p>
      <p>Considerando o diagn&#243;stico de doen&#231;a de Lyme disseminada precocemente com manifesta&#231;&#245;es card&#237;acas de bloqueio AV de alto grau, a paciente foi tratada com ceftriaxona intravenosa durante quatro semanas. A resolu&#231;&#227;o completa das queixas de dor tor&#225;cica e dispneia foi documentada. No entanto, na nossa paciente, o dist&#250;rbio de condu&#231;&#227;o AV (incluindo bloqueio AV de alto grau) persistiu ap&#243;s quatro semanas de tratamento antibi&#243;tico adequado, conforme demonstrado pela monitoriza&#231;&#227;o Holter ( <xref rid="f01" ref-type="fig">Figura 1</xref> ). Portanto, este caso pode ser um curso extremamente raro de CL ou pode ser um dist&#250;rbio de condu&#231;&#227;o AV assintom&#225;tico anterior que se revelou juntamente com a doen&#231;a de Lyme.</p>
      <p>O bloqueio AV parox&#237;stico pode ser categorizado em tr&#234;s tipos diferentes: intr&#237;nseco, vagal extr&#237;nseco e idiop&#225;tico extr&#237;nseco (&#8220;bloqueio AV sens&#237;vel &#224; adenosina&#8221;). Portanto, esta paciente realizou uma investiga&#231;&#227;o diagn&#243;stica para posterior caracteriza&#231;&#227;o. O teste ergom&#233;trico mostrou condu&#231;&#227;o AV normal 1:1 em frequ&#234;ncias card&#237;acas elevadas, sem dist&#250;rbios de condu&#231;&#227;o nem disritmias e toler&#226;ncia normal ao exerc&#237;cio (11,1 METs). O estudo eletrofisiol&#243;gico (EPS) n&#227;o apresentou altera&#231;&#245;es dignas de nota, descartando bloqueio AV parox&#237;stico intr&#237;nseco (bem como quaisquer sequelas cr&#244;nicas de CL). Quanto &#224; possibilidade de bloqueio AV parox&#237;stico vagal extr&#237;nseco, como esses epis&#243;dios ocorreram dois anos ap&#243;s o descondicionamento da gin&#225;stica acrob&#225;tica, era menos prov&#225;vel que o bloqueio AV extr&#237;nseco vagal contribu&#237;sse para o bloqueio AV parox&#237;stico. Por outro lado, considerando que o bloqueio AV parox&#237;stico de alto grau ocorreu sem prolongamento do ciclo PP ou prolongamento do intervalo PR e sem desencadeamento por batimentos prematuros nem por varia&#231;&#245;es de frequ&#234;ncia, essas caracter&#237;sticas favoreceram o diagn&#243;stico de bloqueio AV parox&#237;stico idiop&#225;tico extr&#237;nseco (tamb&#233;m conhecido como &#8220; bloqueio AV sens&#237;vel &#224; adenosina&#8221;).</p>
      <p>A paciente iniciou teofilina 400 mg duas vezes ao dia e, ap&#243;s uma semana de tratamento, o monitoramento Holter demonstrou redu&#231;&#227;o significativa dos dist&#250;rbios de condu&#231;&#227;o AV. O monitoramento Holter antes da teofilina mostrou cerca de 78 ondas P bloqueadas, incluindo bloqueio AV Mobitz I de segundo grau, bloqueio AV 2:1 de segundo grau e bloqueio AV de alto grau (3:1 e 4:1), com duas assistolias ventriculares significativas, a maior das quais foi de 2.960 milissegundos devido ao bloqueio AV de alto grau (4:1) [ <xref rid="f01" ref-type="fig">Figura 1</xref> ]. A monitoriza&#231;&#227;o Holter ap&#243;s a administra&#231;&#227;o de teofilina revelou uma redu&#231;&#227;o not&#225;vel de aproximadamente 38% das ondas P bloqueadas (de 78 para 48), principalmente devido ao bloqueio AV Mobitz I de segundo grau, com apenas dois epis&#243;dios de bloqueio AV 3:1 e sem mais assistolia ventricular mais de 2.000 milissegundos. Considerando que a paciente era assintom&#225;tica e como o &#8220;bloqueio AV sens&#237;vel &#224; adenosina&#8221; n&#227;o evolui para formas persistentes de bloqueio AV, ela recebeu alta sem necessidade de marca-passo permanente.</p>
      <p>Aos 18 meses de acompanhamento, o paciente permanece em terapia com teofilina, com redu&#231;&#227;o dos dist&#250;rbios de condu&#231;&#227;o AV, sem queixas card&#237;acas e sem necessidade de marcapasso permanente.</p>
    </sec>
    <sec sec-type="discussion">
      <title>Discuss&#227;o</title>
      <p>Este &#233; um caso de uma jovem com diagn&#243;stico de doen&#231;a de Lyme disseminada precocemente e manifesta&#231;&#245;es card&#237;acas, na qual os dist&#250;rbios de condu&#231;&#227;o AV persistiram ap&#243;s quatro semanas de tratamento antibi&#243;tico adequado, levando a um diagn&#243;stico alternativo de bloqueio AV parox&#237;stico idiop&#225;tico extr&#237;nseco (&#8220;bloqueio AV sens&#237;vel &#224; adenosina&#8221;).</p>
      <p>A CL &#233; uma manifesta&#231;&#227;o relativamente rara de um est&#225;gio inicial disseminado da doen&#231;a de Lyme. <sup><xref rid="B1" ref-type="bibr">1</xref> , <xref rid="B2" ref-type="bibr">2</xref> </sup> O teste sorol&#243;gico &#233; o principal meio de diagn&#243;stico laboratorial da doen&#231;a de Lyme. <sup><xref rid="B5" ref-type="bibr">5</xref></sup> Sabe-se que a sensibilidade dos testes de dois n&#237;veis utilizando ensaios sorol&#243;gicos dispon&#237;veis comercialmente depende do est&#225;gio da infec&#231;&#227;o. <sup><xref rid="B6" ref-type="bibr">6</xref></sup> Foram observadas faixas de sensibilidade de 40 a 87% em pacientes com doen&#231;a disseminada precocemente (CL), e diferen&#231;as na dura&#231;&#227;o e dissemina&#231;&#227;o da doen&#231;a nos pacientes testados podem explicar essa variabilidade. <sup><xref rid="B6" ref-type="bibr">6</xref></sup> Al&#233;m disso, algumas doen&#231;as semelhantes (como fibromialgia, mononucleose infecciosa, esclerose m&#250;ltipla, artrite reumatoide e s&#237;filis) s&#227;o documentadas como causadoras de reatividade cruzada em ensaios sorol&#243;gicos para a doen&#231;a de Lyme. <sup><xref rid="B6" ref-type="bibr">6</xref></sup> As recomenda&#231;&#245;es atuais incluem o uso de um imunoensaio enzim&#225;tico sens&#237;vel ou ensaio de imunofluoresc&#234;ncia, seguido por um ensaio de imunotransfer&#234;ncia Western para amostras que produzam resultados positivos ou equ&#237;vocos. <sup><xref rid="B5" ref-type="bibr">5</xref></sup> Ensaios sorol&#243;gicos que utilizam um segundo imunoensaio enzim&#225;tico no lugar do ensaio imunoblot ocidental s&#227;o alternativas aceit&#225;veis, embora n&#227;o sejam obrigat&#243;rios para estabelecer o diagn&#243;stico. <sup><xref rid="B5" ref-type="bibr">5</xref></sup> No nosso caso, o exame sorol&#243;gico inicial com teste ELISA mostrou IgM lim&#237;trofe positivo (0,30 RU/mL [&lt;0,20]) com teste IgG ELISA negativo. Assim, foi realizado teste Western-Blot IgM, confirmando positividade e recente Borrelia spp. infec&#231;&#227;o. Al&#233;m disso, testes ELISA IgM e IgG subsequentes foram realizados dois meses depois, o primeiro permanecendo claramente positivo (0,38 RU/mL [&lt; 0,20]) e o &#250;ltimo ainda negativo. Os resultados dos testes da doen&#231;a de Lyme de primeiro e segundo n&#237;veis relatados aqui apoiam a l&#243;gica combinada de sensibilidade e especificidade do algoritmo de dois n&#237;veis, em oposi&#231;&#227;o ao uso de apenas um teste. <sup><xref rid="B6" ref-type="bibr">6</xref></sup> Al&#233;m disso, os testes trepon&#234;micos e n&#227;o trepon&#234;micos foram negativos (excluindo s&#237;filis), assim como todos os demais testes sorol&#243;gicos e imunol&#243;gicos. Portanto, &#233; improv&#225;vel que tenha ocorrido reatividade cruzada no nosso caso, o que permitiu a confirma&#231;&#227;o do diagn&#243;stico de doen&#231;a de Lyme.</p>
      <p>A apresenta&#231;&#227;o mais frequente da CL &#233; o bloqueio AV, caracterizado por r&#225;pidas flutua&#231;&#245;es de grau. <sup><xref rid="B1" ref-type="bibr">1</xref> , <xref rid="B3" ref-type="bibr">3</xref> </sup> O curso cl&#237;nico &#233; geralmente leve, de curta dura&#231;&#227;o e, na maioria dos casos, completamente revers&#237;vel ap&#243;s tratamento antibi&#243;tico adequado. <sup><xref rid="B1" ref-type="bibr">1</xref></sup> Neste caso cl&#237;nico, o dist&#250;rbio de condu&#231;&#227;o AV persistiu ap&#243;s quatro semanas de tratamento antibi&#243;tico adequado. Portanto, levantou-se a hip&#243;tese de que poderia ser uma sequela cr&#244;nica da CL (sendo um curso extremamente raro da doen&#231;a de Lyme), ou que esse paciente poderia ter um dist&#250;rbio de condu&#231;&#227;o AV assintom&#225;tico pr&#233;vio que se revelou junto com a doen&#231;a de Lyme. A literatura atual exp&#245;e tr&#234;s tipos diferentes de bloqueio AV parox&#237;stico: intr&#237;nseco, vagal extr&#237;nseco e idiop&#225;tico extr&#237;nseco. <sup><xref rid="B7" ref-type="bibr">7</xref></sup> O bloqueio AV parox&#237;stico intr&#237;nseco &#233; devido a uma doen&#231;a intr&#237;nseca do sistema de condu&#231;&#227;o AV e progride para formas persistentes de bloqueio AV. <sup><xref rid="B7" ref-type="bibr">7</xref></sup> O bloqueio AV parox&#237;stico vagal extr&#237;nseco est&#225; ligado ao efeito do sistema nervoso parassimp&#225;tico na condu&#231;&#227;o card&#237;aca e est&#225; envolvido na &#8220;s&#237;ncope reflexa&#8221;. <sup><xref rid="B7" ref-type="bibr">7</xref></sup> O bloqueio AV parox&#237;stico idiop&#225;tico extr&#237;nseco est&#225; associado a baixos n&#237;veis de adenosina end&#243;gena e supostamente est&#225; envolvido na &#8220;s&#237;ncope sens&#237;vel &#224; adenosina&#8221;. Caracteriza-se por bloqueio AV parox&#237;stico completo sem prolongamento do ciclo PP ou prolongamento do intervalo PR, n&#227;o &#233; desencadeado por batimentos prematuros nem por varia&#231;&#245;es de frequ&#234;ncia e n&#227;o progride para formas persistentes de bloqueio AV. <sup><xref rid="B8" ref-type="bibr">8</xref></sup> A preval&#234;ncia deste tipo de bloqueio &#233; provavelmente subdiagnosticada devido ao fraco reconhecimento e &#224; sua imprevisibilidade. <sup><xref rid="B7" ref-type="bibr">7</xref></sup> De acordo com as Diretrizes ESC de 2021 sobre estimula&#231;&#227;o card&#237;aca e terapia de ressincroniza&#231;&#227;o card&#237;aca, o diagn&#243;stico de bloqueio AV por hipersensibilidade &#224; adenosina &#233; apoiado por um EPS normal, bem como pela aus&#234;ncia de in&#237;cio do bloqueio por batimentos atriais ou ventriculares prematuros, nem aumento da frequ&#234;ncia card&#237;aca (bloqueio AV taqui-dependente) ou diminui&#231;&#227;o da frequ&#234;ncia card&#237;aca (bloqueio AV bradi-dependente). <sup><xref rid="B8" ref-type="bibr">8</xref> , <xref rid="B9" ref-type="bibr">9</xref> </sup> Como os pacientes com baixos n&#237;veis plasm&#225;ticos de adenosina s&#227;o altamente suscet&#237;veis &#224; adenosina ex&#243;gena e end&#243;gena, o tratamento com teofilina tem sido investigado e parece ser eficaz, podendo ser considerado uma alternativa ao marca-passo permanente em pacientes com s&#237;ncope recorrente. <sup><xref rid="B7" ref-type="bibr">7</xref> , <xref rid="B10" ref-type="bibr">10</xref> , <xref rid="B11" ref-type="bibr">11</xref> </sup> </p>
      <p>Este caso ilustra um cen&#225;rio desafiador de CL com bloqueio AV de alto grau, que persistiu ap&#243;s tratamento antibi&#243;tico apropriado e apresentou caracter&#237;sticas importantes que apoiam o diagn&#243;stico de bloqueio AV parox&#237;stico idiop&#225;tico extr&#237;nseco (&#8220;bloqueio AV sens&#237;vel &#224; adenosina&#8221;). Assim, esta paciente iniciou teofilina, obtendo redu&#231;&#227;o significativa dos dist&#250;rbios de condu&#231;&#227;o AV e, posteriormente, sem necessidade de marca-passo permanente.</p>
    </sec>
    <sec sec-type="conclusions">
      <title>Conclus&#227;o</title>
      <p>&#8220;Bloqueio AV sens&#237;vel &#224; adenosina&#8221; &#233; um tipo de bloqueio AV parox&#237;stico que provavelmente &#233; subdiagnosticado devido &#224; sua imprevisibilidade e fraco reconhecimento. O tratamento com teofilina parece ser eficaz e pode ser considerado uma alternativa ao marca-passo permanente em pacientes de baixo risco.</p>
    </sec>
  </body>
  <back>
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    <fn-group>
      <fn fn-type="other">
        <p>Vincula&#231;&#227;o acad&#234;mica</p>
        <p>N&#227;o h&#225; vincula&#231;&#227;o deste estudo a programas de p&#243;s-gradua&#231;&#227;o.</p>
        <p>Aprova&#231;&#227;o &#233;tica e consentimento informado</p>
        <p>Este artigo n&#227;o cont&#233;m estudos com humanos ou animais realizados por nenhum dos autores.</p>
      </fn>
      <fn fn-type="supported-by">
        <p><bold>Fontes de financiamento:</bold> O presente estudo n&#227;o teve fontes de financiamento externas.</p>
      </fn>
      <app-group>
        <app id="app1">
          <p>*Material suplementar</p>
          <p>Para informa&#231;&#227;o adicional, por favor, <ext-link ext-link-type="uri" xlink:href="http://abccardiol.org/supplementary-material/2024/12101/2023-0228-supplementary.pdf">clique aqui</ext-link> .</p>
        </app>
      </app-group>
    </fn-group>
  </back>
  <sub-article article-type="translation" id="TRen" xml:lang="en">
    <front-stub>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Research Letter</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>An Unusual Presentation of Lyme Carditis and Adenosine-Sensitive Atrioventricular Block</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-2465-2217</contrib-id>
          <name>
            <surname>Alexandre</surname>
            <given-names>Andr&#233;</given-names>
          </name>
          <role>Conception and design of the research</role>
          <role>Acquisition of data and Writing of the manuscript</role>
          <role>Analysis and interpretation of the data</role>
          <xref ref-type="aff" rid="aff1001">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0009-0004-2422-0777</contrib-id>
          <name>
            <surname>Ribeiro</surname>
            <given-names>Diana</given-names>
          </name>
          <role>Acquisition of data and Writing of the manuscript</role>
          <role>Analysis and interpretation of the data</role>
          <xref ref-type="aff" rid="aff1001">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Sousa</surname>
            <given-names>Maria Jo&#227;o</given-names>
          </name>
          <role>Conception and design of the research</role>
          <role>Analysis and interpretation of the data</role>
          <role>Critical revision of the manuscript for important intellectual content</role>
          <xref ref-type="aff" rid="aff1001">
            <sup>1</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Reis</surname>
            <given-names>Hip&#243;lito</given-names>
          </name>
          <role>Conception and design of the research</role>
          <role>Analysis and interpretation of the data</role>
          <role>Critical revision of the manuscript for important intellectual content</role>
          <xref ref-type="aff" rid="aff1001">
            <sup>1</sup>
          </xref>
          <xref ref-type="aff" rid="aff2001">
            <sup>2</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Silveira</surname>
            <given-names>Jo&#227;o</given-names>
          </name>
          <role>Critical revision of the manuscript for important intellectual content</role>
          <xref ref-type="aff" rid="aff1001">
            <sup>1</sup>
          </xref>
          <xref ref-type="aff" rid="aff2001">
            <sup>2</sup>
          </xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Torres</surname>
            <given-names>Severo</given-names>
          </name>
          <role>Critical revision of the manuscript for important intellectual content</role>
          <xref ref-type="aff" rid="aff1001">
            <sup>1</sup>
          </xref>
          <xref ref-type="aff" rid="aff2001">
            <sup>2</sup>
          </xref>
        </contrib>
      </contrib-group>
      <aff id="aff1001">
        <label> 1 </label>
        <country country="PT">Portugal</country>
        <institution content-type="original"> Departamento de Cardiologia, Centro Hospitalar Universit&#225;rio de Santo Ant&#243;nio (CHUDSA), Porto &#8211; Portugal </institution>
      </aff>
      <aff id="aff2001">
        <label>2</label>
        <country country="PT">Portugal</country>
        <institution content-type="original"> ICBAS &#8211; Faculdade de Medicina e Ci&#234;ncias Biom&#233;dicas, Universidade do Porto, Porto &#8211; Portugal </institution>
      </aff>
      <author-notes>
        <corresp id="c01001">Mailing Address: Andr&#233; Alexandre &#8226; Largo do Prof. Abel Salazar, 4099-001, Porto- Portugal E-mail: andrealexandre_1@msn.com</corresp>
        <fn id="fn1001">
          <p>Potential conflict of interest</p>
          <p>No potential conflict of interest relevant to this article was reported.</p>
          <p>Editor responsible for the review: Mauricio Scanavacca</p>
        </fn>
      </author-notes>
      <kwd-group xml:lang="en">
        <kwd>Lyme Disease</kwd>
        <kwd>Atrioventricular Block</kwd>
        <kwd>Cardiomyopathy</kwd>
        <kwd>Adenosine</kwd>
        <kwd>Theophyline</kwd>
      </kwd-group>
    </front-stub>
    <body>
      <sec sec-type="intro">
        <title>Introduction</title>
        <p>Lyme carditis (LC) is a relatively rare manifestation of the early disseminated stage of LC. <sup><xref rid="B1" ref-type="bibr">1</xref> , <xref rid="B2" ref-type="bibr">2</xref> </sup> The most frequent presentation of LC is atrioventricular (AV) block characterized by rapid fluctuations in the grade and that occurs in approximately 80-90% of patients. <sup><xref rid="B1" ref-type="bibr">1</xref> , <xref rid="B3" ref-type="bibr">3</xref> </sup> Other possible clinical manifestations of LC are myocarditis, pericarditis, dilated cardiomyopathy, and heart failure. <sup><xref rid="B1" ref-type="bibr">1</xref> , <xref rid="B4" ref-type="bibr">4</xref> </sup> The clinical course is usually mild, short-term, and in most cases completely reversible after adequate antibiotic treatment. <sup><xref rid="B1" ref-type="bibr">1</xref></sup> Indeed, high-grade AV block associated with Lyme disease typically resolves within the first ten days of antibiotic therapy. <sup><xref rid="B3" ref-type="bibr">3</xref></sup> The authors present a case of a young female diagnosed with early disseminated Lyme disease and cardiac manifestations, in whom AV conduction disturbances persisted after four weeks of appropriate antibiotic treatment and led to an alternative diagnosis.</p>
      </sec>
      <sec sec-type="cases">
        <title>Case Presentation</title>
        <p>A 20-year-old female, practitioner of acrobatic gymnastics from age 12 to 18 years, presented with acute pleuritic chest pain and shortness of breath. At admission, she was hemodynamically stable, mildly tachycardic (100/min), apyretic, with normal lung and cardiac auscultation and no congestive signs.</p>
        <p>The patient had an electrocardiogram showing sinus tachycardia (102/min) and T-wave inversion in inferior and V3-V6 leads (Supplementary <xref rid="f01001" ref-type="fig">Figure 1</xref> ). The chest radiograph was normal. Blood analysis revealed an elevation of cardiac biomarkers (high-sensitivity troponin T 0.085 ng/mL [reference values 0.000&#8211;0.014]) and an elevation of inflammatory parameters (C-reactive protein 135 mg/L [0-5] and erythrocyte sedimentation rate 104 mm [0-19]). Transthoracic echocardiography showed hypokinesis of the basal segment of the anterior interventricular septum, preserved biventricular systolic function, no valvular dysfunction, nor pericardial effusion. Considering the suspicion of acute myocarditis, the patient was admitted to an intensive cardiac care unit. During hospitalization, continuous cardiac monitoring revealed several asymptomatic episodes of paroxysmal AV block (Supplementary Figure 2), including second-degree Mobitz I AV block, second-degree 2:1 AV block, and high-grade AV block (3:1 and 4:1).</p>
        <p>
          <fig id="f01001">
            <label>Figure 1</label>
            <caption>
              <title>&#8211; Holter monitoring demonstrating two episodes of paroxysmal atrioventricular (AV) block after completion of antibiotic treatment. Continuous Holter monitoring revealed that AV conduction disturbances (including paroxysmal high-grade AV block) persisted after four weeks of appropriate antibiotic treatment. Panel A shows a second-degree 2:1 AV block. Panel B shows a high-grade AV block with a ventricular asystole of 2.96 seconds.</title>
            </caption>
            <graphic xlink:href="1678-4170-abc-121-01-e20230228-30228-gf01-en.tif"/></fig>
        </p>
        <p>Despite the absence of a specific epidemiological risk context for <italic>Borrelia spp.</italic> (such as evidence of tick exposure, joint lesions, diarrhea, or skin lesions), the patient was sought for serological testing for Lyme disease. Current recommendations include using a sensitive enzyme-linked immunosorbent assay (ELISA), followed by a western immunoblot assay for specimens yielding positive or equivocal results. <sup><xref rid="B5" ref-type="bibr">5</xref> , <xref rid="B6" ref-type="bibr">6</xref> </sup> In our case, initial serologic examination with ELISA test showed a borderline positive IgM (0.30 RU/mL [&lt; 0.20]) with negative IgG ELISA test. Thus, an IgM Western-Blot test was performed, confirming positivity and recent <italic>Borrelia spp.</italic> infection. Also, subsequent IgM and IgG ELISA tests were performed two months later, the former remaining clearly positive (0.38 RU/mL [&lt; 0.20]) and the latter still negative. The first- and second-tier Lyme disease testing results reported here support the combined sensitivity and specificity rationale of the two-tiered algorithm as opposed to the use of just one test. <sup><xref rid="B6" ref-type="bibr">6</xref></sup> Besides that, treponemal and nontreponemal tests (VDRL; FTA-ABS) were negative, excluding syphilis. Molecular biology tests for an extensive panel of respiratory viruses yielded negative results (RSV, INF-A, INF-B, Parainfluenza 1, 2, 3, 4, Adenovirus, Metapneumovirus, Bocavirus, Rhinovirus, Enterovirus, Coronavirus), as did the serology tests for HIV, HBV, and HCV. The patient was immune to EBV, CMV, Parvovirus, Coxsackievirus, and Enterovirus (IgM negative; IgG positive). Culture tests for <italic>S. pyogenes</italic> and antistreptolysin O titer were negative. Immunological tests were normal. Therefore, it is unlikely that cross-reactivity occurred in our case, which allowed the diagnosis of Lyme disease to be confirmed. Cardiovascular magnetic resonance was performed one week after admission and was unremarkable. Positron emission tomography excluded cardiac sarcoidosis.</p>
        <p>Considering the diagnosis of early disseminated Lyme disease with cardiac manifestations of high-grade AV block, the patient was treated with intravenous ceftriaxone over four weeks. Complete resolution of chest pain and dyspnea complaints were documented. Nevertheless, in our patient, the AV conduction disturbance (including high-grade AV block) persisted after four weeks of appropriate antibiotic treatment, as demonstrated by Holter monitoring ( <xref rid="f01001" ref-type="fig">Figure 1</xref> ). Therefore, this case could be an extremely rare course of LC, or it could be a prior asymptomatic AV conduction disturbance that has revealed itself along with Lyme disease.</p>
        <p>Paroxysmal AV block can be categorized into three different types: intrinsic, extrinsic vagal, and extrinsic idiopathic (&#8220;adenosine-sensitive AV block&#8221;). Hence, this patient pursued a diagnostic workup for further characterization. The exercise stress test showed normal 1:1 AV conduction at high heart rates, no conduction disturbances nor dysrhythmias, and normal exercise tolerance (11.1 METs). The electrophysiology study (EPS) was unremarkable, ruling out intrinsic paroxysmal AV block (as well as any chronic sequelae of LC). As for the possibility of extrinsic vagal paroxysmal AV block, since these episodes occurred two years after deconditioning from acrobatic gymnastics, it was less likely that extrinsic vagal contributed to paroxysmal AV block. On the other hand, considering that paroxysmal high-grade AV block occurred without PP cycle lengthening or PR interval prolongation and without triggering by premature beats nor by rate variations, these features favored the diagnosis of an extrinsic idiopathic paroxysmal AV block (also known as &#8220;adenosine-sensitive AV block&#8221;).</p>
        <p>The patient was started on theophylline 400 mg twice daily, and after one week of treatment, the Holter monitoring demonstrated a significant reduction in AV conduction disturbances. Holter monitoring before theophylline showed around 78 blocked P waves, including second-degree Mobitz I AV block, second-degree 2:1 AV block, and high-grade AV block (3:1 and 4:1), with two significant ventricular asystoles, the largest of which was 2960 milliseconds due to high-grade AV block (4:1) [ <xref rid="f01001" ref-type="fig">Figure 1</xref> ]. Holter monitoring following theophylline administration revealed a noteworthy reduction of approximately 38% of blocked P waves (from 78 to 48), mostly due to second-degree Mobitz I AV block, with only two episodes of 3:1 AV block and no ventricular asystole longer than 2000 milliseconds. Considering the patient was asymptomatic and since &#8220;adenosine-sensitive AV block&#8221; does not progress to persistent forms of AV block, she was discharged without the need for a permanent pacemaker.</p>
        <p>At 18 months of follow-up, the patient remains on theophylline therapy, with a reduction in AV conduction disturbances, no cardiac complaints, and no need for a permanent pacemaker.</p>
      </sec>
      <sec sec-type="discussion">
        <title>Discussion</title>
        <p>This is a case of a young female diagnosed with early disseminated Lyme disease and cardiac manifestations, in whom AV conduction disturbances persisted after four weeks of appropriate antibiotic treatment, leading to an alternative diagnosis of extrinsic idiopathic paroxysmal AV block (&#8220;adenosine-sensitive AV block&#8221;).</p>
        <p>LC is a relatively rare manifestation of an early disseminated stage of Lyme disease. <sup><xref rid="B1" ref-type="bibr">1</xref> , <xref rid="B2" ref-type="bibr">2</xref> </sup> Serologic testing is the principal means of laboratory diagnosis of Lyme disease. <sup><xref rid="B5" ref-type="bibr">5</xref></sup> It is known that the sensitivity of two-tiered testing using commercially available serology-based assays is dependent on the stage of infection. <sup><xref rid="B6" ref-type="bibr">6</xref></sup> Sensitivity ranges from 40 to 87% were observed in patients with early disseminated disease (LC), and differences in disease duration and dissemination in tested patients may explain this variability. <sup><xref rid="B6" ref-type="bibr">6</xref></sup> In addition, some look-alike diseases (such as fibromyalgia, infectious mononucleosis, multiple sclerosis, rheumatoid arthritis, and syphilis) are documented as causing cross-reactivity in serologic assays for Lyme disease. <sup><xref rid="B6" ref-type="bibr">6</xref></sup> Current recommendations include using a sensitive enzyme immunoassay or immunofluorescence assay, followed by a western immunoblot assay for specimens yielding positive or equivocal results. <sup><xref rid="B5" ref-type="bibr">5</xref></sup> Serologic assays that utilize a second enzyme immunoassay in place of western immunoblot assay are acceptable alternatives, although not mandatory to establish the diagnosis. <sup><xref rid="B5" ref-type="bibr">5</xref></sup> In our case, initial serologic examination with ELISA test showed a borderline positive IgM (0.30 RU/mL [&lt; 0.20]) with negative IgG ELISA test. Thus, an IgM Western-Blot test was performed, confirming positivity and recent Borrelia spp. infection. Also, subsequent IgM and IgG ELISA tests were performed two months later, the former remaining clearly positive (0.38 RU/mL [&lt; 0.20]) and the latter still negative. The first- and second-tier Lyme disease testing results reported here support the combined sensitivity and specificity rationale of the two-tiered algorithm as opposed to use of just one test. <sup><xref rid="B6" ref-type="bibr">6</xref></sup> Besides that, treponemal and nontreponemal tests were negative (excluding syphilis), as were all other serological and immunological tests. Therefore, it is unlikely that cross-reactivity occurred in our case, which allowed the diagnosis of Lyme disease to be confirmed.</p>
        <p>The most frequent presentation of LC is AV block, characterized by rapid fluctuations in the grade. <sup><xref rid="B1" ref-type="bibr">1</xref> , <xref rid="B3" ref-type="bibr">3</xref> </sup> The clinical course is usually mild, short-term, and, in most cases, completely reversible after adequate antibiotic treatment. <sup><xref rid="B1" ref-type="bibr">1</xref></sup> In this clinical case, the AV conduction disturbance persisted after four weeks of appropriate antibiotic treatment. Therefore, it was hypothesized that it might be a chronic sequela of LC (being an extremely rare course of Lyme disease), or this patient might have a prior asymptomatic AV conduction disturbance that revealed itself along with Lyme disease. Current literature exposes three different types of paroxysmal AV block: intrinsic, extrinsic vagal, and extrinsic idiopathic. <sup><xref rid="B7" ref-type="bibr">7</xref></sup> Intrinsic paroxysmal AV block is due to an intrinsic disease of the AV conduction system and progresses to persistent forms of AV block. <sup><xref rid="B7" ref-type="bibr">7</xref></sup> Extrinsic vagal paroxysmal AV block is linked to the effect of the parasympathetic nervous system on cardiac conduction and is involved in &#8220;reflex syncope&#8221;. <sup><xref rid="B7" ref-type="bibr">7</xref></sup> Extrinsic idiopathic paroxysmal AV block is associated with low levels of endogenous adenosine and is supposed to be involved in &#8220;adenosine-sensitive syncope&#8221;. It is characterized by paroxysmal complete AV block without PP cycle lengthening or PR interval prolongation, is not triggered by premature beats nor by rate variations, and does not progress to persistent forms of AV block. <sup><xref rid="B8" ref-type="bibr">8</xref></sup> The prevalence of this type of block is likely underdiagnosed due to poor recognition and its unpredictability. <sup><xref rid="B7" ref-type="bibr">7</xref></sup> According to 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy, the diagnosis of adenosine hypersensitivity AV block is supported by an unremarkable EPS, as well as the absence of initiation of the block by atrial or ventricular premature beats, nor increased heart rate (tachy-dependent AV block) or decreased heart rate (brady-dependent AV block). <sup><xref rid="B8" ref-type="bibr">8</xref> , <xref rid="B9" ref-type="bibr">9</xref> </sup> Since patients with low plasma adenosine levels are highly susceptible to exogenous and endogenous adenosine, theophylline treatment has been investigated and it seems to be effective and may be considered an alternative to permanent pacing in patients with recurrent syncope. <sup><xref rid="B7" ref-type="bibr">7</xref> , <xref rid="B10" ref-type="bibr">10</xref> , <xref rid="B11" ref-type="bibr">11</xref> </sup> </p>
        <p>This case illustrates a challenging scenario of LC with high-grade AV block, which persisted after appropriate antibiotic treatment and had key features supporting the diagnosis of extrinsic idiopathic paroxysmal AV block (&#8220;adenosine-sensitive AV block&#8221;). In accordance, this patient was started on theophylline, achieving a significant reduction in AV conduction disturbances and, subsequently, no need for a permanent pacemaker.</p>
      </sec>
      <sec sec-type="conclusions">
        <title>Conclusion</title>
        <p>&#8220;Adenosine-sensitive AV block&#8221; is a type of paroxysmal AV block that is likely underdiagnosed due to its unpredictability and poor recognition. Theophylline treatment seems to be effective and may be considered an alternative to permanent pacing in low-risk patients.</p>
      </sec>
    </body>
    <back>
      <fn-group>
        <fn fn-type="other">
          <p>Study association</p>
          <p>This study is not associated with any thesis or dissertation work.</p>
          <p>Ethics approval and consent to participate</p>
          <p>This article does not contain any studies with human participants or animals performed by any of the authors.</p>
        </fn>
        <fn fn-type="supported-by">
          <p>Sources of funding: There were no external funding sources for this study.</p>
        </fn>
        <app-group>
          <app id="app2">
            <p>*Material suplementar</p>
            <p>Para informa&#231;&#227;o adicional, por favor, <ext-link ext-link-type="uri" xlink:href="http://abccardiol.org/supplementary-material/2024/12101/2023-0228-supplementary.pdf">clique aqui</ext-link> .</p>
          </app>
        </app-group>
      </fn-group>
    </back>
  </sub-article>
</article>
