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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">wjk7QHKStwMZjhR6TvtsZNn</article-id>
      <article-id specific-use="scielo-v2" pub-id-type="publisher-id">S0066-782X2020001200646</article-id>
      <article-id pub-id-type="publisher-id">abc.20200522</article-id>
      <article-id pub-id-type="doi">10.36660/abc.20200522</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Minieditorial</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>O Paradoxo da Obesidade na Insufici&#234;ncia Card&#237;aca Depende da Aptid&#227;o Cardiorrespirat&#243;ria?</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="editor">
          <contrib-id contrib-id-type="orcid">0000-0002-3738-1586</contrib-id>
          <name>
            <surname>Laukkanen</surname>
            <given-names>Jari A.</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
          <xref ref-type="aff" rid="aff2">
            <sup>2</sup>
          </xref>
          <xref ref-type="aff" rid="aff3">
            <sup>3</sup>
          </xref>
          <xref ref-type="corresp" rid="c1"/>
        </contrib>
        <contrib contrib-type="editor">
          <name>
            <surname>Kunutsor</surname>
            <given-names>Setor K.</given-names>
          </name>
          <xref ref-type="aff" rid="aff4">
            <sup>4</sup>
          </xref>
          <xref ref-type="aff" rid="aff5">
            <sup>5</sup>
          </xref>
        </contrib>
        <aff id="aff1">
          <label>1</label>
          <institution content-type="orgname">University of Eastern Finland</institution>
          <institution content-type="orgdiv1">Institute of Clinical Medicine</institution>
          <addr-line>
            <named-content content-type="city">Kuopio</named-content>
          </addr-line>
          <country country="FI">Finl&#226;ndia</country>
          <institution content-type="original">Institute of Clinical Medicine, University of Eastern Finland, Kuopio - Finl&#226;ndia</institution>
        </aff>
        <aff id="aff2">
          <label>2</label>
          <institution content-type="orgname">Central Finland Health Care District</institution>
          <institution content-type="orgdiv1">Departamento de Medicina</institution>
          <addr-line>
            <named-content content-type="city">Jyv&#228;skyl&#228;</named-content>
          </addr-line>
          <country country="FI">Finl&#226;ndia</country>
          <institution content-type="original">Departamento de Medicina, Central Finland Health Care District, Jyv&#228;skyl&#228; - Finl&#226;ndia</institution>
        </aff>
        <aff id="aff3">
          <label>3</label>
          <institution content-type="orgname">University of Eastern Finland</institution>
          <institution content-type="orgdiv1">Institute of Public Health and Clinical Nutrition</institution>
          <addr-line>
            <named-content content-type="city">Kuopio</named-content>
          </addr-line>
          <country country="FI">Finl&#226;ndia</country>
          <institution content-type="original">Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio - Finl&#226;ndia</institution>
        </aff>
        <aff id="aff4">
          <label>4</label>
          <institution content-type="orgname">University of Bristol</institution>
          <institution content-type="orgdiv1">University Hospitals Bristol NHS Foundation Trust</institution>
          <institution content-type="orgdiv2">National Institute for Health Research Bristol Biomedical Research Centre</institution>
          <addr-line>
            <named-content content-type="city">Bristol</named-content>
          </addr-line>
          <country country="GB">Reino Unido</country>
          <institution content-type="original">National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol - Reino Unido</institution>
        </aff>
        <aff id="aff5">
          <label>5</label>
          <institution content-type="orgname">University of Bristol</institution>
          <institution content-type="orgdiv1">Bristol Medical School</institution>
          <institution content-type="orgdiv2">Translational Health Sciences</institution>
          <addr-line>
            <named-content content-type="city">Bristol</named-content>
          </addr-line>
          <country country="GB">Reino Unido</country>
          <institution content-type="original">Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, Learning &amp; Research Building (Level 1), Southmead Hospital, Bristol - Reino Unido</institution>
        </aff>
      </contrib-group>
      <author-notes>
        <corresp id="c1"><bold>Correspond&#234;ncia: Jari A. Laukkanen&#8226;</bold> Institute of Clinical Medicine, Department of Medicine, University of Eastern Finland, P.O. Box 1627, <postal-code>FIN-70211</postal-code> Kuopio - Finland E-mail: <email>jariantero.laukkanen@uef.fi</email></corresp>
      </author-notes>
      <pub-date publication-format="electronic" date-type="pub">
        <day>23</day>
        <month>10</month>
        <year>2020</year>
      </pub-date>
      <pub-date publication-format="electronic" date-type="collection">
        <month>10</month>
        <year>2020</year>
      </pub-date>
      <volume>115</volume>
      <issue>4</issue>
      <fpage>646</fpage>
      <lpage>648</lpage>
      <permissions>
        <license license-type="open-access" xml:lang="en" xlink:href="https://creativecommons.org/licenses/by/4.0/">
          <license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License</license-p>
        </license>
      </permissions>
      <kwd-group xml:lang="pt">
        <title>Palavras-chave</title>
        <kwd>Insufici&#234;ncia Card&#237;aca</kwd>
        <kwd>Obesidade</kwd>
        <kwd>Aptid&#227;o Cardiorrespirat&#243;ria</kwd>
        <kwd>&#205;ndice de Massa Corporal</kwd>
        <kwd>Exerc&#237;cio</kwd>
        <kwd>Hospitaliza&#231;&#227;o</kwd>
        <kwd>Morbidade e Mortalidade</kwd>
      </kwd-group>
      <counts>
        <fig-count count="0"/>
        <table-count count="0"/>
        <equation-count count="0"/>
        <ref-count count="16"/>
        <page-count count="3"/>
      </counts>
    </article-meta>
  </front>
  <body>
    <p>A insufici&#234;ncia card&#237;aca (IC) &#233; uma amea&#231;a global &#224; sa&#250;de p&#250;blica, associada ao aumento de hospitaliza&#231;&#245;es, morbidade, mortalidade e altos custos econ&#244;micos.<xref ref-type="bibr" rid="B1"><sup>1</sup></xref> Entretanto, a IC, a qual tem a doen&#231;a card&#237;aca isqu&#234;mica como doen&#231;a subjacente comum, &#233; uma condi&#231;&#227;o pelo menos parcialmente evit&#225;vel. A aptid&#227;o cardiorrespirat&#243;ria (ACR) &#233; um &#237;ndice dos n&#237;veis habituais de atividade f&#237;sica e &#233; considerado o padr&#227;o ouro para a capacidade de exerc&#237;cio aer&#243;bico. A aptid&#227;o cardiorrespirat&#243;ria, um componente importante da aptid&#227;o f&#237;sica e medida diretamente pelo consumo de oxig&#234;nio de pico (VO<sub>2</sub> pico) e a inclina&#231;&#227;o da efici&#234;ncia ventilat&#243;ria (inclina&#231;&#227;o VE/VCO<sub>2</sub>), foi identificada como um dos preditores mais importantes dos desfechos de sa&#250;de e sobreviv&#234;ncia.<xref ref-type="bibr" rid="B2"><sup>2</sup></xref> Relatamos anteriormente que o VO<sub>2</sub> pico, quando diretamente avaliado, est&#225; forte, independente e inversamente relacionado a um risco reduzido de condi&#231;&#245;es cardiometab&#243;licas, como IC,<xref ref-type="bibr" rid="B2"><sup>2</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B3"><sup>3</sup></xref> fibrila&#231;&#227;o atrial,<xref ref-type="bibr" rid="B3"><sup>3</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B4"><sup>4</sup></xref> fibrila&#231;&#227;o ventricular<xref ref-type="bibr" rid="B5"><sup>5</sup></xref> diabetes,<xref ref-type="bibr" rid="B6"><sup>6</sup></xref> bem como mortalidade por doen&#231;as cardiovasculares (DCV).<xref ref-type="bibr" rid="B7"><sup>7</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B8"><sup>8</sup></xref> Nosso recente estudo de base populacional baseado no <italic>UK Biobank</italic> sugere que a ACR &#233; um forte indicador de risco para mortalidade e a adi&#231;&#227;o da ACR ao escore dos fatores de risco convencional melhorou a discrimina&#231;&#227;o geral do risco de mortalidade e, mais importante, o valor preditivo da ACR variou atrav&#233;s dos n&#237;veis de alguns fatores de risco relevantes, incluindo idade, sexo e tabagismo.<xref ref-type="bibr" rid="B8"><sup>8</sup></xref> Este fato &#233; um indicador de que a ACR &#233; uma ferramenta potencialmente valiosa de avalia&#231;&#227;o de risco na cl&#237;nica pr&#225;tica.</p>
    <p>Sabe-se que a obesidade, medida pelo &#237;ndice de massa corporal (IMC), est&#225; relacionada ao desenvolvimento de desfechos cardiovasculares. No entanto, o efeito combinado da obesidade e da ACR no risco de IC futura ainda requer estudos adicionais. &#201; de relev&#226;ncia cl&#237;nica entender se a ACR atenua a associa&#231;&#227;o da obesidade com o risco posterior de IC devido a outras DCV subjacentes.<xref ref-type="bibr" rid="B9"><sup>9</sup></xref> A maioria dos estudos anteriores sobre IMC mais alto, outros par&#226;metros de obesidade e risco de IC n&#227;o levou em considera&#231;&#227;o as diferen&#231;as nos n&#237;veis de ACR. Embora o IMC alto seja um fator de risco para IC, h&#225; achados de uma rela&#231;&#227;o n&#227;o-linear entre os resultados de IMC e DCV em pacientes com IC, o que indica uma rela&#231;&#227;o incomum. Em pacientes com IC estabelecida, evid&#234;ncias acumuladas sugerem que indiv&#237;duos com sobrepeso e obesidade (IMC mais alto) apresentaram melhor sobrevida em compara&#231;&#227;o com aqueles com IMC normal, um conceito conhecido que foi chamado de &#8220;paradoxo da obesidade&#8221; ou &#8220;epidemiologia reversa&#8221;.<xref ref-type="bibr" rid="B10"><sup>10</sup></xref> Alguns mecanismos t&#234;m sido propostos para explicar o paradoxo da obesidade da IC, que inclui a terapia da IC ser mais eficaz em pacientes obesos. Foi relatado que a ACR tamb&#233;m pode desempenhar um papel, mitigando ou negando o &#8220;paradoxo da obesidade&#8221;.<xref ref-type="bibr" rid="B10"><sup>10</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B11"><sup>11</sup></xref></p>
    <p>H&#225; evid&#234;ncias limitadas sobre a associa&#231;&#227;o e intera&#231;&#245;es entre ACR, IMC, IC e desfechos da IC. Essa foi a justificativa para o novo estudo de Moreira et al. publicado na edi&#231;&#227;o recente da revista, que teve como objetivo investigar o impacto da toler&#226;ncia ao exerc&#237;cio e da capacidade cardiorrespirat&#243;ria no paradoxo da obesidade em pacientes com IC com baixa fra&#231;&#227;o de eje&#231;&#227;o.<xref ref-type="bibr" rid="B12"><sup>12</sup></xref> Todos os pacientes encaminhados para os Ambulat&#243;rios de Insufici&#234;ncia Card&#237;aca foram submetidos a avalia&#231;&#227;o cl&#237;nica com coleta laboratorial, eletro- e ecocardiografia, e teste de esfor&#231;o cardiopulmonar. Um teste de exerc&#237;cio cardiopulmonar m&#225;ximo em esteira limitado por sintomas foi realizado utilizando o protocolo de Bruce modificado (esteira GE Marquette Series 2000). A ventila&#231;&#227;o minuto, consumo de oxig&#234;nio e a produ&#231;&#227;o de di&#243;xido de carbono foram avaliadas utilizando-se um analisador de gases respira&#231;&#227;o por respira&#231;&#227;o. Foram inclu&#237;dos 282 pacientes com IC (75,5% do sexo masculino), com m&#233;dia de idade de 53,7 anos e IMC de 28,6 kg/m<sup>2</sup>. Os pacientes foram acompanhados por 60 meses para um <italic>endpoint</italic> composto combinado, consistindo em morte card&#237;aca, transplante card&#237;aco urgente ou necessidade de suporte circulat&#243;rio mec&#226;nico.<xref ref-type="bibr" rid="B12"><sup>12</sup></xref> Curiosamente, pacientes com IMC maior apresentaram FEVE mais alta, mas menor inclina&#231;&#227;o da efici&#234;ncia ventilat&#243;ria (VE / VCO<sub>2</sub>).<xref ref-type="bibr" rid="B12"><sup>12</sup></xref> A an&#225;lise de associa&#231;&#227;o mostrou que o IMC, a inclina&#231;&#227;o VE / VCO<sub>2</sub> e o VO<sub>2</sub> pico s&#227;o indicadores do desfecho prim&#225;rio. Entretanto, a associa&#231;&#227;o entre IMC e desfecho foi atenuada para nula quando os pacientes foram agrupados em ACR baixa e alta (com base na VE / VCO<sub>2</sub>) e ap&#243;s o controle da VE / VCO<sub>2</sub> ou VO<sub>2</sub> pico.</p>
    <p>Consistente com os achados deste estudo, Chase et al. demonstraram anteriormente que a inclina&#231;&#227;o VE / VCO<sub>2</sub> mantinha seu valor progn&#243;stico independentemente do IMC em pacientes com IC.<xref ref-type="bibr" rid="B13"><sup>13</sup></xref> No entanto, quando a inclina&#231;&#227;o VE / VCO<sub>2</sub> ou o VO<sub>2</sub> pico foram levados em considera&#231;&#227;o em suas an&#225;lises, a associa&#231;&#227;o entre o IMC e os desfechos card&#237;acos n&#227;o foi significativa. Al&#233;m disso, quando os pacientes foram agrupados e analisados de acordo com os subgrupos da ACR, o IMC n&#227;o foi relacionado aos desfechos.<xref ref-type="bibr" rid="B13"><sup>13</sup></xref></p>
    <p>Dado que o risco absoluto de resultados adversos de DCV depende muito da idade, o emprego de uma &#250;nica m&#233;trica relativa n&#227;o pode permitir a quantifica&#231;&#227;o de diferen&#231;as absolutas de risco em idades crescentes com diferentes n&#237;veis de IMC. Zaccardi et al.,<xref ref-type="bibr" rid="B14"><sup>14</sup></xref> Recentemente, sugeriu uma nova abordagem para avaliar a intera&#231;&#227;o para estimar a expectativa de vida residual entre os n&#237;veis de ACR e IMC.<xref ref-type="bibr" rid="B14"><sup>14</sup></xref> Com base na grande coorte do Reino Unido do <italic>Biobank</italic>, incluindo 474.919 participantes, os autores demonstraram que os participantes com um ritmo acelerado de caminhada t&#234;m uma expectativa de vida mais longa no espectro do IMC e outras medidas de obesidade, fornecendo dados adicionais de evid&#234;ncias de que o ritmo de caminhada, como marcador do n&#237;vel de condicionamento f&#237;sico, &#233; um indicador facilmente dispon&#237;vel do estado de sa&#250;de.</p>
    <p>Os pontos fortes do presente estudo incluem o uso de uma amostra clinicamente relevante com base em pacientes com IC de alto risco e a avalia&#231;&#227;o de medidas de ACR utilizando an&#225;lise confi&#225;vel de gases respirat&#243;rios, que &#233; um m&#233;todo de avalia&#231;&#227;o mais objetivo e quantitativo da ACR. V&#225;rias limita&#231;&#245;es incluem (i) o pequeno tamanho da amostra; (ii) incapacidade de ajuste para muitos fatores de confus&#227;o em potencial; (iii) falta de dados sobre medicamentos, biomarcadores e padr&#245;es de atividade f&#237;sica durante o seguimento, o que poderia ter pelo menos parcialmente influenciado os n&#237;veis de ACR e IMC; (iv) falta de an&#225;lises formais de previs&#227;o de risco, pois as medidas de associa&#231;&#227;o s&#227;o insuficientes para fazer julgamentos cl&#237;nicos sobre a relev&#226;ncia progn&#243;stica de uma exposi&#231;&#227;o; e (v) o potencial de dilui&#231;&#227;o de regress&#227;o, dada a aus&#234;ncia de medidas repetidas de ACR, devido ao potencial de altera&#231;&#245;es nos n&#237;veis de ACR devido a erros nas medi&#231;&#245;es e altera&#231;&#245;es no curso cl&#237;nico da doen&#231;a. Em nossos sub-estudos de reprodutibilidade das medidas de ACR no estudo de coorte prospectivo <italic>Kuopio Ischemic Heart Disease</italic> (KIHD), demonstramos uma alta variabilidade intrapessoal nos n&#237;veis de ACR medidos com muitos anos de diferen&#231;a (raz&#227;o de dilui&#231;&#227;o de regress&#227;o = 0,58),<xref ref-type="bibr" rid="B15"><sup>15</sup></xref> o que sugere que as an&#225;lises utilizando apenas medi&#231;&#245;es basais &#250;nicas da ACR poderiam subestimar as associa&#231;&#245;es com os desfechos. Em geral, essas novas descobertas destacam o fato de que existe um &#8220;paradoxo da obesidade&#8221; em pacientes com IC e h&#225; uma intera&#231;&#227;o entre obesidade, ACR e desfechos na IC. A aptid&#227;o cardiorrespirat&#243;ria medida pela VE/VCO<sub>2</sub> ou VO<sub>2</sub> pico pareceu negar o paradoxo da obesidade.<xref ref-type="bibr" rid="B12"><sup>12</sup></xref></p>
    <p>A ACR &#233; influenciada por fatores gen&#233;ticos e ambientais; aproximadamente 50% da varia&#231;&#227;o da ACR foi atribu&#237;da a fatores heredit&#225;rios, com a contribui&#231;&#227;o de fatores herdados para a resposta da ACR &#224; atividade f&#237;sica e ao treinamento f&#237;sico.<xref ref-type="bibr" rid="B7"><sup>7</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B8"><sup>8</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B11"><sup>11</sup></xref> Tamb&#233;m depende de v&#225;rios fatores, como status de sa&#250;de e condicionamento f&#237;sico basais, tipo, dura&#231;&#227;o e intensidade da AF. O n&#237;vel de ACR tamb&#233;m &#233; um indicador de uma cadeia de m&#250;ltiplos processos fisiol&#243;gicos que incluem: ventila&#231;&#227;o pulmonar e fun&#231;&#227;o vascular, fun&#231;&#227;o ventricular direita e esquerda, capacidade da vasculatura em transportar sangue do cora&#231;&#227;o com efici&#234;ncia para outros &#243;rg&#227;os, atendendo suas necessidades de oxig&#234;nio, a capacidade das c&#233;lulas musculares em utilizar o oxig&#234;nio e os nutrientes essenciais e a capacidade de ativar todas as fibras musculares necess&#225;rias para o movimento corporal.<xref ref-type="bibr" rid="B11"><sup>11</sup></xref> O volume sist&#243;lico ventricular esquerdo, a frequ&#234;ncia card&#237;aca m&#225;xima e a diferen&#231;a arteriovenosa de oxig&#234;nio no exerc&#237;cio determinaram essencialmente os n&#237;veis de ACR. A fun&#231;&#227;o ventricular esquerda &#233; uma medida-chave da IC e o n&#237;vel da ACR pode refletir a fun&#231;&#227;o do VE. Como a ACR est&#225; relacionada &#224; integra&#231;&#227;o da fun&#231;&#227;o do corpo humano sob condi&#231;&#245;es de estresse fisiol&#243;gico, ela pode ser empregada como um indicador muito preciso do risco de IC, refletindo o estado funcional do corpo inteiro em pacientes com IC existente. Dado o papel central que a fun&#231;&#227;o card&#237;aca normal desempenha na defini&#231;&#227;o da capacidade aer&#243;bica m&#225;xima, doen&#231;a ou disfun&#231;&#227;o que afeta negativamente o d&#233;bito card&#237;aco, tamb&#233;m comprometer&#225; o VO<sub>2</sub> m&#225;ximo. O treinamento aer&#243;bico de alta intensidade &#233; seguro e eficaz para melhorar a capacidade funcional em muitas popula&#231;&#245;es de pacientes com problemas card&#237;acos.<xref ref-type="bibr" rid="B11"><sup>11</sup></xref> A participa&#231;&#227;o em um programa de treinamento aer&#243;bico de longo prazo produz uma s&#233;rie de adapta&#231;&#245;es cardiovasculares morfol&#243;gicas e fisiol&#243;gicas positivas em indiv&#237;duos aparentemente saud&#225;veis, independentemente de idade e sexo. Adapta&#231;&#245;es morfol&#243;gicas comumente relatadas associadas ao treinamento aer&#243;bico regular &#233; a dilata&#231;&#227;o do ventr&#237;culo esquerdo (aumento do di&#226;metro diast&#243;lico final) e hipertrofia (aumento da espessura da parede), conhecido como remodelamento card&#237;aco induzido pelo treinamento com exerc&#237;cios.<xref ref-type="bibr" rid="B16"><sup>16</sup></xref></p>
    <p>Os achados atuais lan&#231;am mais luz sobre uma poss&#237;vel intera&#231;&#227;o entre ACR, obesidade e desfechos na IC. No entanto, dadas as limita&#231;&#245;es do pequeno tamanho da amostra e a incapacidade de se ajustar &#224;s covari&#225;veis relevantes, esses achados observacionais do estudo precisam de cautela ao serem interpretados. Os achados aumentam o arsenal de evid&#234;ncias acumuladas de que a ACR (usando o VO<sub>2</sub> pico e medidas de efici&#234;ncia ventilat&#243;ria) &#233; uma ferramenta clinicamente &#250;til na avalia&#231;&#227;o de risco de IC. Altos n&#237;veis de ACR podem ser alcan&#231;ados por meio de atividade f&#237;sica regular e isso deve ser promovido extensivamente atrav&#233;s de abordagens em toda a popula&#231;&#227;o. Os benef&#237;cios de sa&#250;de associados &#224; atividade f&#237;sica regular, que incluem componentes aer&#243;bicos e de treinamento de for&#231;a, n&#227;o podem ser enfatizados em excesso.<xref ref-type="bibr" rid="B11"><sup>11</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B14"><sup>14</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B16"><sup>16</sup></xref> Os esfor&#231;os para melhorar a ACR com um peso corporal saud&#225;vel podem se tornar uma parte padr&#227;o dos encontros cl&#237;nicos para o tratamento da IC com baixa fra&#231;&#227;o de eje&#231;&#227;o.</p>
  </body>
  <back>
    <fn-group>
      <fn fn-type="other" id="fn1">
        <p>Minieditorial referente ao artigo: O Impacto da Aptid&#227;o Cardiorrespirat&#243;ria no Paradoxo da Obesidade em Insufici&#234;ncia Card&#237;aca com Fra&#231;&#227;o de Eje&#231;&#227;o Reduzida</p>
      </fn>
    </fn-group>
    <ref-list>
      <title>Refer&#234;ncias</title>
      <ref id="B1">
        <label>1</label>
        <element-citation publication-type="journal">
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              <surname>Yancy</surname>
              <given-names>CW</given-names>
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              <surname>Jessup</surname>
              <given-names>M</given-names>
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            <name>
              <surname>Bozkurt</surname>
              <given-names>B</given-names>
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    <front-stub>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Short Editorial</subject>
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        <article-title>Is the Obesity Paradox in Heart Failure Dependent on Cardiorespiratory Fitness?</article-title>
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          </addr-line>
          <country country="FI">Finland</country>
          <institution content-type="original">Department of Medicine, Central Finland Health Care District, Jyv&#228;skyl&#228; - Finland</institution>
        </aff>
        <aff id="aff8">
          <label>3</label>
          <addr-line>
            <named-content content-type="city">Kuopio</named-content>
          </addr-line>
          <country country="FI">Finland</country>
          <institution content-type="original">Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio - Finland</institution>
        </aff>
        <aff id="aff9">
          <label>4</label>
          <addr-line>
            <named-content content-type="city">Bristol</named-content>
          </addr-line>
          <country country="GB">UK</country>
          <institution content-type="original">National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol - UK</institution>
        </aff>
        <aff id="aff10">
          <label>5</label>
          <addr-line>
            <named-content content-type="city">Bristol</named-content>
          </addr-line>
          <country country="GB">UK</country>
          <institution content-type="original">Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, Learning &amp; Research Building (Level 1), Southmead Hospital, Bristol - UK</institution>
        </aff>
      </contrib-group>
      <author-notes>
        <corresp id="c2"><bold>Mailing Address: Jari A. Laukkanen &#8226;</bold> Institute of Clinical Medicine, Department of Medicine, University of Eastern Finland, P.O. Box 1627, <postal-code>FIN-70211</postal-code> Kuopio - Finland, E-mail: <email>jariantero.laukkanen@uef.fi</email></corresp>
      </author-notes>
      <kwd-group xml:lang="en">
        <title>Keywords</title>
        <kwd>Heart Failure</kwd>
        <kwd>Obesity</kwd>
        <kwd>Cardiorespiratory Fitness</kwd>
        <kwd>Body Mass Index</kwd>
        <kwd>Exercise</kwd>
        <kwd>Hospitalization</kwd>
        <kwd>Morbity and Mortality</kwd>
      </kwd-group>
    </front-stub>
    <body>
      <p>Heart failure (HF) is a global public health menace which is associated with increased hospitalization, morbidity, mortality and high economic costs.<xref ref-type="bibr" rid="B1"><sup>1</sup></xref> However, HF which has ischemic heart disease as a common underlying disease, is a preventable condition. Cardiorespiratory fitness (CRF) is an index of habitual physical activity levels and is considered the gold standard for aerobic exercise capacity. Cardiorespiratory fitness, an important component of physical fitness and directly measured by peak oxygen uptake (pVO<sub>2</sub>), and ventilatory efficiency slope (VE/VCO<sub>2</sub> slope), has been identified as one of the most important predictors of health outcomes and survival.<xref ref-type="bibr" rid="B2"><sup>2</sup></xref> We have previously reported that directly assessed pVO<sub>2</sub> is strongly, independently and inversely related to a lowered risk of cardiometabolic conditions such as HF,<xref ref-type="bibr" rid="B2"><sup>2</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B3"><sup>3</sup></xref> atrial fibrillation,<xref ref-type="bibr" rid="B3"><sup>3</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B4"><sup>4</sup></xref> ventricular fibrillation,<xref ref-type="bibr" rid="B5"><sup>5</sup></xref> diabetes<xref ref-type="bibr" rid="B6"><sup>6</sup></xref> as well as mortality from cardiovascular diseases (CVDs).<xref ref-type="bibr" rid="B7"><sup>7</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B8"><sup>8</sup></xref> Our recent population-based study based on UK Biobank suggests that CRF is a strong risk indicator for mortality and addition of CRF to a conventional risk factor score improved the overall discrimination of mortality risk and, more importantly, the predictive value of CRF varied across levels of some relevant risk factors, including age, sex, and smoking.<xref ref-type="bibr" rid="B8"><sup>8</sup></xref> This is an indicator of the potential of CRF to be a valuable risk assessment tool in clinical practice.</p>
      <p>It is well-known that obesity, as measured by body mass index (BMI), is related to the development of cardiovascular outcomes. However, the combined effect of obesity and CRF on the risk of future HF still requires further study. It is of clinical relevance to understand if CRF attenuates the association of obesity with later risk of HF due to other underlying CVDs.<xref ref-type="bibr" rid="B9"><sup>9</sup></xref> The majority of previous studies on higher BMI, other obesity parameters, and HF risk have not taken into account the differences in CRF levels. Though high BMI is a risk factor for HF, there are findings of a non-linear relationship between BMI and CVD outcomes in HF patients which indicates an unusual relationship. In patients with established HF, accumulating evidence suggests that overweight and obese (higher BMI) individuals have improved survival compared to those with normal BMI, a known concept which has been called the &#8220;obesity paradox&#8221; or &#8220;reverse epidemiology&#8221;.<xref ref-type="bibr" rid="B10"><sup>10</sup></xref> Some mechanisms have been proposed to explain the HF obesity paradox which includes HF therapy being more effective in obese patients. It has been reported that CRF might play also play a role by either mitigating or negating the &#8220;obesity paradox&#8221;.<xref ref-type="bibr" rid="B10"><sup>10</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B11"><sup>11</sup></xref></p>
      <p>There is limited evidence on the association and interactions between CRF, BMI, HF and HF outcomes. This was the rationale for the new study by Moreira et al. published in the recent issue of the journal, which aimed to investigate the impact of exercise tolerance and cardiorespiratory capacity on the obesity paradox among HF patients with low ejection fraction.<xref ref-type="bibr" rid="B12"><sup>12</sup></xref> All patients referred to the Heart Failure Clinics underwent clinical evaluation with collection of laboratory, electro- and echocardiographic, and cardiopulmonary exercise test data. A maximal symptom-limited treadmill cardiopulmonary exercise test was performed using the modified Bruce protocol (GE Marquette Series 2000 treadmill). Minute ventilation, oxygen uptake, and carbon dioxide production were acquired using a breath-by-breath gas analyzer. A total of 282 HF patients were included (75.5% male) with a mean age of 53.7 years and BMI of 28.6 kg/m<sup>2</sup>. Patients were followed-up for 60 months for a combined composite endpoint comprising of cardiac death, urgent heart transplant, or need for mechanical circulatory support.<xref ref-type="bibr" rid="B12"><sup>12</sup></xref> Interestingly, patients with higher BMI had higher LVEF but lower ventilatory efficiency (VE/VCO<sub>2</sub>) slope.<xref ref-type="bibr" rid="B12"><sup>12</sup></xref> Association analysis showed BMI, VE/VCO<sub>2</sub> slope and pVO<sub>2</sub> to be each an indicator of the primary outcome. However, the association between BMI and outcome was attenuated to null when patients were grouped into low and high CRF (based on VE/VCO<sub>2</sub>) and after controlling for VE/VCO<sub>2</sub> or pVO<sub>2</sub>.</p>
      <p>Consistent with findings of this study, Chase et al. have earlier demonstrated that VE/VCO<sub>2</sub> slope maintained its prognostic value irrespective of BMI in patients with HF.<xref ref-type="bibr" rid="B13"><sup>13</sup></xref> However, when either VE/VCO<sub>2</sub> slope or pVO<sub>2</sub> were taken into account in their analyses, the association between BMI and cardiac outcomes were not significant. Moreover, when the patients were grouped and analyzed according to their CRF subgroups, BMI was not related to outcomes.<xref ref-type="bibr" rid="B13"><sup>13</sup></xref></p>
      <p>Given that the absolute risk of adverse CVD outcomes depends largely on age, employing a single relative metric cannot allow quantification of absolute risk differences across increasing ages with different BMI levels. Zaccardi et al.<xref ref-type="bibr" rid="B14"><sup>14</sup></xref> recently suggested a new approach to evaluate the interplay were to estimate residual life expectancy across CRF levels and BMI.<xref ref-type="bibr" rid="B14"><sup>14</sup></xref> Based on the large UK Biobank cohort including 474,919 participants, the authors demonstrated that participants with a brisk walking pace have a longer life expectancy across the spectrum of BMI and other fatness measures, providing additional data evidence that walking pace, as a marker of fitness level, is an easily available indicator of health status.</p>
      <p>The strengths of the current study include the use of a clinically relevant sample based on high-risk HF patients and the assessment of CRF measures using reliable respiratory gas analysis, which is a more objective and quantitative assessment method for CRF. Several limitations include (i) the small sample size; (ii) inability to adjust for many potential confounders; (iii) lack of data on medications, biomarkers, and physical activity patterns during follow-up, which could have at least partly influenced CRF and BMI levels; (iv) lack of formal risk prediction analyses as measures of association are insufficient for making clinical judgments about the prognostic relevance of an exposure; and (v) the potential for regression dilution given the absence of repeat measurements of CRF, given the potential for changes in CRF levels due to errors in measurements and changes in the clinical course of the disease. In our reproducibility substudies of CRF measurements within the Kuopio Ischemic Heart Disease (KIHD) prospective cohort study, we have demonstrated a high within-person variability in CRF levels measured many years apart (regression dilution ratio=0.58);<xref ref-type="bibr" rid="B15"><sup>15</sup></xref> which suggests that analyses using only single baseline measurements of CRF could underestimate associations with outcomes. Overall, these new findings highlight the fact that an &#8220;obesity paradox&#8221; exists in HF patients and there is an interplay between obesity, CRF and outcomes in HF. Cardiorespiratory fitness as measured by VE/VCO<sub>2</sub> or pVO<sub>2</sub> appeared to negate the obesity paradox.<xref ref-type="bibr" rid="B12"><sup>12</sup></xref></p>
      <p>CRF is influenced by genetic and environmental factors; approximately 50 % of the variation in CRF has been attributed to heritable factors, with the contribution of inherited factors to the response of CRF to physical activity and exercise training.<xref ref-type="bibr" rid="B7"><sup>7</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B8"><sup>8</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B11"><sup>11</sup></xref> It also depends on several factors such as baseline health and fitness status, type, duration, and intensity of PA. The level of CRF is also an indicator of a chain of multiple physiological processes that include: pulmonary ventilation and vascular function, right and left ventricular function, the capacity of the vasculature to ef&#64257;ciently transport blood from the heart to other organs matching their oxygen requirements, the ability of the muscle cells to use the oxygen and essential nutrients, and the ability to activate all necessary muscle &#64257;bres needed for body movement.<xref ref-type="bibr" rid="B11"><sup>11</sup></xref> Left ventricular stroke volume, maximal heart rate, and arteriovenous oxygen difference at exercise have essentially determined CRF levels. Left ventricular function is a key measure of HF and CRF level may reflect LV function. As CRF is related to the integration of human body function under physiological stress conditions, it can be employed as a very accurate indicator of the risk for HF, re&#64258;ecting whole body functional status among patients with existing HF. Given the central role normal cardiac function plays in defining maximal aerobic capacity, disease, or dysfunction that detrimentally affects cardiac output will also compromise maximal VO<sub>2</sub>. High-intensity aerobic exercise training is safe and effective in improving functional capacity in many patient populations with cardiac conditions.<xref ref-type="bibr" rid="B11"><sup>11</sup></xref> Participation in a long-term aerobic exercise training program produces a host of positive morphological and physiological cardiovascular adaptations in apparently healthy individuals, irrespective of age and sex. Commonly reported morphological adaptations associated with regular aerobic exercise training is left ventricular dilation (ie, increased end-diastolic diameter) and hypertrophy (ie, increased wall thickness), referred to as exercise training-induced cardiac remodelling.<xref ref-type="bibr" rid="B16"><sup>16</sup></xref></p>
      <p>The current findings throw more light on a possible interaction between CRF, obesity and outcomes in HF. However, given the limitations of small sample size and inability to adjust for relevant covariates, these observational study findings need caution when being interpreted. Findings add to the minefield of accumulating evidence that CRF (using peak VO<sub>2</sub> and measures of ventilatory efficiency) is a clinically useful tool in HF risk assessment. High levels of CRF can be achieved through regular physical activity and this should be promoted extensively via population wide approaches. The health benefits associated with regular physical activity, which includes aerobic and strength training components, cannot be overemphasized.<xref ref-type="bibr" rid="B11"><sup>11</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B14"><sup>14</sup></xref><sup>,</sup><xref ref-type="bibr" rid="B16"><sup>16</sup></xref> Efforts to improve CRF with a healthy body weight could become a standard part of clinical encounters for the treatment of HF with low ejection fraction.</p>
    </body>
    <back>
      <fn-group>
        <fn fn-type="other" id="fn2">
          <p>Short Editoral related to the article: Impact of Cardiorespiratory Fitness on the Obesity Paradox in Heart Failure with Reduced Ejection Fraction</p>
        </fn>
      </fn-group>
    </back>
  </sub-article>
</article>
