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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">PnrWq3HhwcNJsxkSfnYT93c</article-id>
      <article-id specific-use="scielo-v2" pub-id-type="publisher-id">S0066-782X2022000800342</article-id>
      <article-id pub-id-type="publisher-id">abc.20211029</article-id>
      <article-id pub-id-type="doi">10.36660/abc.20211029</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Ponto de Vista</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Medicina Translacional e Ci&#234;ncia da Implementa&#231;&#227;o: Como Transformar o que Sabemos no que Efetivamente Fazemos</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-2451-5570</contrib-id>
          <name>
            <surname>Luz</surname>
            <given-names>Prot&#225;sio Lemos da</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
          <xref ref-type="corresp" rid="c1"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Laurindo</surname>
            <given-names>Francisco Rafael Martins</given-names>
          </name>
          <xref ref-type="aff" rid="aff1">
            <sup>1</sup>
          </xref>
        </contrib>
        <aff id="aff1">
          <label>1</label>
          <institution content-type="orgname">Universidade de S&#227;o Paulo</institution>
          <institution content-type="orgdiv1">Faculdade de Medicina</institution>
          <institution content-type="orgdiv2">Instituto do Cora&#231;&#227;o (InCor)</institution>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brasil</country>
          <institution content-type="original">Instituto do Cora&#231;&#227;o (InCor) da Faculdade de Medicina da Universidade de S&#227;o Paulo HC-FMUSP, S&#227;o Paulo, SP &#8211; Brasil</institution>
        </aff>
      </contrib-group>
      <author-notes>
        <corresp id="c1"><bold>Correspond&#234;ncia: Prot&#225;sio Lemos da Luz</bold> &#8226; Av. Dr. En&#233;as de Carvalho Aguiar, 44, 5 andar, Bloco II, sala 08. CEP <postal-code>05403-000</postal-code>, Cerqueira C&#233;sar, S&#227;o Paulo, SP &#8211; Brasil. E-mail: <email>protasio.luz@incor.usp.br</email> </corresp>
        <fn fn-type="con">
          <p>
            <bold>Contribui&#231;&#227;o dos autores</bold>
          </p>
          <p>Reda&#231;&#227;o do manuscrito: Luz PL, Laurindo FRM.</p>
        </fn>
        <fn fn-type="conflict">
          <p>
            <bold>Potencial Conflito de Interesse</bold>
          </p>
          <p>Declaro n&#227;o haver conflito de interesses pertinentes.</p>
        </fn>
      </author-notes>
      <pub-date date-type="pub" publication-format="electronic">
        <day>05</day>
        <month>08</month>
        <year>2022</year>
      </pub-date>
      <pub-date date-type="collection" publication-format="electronic">
        <month>08</month>
        <year>2022</year>
      </pub-date>
      <volume>119</volume>
      <issue>2</issue>
      <fpage>342</fpage>
      <lpage>345</lpage>
      <history>
        <date date-type="received">
          <day>16</day>
          <month>12</month>
          <year>2021</year>
        </date>
        <date date-type="rev-recd">
          <day>20</day>
          <month>01</month>
          <year>2022</year>
        </date>
        <date date-type="accepted">
          <day>09</day>
          <month>02</month>
          <year>2022</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</license-p>
        </license>
      </permissions>
      <kwd-group xml:lang="pt">
        <title>Palavras-chave</title>
        <kwd>Pesquisa M&#233;dica Translacional/tend&#234;ncias</kwd>
        <kwd>Colesterol</kwd>
        <kwd>Aterosclerose</kwd>
        <kwd>Genoma Humano</kwd>
        <kwd>Inibidores de Hidroximetilglutaril-CoA Redutases/uso terap&#234;utico</kwd>
        <kwd>Doen&#231;as Cardiovasculares/mortalidade</kwd>
        <kwd>Exerc&#237;cios</kwd>
        <kwd>Qualidade de Vida</kwd>
        <kwd>Medicina Preventiva</kwd>
      </kwd-group>
      <counts>
        <fig-count count="0"/>
        <table-count count="0"/>
        <equation-count count="0"/>
        <ref-count count="23"/>
        <page-count count="4"/>
      </counts>
    </article-meta>
  </front>
  <body>
    <p>A Medicina Translacional engloba basicamente tr&#234;s &#225;reas: 1) a acelera&#231;&#227;o de transmiss&#227;o de conhecimentos de pesquisa b&#225;sica &#224; aplica&#231;&#227;o cl&#237;nica; 2) an&#225;lise causal e da fisiopatologia de observa&#231;&#245;es cl&#237;nicas, pela intera&#231;&#227;o com ci&#234;ncia b&#225;sica; e 3) implementa&#231;&#227;o, na popula&#231;&#227;o geral, de conhecimentos b&#225;sicos e conceitos oriundos de pesquisas cl&#237;nicas e experimentais, tamb&#233;m chamada Ci&#234;ncia da Implementa&#231;&#227;o. No passado, muitas descobertas fundamentais ficaram apenas no dom&#237;nio das ci&#234;ncias b&#225;sicas, levando-se muitos anos at&#233; se transformarem em instrumentos diagn&#243;sticos ou tratamentos aplic&#225;veis &#224; pr&#225;tica m&#233;dica.</p>
    <p>Um exemplo elucidativo &#233; a rela&#231;&#227;o entre colesterol e aterosclerose. As primeiras demonstra&#231;&#245;es de que colesterol induzia aterosclerose foram feitas pelos russos, em coelhos, entre 1908 e 1913.<sup><xref ref-type="bibr" rid="B1">1</xref></sup> O Framingham Heart Study,<sup><xref ref-type="bibr" rid="B2">2</xref></sup> publicado em 1961, foi o primeiro estudo demostrando esse fato em humanos. No entanto, a primeira estatina s&#243; foi produzida em 1976, inaugurando a era atual do tratamento medicamentoso da aterosclerose.<sup><xref ref-type="bibr" rid="B3">3</xref></sup> Esse enorme hiato ocorreu em muitas outras circunst&#226;ncias e representa um desperd&#237;cio do conhecimento e de vidas humanas.</p>
    <sec>
      <title>Base da medicina preventiva: estilo de vida sadio</title>
      <p>Quando se procura aplicar conhecimentos m&#233;dicos &#224; popula&#231;&#227;o geral, o conceito de estilo de vida sadio deve ser salientado, sobretudo quando se pretende enfatizar a medicina preventiva.</p>
      <p>A maioria dos eventos cardiovasculares, tais como infarto do mioc&#225;rdio e morte, est&#227;o associados a fatores de risco como dislipidemia, tabagismo, hipertens&#227;o e diabetes.<sup><xref ref-type="bibr" rid="B4">4</xref></sup> Fatores gen&#233;ticos representam a minoria. Outro exemplo &#233; o estudo Whitehall, conduzido na Inglaterra,<sup><xref ref-type="bibr" rid="B5">5</xref></sup> que mostrou que trabalhadores p&#250;blicos que ocupavam posi&#231;&#245;es hier&#225;rquicas inferiores no trabalho morriam tr&#234;s a quatro vezes mais que aqueles em posi&#231;&#245;es superiores. A base da medicina preventiva depende de estilo de vida sadio, incluindo dieta predominante em vegetais, frutas e peixes, associada &#224; baixa ingest&#227;o de carnes vermelhas e carboidratos. Exerc&#237;cios aer&#243;bicos e de for&#231;a, no m&#237;nimo 150 minutos/semana s&#227;o fortemente indicados, inclusive para prote&#231;&#227;o de fun&#231;&#245;es cognitivas e preven&#231;&#227;o de Alzheimer.<sup><xref ref-type="bibr" rid="B6">6</xref></sup></p>
      <p>Exerc&#237;cios e dieta s&#227;o essenciais na preven&#231;&#227;o e tratamento do diabetes, hipertens&#227;o e obesidade, e v&#225;rios programas para combate ao tabagismo est&#227;o dispon&#237;veis, com consider&#225;veis &#237;ndices de sucesso. No livro Zonas Azuis,<sup><xref ref-type="bibr" rid="B7">7</xref></sup> pesquisadores americanos analisaram o estilo de vida das cinco popula&#231;&#245;es mais longevas do mundo: Okinawa (Jap&#227;o), Sardenha (It&#225;lia), Ikaria (Gr&#233;cia), Loma Linda (Calif&#243;rnia) e Nicoya (Costa Rica). Alguns costumes s&#227;o comuns a todos: dieta baseada em gr&#227;os, frutas, vegetais e peixes com pouca carne vermelha; vida social intensa; religiosidade; valoriza&#231;&#227;o da fam&#237;lia; trabalhos bra&#231;ais rotineiros como andar a p&#233; e cuidar de animais, cozinhar e cuidar da casa; e uso restrito de medicamentos. Fatores gen&#233;ticos n&#227;o parecem ser a &#250;nica explica&#231;&#227;o dessa longevidade visto que s&#227;o popula&#231;&#245;es de diferentes pa&#237;ses e sem qualquer parentesco.</p>
      <p>Estresses emocionais de qualquer origem s&#227;o fatores causais de eventos cardiovasculares. O aumento exponencial de tais condi&#231;&#245;es durante a pandemia COVID-19 confirmam essas circunst&#226;ncias.<sup><xref ref-type="bibr" rid="B8">8</xref>,<xref ref-type="bibr" rid="B9">9</xref></sup></p>
      <p>Um aspecto peculiar do estilo de vida saud&#225;vel &#233; a dificuldade de implementa&#231;&#227;o em adultos, e isso representa importante desafio para a medicina translacional no seu terceiro componente que &#233; justamente a popula&#231;&#227;o geral. Por exemplo, resultados de iniciativas para implementar h&#225;bitos saud&#225;veis em crian&#231;as e adolescentes, como demonstrado no Brasil e outros pa&#237;ses<sup><xref ref-type="bibr" rid="B10">10</xref>,<xref ref-type="bibr" rid="B11">11</xref></sup> impressionam &#8211; as crian&#231;as vigiando os pais para que n&#227;o fumem, fa&#231;am exerc&#237;cios e sigam uma boa dieta! Hulsegge et al.,<sup><xref ref-type="bibr" rid="B12">12</xref></sup> observaram que indiv&#237;duos que mantiveram 4-5 h&#225;bitos sadios por cinco anos tiveram 2,5 vezes menos risco de doen&#231;as cardiovasculares e mortalidade global comparados aos que n&#227;o fizeram.</p>
      <p>&#201; importante considerar o contexto em que tal implementa&#231;&#227;o ocorre, ou seja, em hospitais, em programas educacionais, no Sistema &#218;nico de Sa&#250;de (SUS) ou na medicina privada, em consultas <italic>online</italic> e outros. Estrat&#233;gias diferentes s&#227;o necess&#225;rias dependendo do contexto.</p>
    </sec>
    <sec>
      <title>Medicina de precis&#227;o</title>
      <p>Hoje prescrevemos medica&#231;&#245;es com base em resultados de pesquisas que demonstraram que determinadas doses de medicamentos s&#227;o eficientes. Isso n&#227;o leva em considera&#231;&#227;o respostas individuais; ou seja, tratamos a m&#233;dia, sem identificar quem s&#227;o os respondedores e os n&#227;o respondedores. Os efeitos colaterais tamb&#233;m s&#227;o relatados assim. Por outro lado, os estudos randomizados n&#227;o incluem pacientes com comorbidades, e estudam apenas 6-8% da popula&#231;&#227;o doente, o que n&#227;o representa o mundo real. Evidentemente, isso causa erros e dificuldades no ajuste de doses.</p>
      <p>A farmacogen&#233;tica permite uma caracteriza&#231;&#227;o mais precisa dos pacientes quanto &#224; resposta a agentes externos, e permitir&#225; uma individualiza&#231;&#227;o de tratamentos, como por exemplo, na preven&#231;&#227;o de rea&#231;&#245;es al&#233;rgicas. Em suma, o conhecimento do genoma humano e das respostas do organismo permitir&#227;o a individualiza&#231;&#227;o de tratamentos considerando a resposta a contraste, intoler&#226;ncia a agentes externos, e sensibilidade a sal, antiagregantes plaquet&#225;rios e anticoagulantes. Claro que isso ainda n&#227;o &#233; pr&#225;tica corrente; mas logo ser&#225;.</p>
    </sec>
    <sec>
      <title>Desigualdades socioecon&#244;micas tem grande impacto na incid&#234;ncia de doen&#231;as</title>
      <p>O Whitehall Study<sup><xref ref-type="bibr" rid="B5">5</xref></sup> mostrou uma rela&#231;&#227;o entre menor n&#237;vel de satisfa&#231;&#227;o no emprego e maior mortalidade. Desde ent&#227;o, in&#250;meros estudos mostraram que o n&#237;vel educacional, recursos financeiros e n&#237;veis sociais influenciam na preval&#234;ncia de doen&#231;a e mortalidade;<sup><xref ref-type="bibr" rid="B13">13</xref></sup> a causa n&#227;o &#233; apenas psicol&#243;gica. Indiv&#237;duos melhor posicionados t&#234;m mais conhecimento das doen&#231;as, t&#234;m acesso a melhores centros m&#233;dicos e podem pagar gastos com sa&#250;de. Esse &#233; um problema universal, mais relacionado &#224; economia e desenvolvimento social, mas que se reflete na sa&#250;de.</p>
    </sec>
    <sec>
      <title>Comorbidades em idosos e multidisciplinaridade</title>
      <p>A popula&#231;&#227;o est&#225; envelhecendo. Comorbidades como doen&#231;as cardiovasculares, c&#226;nceres, doen&#231;as reum&#225;ticas, renais, metab&#243;licas, inflamat&#243;rias, urol&#243;gicas, respirat&#243;rias, neurol&#243;gicas (dem&#234;ncias, Alzheimer) e psiqui&#225;tricas s&#227;o muito frequentes entre idosos. Raramente se encontra um paciente idoso com uma s&#243; doen&#231;a. Da&#237; a necessidade de m&#250;ltiplos especialistas para se tomar a melhor conduta em casos mais complexos.<sup><xref ref-type="bibr" rid="B14">14</xref>,<xref ref-type="bibr" rid="B15">15</xref></sup> Em conson&#226;ncia com esse conceito, uma metan&#225;lise concluiu que um trabalho em equipe (<italic>teamwork</italic>) relaciona-se positivamente com o desempenho cl&#237;nico.<sup><xref ref-type="bibr" rid="B16">16</xref></sup></p>
    </sec>
    <sec>
      <title>Estabelecimento de riscos a m&#233;dio e longo prazo</title>
      <p>Embora escores de risco para doen&#231;as cardiovasculares sejam imperfeitos, s&#227;o muito &#250;teis quando se trata de convencer pacientes em adotar um estilo de vida saud&#225;vel, em realizar avalia&#231;&#245;es peri&#243;dicas e a usar as medica&#231;&#245;es. Como algumas doen&#231;as s&#227;o silenciosas (hipertens&#227;o, diabetes mellitus, aterosclerose) estabelecer riscos &#233; de suma import&#226;ncia pr&#225;tica. Embora os escores mais usados projetam riscos para 10 anos, hoje se calculam riscos em 30 anos.</p>
      <p>T&#233;cnicas e par&#226;metros especiais, como o escore de c&#225;lcio coron&#225;rio, radiois&#243;topos e ecocardiograma permitem recalcular riscos, mais precisamente reclassificar indiv&#237;duos.<sup><xref ref-type="bibr" rid="B17">17</xref></sup> &#205;ndices inflamat&#243;rios como PCR ultrassens&#237;vel e escores gen&#244;micos tamb&#233;m podem contribuir para aperfei&#231;oar proje&#231;&#227;o de riscos. Lipoprote&#237;nas n&#227;o convencionais como lipoprote&#237;na (a), colesterol n&#227;o HDL, part&#237;culas ricas em triglic&#233;ride, apolipoprote&#237;na CIII, <italic>angiopoietin-like protein 3</italic> (ANGPTL3), <italic>angiopoietin-like protein</italic> 4 (ANGPTL4), apolipoprote&#237;na IV, apolipoprote&#237;na E, e variantes g&#234;nicas, como PCSK9 podem influenciar no risco cardiovascular.<sup><xref ref-type="bibr" rid="B18">18</xref></sup> O grande m&#233;rito de calcular riscos &#233; poder argumentar junto aos pacientes sobre a necessidade de vigil&#226;ncia constante e tomada de decis&#245;es.</p>
    </sec>
    <sec>
      <title>Uso criterioso de tecnologias: risco versus benef&#237;cio</title>
      <p>Novos avan&#231;os tecnol&#243;gicos s&#227;o em geral ben&#233;ficos, por&#233;m t&#234;m seu lado perigoso. Exemplos s&#227;o diagn&#243;sticos de les&#245;es tireoidianas, mam&#225;rias e prost&#225;ticas m&#237;nimas que desencadearam interven&#231;&#245;es &#8220;preventivas&#8221; desnecess&#225;rias.<sup><xref ref-type="bibr" rid="B19">19</xref></sup> O mesmo pode-se dizer das t&#233;cnicas de imagem &#8211; cintilografia, tomografias coron&#225;rias e interven&#231;&#245;es percut&#226;neas &#8211; o uso indiscriminado de tais tecnologias sobrecarrega o sistema de sa&#250;de, aumenta custos e cria ang&#250;stia nos pacientes. Pa&#237;ses como Reino Unido e Canad&#225; j&#225; adotam medidas para evitar &#8220;excessos&#8221;. No Brasil, tamb&#233;m dever&#237;amos adotar medidas para avaliar a qualidade do exerc&#237;cio profissional na medicina (como efetuado, por exemplo, pela Ordem dos Advogados do Brasil). O or&#231;amento federal &#233; insuficiente para atender a maioria da popula&#231;&#227;o, que depende do SUS, e n&#227;o pode admitir desperdi&#231;o. Saliente-se aqui a import&#226;ncia dos hospitais de ensino, nos quais t&#233;cnicas inovadoras podem ser criticamente avaliadas.</p>
    </sec>
    <sec>
      <title>Trabalho em equipe (&#8220;<italic>Teamwork</italic>&#8221;)</title>
      <p>Dada a complexidade de certos casos, comorbidades, diferentes capacidades institucionais e experi&#234;ncias individuais, trabalhar em equipes multiprofissionais &#233; uma maneira eficiente de oferecer o melhor aos pacientes. No caso da cardiologia, normalmente um cl&#237;nico, um intervencionista, um cirurgi&#227;o ou arritmologista devem compor a equipe.<sup><xref ref-type="bibr" rid="B20">20</xref>,<xref ref-type="bibr" rid="B21">21</xref></sup></p>
      <p>Na pr&#225;tica, a indica&#231;&#245;es de procedimentos &#233; influenciada pela experi&#234;ncia individual; por exemplo, hemodinamicistas podem ter prefer&#234;ncias por interven&#231;&#245;es percut&#226;neas enquanto cirurgi&#245;es podem se inclinar por cirurgias. Na verdade, h&#225; argumentos que apoiam um ou outro procedimento, baseados no car&#225;ter n&#227;o-invasivo, em registros sobre a evolu&#231;&#227;o a longo prazo bem como na efici&#234;ncia de tratamentos medicamentosos e estilo de vida do paciente. Al&#233;m disso, a r&#225;pida evolu&#231;&#227;o de t&#233;cnicas de investiga&#231;&#227;o e tratamentos, e sobretudo a experi&#234;ncia particular dos m&#233;dicos e centros m&#233;dicos tamb&#233;m contribuem para poss&#237;veis diferen&#231;as de opini&#245;es. Portanto, o <italic>Heart Team</italic> serve para minimizar esses vieses. Em meio a estas circunst&#226;ncias, &#233; preciso lembrar que o paciente deve ser esclarecido e consultado sobre suas prefer&#234;ncias.</p>
    </sec>
    <sec>
      <title>Qualidade da pesquisa &#8211; base do processo de transla&#231;&#227;o</title>
      <p>Os argumentos acima nos levam ao conceito fundamental de que a medicina translacional necessita de alta qualidade cient&#237;fica em todas as suas etapas. Desde a obten&#231;&#227;o de dados experimentais <italic>in vitro</italic>, <italic>ex vivo</italic> ou <italic>in vivo</italic> passando por estudos cl&#237;nicos de fases I a III, at&#233; a implementa&#231;&#227;o do conhecimento na popula&#231;&#227;o, o rigor cient&#237;fico deve ser observado. Idealmente, estudos cl&#237;nicos randomizados, com desfechos relevantes e bem definidos, e n&#250;mero de pacientes e tempo de evolu&#231;&#227;o adequados s&#227;o prefer&#237;veis. Uma dificuldade inerente aos estudos randomizados s&#227;o os altos custos e a demora na obten&#231;&#227;o dos resultados. H&#225; fatores que influenciam claramente a implementa&#231;&#227;o de boas pr&#225;ticas &#224; popula&#231;&#227;o, como o uso <italic>off label</italic> de medicamentos, influ&#234;ncias econ&#244;micas, e concep&#231;&#227;o err&#244;nea da aplica&#231;&#227;o do livre arb&#237;trio m&#233;dico. Por outro lado, existem hoje t&#233;cnicas de randomiza&#231;&#227;o mendeliana, estudos de associa&#231;&#227;o do genoma completo (<italic>GWAS, Genome Wide Association Studies</italic>), e &#8220;big data&#8221; com contribui&#231;&#245;es da intelig&#234;ncia artificial e inform&#225;tica, que possibilitam investiga&#231;&#245;es mais aprofundadas com elucida&#231;&#245;es de causas e mecanismos fisiopatol&#243;gicos.<sup><xref ref-type="bibr" rid="B22">22</xref>,<xref ref-type="bibr" rid="B23">23</xref></sup> No caso de interven&#231;&#245;es, a efici&#234;ncia cl&#237;nica &#233; o mais importante para o m&#233;dico. No final, a medicina tem sua credibilidade alicer&#231;ada em princ&#237;pios do m&#233;todo cient&#237;fico.</p>
    </sec>
  </body>
  <back>
    <fn-group>
      <fn fn-type="supported-by" id="fn1">
        <p>
          <bold>Fontes de Financiamento</bold>
        </p>
        <p>O presente estudo foi financiado por F. Zerbini &#8211; Banco Bradesco SA.</p>
      </fn>
      <fn fn-type="other" id="fn2">
        <p>
          <bold>Vincula&#231;&#227;o Acad&#234;mica</bold>
        </p>
        <p>N&#227;o h&#225; vincula&#231;&#227;o deste estudo a programas de p&#243;s-gradua&#231;&#227;o.</p>
      </fn>
      <fn fn-type="other" id="fn3">
        <p>
          <bold>Aprova&#231;&#227;o &#233;tica e consentimento informado</bold>
        </p>
        <p>Este artigo n&#227;o cont&#233;m estudos com humanos ou animais realizados por nenhum dos autores.</p>
      </fn>
    </fn-group>
    <ref-list>
      <title>Refer&#234;ncias</title>
      <ref id="B1">
        <label>1</label>
        <element-citation publication-type="book">
          <person-group person-group-type="author">
            <name>
              <surname>da Luz</surname>
              <given-names>PL</given-names>
            </name>
          </person-group>
          <source>As novas faces da medicina</source>
          <publisher-loc>S&#227;o Paulo</publisher-loc>
          <publisher-name>Editora Manole</publisher-name>
          <year>2014</year>
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  <sub-article article-type="translation" id="S01" xml:lang="en">
    <front-stub>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Viewpoint</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Translational Medicine and Implementation Science: How to Transform What We Know Into What We Do</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <contrib-id contrib-id-type="orcid">0000-0003-2451-5570</contrib-id>
          <name>
            <surname>Luz</surname>
            <given-names>Prot&#225;sio Lemos da</given-names>
          </name>
          <xref ref-type="aff" rid="aff2">
            <sup>1</sup>
          </xref>
          <xref ref-type="corresp" rid="c2"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Laurindo</surname>
            <given-names>Francisco Rafael Martins</given-names>
          </name>
          <xref ref-type="aff" rid="aff2">
            <sup>1</sup>
          </xref>
        </contrib>
        <aff id="aff2">
          <label>1</label>
          <addr-line>
            <named-content content-type="city">S&#227;o Paulo</named-content>
            <named-content content-type="state">SP</named-content>
          </addr-line>
          <country country="BR">Brazil</country>
          <institution content-type="original">Instituto do Cora&#231;&#227;o (InCor) da Faculdade de Medicina da Universidade de S&#227;o Paulo HC-FMUSP, S&#227;o Paulo, SP &#8211; Brazil</institution>
        </aff>
      </contrib-group>
      <author-notes>
        <corresp id="c2"><bold>Mailing Address: Prot&#225;sio Lemos da Luz</bold> &#8226; Av. Dr. En&#233;ias de Carvalho Aguiar, 44, 5 andar, Bloco II, sala 08. Postal Code <postal-code>05403-000</postal-code>, Cerqueira C&#233;sar, S&#227;o Paulo, SP &#8211; Brazil. E-mail: <email>protasio.luz@incor.usp.br</email> </corresp>
        <fn fn-type="con">
          <p>
            <bold>Author Contributions</bold>
          </p>
          <p>Writing of the manuscript: Luz PL, Laurindo FRM.</p>
        </fn>
        <fn fn-type="conflict">
          <p>
            <bold>Potential Conflict of Interest</bold>
          </p>
          <p>No potential conflict of interest relevant to this article was reported.</p>
        </fn>
      </author-notes>
      <kwd-group xml:lang="en">
        <title>Keywords</title>
        <kwd>Translational Medical Research</kwd>
        <kwd>Cholesterol</kwd>
        <kwd>Atherosclerosis</kwd>
        <kwd>Genome Human</kwd>
        <kwd>Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use</kwd>
        <kwd>Cardiovascular Diseases/mortality</kwd>
        <kwd>Exercises</kwd>
        <kwd>Quality of Life</kwd>
        <kwd>Preventive Medicine</kwd>
      </kwd-group>
    </front-stub>
    <body>
      <p>Translational Medicine encompasses three areas: 1) acceleration of knowledge transmission from basic science to clinical practice; 2) analysis of the causes and pathophysiology of clinical observations through interaction with basic science; and 3) implementation of basic knowledge and concepts produced by clinical and experimental research in the general population, which is also known as &#8220;implementation science&#8221;. In the past, some fundamental discoveries stayed confined to the basic science for long years before becoming diagnostic instruments or therapies applicable to practice.</p>
      <p>An instructive example is the relationship between cholesterol and atherosclerosis. The first evidence that cholesterol induced atherosclerosis came from studies conducted on rabbits by Russians between 1908 and 1913.<sup><xref ref-type="bibr" rid="B1">1</xref></sup> The Framingham Heart Study,<sup><xref ref-type="bibr" rid="B2">2</xref></sup> published in 1961, was the first to demonstrate this fact in humans. However, statin was first produced only in 1976, starting the current era of pharmacological treatment of atherosclerosis.<sup><xref ref-type="bibr" rid="B3">3</xref></sup> This huge gap occurred in other contexts and represents a waste of knowledge and human lives.</p>
      <sec>
        <title>Basis of preventive medicine: a healthy lifestyle</title>
        <p>When medical knowledge is to be applied to the general population, the concept of healthy lifestyle should be highlighted, especially in terms of preventive medicine.</p>
        <p>Most cardiovascular events, such as myocardial infarction and death, are associated with risk factors such as dyslipidemia, smoking, hypertension and diabetes.<sup><xref ref-type="bibr" rid="B4">4</xref></sup> Genetic factors are less representative. Another example is the Whitehall study, conducted with British civil servants,<sup><xref ref-type="bibr" rid="B5">5</xref></sup> that showed that servants in lower grades of employments had a mortality rate three to four times higher than of those in the higher grades. The basis of preventive medicine is related to a healthy lifestyle, including a diet composed predominantly of fruit, vegetable and fish, and low intake of meat and carbohydrates. At least 150 minutes per week of aerobic and strength exercises are strongly recommended, including for protection of cognitive functions and Alzheimer prevention.<sup><xref ref-type="bibr" rid="B6">6</xref></sup></p>
        <p>Exercise and diet are essential for preventing and treating diabetes, hypertension and obesity, and several anti-smoking programs are currently available, with remarkable success rates. In the book &#8220;Blue Zones&#8221;,<sup><xref ref-type="bibr" rid="B7">7</xref></sup> American researchers evaluated the lifestyle of the five longest-lived communities in the world &#8211; Okinawa (Japan), Sardinia (Italy), Ikaria (Greece), Loma Lima (California) and Nicoya (Costa Rica). Some habits were shared by these communities &#8211; a diet mainly consisting of grains, fruits, vegetables, and fish, and poor in meat; active social life; religiosity; putting family first; manual labors like walking, taking care of animals, cooking, and taking care of the house; and restricted use of medications. Genetic factors cannot solely explain longevity of these populations, as they live in different countries and have no family relationship.</p>
        <p>Emotional stress of any cause is a causal factor of cardiovascular events. The exponential increase of these conditions during the COVID-19 pandemic confirms these circumstances.<sup><xref ref-type="bibr" rid="B8">8</xref>,<xref ref-type="bibr" rid="B9">9</xref></sup></p>
        <p>It is noteworthy, however, that a healthy lifestyle is difficult to be implemented in adults. This represents an important challenge for translational medicine, particularly for its third component that concerns the general population. Results of initiatives to implement healthy habits in children and adolescents, as reported in Brazil and other countries,<sup><xref ref-type="bibr" rid="B10">10</xref>,<xref ref-type="bibr" rid="B11">11</xref></sup> for example, are impressive &#8211; children asking their parents not to smoke, to exercise and to follow a good diet! Hulsegge et al.<sup><xref ref-type="bibr" rid="B12">12</xref></sup> found that individuals who maintained four to five healthy lifestyle factors over a five-year period had 2.5 times lower risk of cardiovascular disease and all-cause mortality than those who did not.</p>
        <p>In addition, it is important to consider in which context these initiatives have been implemented &#8211; in hospitals, educational programs, in the unified health system facilities or in private centers, by online consultations or others. Different contexts require different strategies.</p>
      </sec>
      <sec>
        <title>Precision medicine</title>
        <p>Today, medications are prescribed based on results of studies that showed their effective doses, which does not take into account individual responses, <italic>i.e</italic>., doses have been established based on mean responses, without identifying who are responders and non-responders to the treatment. Side effects are described in a similar manner. On the other hand, randomized trials do not include patients with comorbidities and study only 6-8% of patients with the disease, which does not represent the real world. This causes errors and difficulties in adjusting medication doses.</p>
        <p>Pharmacogenetics provides a more precise characterization of patients in terms of individualized responses to external agents and may form the basis for tailored therapies, as in preventing allergic reactions. Briefly, the knowledge of the human genome and the body responses will allow individualization of treatments considering the response to contrasts, intolerance to external agents, and sensitivity to salt, antiplatelet agents, and anticoagulants. Although this is not a current practice, it will be soon.</p>
      </sec>
      <sec>
        <title>Socioeconomic inequality has a great impact on disease incidence</title>
        <p>The Whitehall study<sup><xref ref-type="bibr" rid="B5">5</xref></sup> showed a relationship between a lower level of job satisfaction and higher mortality. Since then, several studies have shown that educational attainment, financial resources and social level have an influence on disease prevalence and mortality<sup><xref ref-type="bibr" rid="B13">13</xref></sup> due to factors other than psychological ones. Individuals with higher status are more aware of their diseases, have greater access to better health care and are more able to pay health costs. This is a universal problem that is more related to economy and social development, but affects health.</p>
      </sec>
      <sec>
        <title>Comorbidities in the elderly and Multidisciplinarity</title>
        <p>The population is aging. Comorbidities like cardiovascular diseases, cancers, rheumatic, renal, metabolic, inflammatory, urological, respiratory, neurological (dementia, Alzheimer disease) and psychiatric diseases are far more common among the elderly. It is rare to find an older patient with only one disease. For this reason, several specialists would be needed to provide the best care for patients with complex conditions.<sup><xref ref-type="bibr" rid="B14">14</xref>,<xref ref-type="bibr" rid="B15">15</xref></sup> In fact, a meta-analysis concluded that a teamwork is positively related to clinical performance.<sup><xref ref-type="bibr" rid="B16">16</xref></sup></p>
      </sec>
      <sec>
        <title>Establishment of medium and long-term risks</title>
        <p>Although cardiovascular risk scores are imperfect, they are helpful in convincing patients to adopt a healthy lifestyle, to undergo periodic evaluations and to comply with medication regimens. Some diseases (e.g. hypertension, diabetes mellitus and atherosclerosis) are &#8220;silent&#8221; and hence the establishment of risks is of highly practical importance. Although the most used scores estimate 10-year risks, today the risk level of cardiovascular risks is estimated over a 30-year period.</p>
        <p>Special techniques and parameters, like the coronary calcium score, radioisotopes and echocardiography allow recalculation of the risk, or more precisely, reclassification of patients.<sup><xref ref-type="bibr" rid="B17">17</xref></sup> Inflammatory markers like high-sensitivity C-reactive protein and genomic scores can also improve risk projections. Unconventional lipoproteins may also be helpful, including the lipoprotein(a), non-HDL cholesterol, triglyceride-rich lipoproteins, apolipoprotein CIII, angiopoietin-like protein 3 (ANGPTL3), angiopoietin-like protein 4 (ANGPTL4), apolipoprotein IV, apolipoprotein E, and genetic variants like PCSK9 can influence the cardiovascular risk.<sup><xref ref-type="bibr" rid="B18">18</xref></sup> The great advantage of risk calculation is to use it as an instrument to show patients the importance of continuous monitoring and decision making.</p>
      </sec>
      <sec>
        <title>Judicious use of technologies: risks versus benefits</title>
        <p>Technological advances are generally beneficial but may be hazardous. For example, the diagnosis of minimal lesions of thyroid, breast and prostate has led to &#8220;preventive&#8221;, unnecessary interventions.<sup><xref ref-type="bibr" rid="B19">19</xref></sup> The same is true for imaging tests &#8211; scintigraphy, coronary computed tomography and percutaneous interventions &#8211; the indiscriminate use of these technologies overburdens the health care system, increases costs and causes patient anxiety. Countries like the United Kingdom and Canada have adopted measures to prevent &#8220;excesses&#8221;. In Brazil, the quality of medical practice should be systematically evaluated (as performed by the Order of Attorneys of Brazil). The federal budget is insufficient to cover the health costs of the majority of the population, users of the federal public health system, and thus waste cannot be accepted. In addition, medical school hospitals play an important role in critically evaluating the innovative techniques.</p>
      </sec>
      <sec>
        <title>Teamwork</title>
        <p>Due to the complexity of some cases, presence of comorbidities, different institutional capacities and individual experiences, multidisciplinary teams are an effective way to provide the best care to the patients. In Cardiology, multidisciplinary teams should include a clinician, an interventionist, a surgeon and an arrhythmia specialist.<sup><xref ref-type="bibr" rid="B20">20</xref>,<xref ref-type="bibr" rid="B21">21</xref></sup></p>
        <p>In clinical practice, the indication for procedures is influenced by individual experiences. For example, while catheterization specialists may prefer percutaneous interventions, surgeons may be inclined to surgeries. In fact, there are arguments to support one or the other treatment option, based on its non-invasive character, long-term outcomes of the disease, as well as efficacy of previous drug treatments and patient lifestyle. Also, the fast development of assessment tools and therapeutic strategies, and individual experience of physicians and medical centers also contribute to differences of opinions. In this context, the Heart Team serves to minimize these biases. It is also worth emphasizing that the patient should be informed and asked about his/her preferences.</p>
      </sec>
      <sec>
        <title>Research quality &#8211; basis of the translational process</title>
        <p>The arguments mentioned above lead to the fundamental concept that translational medicine requires high-quality science in its every step. Scientific accuracy must exist from the collection of <italic>in vitro</italic>, <italic>ex vivo</italic> and <italic>in vivo</italic> data, development of phase I and II clinical trials, until the application of knowledge. Ideally, randomized clinical trials, with well-defined, relevant outcomes, and adequate number of patients and time of follow-up are preferred. A difficulty inherent to randomized studies is the high costs and long time to obtain results. There are some factors that have a clear influence on the implementation of good practice in the population, like the off-label use of drugs, economic issues, and an erroneous notion of free will among physicians. On the other hand, methods such as Mendelian randomization, Genome Wide Association Studies (GWAS), and the Big Data, with contributions from artificial intelligence and informatics, allow deeper investigations and elucidation of causes and pathophysiological mechanisms.<sup><xref ref-type="bibr" rid="B22">22</xref>,<xref ref-type="bibr" rid="B23">23</xref></sup> Regarding interventions, clinical efficacy is the most important issue for physicians. Credibility in Medicine is then grounded in the principles of scientific method.</p>
      </sec>
    </body>
    <back>
      <fn-group>
        <fn fn-type="supported-by" id="fn4">
          <p>
            <bold>Sources of Funding</bold>
          </p>
          <p>This study was funded by F. Zerbini &#8211; Banco Bradesco SA.</p>
        </fn>
        <fn fn-type="other" id="fn5">
          <p>
            <bold>Study Association</bold>
          </p>
          <p>This study is not associated with any thesis or dissertation work.</p>
        </fn>
        <fn fn-type="other" id="fn6">
          <p>
            <bold>Ethics approval and consent to participate</bold>
          </p>
          <p>This article does not contain any studies with human participants or animals performed by any of the authors.</p>
        </fn>
      </fn-group>
    </back>
  </sub-article>
</article>
