<!DOCTYPE article PUBLIC "-//NLM//DTD JATS (Z39.96) Journal Publishing DTD v1.1 20151215//EN" "https://jats.nlm.nih.gov/publishing/1.1/JATS-journalpublishing1.dtd">
<article xmlns:xlink="http://www.w3.org/1999/xlink" specific-use="sps-1.9" dtd-version="1.1" xml:lang="pt" article-type="research-article">
  <front>
    <journal-meta>
      <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-loc>S&#227;o Paulo, SP, Brazil</publisher-loc>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v3">FPDHKsWxVdDbkKQnjChFDws</article-id>
      <article-id pub-id-type="other">00012</article-id>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v2">S0066-782X2010001200012</article-id>
      <article-id pub-id-type="publisher-id" specific-use="scielo-v1">S0066-782X(10)09500212</article-id>
      <article-id pub-id-type="doi">10.1590/S0066-782X2010005000086</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Artigos Originais</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Oftalmoscopia direta versus retinografia da detec&#231;&#227;o de retinopatia hipertensiva: estudo comparativo</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Figueiredo Neto</surname>
            <given-names>Jos&#233; Albuquerque de</given-names>
          </name>
          <xref ref-type="aff" rid="aff01"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Pal&#225;cio</surname>
            <given-names>Guilherme Lima</given-names>
          </name>
          <xref ref-type="aff" rid="aff01"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Santos</surname>
            <given-names>Allison Nobrega dos</given-names>
          </name>
          <xref ref-type="aff" rid="aff01"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Chaves</surname>
            <given-names>Pamela Suelen Serra</given-names>
          </name>
          <xref ref-type="aff" rid="aff01"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Gomes</surname>
            <given-names>Germana Viana</given-names>
          </name>
          <xref ref-type="aff" rid="aff01"/>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Cabral</surname>
            <given-names>Tassiane Soares</given-names>
          </name>
          <xref ref-type="aff" rid="aff01"/>
        </contrib>
      </contrib-group>
      <aff id="aff01">
        <addr-line>
          <named-content content-type="city">S&#227;o Luiz</named-content>
          <named-content content-type="state">Maranh&#227;o</named-content>
        </addr-line>
        <institution content-type="orgname">Universidade Federal do Maranh&#227;o</institution>
        <country country="BR">Brazil</country>
      </aff>
      <pub-date date-type="collection" publication-format="electronic">
        <month>08</month>
        <year>2010</year>
      </pub-date>
      <volume>95</volume>
      <issue>2</issue>
      <fpage>215</fpage>
      <lpage>222</lpage>
      <history>
        <date date-type="received">
          <day>09</day>
          <month>09</month>
          <year>2009</year>
        </date>
        <date date-type="rev-recd">
          <day>23</day>
          <month>11</month>
          <year>2009</year>
        </date>
        <date date-type="accepted">
          <day>29</day>
          <month>12</month>
          <year>2009</year>
        </date>
      </history>
      <permissions>
        <license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/" xml:lang="en">
          <license-p>This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.</license-p>
        </license>
      </permissions>
      <abstract>
        <p>FUNDAMENTO: Detec&#231;&#227;o de retinopatia hipertensiva (RH) com oftalmoscopia direta &#233; parte da avalia&#231;&#227;o de pacientes hipertensos. Sua utiliza&#231;&#227;o tem sido questionada devido a sua subjetividade e alta variabilidade interobservador. OBJETIVO: Determinar a preval&#234;ncia de RH em hipertensos em acompanhamento ambulatorial, a concord&#226;ncia do diagn&#243;stico com a oftalmoscopia e a retinografia e correlacion&#225;-la com outras les&#245;es de &#243;rg&#227;o-alvo. M&#201;TODOS: Estudo observacional, anal&#237;tico e transversal, com a avalia&#231;&#227;o de 99 pacientes. Oftalmoscopia direta e retinografia realizadas por dois examinadores de forma independente. Classifica&#231;&#227;o da RH, conforme descrito por Keith, Wagener e Barker. RESULTADOS: A preval&#234;ncia da RH de qualquer grau foi maior que 90,0%, por ambos os m&#233;todos. Na oftalmoscopia, observamos altera&#231;&#245;es de grau I em 51,0%, e de grau II em 43,0%, com um paciente apresentando RH de grau III. Na retinografia, observamos altera&#231;&#245;es de grau I em 42,0%, e grau II em 52,0%, sendo detectados tr&#234;s pacientes com RH de grau III, dois dos quais n&#227;o detectados pela oftalmoscopia. A concord&#226;ncia entre os observadores para a presen&#231;a e gravidade de RH foi fraca com oftalmoscopia direta e boa com a retinografia. Disfun&#231;&#227;o renal, altera&#231;&#245;es eletrocardiogr&#225;ficas (hipertrofia ventricular, onda q patol&#243;gica, altera&#231;&#227;o de repolariza&#231;&#227;o), e hist&#243;ria de acidente vascular cerebral foram observadas em 70,0%, 27,0% e 10,0% dos pacientes, respectivamente. N&#227;o houve rela&#231;&#227;o entre a gravidade da RH e as demais les&#245;es de &#243;rg&#227;o-alvo. CONCLUS&#195;O: Foi observada uma alta preval&#234;ncia de RH por ambos os m&#233;todos. A concord&#226;ncia entre os observadores para o diagn&#243;stico e determina&#231;&#227;o da gravidade da RH foi melhor com a retinografia. N&#227;o houve, na amostra estudada, associa&#231;&#227;o da gravidade da RH com outras les&#245;es de &#243;rg&#227;o-alvo.</p>
      </abstract>
      <kwd-group xml:lang="pt" kwd-group-type="author-generated">
        <kwd>Oftalmoscopia</kwd>
        <kwd>retina</kwd>
        <kwd>hipertens&#227;o</kwd>
      </kwd-group>
      <pub-date publication-format="electronic" date-type="pub">
        <day>09</day>
        <month>07</month>
        <year>2010</year>
      </pub-date>
    </article-meta>
  </front>
  <body>
    <p>ARTIGO ORIGINAL </p>
    <p> HIPERTENS&#195;O ARTERIAL SIST&#202;MICA</p>
    <p>
      <bold>Oftalmoscopia direta <italic>versus</italic> retinografia da detec&#231;&#227;o de retinopatia hipertensiva: estudo comparativo</bold>
    </p>
    <p>
      <bold>Jos&#233; Albuquerque de Figueiredo Neto; Guilherme Lima Pal&#225;cio; Allison Nobrega dos Santos; Pamela Suelen Serra Chaves; Germana Viana Gomes; Tassiane Soares Cabral</bold>
    </p>
    <p>Universidade Federal do Maranh&#227;o, S&#227;o Luiz, MA - Brasil</p>
    <p>
      <xref ref-type="corresp" rid="endb">Correspond&#234;ncia</xref>
    </p>
    <p>
      <bold>RESUMO</bold>
    </p>
    <p><bold>FUNDAMENTO:</bold> Detec&#231;&#227;o de retinopatia hipertensiva (RH) com oftalmoscopia direta &#233; parte da avalia&#231;&#227;o de pacientes hipertensos. Sua utiliza&#231;&#227;o tem sido questionada devido a sua subjetividade e alta variabilidade interobservador. </p>
    <p><bold>OBJETIVO:</bold> Determinar a preval&#234;ncia de RH em hipertensos em acompanhamento ambulatorial, a concord&#226;ncia do diagn&#243;stico com a oftalmoscopia e a retinografia e correlacion&#225;-la com outras les&#245;es de &#243;rg&#227;o-alvo. </p>
    <p><bold>M&#201;TODOS:</bold> Estudo observacional, anal&#237;tico e transversal, com a avalia&#231;&#227;o de 99 pacientes. Oftalmoscopia direta e retinografia realizadas por dois examinadores de forma independente. Classifica&#231;&#227;o da RH, conforme descrito por Keith, Wagener e Barker. </p>
    <p><bold>RESULTADOS:</bold> A preval&#234;ncia da RH de qualquer grau foi maior que 90,0%, por ambos os m&#233;todos. Na oftalmoscopia, observamos altera&#231;&#245;es de grau I em 51,0%, e de grau II em 43,0%, com um paciente apresentando RH de grau III. Na retinografia, observamos altera&#231;&#245;es de grau I em 42,0%, e grau II em 52,0%, sendo detectados tr&#234;s pacientes com RH de grau III, dois dos quais n&#227;o detectados pela oftalmoscopia. A concord&#226;ncia entre os observadores para a presen&#231;a e gravidade de RH foi fraca com oftalmoscopia direta e boa com a retinografia. Disfun&#231;&#227;o renal, altera&#231;&#245;es eletrocardiogr&#225;ficas (hipertrofia ventricular, onda q patol&#243;gica, altera&#231;&#227;o de repolariza&#231;&#227;o), e hist&#243;ria de acidente vascular cerebral foram observadas em 70,0%, 27,0% e 10,0% dos pacientes, respectivamente. N&#227;o houve rela&#231;&#227;o entre a gravidade da RH e as demais les&#245;es de &#243;rg&#227;o-alvo. </p>
    <p><bold>CONCLUS&#195;O:</bold> Foi observada uma alta preval&#234;ncia de RH por ambos os m&#233;todos. A concord&#226;ncia entre os observadores para o diagn&#243;stico e determina&#231;&#227;o da gravidade da RH foi melhor com a retinografia. N&#227;o houve, na amostra estudada, associa&#231;&#227;o da gravidade da RH com outras les&#245;es de &#243;rg&#227;o-alvo.</p>
    <p><bold>Palavras-chave:</bold> Oftalmoscopia, retina/les&#245;es, hipertens&#227;o.</p>
    <p>
      <bold>Introdu&#231;&#227;o</bold>
    </p>
    <p>Retinopatia hipertensiva (RH) &#233; uma condi&#231;&#227;o caracterizada por um espectro de sinais vasculares retinianos que se desenvolvem em pessoas com hipertens&#227;o arterial<sup>1</sup>. Sua detec&#231;&#227;o com oftalmoscopia direta (OD) &#233; parte da avalia&#231;&#227;o de pacientes hipertensos<sup>2</sup>, mas sua utiliza&#231;&#227;o tem sido questionada devido a sua subjetividade e a alta variabilidade do interobservador<sup> 3</sup>.</p>
    <p>O s&#233;timo <italic>"Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" </italic>e as V Diretrizes Brasileiras de Hipertens&#227;o Arterial listam a RH como um dos marcadores de les&#227;o de &#243;rg&#227;o-alvo, sendo, portanto, crit&#233;rio para indica&#231;&#227;o de tratamento<sup>4,5</sup>.</p>
    <p>Estudos cl&#225;ssicos sobre altera&#231;&#245;es retinianas em HA s&#227;o atualmente questionados devido a alguns fatores<sup>6,7</sup>: inclus&#227;o de pacientes n&#227;o tratados ou n&#227;o controlados, diagn&#243;stico realizado somente com OD e associa&#231;&#227;o da RH com mortalidade em estudos onde n&#227;o havia controle de outros fatores de risco atualmente conhecidos, que poderiam atuar com fatores de confus&#227;o<sup>8-11</sup>.</p>
    <p>Estudos recentes, utilizando retinografia<sup>12-17</sup>, mostraram alta reprodutibilidade na avalia&#231;&#227;o de microaneurismas, hemorragias, cruzamentos arteriovenosos anormais, estreitamentos arteriolares focais ou generalizados. Contudo, poucos estudos comparam a sensibilidade e reprodutibilidade entre a retinografia e a OD na detec&#231;&#227;o de RH<sup>18</sup>.</p>
    <p>Outro questionamento no estudo da RH &#233; que alguns sinais parecem estar associados a determinadas condi&#231;&#245;es cl&#237;nicas<sup>19</sup>.</p>
    <p>Realizamos este estudo devido a import&#226;ncia da HA como causa de morbimortalidade, a aus&#234;ncia de dados sobre a preval&#234;ncia de RH em nosso meio, a aus&#234;ncia de estudos comparando a OD com a retinografia no seu diagn&#243;stico e as incertezas quanto &#224; utilidade da sua detec&#231;&#227;o na avalia&#231;&#227;o do risco cardiovascular e associa&#231;&#227;o com outras les&#245;es de &#243;rg&#227;o-alvo.</p>
    <p>Os objetivos foram determinar a preval&#234;ncia da RH em pacientes em acompanhamento numa Liga de Hipertens&#227;o Arterial de um Hospital Universit&#225;rio, avaliar a concord&#226;ncia entre a OD e a retinografia digital (RD) na detec&#231;&#227;o de RH; estudar a associa&#231;&#227;o de RH com outras les&#245;es de &#243;rg&#227;o-alvo.</p>
    <p>
      <bold>Metodologia</bold>
    </p>
    <p>
      <bold>Tipo de estudo</bold>
    </p>
    <p>Estudo transversal, anal&#237;tico, realizado de jun-dez/2008, em uma Liga de Hipertens&#227;o Arterial de um Hospital Universit&#225;rio.</p>
    <p>Amostra</p>
    <p>Os pacientes foram selecionados por conveni&#234;ncia &#224; propor&#231;&#227;o que se apresentaram para as consultas de rotina, observando-se os crit&#233;rios de exclus&#227;o do estudo, que foram:</p>
    <disp-quote>
      <p>a. Diabete melito; </p>
      <p>b. Opacidades de meios (leucoma, hemorragia v&#237;trea, catarata); </p>
      <p>c. Descolamento de retina; </p>
      <p>d. Falta de dados cl&#237;nicos sist&#234;micos no prontu&#225;rio da Liga de Hipertens&#227;o.</p>
    </disp-quote>
    <p>Foram examinados consecutivamente 131 pacientes. Foram exclu&#237;dos 32 pacientes: um por duplicidade de avalia&#231;&#227;o, tr&#234;s por opacidade de meios ao exame oftalmol&#243;gico, 6 devido a dados insuficientes em seu prontu&#225;rio e 22 por apresentar diabete. Foram avaliados 99 pacientes.</p>
    <p>
      <bold>Coleta de dados</bold>
    </p>
    <p>Realizada atrav&#233;s de exames cl&#237;nicos e oftalmol&#243;gicos, a saber:</p>
    <disp-quote>
      <p>a. Exames cl&#237;nicos - os pacientes foram submetidos a exame cl&#237;nico sist&#234;mico, sendo avaliada a presen&#231;a de fatores de risco para doen&#231;a cardiovascular e categorizada a sua hipertens&#227;o, quanto &#224; gravidade, de acordo com as V Diretrizes Brasileiras de Hipertens&#227;o Arterial<sup>4</sup>.</p>
      <p> b. Exames laboratoriais de rotina - an&#225;lise de urina, pot&#225;ssio e creatinina, glicemia de jejum, colesterol total, LDL, HDL e triglic&#233;rides - de acordo com a V Diretrizes Brasileiras de Hipertens&#227;o Arterial<sup>4</sup>. </p>
      <p>c. Eletrocardiograma de 12 deriva&#231;&#245;es, sendo avaliada altera&#231;&#245;es compat&#237;veis com sobrecarga ventricular esquerda (crit&#233;rio Cornell), e avaliada presen&#231;a de onda q patol&#243;gica e altera&#231;&#227;o da repolariza&#231;&#227;o ventricular.</p>
    </disp-quote>
    <p>O <italic>cleareance</italic> estimado de creatinina foi calculado de acordo com a f&#243;rmula de Cockcroft-Gault. A diminui&#231;&#227;o da fun&#231;&#227;o renal foi considerada quando menor de 60 ml/min. </p>
    <p>Exame oftalmol&#243;gico foi realizado, incluindo medida da acuidade visual, biomicroscopia e tonometria de aplana&#231;&#227;o. Tamb&#233;m se realizaram oftalmoscopia direta com oftalmosc&#243;pio coaxial 3.5 V (Welch Allyn, Skaneateles Falls, Estados Unidos) e retinografia com equipamento CF60 Uvi (Canon, T&#243;quio, Jap&#227;o) com sistema digital Eye Q Pro (Canon, T&#243;quio, Jap&#227;o), ap&#243;s dilata&#231;&#227;o pupilar com Tropicamida 1,0% col&#237;rio. As imagens foram obtidas em campo de 60 graus, centradas no centro da m&#225;cula. </p>
    <p>Cada paciente foi submetido &#224; fundoscopia por dois oftalmologistas, com experi&#234;ncia semelhante e de forma independente. As retinografias tamb&#233;m foram interpretadas por esses m&#233;dicos, sem conhecimento pr&#233;vio das condi&#231;&#245;es cl&#237;nicas dos pacientes, de forma independente. Em um segundo momento, foi realizada uma nova interpreta&#231;&#227;o de forma consensual. Foi realizada classifica&#231;&#227;o da RH conforme descrito por Keith, Wagener e Barker<sup>6</sup>. </p>
    <p>
      <bold>An&#225;lise estat&#237;stica</bold>
    </p>
    <p>Os dados foram avaliados pelo programa Epi Info 3.4.3 (2007). As vari&#225;veis quantitativas foram apresentadas em m&#233;dias e desvio-padr&#227;o. As vari&#225;veis qualitativas foram apresentadas em frequ&#234;ncias e porcentagens.</p>
    <p>Quanto aos achados fundosc&#243;picos e retinogr&#225;ficos, foi avaliado o coeficiente de concord&#226;ncia Kappa entre os examinadores. A concord&#226;ncia foi considerada pobre em casos de coeficiente Kappa menor que 0,20; fraca, entre 0,21-0,40; moderada, entre 0,41-0,60; boa, entre 0,61-0,80; e muito boa quando foi maior do que 0,80.</p>
    <p>Para verificar a associa&#231;&#227;o entre os fatores de risco e a gravidade da RH foi utilizado o teste exato de Fisher. Foi adotado um n&#237;vel de signific&#226;ncia de 5,0%.</p>
    <p>
      <bold>Aspectos &#233;ticos</bold>
    </p>
    <p>Os dados foram coletados ap&#243;s a aprova&#231;&#227;o pelo Comit&#234; de &#201;tica em Pesquisa da institui&#231;&#227;o (Processo 33104-178/2007) e os pacientes assinaram um Termo de Consentimento Livre e Esclarecido.</p>
    <p>
      <bold>Resultados</bold>
    </p>
    <p>Foram avaliados 99 pacientes, cujos aspectos demogr&#225;ficos se apresentam na <xref ref-type="table" rid="tab1">Tabela 1</xref>.</p>
    <table-wrap id="tab1">
      <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt01.jpg"/></table-wrap>
    <p>A an&#225;lise da presen&#231;a de fatores de risco para doen&#231;as cardiovasculares revelou que os mesmos n&#227;o possu&#237;am fator de risco, al&#233;m da HA em 9,1% dos casos, um ou dois fatores em 45,5% e tr&#234;s ou mais fatores ou doen&#231;a cardiovascular em 24,2% (<xref ref-type="table" rid="tab2">Tabela 2</xref>).</p>
    <table-wrap id="tab2">
      <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt02.jpg"/></table-wrap>
    <p>Quanto ao tempo de diagn&#243;stico da hipertens&#227;o, 42,4% dos pacientes tinham menos que 6 anos, 21,2%, entre 6 e 10, e 36,4% mais do que 10 anos. N&#227;o foi observada associa&#231;&#227;o entre o tempo de diagn&#243;stico e a presen&#231;a de retinopatia (p &gt; 0,05). </p>
    <p>O estadiamento da HA pode ser observado na <xref ref-type="table" rid="aop08110a02tab03m">Tabela 3</xref>. </p>
    <p content-type="asset">
      <table-wrap id="aop08110a02tab03m">
        <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt03.jpg"/></table-wrap>
    </p>
    <p>A frequ&#234;ncia das les&#245;es de &#243;rg&#227;o-alvo consta na <xref ref-type="table" rid="aop08110a02tab04m">Tabela 4</xref>.</p>
    <p content-type="asset">
      <table-wrap id="aop08110a02tab04m">
        <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt04.jpg"/></table-wrap>
    </p>
    <p>A preval&#234;ncia de RH utilizando a OD e a retinografia digital, bem como o consenso da retinografia pelos dois observadores, est&#225; representada na <xref ref-type="table" rid="aop08110a02tab05m">Tabela 5</xref>.</p>
    <p content-type="asset">
      <table-wrap id="aop08110a02tab05m">
        <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt05.jpg"/></table-wrap>
    </p>
    <p>O coeficiente de concord&#226;ncia entre os observadores para a presen&#231;a de RH com OD foi fraco, com Kappa igual a 0,22 IC 95% [0,38 - 0,83].</p>
    <p>Entretanto, houve bom coeficiente de concord&#226;ncia para a presen&#231;a de RH com retinografia digital, com valor de Kappa igual a 0,66 IC 95% [0,00 - 1,37].</p>
    <p>Quando avaliamos o coeficiente de concord&#226;ncia entre os observadores na distin&#231;&#227;o de retinopatia grau I e grau II atrav&#233;s da OD, este mostrou-se fraco, com Kappa igual a 0,33 IC 95% [0,13 - 0,52].</p>
    <p>Nessa mesma an&#225;lise de distin&#231;&#227;o de gravidade de RH entre os graus I e II, observou-se boa concord&#226;ncia quando utilizada a retinografia digital, com Kappa igual a 0,70 IC 95% [0,55 - 0,84].</p>
    <p>N&#227;o foi observada rela&#231;&#227;o entre a gravidade da RH e os est&#225;gios de HA quando utilizado o consenso entre os examinadores pela retinografia digital (<xref ref-type="table" rid="aop08110a02tab06m">Tabela 6</xref>).</p>
    <p content-type="asset">
      <table-wrap id="aop08110a02tab06m">
        <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt06.jpg"/></table-wrap>
    </p>
    <p>Disfun&#231;&#227;o renal esteve presente em 20,2% dos pacientes. N&#227;o foi observada rela&#231;&#227;o entre o grau da retinopatia e a gravidade da disfun&#231;&#227;o renal (<xref ref-type="table" rid="aop08110a02tab07m">Tabela 7</xref>).</p>
    <p content-type="asset">
      <table-wrap id="aop08110a02tab07m">
        <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt07.jpg"/></table-wrap>
    </p>
    <p>Foram analisados eletrocardiogramas de 90 pacientes e observadas altera&#231;&#245;es eletrocardiogr&#225;ficas em 27,3% destes. N&#227;o foi observada rela&#231;&#227;o entre o grau de retinopatia e altera&#231;&#245;es eletrocardiogr&#225;ficas (<xref ref-type="table" rid="aop08110a02tab08m">Tabela 8</xref>).</p>
    <p content-type="asset">
      <table-wrap id="aop08110a02tab08m">
        <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt08.jpg"/></table-wrap>
    </p>
    <p>Hist&#243;ria de acidente vascular cerebral esteve presente em 10 pacientes da amostra. No entanto, n&#227;o foi estabelecida rela&#231;&#227;o entre hist&#243;ria positiva de AVC e a gravidade da RH.</p>
    <p>N&#227;o houve associa&#231;&#227;o entre a ra&#231;a e a gravidade da RH.</p>
    <p>
      <bold>Discuss&#227;o</bold>
    </p>
    <p>Diretrizes internacionais consideram os achados retinianos de forma diferente. Para a Sociedade Europeia de Hipertens&#227;o e a Sociedade Europeia de Cardiologia, a RH grau III e IV da classifica&#231;&#227;o de Keith, Wagener e Barker &#233; considerada condi&#231;&#227;o cl&#237;nica associada<sup>6,20</sup>. A Sociedade Internacional de Hipertens&#227;o da Organiza&#231;&#227;o Mundial de Sa&#250;de e as Diretrizes da Sociedade Brit&#226;nica de Hipertens&#227;o consideram os graus III e IV de Keith, Wagener e Barker como les&#227;o de &#243;rg&#227;o-alvo<sup>21,22</sup>.J&#225; o Comit&#234; Nacional de Preven&#231;&#227;o, Detec&#231;&#227;o, Avalia&#231;&#227;o e Tratamento de Hipertens&#227;o Arterial dos Estados Unidos e as V Diretrizes Brasileiras de Hipertens&#227;o Arterial consideram a presen&#231;a de qualquer sinal de retinopatia como les&#227;o de &#243;rg&#227;o-alvo<sup>4,5</sup>.</p>
    <p>Neste estudo, utilizando a OD e considerando a presen&#231;a de qualquer sinal de retinopatia, observamos preval&#234;ncia acima de 90,0%, com altera&#231;&#245;es de grau I em 51,0%, e de grau II em 43%. Um paciente apresentou RH grau III, n&#227;o sendo observado nenhum paciente com grau IV. Os achados mais frequentes foram estreitamento arteriolar difuso e opacidades da parede arteriolar e cruzamentos arteriovenosos patol&#243;gicos. Considerando apenas les&#245;es avan&#231;adas (Grau III e IV), a preval&#234;ncia de RH seria de 1,0%. </p>
    <p>No <italic>Framingham Eye Study</italic>, com OD, em uma popula&#231;&#227;o geral, com idade entre 52-85 anos, a preval&#234;ncia de retinopatia foi de 0,8%, exclu&#237;dos os pacientes diab&#233;ticos. O conceito de retinopatia inclu&#237;a somente formas avan&#231;adas como hemorragias e exsudatos retinianos, sem considerar altera&#231;&#245;es da parede arteriolar<sup>18</sup>.</p>
    <p>McDonough, Garrison e Hames<sup>23</sup>, utilizando OD, avaliando 2.210 pessoas, observaram que 2,2% apresentavam retinopatia, definida como a presen&#231;a de microaneurismas, hemorragias ou exsudatos. Quando avaliados sinais mais precoces de retinopatia, 34,0% apresentavam estreitamento arteriolar generalizado ou focal, e 13,2%, cruzamentos AV patol&#243;gicos<sup>23</sup>.</p>
    <p>Besharati e cols.<sup>24</sup>, estudando 213 pacientes hipertensos com OD, encontraram preval&#234;ncia de 39,9%, considerando qualquer sinal de retinopatia. Naqueles com hipertens&#227;o leve, a preval&#234;ncia foi de 25,3%, nos paciente com hipertens&#227;o moderada foi de 34,5%, e com hipertens&#227;o severa foi de 84,6%. Os achados mais comuns foram estreitamento arteriolar (35,13%), cruzamento arteriovenoso patol&#243;gico (17,12%) e manchas algodonosas (9,0%)<sup>24</sup>.</p>
    <p>Neste estudo, o coeficiente de concord&#226;ncia, para o diagn&#243;stico e a gravidade da RH, mostrou uma concord&#226;ncia fraca, utilizando-se a OD. </p>
    <p>A utiliza&#231;&#227;o da OD na avalia&#231;&#227;o de pacientes hipertensos apresenta imprecis&#227;o e grande variabilidade interobservador, sendo particularmente impreciso nas pessoas com hipertens&#227;o de leve a moderada<sup>2,8</sup>.</p>
    <p>Neste estudo, a detec&#231;&#227;o de RH utilizando a retinografia foi superior a 90,0%, com altera&#231;&#245;es de grau I em 42,0% e de grau II em 52,0%, sendo detectados tr&#234;s pacientes com RH grau III, dois dos quais n&#227;o detectados pela OD. Nenhum paciente com grau IV foi observado. Considerando apenas les&#245;es avan&#231;adas (Grau III e IV), a preval&#234;ncia de RH seria de 3,0%.</p>
    <p>Utilizando retinografia e metodologia padronizada para documenta&#231;&#227;o e defini&#231;&#227;o dos v&#225;rios sinais de RH, estudos epidemiol&#243;gicos mostraram preval&#234;ncia variando de 2-15,0% na popula&#231;&#227;o geral<sup>10,12,25-27</sup>. </p>
    <p>O <italic>Beaver Dam Eye Study</italic><sup>12</sup>, utlizando retinografia, avaliou 2.375 pessoas n&#227;o diab&#233;ticas, de 43-86 anos, encontrou estreitamento arteriolar focal em 14,0%, retinopatia em 8,0%, e cruzamentos AV patol&#243;gicos em 2,0%. Quando hipertensos foram exclu&#237;dos, observou-se estreitamento arteriolar focal em 11,0%, retinopatia em 6,0% e cruzamentos AV patol&#243;gicos em 2,0%. Inferindo-se, portante, que as anormalidades microvasculares retinianas s&#227;o comuns em popula&#231;&#245;es n&#227;o diab&#233;ticas, embora sejam mais prevalentes em pacientes com hipertens&#227;o<sup>12</sup>.</p>
    <p>No <italic>Blue Mountains Eye Study</italic><sup>27</sup>, 3.275 pessoas n&#227;o diab&#233;ticas foram submetidas &#224; retinografia. A preval&#234;ncia de retinopatia foi de 9,9%. J&#225; o <italic>Atherosclerossis Risk in Communities</italic> (ARIC) <italic>Study</italic><sup>25</sup> estudou atrav&#233;s de retinografia, 9.300 pessoas acima de 49 anos, sem diabete. A preval&#234;ncia de estreitamento arteriolar focal foi de 6,0%, retinopatia de 3,0% e cruzamento AV patol&#243;gico de 6,0%. </p>
    <p>A maior preval&#234;ncia de retinopatia observada nesses estudos, comparados ao estudo <italic>Framingham</italic>, pode ser devido &#224; maior sensibilidade das t&#233;cnicas de avalia&#231;&#227;o fotogr&#225;fica que a oftalmoscopia. Contudo, tais estudos n&#227;o inclu&#237;am o sinal mais precoce de RH, o estreitamento arteriolar generalizado<sup>13</sup>.</p>
    <p>Neste estudo, o coeficiente de concord&#226;ncia para a detec&#231;&#227;o e avalia&#231;&#227;o da gravidade da RH utilizando a retinografia foi superior &#224;quele encontrado com a utiliza&#231;&#227;o da OD.</p>
    <p>Cuspidi e cols.<sup>28</sup> avaliaram 197 pacientes com HA grau I (73,0%) e II, sem tratamento pr&#233;vio, atrav&#233;s de retinografia digital, com dois observadores independentes. A preval&#234;ncia geral de altera&#231;&#245;es retinianas foi de 84,3% e 84,7%, respectivamente.</p>
    <p>Neste estudo, n&#227;o foi encontrada rela&#231;&#227;o da retinopatia com a idade, sexo, tempo de diagn&#243;stico e est&#225;gio da HA. Dados do estudo <italic>Beaver Dam </italic>e <italic>ARIC </italic>sugerem que a preval&#234;ncia de estreitamento arteriolar e cruzamento AV patol&#243;gico parecem ter rela&#231;&#227;o direta com a idade. A preval&#234;ncia de retinopatia tamb&#233;m foi idade dependente no estudo <italic>Blue Mountains</italic><sup>12,24,26</sup>.</p>
    <p>A preval&#234;ncia de retinopatia foi maior no sexo masculino, quando ajustada &#224; idade, tanto no estudo <italic>Beaver Dam </italic>quanto no <italic>ARIC</italic>. No entanto, no <italic>Blue Mountains, </italic>nenhuma diferen&#231;a foi observada<sup>11,25,27</sup>.</p>
    <p>Na literatura, &#233; relatado que estreitamento arteriolar generalizado e cruzamentos arteriovenosos patol&#243;gicos podem ser observados mais comumente em pacientes com maior tempo de diagn&#243;stico de HA, sendo, portanto, sinais de dano vascular cr&#244;nico. Por outro lado, estreitamento arteriolar focal, hemorragias retinianas, microaneurismas e manchas algodonosas estariam relacionados ao estado atual do n&#237;vel de HA<sup>13,19</sup>.</p>
    <p>A distribui&#231;&#227;o da gravidade da RH, neste estudo, de acordo com a classifica&#231;&#227;o de Keith, Wagener e Barker se apresentou da seguinte forma: Grau I - 42 pacientes (42,4%), grau II - 52 pacientes (52,6%), grau III - 3 pacientes (3%) e grau IV - nenhum paciente. </p>
    <p>A alta frequ&#234;ncia de sinais precoces de retinopatia, incluindo os graus I e II de Keith, Wagener e Barker, e a baixa frequ&#234;ncia de sinais mais intensos, graus III e IV, podem estar associada ao tempo de evolu&#231;&#227;o da HA e ao tratamento e controle regular dos n&#237;veis press&#243;ricos<sup>6</sup>.</p>
    <p>Neste estudo, foi observada disfun&#231;&#227;o renal em 20,2% dos pacientes. Contudo, n&#227;o foi estabelecida associa&#231;&#227;o entre a disfun&#231;&#227; renal e a presen&#231;a e gravidade da RH. No estudo <italic>ARIC</italic>, indiv&#237;duos com retinopatia (odds ratio 2,0; intervalo de confian&#231;a de 95,0%, 1,4-2,8), microaneurismas (OR, 2,0; IC 95,0%,1,3-3,1), hemorragias retinianas (OR, 2,6; IC 95,0%,1,6-4,0), manchas algodonosas(OR, 2,7; IC 95,0%,1,6-4,8) e cruzamentos arteriovenosos patol&#243;gicos (OR, 1,4; IC 95,0%,1,0-1,9) apresentaram maior chance de desenvolver disfun&#231;&#227;o renal que indiv&#237;duos sem altera&#231;&#245;es retinianas<sup>11</sup>.</p>
    <p>Foram observadas altera&#231;&#245;es eletrocardiogr&#225;ficas compat&#237;veis com hipertrofia ventricular esquerda, presen&#231;a de ondas q patol&#243;gicas e altera&#231;&#245;es de repolariza&#231;&#227;o ventricular em 27,0% dos pacientes. Gillum<sup>29</sup> observou que o estreitamento arteriolar retiniano detectado pela oftalmoscopia determinava de 2-6 vezes mais chances de apresentar doen&#231;a card&#237;aca isqu&#234;mica, ap&#243;s an&#225;lise controlada para hipertens&#227;o, diabete e hipercolesterolemia.</p>
    <p> Duncan e cols.<sup>30</sup> demonstraram que a presen&#231;a de RH em homens duplicava a chance de doen&#231;a card&#237;aca isqu&#234;mica (risco relativo 2,1; intervalo de confian&#231;a de 95%, 1,0 - 4,2). Por outro lado, o estudo <italic>ARIC</italic><sup>31</sup> demonstrou associa&#231;&#227;o entre estreitamento arteriolar generalizado e doen&#231;a card&#237;aca isqu&#234;mica em mulheres (risco relativo 2,2, intervalo de confian&#231;a de 95%, 1,0 - 4,6), mas n&#227;o em homens (risco relativo 1,1, intervalo de confian&#231;a de 95%, 0,7 - 1,8).</p>
    <p>As limita&#231;&#245;es do estudo devem ser salientadas. O n&#250;mero de pacientes avaliados pode ter sido insuficiente para demonstrar rela&#231;&#227;o entre sinais espec&#237;ficos de RH e les&#245;es de &#243;rg&#227;o-alvo. A preval&#234;ncia de anormalidades foi maior do que o usualmente referido na literatura, e pode ter decorrido de vi&#233;s de aferi&#231;&#227;o, dada a subjetividade de definir anormalidade em di&#226;metros vasculares. M&#233;todos precisos de aferi&#231;&#227;o podem mudar tais estimativas. Outro aspecto &#233; que a popula&#231;&#227;o estudada era de pacientes de uma Liga de HA em tratamento e acompanhamento cl&#237;nico regular, o que poderia justificar a baixa frequ&#234;ncia de sinais mais graves de RH.</p>
    <p>A relev&#226;ncia deste estudo tamb&#233;m deve ser ressaltada. A escassez de estudos acerca do tema em nosso pa&#237;s e regi&#227;o faz com que o conhecimento da frequ&#234;ncia de sinais de RH na popula&#231;&#227;o estudada sirva de par&#226;metro para outros estudos. Este estudo tamb&#233;m &#233; &#250;til ao mostrar o perfil de achados fundosc&#243;picos em pacientes sob tratamento regular, em sua maioria classificados nos est&#225;gios iniciais de RH. A grande frequ&#234;ncia observada lan&#231;a d&#250;vidas da sua relev&#226;ncia na estratifica&#231;&#227;o de risco de pacientes hipertensos. Tais achados foram desproporcionais &#224; frequ&#234;ncia de outras les&#245;es em &#243;rg&#227;o-alvo. O trabalho tamb&#233;m &#233; original na compara&#231;&#227;o de t&#233;cnicas diagn&#243;sticas de RH, uma vez que n&#227;o encontramos na literatura outros trabalhos comparando OD e retinografia na detec&#231;&#227;o de RH. Os achados superiores da retinografia abrem discuss&#227;o do papel desta t&#233;cnica diagnostica na avalia&#231;&#227;o de pacientes hipertensos.</p>
    <p>
      <bold>Conclus&#227;o</bold>
    </p>
    <p>RH &#233; frequente em pacientes hipertensos atendidos em programas de aten&#231;&#227;o b&#225;sica. A concord&#226;ncia diagn&#243;stica entre oftalmologistas &#233; maior na an&#225;lise de retinografias do que na oftalmoscopia direta. A aus&#234;ncia de associa&#231;&#227;o entre anormalidades fundosc&#243;picas e outras evid&#234;ncias de dano em &#243;rg&#227;o-alvo podem ter rela&#231;&#227;o com o pequeno tamanho da amostra estudada. </p>
    <p>
      <bold>Potencial Conflito de Interesses</bold>
    </p>
    <p>Declaro n&#227;o haver conflito de interesses pertinentes.</p>
    <p>
      <bold>Fontes de Financiamento</bold>
    </p>
    <p>O presente estudo n&#227;o teve fontes de financiamento externas.</p>
    <p>
      <bold>Vincula&#231;&#227;o Acad&#234;mica</bold>
    </p>
    <p>Este artigo &#233; parte de disserta&#231;&#227;o de Mestrado de Guilherme Lima Pal&#225;cio pela Universidade Federal do Maranh&#227;o.</p>
    <p>
      <fn id="endb" fn-type="corresp">
        <label>
          <bold>Correspond&#234;ncia:</bold>
        </label>
        <p> Jos&#233; Albuquerque de Figueiredo Neto </p>
        <p> Rua Rui Ribeiro Mesquita - Ed. Dom Gabriel, apto 402 - Calhau </p>
        <p> 65075-260 - S&#227;o Luiz, MA - Brasil </p>
        <p> E-mail: </p>
        <p><email xlink:href="jafneto@cardiol.br">jafneto@cardiol.br</email>, </p>
        <p>
          <email xlink:href="jafneto@terra.com.br">jafneto@terra.com.br</email>
        </p>
      </fn>
    </p>
    <p>Artigo recebido em 09/09/09; revisado recebido em 23/11/09; aceito em 29/12/09.</p>
  </body>
  <back>
    <ref-list>
      <ref id="B1">
        <mixed-citation>1. Walsh JB. Hypertensive retinopathy: description, classification, and prognosis. Ophthalmology. 1982; 89 (1): 1127-31.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Hypertensive retinopathy: description, classification, and prognosis</article-title>
          <source>Ophthalmology</source>
          <date>
            <year>1982</year>
          </date>
          <fpage>1127</fpage>
          <lpage>31</lpage>
          <issue>1</issue>
          <volume>89</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Walsh</surname>
              <given-names>JB</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B2">
        <mixed-citation>2. World Health Organization. International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertens. 1999; 17 (1): 151-83.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>International Society of Hypertension Guidelines for the Management of Hypertension</article-title>
          <source>J Hypertens</source>
          <date>
            <year>1999</year>
          </date>
          <fpage>151</fpage>
          <lpage>83</lpage>
          <issue>1</issue>
          <volume>17</volume>
        </element-citation>
      </ref>
      <ref id="B3">
        <mixed-citation>3. Maestri MM, Fuchs SC,Ferlin E, Pakter HM, Nunes G, Moraes RS, et al. Detection of arteriolar narrowing in fundoscopic examination: evidence of a low performance of direct ophthalmoscopy in comparison with a microdensitometric method. Am J Hypertens. 2007; 20 (5): 501-5.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Detection of arteriolar narrowing in fundoscopic examination: evidence of a low performance of direct ophthalmoscopy in comparison with a microdensitometric method</article-title>
          <source>Am J Hypertens</source>
          <date>
            <year>2007</year>
          </date>
          <fpage>501</fpage>
          <lpage>5</lpage>
          <issue>5</issue>
          <volume>20</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Maestri</surname>
              <given-names>MM</given-names>
            </name>
            <name>
              <surname>Fuchs</surname>
              <given-names>SC</given-names>
            </name>
            <name>
              <surname>Ferlin</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Pakter</surname>
              <given-names>HM</given-names>
            </name>
            <name>
              <surname>Nunes</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Moraes</surname>
              <given-names>RS</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B4">
        <mixed-citation>4. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JR, et al. The seventh report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure: the JNC 7 report. JAMA. 2003, 19 (1): 2560-72.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>The seventh report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure: the JNC 7 report</article-title>
          <source>JAMA</source>
          <date>
            <year>2003</year>
          </date>
          <fpage>2560</fpage>
          <lpage>72</lpage>
          <issue>1</issue>
          <volume>19</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Chobanian</surname>
              <given-names>AV</given-names>
            </name>
            <name>
              <surname>Bakris</surname>
              <given-names>GL</given-names>
            </name>
            <name>
              <surname>Black</surname>
              <given-names>HR</given-names>
            </name>
            <name>
              <surname>Cushman</surname>
              <given-names>WC</given-names>
            </name>
            <name>
              <surname>Green</surname>
              <given-names>LA</given-names>
            </name>
            <name>
              <surname>Izzo</surname>
              <given-names>JR</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B5">
        <mixed-citation>5. Sociedade Brasileira de Cardiologia, Sociedade Brasileira de Hipertens&#227;o, Sociedade Brasileira de Nefrologia. V Diretrizes brasileiras de hipertens&#227;o arterial. Arq Bras Cardiol. 2007; 89 (3): e24-79.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>V Diretrizes brasileiras de hipertens&#227;o arterial</article-title>
          <source>Arq Bras Cardiol</source>
          <date>
            <year>2007</year>
          </date>
          <fpage>e24</fpage>
          <lpage>79</lpage>
          <issue>3</issue>
          <volume>89</volume>
        </element-citation>
      </ref>
      <ref id="B6">
        <mixed-citation>6. Keith NM, Wagener HP, Barker NW. Some different types of essential hypertension: their course and prognosis. Am J Med Sci. 1974; 268 (6): 336-45.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Some different types of essential hypertension: their course and prognosis</article-title>
          <source>Am J Med Sci</source>
          <date>
            <year>1974</year>
          </date>
          <fpage>336</fpage>
          <lpage>45</lpage>
          <issue>6</issue>
          <volume>268</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Keith</surname>
              <given-names>NM</given-names>
            </name>
            <name>
              <surname>Wagener</surname>
              <given-names>HP</given-names>
            </name>
            <name>
              <surname>Barker</surname>
              <given-names>NW</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B7">
        <mixed-citation>7. Scheie HG. Evaluation of ophthalmic changes of hypertension and arteriolar sclerosis. AMA Arch Ophthalmol. 1953, 49 (1):117-38.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Evaluation of ophthalmic changes of hypertension and arteriolar sclerosis</article-title>
          <source>AMA Arch Ophthalmol</source>
          <date>
            <year>1953</year>
          </date>
          <fpage>117</fpage>
          <lpage>38</lpage>
          <issue>1</issue>
          <volume>49</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Scheie</surname>
              <given-names>HG</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B8">
        <mixed-citation>8. Dimmitt SB, West JN, Eames SM, Gibson JM, Gosling P, Littler WA. Usefulness of ophthalmoscopy in mild to moderate hypertension. Lancet. 1989, 1 (1): 1103-06.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Usefulness of ophthalmoscopy in mild to moderate hypertension</article-title>
          <source>Lancet</source>
          <date>
            <year>1989</year>
          </date>
          <fpage>1103</fpage>
          <lpage>06</lpage>
          <issue>1</issue>
          <volume>1</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Dimmitt</surname>
              <given-names>SB</given-names>
            </name>
            <name>
              <surname>West</surname>
              <given-names>JN</given-names>
            </name>
            <name>
              <surname>Eames</surname>
              <given-names>SM</given-names>
            </name>
            <name>
              <surname>Gibson</surname>
              <given-names>JM</given-names>
            </name>
            <name>
              <surname>Gosling</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Littler</surname>
              <given-names>WA</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B9">
        <mixed-citation>9. Kagan A, Aureli E, Dobree J. A note on signs in the fundus oculi and arterial hypertension: conventional assessment and significance. Bull World Heath Organ.1966, 34 (6): 955-60.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>A note on signs in the fundus oculi and arterial hypertension: conventional assessment and significance</article-title>
          <source>Bull World Heath Organ</source>
          <date>
            <year>1966</year>
          </date>
          <fpage>955</fpage>
          <lpage>60</lpage>
          <issue>6</issue>
          <volume>34</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Kagan</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Aureli</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Dobree</surname>
              <given-names>J</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B10">
        <mixed-citation>10. Wong TY, Mitchell P. Hypertensive retinopathy. N Engl J Med. 2004; 351 (22): 2310-7.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Hypertensive retinopathy</article-title>
          <source>N Engl J Med</source>
          <date>
            <year>2004</year>
          </date>
          <fpage>2310</fpage>
          <lpage>7</lpage>
          <issue>22</issue>
          <volume>351</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Wong</surname>
              <given-names>TY</given-names>
            </name>
            <name>
              <surname>Mitchell</surname>
              <given-names>P</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B11">
        <mixed-citation>11. Wong TY , Coresh J, Klein R, Muntner P, Couper DJ , Sharrett AR, et al. Retinal microvascular abnormalities and renal dysfunction: the atherosclerosis risk in communities study. J Am Soc Nephrol. 2004, 15 (1): 2469-76.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Retinal microvascular abnormalities and renal dysfunction: the atherosclerosis risk in communities study</article-title>
          <source>J Am Soc Nephrol</source>
          <date>
            <year>2004</year>
          </date>
          <fpage>2469</fpage>
          <lpage>76</lpage>
          <issue>1</issue>
          <volume>15</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Wong</surname>
              <given-names>TY</given-names>
            </name>
            <name>
              <surname>Coresh</surname>
              <given-names>J</given-names>
            </name>
            <name>
              <surname>Klein</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Muntner</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Couper</surname>
              <given-names>DJ</given-names>
            </name>
            <name>
              <surname>Sharrett</surname>
              <given-names>AR</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B12">
        <mixed-citation>12. Klein R, Klein BE, Moss SE. The relation of systemic hypertension to changes in the retinal vasculature: the Beaver Dam Eye Study. Trans Am Ophthalmol Soci. 1997; 95: 329-50.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>The relation of systemic hypertension to changes in the retinal vasculature: the Beaver Dam Eye Study</article-title>
          <source>Trans Am Ophthalmol Soci</source>
          <date>
            <year>1997</year>
          </date>
          <fpage>329</fpage>
          <lpage>50</lpage>
          <volume>95</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Klein</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Klein</surname>
              <given-names>BE</given-names>
            </name>
            <name>
              <surname>Moss</surname>
              <given-names>SE</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B13">
        <mixed-citation>13. Wong TY, Klein R, Nieto FJ, Klein BE, Sharrett AR, Meuer SM, et al. Retinal microvascular abnormalities and 10-year cardiovascular mortality: a population-based case-control study. Ophthalmology. 2003, 110 (1): 933-40.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Retinal microvascular abnormalities and 10-year cardiovascular mortality: a population-based case-control study</article-title>
          <source>Ophthalmology</source>
          <date>
            <year>2003</year>
          </date>
          <fpage>933</fpage>
          <lpage>40</lpage>
          <issue>1</issue>
          <volume>110</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Wong</surname>
              <given-names>TY</given-names>
            </name>
            <name>
              <surname>Klein</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Nieto</surname>
              <given-names>FJ</given-names>
            </name>
            <name>
              <surname>Klein</surname>
              <given-names>BE</given-names>
            </name>
            <name>
              <surname>Sharrett</surname>
              <given-names>AR</given-names>
            </name>
            <name>
              <surname>Meuer</surname>
              <given-names>SM</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B14">
        <mixed-citation>14. van Leiden HA ,Dekker JM, Moll AC ,Nijpels G,Heine RJ,Bouter LM, et al. Risk factors for incident retinopathy in a diabetic and nondiabetic population: the Hoorn study. Arch Ophthalmol. 2003, 121 (1): 245-51.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Risk factors for incident retinopathy in a diabetic and nondiabetic population: the Hoorn study</article-title>
          <source>Arch Ophthalmol</source>
          <date>
            <year>2003</year>
          </date>
          <fpage>245</fpage>
          <lpage>51</lpage>
          <issue>1</issue>
          <volume>121</volume>
          <person-group person-group-type="author">
            <name>
              <surname>van Leiden</surname>
              <given-names>HA</given-names>
            </name>
            <name>
              <surname>Dekker</surname>
              <given-names>JM</given-names>
            </name>
            <name>
              <surname>Moll</surname>
              <given-names>AC</given-names>
            </name>
            <name>
              <surname>Nijpels</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Heine</surname>
              <given-names>RJ</given-names>
            </name>
            <name>
              <surname>Bouter</surname>
              <given-names>LM</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B15">
        <mixed-citation>15. Couper DJ, Klein R, Hubbard LD, Wong TY, Sorlie PD, Cooper LS, et al. Reliability of retinal photography in the assessment of retinal microvascular characteristics: the Atherosclerosis Risk in Communities Study. Am J Ophthalmol. 2002, 133 (1): 78-88.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Reliability of retinal photography in the assessment of retinal microvascular characteristics: the Atherosclerosis Risk in Communities Study</article-title>
          <source>Am J Ophthalmol</source>
          <date>
            <year>2002</year>
          </date>
          <fpage>78</fpage>
          <lpage>88</lpage>
          <issue>1</issue>
          <volume>133</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Couper</surname>
              <given-names>DJ</given-names>
            </name>
            <name>
              <surname>Klein</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Hubbard</surname>
              <given-names>LD</given-names>
            </name>
            <name>
              <surname>Wong</surname>
              <given-names>TY</given-names>
            </name>
            <name>
              <surname>Sorlie</surname>
              <given-names>PD</given-names>
            </name>
            <name>
              <surname>Cooper</surname>
              <given-names>LS</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B16">
        <mixed-citation>16. Wang JJ, Mitchell P, Leung H, Rochtchina E, Wong TY, Klein R. Hypertensive retinal vessel wall signs in a general older population: the Blue Mountains Eye Study. Hypertension. 2003, 42 (1): 534-41.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Hypertensive retinal vessel wall signs in a general older population: the Blue Mountains Eye Study</article-title>
          <source>Hypertension</source>
          <date>
            <year>2003</year>
          </date>
          <fpage>534</fpage>
          <lpage>41</lpage>
          <issue>1</issue>
          <volume>42</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Wang</surname>
              <given-names>JJ</given-names>
            </name>
            <name>
              <surname>Mitchell</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Leung</surname>
              <given-names>H</given-names>
            </name>
            <name>
              <surname>Rochtchina</surname>
              <given-names>E</given-names>
            </name>
            <name>
              <surname>Wong</surname>
              <given-names>TY</given-names>
            </name>
            <name>
              <surname>Klein</surname>
              <given-names>R</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B17">
        <mixed-citation>17. Hubbard LD, Brothers RJ, King WN, Clegg LX, Klein R, Cooper LS, et al. Methods for evaluation of retinal microvascular abnormalities associated with hypertensios/sclerosis in the Atherosclerosis Risk in Communities Study. Ophthalmology. 1999, 106(12): 2269-80.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Methods for evaluation of retinal microvascular abnormalities associated with hypertensios: sclerosis in the Atherosclerosis Risk in Communities Study</article-title>
          <source>Ophthalmology</source>
          <date>
            <year>1999</year>
          </date>
          <fpage>2269</fpage>
          <lpage>80</lpage>
          <issue>12</issue>
          <volume>106</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Hubbard</surname>
              <given-names>LD</given-names>
            </name>
            <name>
              <surname>Brothers</surname>
              <given-names>RJ</given-names>
            </name>
            <name>
              <surname>King</surname>
              <given-names>WN</given-names>
            </name>
            <name>
              <surname>Clegg</surname>
              <given-names>LX</given-names>
            </name>
            <name>
              <surname>Klein</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Cooper</surname>
              <given-names>LS</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B18">
        <mixed-citation>18. Leibowitz HM, Krueger DE, Maunder LR, Milton RC, Kini MM, Kahn HA, et al. The Framingham Eye Study monograph: an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975. Surv Ophthalmol. 1980; 24 (1): 335-610.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>The Framingham Eye Study monograph: an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975</article-title>
          <source>Surv Ophthalmol</source>
          <date>
            <year>1980</year>
          </date>
          <fpage>335</fpage>
          <lpage>610</lpage>
          <issue>1</issue>
          <volume>24</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Leibowitz</surname>
              <given-names>HM</given-names>
            </name>
            <name>
              <surname>Krueger</surname>
              <given-names>DE</given-names>
            </name>
            <name>
              <surname>Maunder</surname>
              <given-names>LR</given-names>
            </name>
            <name>
              <surname>Milton</surname>
              <given-names>RC</given-names>
            </name>
            <name>
              <surname>Kini</surname>
              <given-names>MM</given-names>
            </name>
            <name>
              <surname>Kahn</surname>
              <given-names>HA</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B19">
        <mixed-citation>19. Sharrett AR, Hubbard LD, Cooper LS, Sorlie PD, Brothers RJ, Nieto FJ, et al. Retinal arteriolar diameters and elevated blood pressure: the Atherosclerosis Risk in Communities Study. Am J Epidemiol. 1999; 150 (1): 263-70.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Retinal arteriolar diameters and elevated blood pressure: the Atherosclerosis Risk in Communities Study</article-title>
          <source>Am J Epidemiol</source>
          <date>
            <year>1999</year>
          </date>
          <fpage>263</fpage>
          <lpage>70</lpage>
          <issue>1</issue>
          <volume>150</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Sharrett</surname>
              <given-names>AR</given-names>
            </name>
            <name>
              <surname>Hubbard</surname>
              <given-names>LD</given-names>
            </name>
            <name>
              <surname>Cooper</surname>
              <given-names>LS</given-names>
            </name>
            <name>
              <surname>Sorlie</surname>
              <given-names>PD</given-names>
            </name>
            <name>
              <surname>Brothers</surname>
              <given-names>RJ</given-names>
            </name>
            <name>
              <surname>Nieto</surname>
              <given-names>FJ</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B20">
        <mixed-citation>20. Guidelines Committe. 2003 European Society of Hypertension/ European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens. 2003; 21 (1): 1011-53.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>2003 European Society of Hypertension: European Society of Cardiology guidelines for the management of arterial hypertension</article-title>
          <source>J Hypertens</source>
          <date>
            <year>2003</year>
          </date>
          <fpage>1011</fpage>
          <lpage>53</lpage>
          <issue>1</issue>
          <volume>21</volume>
        </element-citation>
      </ref>
      <ref id="B21">
        <mixed-citation>21. Whitworth JA; World Health Organization, International Society of Hipertension Wrinting Group. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens. 2003; 21(1): 1983-92.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension</article-title>
          <source>J Hypertens</source>
          <date>
            <year>2003</year>
          </date>
          <fpage>1983</fpage>
          <lpage>92</lpage>
          <issue>1</issue>
          <volume>21</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Whitworth</surname>
              <given-names>JA</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B22">
        <mixed-citation>22. Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT, Potter JF, et al. British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary. BMJ. 2004, 328 (1): 634-40.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary</article-title>
          <source>BMJ</source>
          <date>
            <year>2004</year>
          </date>
          <fpage>634</fpage>
          <lpage>40</lpage>
          <issue>1</issue>
          <volume>328</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Williams</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Poulter</surname>
              <given-names>NR</given-names>
            </name>
            <name>
              <surname>Brown</surname>
              <given-names>MJ</given-names>
            </name>
            <name>
              <surname>Davis</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>McInnes</surname>
              <given-names>GT</given-names>
            </name>
            <name>
              <surname>Potter</surname>
              <given-names>JF</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B23">
        <mixed-citation>23. Mcdonugh JR, Garrinson GE, Hames CG. Blood pressure and hypertensive disease among negroes and whites: a study in Evans County, Georgia. Ann Intern Med. 1964, 61 (1): 208-28.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Blood pressure and hypertensive disease among negroes and whites: a study in Evans County , Georgia</article-title>
          <source>Ann Intern Med</source>
          <date>
            <year>1964</year>
          </date>
          <fpage>208</fpage>
          <lpage>28</lpage>
          <issue>1</issue>
          <volume>61</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Mcdonugh</surname>
              <given-names>JR</given-names>
            </name>
            <name>
              <surname>Garrinson</surname>
              <given-names>GE</given-names>
            </name>
            <name>
              <surname>Hames</surname>
              <given-names>CG</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B24">
        <mixed-citation>24. Besharati MR, Rastegar A, Shoja MR, Mayobi ME. Prevalence of retinopathy in hypertensive patients. Saudi Medical Journal. 2006, 27 (11): 1725-8.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Prevalence of retinopathy in hypertensive patients</article-title>
          <source>Saudi Medical Journal</source>
          <date>
            <year>2006</year>
          </date>
          <fpage>1725</fpage>
          <lpage>8</lpage>
          <issue>11</issue>
          <volume>27</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Besharati</surname>
              <given-names>MR</given-names>
            </name>
            <name>
              <surname>Rastegar</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Shoja</surname>
              <given-names>MR</given-names>
            </name>
            <name>
              <surname>Mayobi</surname>
              <given-names>ME</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B25">
        <mixed-citation>25. Klein R, Sharret AR, Klein BE, Chambless LE, Cooper LS, Hubbard LD, et al. Are retinal arteriolar abnormalities related to atherosclerosis? The Atherosclerosis Risk in Communities Study. Arterioscler Thromb Vasc Biol. 2000, 20 (6): 1644-50.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Are retinal arteriolar abnormalities related to atherosclerosis?: The Atherosclerosis Risk in Communities Study</article-title>
          <source>Arterioscler Thromb Vasc Biol</source>
          <date>
            <year>2000</year>
          </date>
          <fpage>1644</fpage>
          <lpage>50</lpage>
          <issue>6</issue>
          <volume>20</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Klein</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Sharret</surname>
              <given-names>AR</given-names>
            </name>
            <name>
              <surname>Klein</surname>
              <given-names>BE</given-names>
            </name>
            <name>
              <surname>Chambless</surname>
              <given-names>LE</given-names>
            </name>
            <name>
              <surname>Cooper</surname>
              <given-names>LS</given-names>
            </name>
            <name>
              <surname>Hubbard</surname>
              <given-names>LD</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B26">
        <mixed-citation>26. Stolk RP, Vingerling JR, de Jong PT, Dielemans I, Hofman A, Lamberts SW, et al. Retinopathy, glucose, and insulin in an elderly population: the Rotterdam Study. Diabetes. 1995; 44 (1): 11-5.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Retinopathy, glucose, and insulin in an elderly population: the Rotterdam Study</article-title>
          <source>Diabetes</source>
          <date>
            <year>1995</year>
          </date>
          <fpage>11</fpage>
          <lpage>5</lpage>
          <issue>1</issue>
          <volume>44</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Stolk</surname>
              <given-names>RP</given-names>
            </name>
            <name>
              <surname>Vingerling</surname>
              <given-names>JR</given-names>
            </name>
            <name>
              <surname>de Jong</surname>
              <given-names>PT</given-names>
            </name>
            <name>
              <surname>Dielemans</surname>
              <given-names>I</given-names>
            </name>
            <name>
              <surname>Hofman</surname>
              <given-names>A</given-names>
            </name>
            <name>
              <surname>Lamberts</surname>
              <given-names>SW</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B27">
        <mixed-citation>27. Yu T, Mitchell P, Berry G, Li W, Wang JJ. Retinopathy in older persons without diabetes and its relationship to hypertension. Arch Ophthalmol. 1998, 116 (1): 83-9.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Retinopathy in older persons without diabetes and its relationship to hypertension</article-title>
          <source>Arch Ophthalmol</source>
          <date>
            <year>1998</year>
          </date>
          <fpage>83</fpage>
          <lpage>9</lpage>
          <issue>1</issue>
          <volume>116</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Yu</surname>
              <given-names>T</given-names>
            </name>
            <name>
              <surname>Mitchell</surname>
              <given-names>P</given-names>
            </name>
            <name>
              <surname>Berry</surname>
              <given-names>G</given-names>
            </name>
            <name>
              <surname>Li</surname>
              <given-names>W</given-names>
            </name>
            <name>
              <surname>Wang</surname>
              <given-names>JJ</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B28">
        <mixed-citation>28. Cuspidi C, Meani S, Salerno M, Fusi V, Severgnini B, Valerio C, et al. Retinal microvascular changes and target organ damage in untreated essential hypertensives. J Hypertens. 2004, 22 (11): 2095-102.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Retinal microvascular changes and target organ damage in untreated essential hypertensives</article-title>
          <source>J Hypertens</source>
          <date>
            <year>2004</year>
          </date>
          <fpage>2095</fpage>
          <lpage>102</lpage>
          <issue>11</issue>
          <volume>22</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Cuspidi</surname>
              <given-names>C</given-names>
            </name>
            <name>
              <surname>Meani</surname>
              <given-names>S</given-names>
            </name>
            <name>
              <surname>Salerno</surname>
              <given-names>M</given-names>
            </name>
            <name>
              <surname>Fusi</surname>
              <given-names>V</given-names>
            </name>
            <name>
              <surname>Severgnini</surname>
              <given-names>B</given-names>
            </name>
            <name>
              <surname>Valerio</surname>
              <given-names>C</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B29">
        <mixed-citation>29. Gillum RF. Retinal arteriolar findings and coronary heart disease. Am Heart J. 1991, 122 (1 Pt 1): 262-3.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Retinal arteriolar findings and coronary heart disease</article-title>
          <source>Am Heart J</source>
          <date>
            <year>1991</year>
          </date>
          <fpage>262</fpage>
          <lpage>3</lpage>
          <issue>1 Pt 1</issue>
          <volume>122</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Gillum</surname>
              <given-names>RF</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B30">
        <mixed-citation>30.  Duncan BB, Wong TY, Tyroler HA, Davis CE, Fuchs FD. Hypertensive retinopathy and incident coronary heart disease in high risk men. Br J Ophthalmol. 2002; 86(1): 1002-6.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Hypertensive retinopathy and incident coronary heart disease in high risk men</article-title>
          <source>Br J Ophthalmol</source>
          <date>
            <year>2002</year>
          </date>
          <fpage>1002</fpage>
          <lpage>6</lpage>
          <issue>1</issue>
          <volume>86</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Duncan</surname>
              <given-names>BB</given-names>
            </name>
            <name>
              <surname>Wong</surname>
              <given-names>TY</given-names>
            </name>
            <name>
              <surname>Tyroler</surname>
              <given-names>HA</given-names>
            </name>
            <name>
              <surname>Davis</surname>
              <given-names>CE</given-names>
            </name>
            <name>
              <surname>Fuchs</surname>
              <given-names>FD</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
      <ref id="B31">
        <mixed-citation>31.  Wong TY, Klein R, Sharrett AR, Duncan BB, Couper DJ, Tielsch JM, et al. Retinal arteriolar narrowing and risk of coronary heart disease in men and women: the Atherosclerosis Risk in Communities Study. JAMA. 2002; 287 (9): 1153-9.</mixed-citation>
        <element-citation publication-type="journal">
          <article-title>Retinal arteriolar narrowing and risk of coronary heart disease in men and women: the Atherosclerosis Risk in Communities Study</article-title>
          <source>JAMA</source>
          <date>
            <year>2002</year>
          </date>
          <fpage>1153</fpage>
          <lpage>9</lpage>
          <issue>9</issue>
          <volume>287</volume>
          <person-group person-group-type="author">
            <name>
              <surname>Wong</surname>
              <given-names>TY</given-names>
            </name>
            <name>
              <surname>Klein</surname>
              <given-names>R</given-names>
            </name>
            <name>
              <surname>Sharrett</surname>
              <given-names>AR</given-names>
            </name>
            <name>
              <surname>Duncan</surname>
              <given-names>BB</given-names>
            </name>
            <name>
              <surname>Couper</surname>
              <given-names>DJ</given-names>
            </name>
            <name>
              <surname>Tielsch</surname>
              <given-names>JM</given-names>
            </name>
          </person-group>
        </element-citation>
      </ref>
    </ref-list>
  </back>
  <sub-article article-type="translation" id="TRen" xml:lang="en">
    <front-stub>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original Articles</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title xml:lang="en">Direct ophthalmoscopy versus detection of hypertensive retinopathy: a comparative study</article-title>
      </title-group>
      <abstract xml:lang="en">
        <p>BACKGROUND: Detection of hypertensive retinopathy (HR) with direct ophthalmoscopy is part of the assessment of hypertensive patients. Its use has been questioned because of its subjectivity and high interobserver variability. OBJECTIVE: To determine the prevalence of HR in hypertensive patients under outpatient monitoring, the correlation between diagnosis and ophthalmoscopy and angiography, and to correlate it with other target organ damages. METHODS: An observational, analytical and cross-sectional evaluation of 99 patients. Direct ophthalmoscopy and angiography performed by two investigators independently. Classification of RH, as described by Keith, Wagener and Barker. RESULTS: The prevalence of HR of any grade was higher than 90.0% by both methods. On ophthalmoscopy, we observed grade I abnormalities in 51.0%, grade II in 43.0%, with one patient with grade III HR. On angiography, we observed grade I abnormalities in 42.0% and grade II in 52.0%. We detected three patients with grade III HR, two of which were not detected by ophthalmoscopy. Observers' agreement for the presence and severity of HR was poor with direct ophthalmoscopy and good with angiography. Renal dysfunction, ECG abnormalities (ventricular hypertrophy, pathological Q wave, repolarization abnormalities), and history of stroke were observed in 70.0%, 27.0% and 10.0% of patients, respectively. There was no relationship between the severity of HR and other target organ damages. CONCLUSION: We observed a high prevalence of HR using both methods. Observers' agreement for the diagnosis and determination of the severity of HR was better with angiography. In our sample, there was no association of the severity of HR with other target organ damages.</p>
      </abstract>
      <kwd-group xml:lang="en">
        <kwd>Ophthalmoscopy</kwd>
        <kwd>retina</kwd>
        <kwd>hypertension</kwd>
      </kwd-group>
    </front-stub>
    <body>
      <p>
        <fn id="enda-body2">
          <label>
            <bold>Direct ophthalmoscopy <italic>versus</italic> detection of hypertensive retinopathy: a comparative study</bold>
          </label>
          <p>
            <bold>Jos&#233; Albuquerque de Figueiredo Neto; Guilherme Lima Pal&#225;cio; Allison Nobrega dos Santos; Pamela Suelen Serra Chaves; Germana Viana Gomes; Tassiane Soares Cabral</bold>
          </p>
        </fn>
      </p>
      <p>Universidade Federal do Maranh&#227;o, S&#227;o Luiz, MA - Brasil</p>
      <p>Mailing address</p>
      <p>
        <bold>ABSTRACT</bold>
      </p>
      <p><bold>BACKGROUND:</bold> Detection of hypertensive retinopathy (HR) with direct ophthalmoscopy is part of the assessment of hypertensive patients. Its use has been questioned because of its subjectivity and high interobserver variability.</p>
      <p><bold>OBJECTIVE:</bold> To determine the prevalence of HR in hypertensive patients under outpatient monitoring, the correlation between diagnosis and ophthalmoscopy and angiography, and to correlate it with other target organ damages.</p>
      <p><bold>METHODS:</bold> An observational, analytical and cross-sectional evaluation of 99 patients. Direct ophthalmoscopy and angiography performed by two investigators independently. Classification of RH, as described by Keith, Wagener and Barker.</p>
      <p><bold>RESULTS:</bold> The prevalence of HR of any grade was higher than 90.0% by both methods. On ophthalmoscopy, we observed grade I abnormalities in 51.0%, grade II in 43.0%, with one patient with grade III HR. On angiography, we observed grade I abnormalities in 42.0% and grade II in 52.0%. We detected three patients with grade III HR, two of which were not detected by ophthalmoscopy. Observers' agreement for the presence and severity of HR was poor with direct ophthalmoscopy and good with angiography. Renal dysfunction, ECG abnormalities (ventricular hypertrophy, pathological Q wave, repolarization abnormalities), and history of stroke were observed in 70.0%, 27.0% and 10.0% of patients, respectively. There was no relationship between the severity of HR and other target organ damages.</p>
      <p><bold>CONCLUSION:</bold> We observed a high prevalence of HR using both methods. Observers' agreement for the diagnosis and determination of the severity of HR was better with angiography. In our sample, there was no association of the severity of HR with other target organ damages. </p>
      <p><bold>Key words:</bold> Ophthalmoscopy; retina/injuries; hypertension.</p>
      <p>
        <bold>Introduction</bold>
      </p>
      <p>Hypertensive retinopathy (HR) is a condition characterized by a spectrum of retinal vascular signs that develop in people with hypertension<sup>1</sup>. Its detection with direct ophthalmoscopy (DO) is part of the assessment of hypertensive patients<sup>2</sup>, but its use has been questioned due to its high subjectivity and interobserver variability<sup>3</sup>.</p>
      <p>The Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and the V Brazilian Guidelines on Hypertension list HR as a marker of target organ damage. Therefore, it is a criterion for prescription of treatment<sup>4,5</sup>.</p>
      <p>Classic studies on retinal abnormalities in hypertension are currently questioned due to some factors<sup>6,7</sup>: inclusion of patients untreated or uncontrolled, diagnosis made only with the DO and association of HR with mortality in studies where there was no control of other risk factors currently known, which may act with confusion factors<sup>8-11</sup>.</p>
      <p>Recent studies using angiography<sup>12-17</sup> showed high reproducibility in the evaluation of microaneurysms, hemorrhages, arteriovenous crossing abnormalities, focal or generalized arteriolar narrowing. However, few studies have compared the sensitivity and reproducibility between DO and angiography in the detection of HR<sup>18</sup>.</p>
      <p>Another issue in the study of HR is that some signs seem to be associated with certain clinical conditions<sup>19</sup>.</p>
      <p>We performed this study because of the importance of hypertension as a cause of morbidity and mortality, lack of data on the prevalence of HR in our environment, the absence of studies comparing DO with angiography in diagnosis and the uncertainty regarding the usefulness of its detection in the evaluation of cardiovascular risk and associated target organ damages.</p>
      <p>The objectives were to determine the prevalence of RH in patients monitored in a League of Hypertension of a University Hospital; to evaluate the correlation between DO and digital angiography (DA) in detecting RH; to study the association of HR with other target organ damages.</p>
      <p>
        <bold>Methodology</bold>
      </p>
      <p>
        <bold>Type of study</bold>
      </p>
      <p>Analytical cross-sectional study conducted from June to December/2008 in a League of Hypertension of a University Hospital.</p>
      <p>
        <bold>Sample</bold>
      </p>
      <p>For convenience purposes, patients were selected as they came for routine medical appointments, observing the exclusion criteria of the study, namely:</p>
      <disp-quote>
        <p>a. Diabetes mellitus;</p>
        <p> b. Media opacity (scarring, vitreous hemorrhage, cataract);</p>
        <p> c. Retinal detachment;</p>
        <p> d. Lack of systemic clinical data in the medical records of the League of Hypertension.</p>
      </disp-quote>
      <p>We examined 131 consecutive patients. We excluded 32 patients: one, because of double evaluation, three because of media opacity on ophthalmological test, 6 due to insufficient data in their files and 22 have developed diabetes. We evaluated 99 patients.</p>
      <p>
        <bold>Data collection</bold>
      </p>
      <p>Performed by clinical and ophthalmological tests, namely:</p>
      <disp-quote>
        <p>a. Clinical examinations - the patients underwent systemic clinical examination for the presence of risk factors for cardiovascular disease and categorization of their blood pressure as for severity, according to the V Brazilian Guidelines on Hypertension<sup>4</sup>.</p>
        <p>b. Routine laboratory tests - urinalysis, potassium and creatinine, fasting glucose, total cholesterol, LDL, HDL and triglycerides - in accordance with the V Brazilian Guidelines on Hypertension<sup>4</sup>.</p>
        <p>c. 12-lead electrocardiogram assessed abnormalities consistent with left ventricular hypertrophy (Cornell criteria), and assessment of the presence of pathological Q wave and ventricular repolarization abnormality.</p>
      </disp-quote>
      <p>The cleareance estimated of creatinine was calculated according to Cockcroft-Gault formula. Decreased renal function was defined as smaller than 60 ml/min.</p>
      <p>Ophthalmologic examination was performed, including visual acuity, biomicroscopy and applanation tonometry. Direct ophthalmoscopy was also performed with coaxial ophthalmoscope 3.5 V (Welch Allyn, Skaneateles Falls, United States) and angiography with equipment CF60 UVi (Canon, Tokyo, Japan) with digital system Eye Q Pro (Canon, Tokyo, Japan) after pulilar dilation with 1.0% tropicamide eye drops. The images were obtained in the field of 60 degrees, centered on the macula.</p>
      <p>Each patient underwent fundoscopy by two ophthalmologists, with similar experience and independently. Angiographies were also interpreted by these physicians without prior knowledge of patients' clinical conditions, independently. In a second step, a new interpretation was made by consensus. We performed classification of HR as described by Keith, Wagener and Barker<sup>6</sup>. </p>
      <p>
        <bold>Statistical analysis</bold>
      </p>
      <p>Data were analyzed using Epi Info 3.4.3 (2007). Quantitative variables were presented as averages and standard deviation. Qualitative variables were presented as frequencies and percentages.</p>
      <p>As for fundus and angiography findings, we measured the Kappa coefficient of agreement among examiners. Agreement was considered poor in cases of Kappa coefficient smaller than 0.20; weak, between 0.21-0.40; moderate between 0.41-0.60; good between 0.61-0.80; and very good when it was higher than 0.80.</p>
      <p>To test the association between risk factors and severity of HR, we used Fisher's exact test. A significance level of 5.0% was adopted.</p>
      <p>
        <bold>Ethical aspects</bold>
      </p>
      <p>Data were collected after approval by the Research Ethics Committee (Process 33104-178/2007) and the patients signed a consent form.</p>
      <p>
        <bold>Results</bold>
      </p>
      <p>We evaluated 99 patients whose demographics are presented in <xref ref-type="table" rid="tab1-body2">Table 1</xref>.</p>
      <table-wrap id="tab1-body2">
        <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt01-en.jpg"/></table-wrap>
      <p>Analysis of the presence of risk factors for cardiovascular diseases revealed that they had no risk factor in addition to hypertension in 9.1% of the cases, one or two factors in 45.5% and three or more risk factors or cardiovascular disease in 24.2%. (<xref ref-type="table" rid="tab2-body2">Table 2</xref>).</p>
      <table-wrap id="tab2-body2">
        <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt02-en.jpg"/></table-wrap>
      <p>As for the time of diagnosis of hypertension, 42.4% of patients were younger than 6, 21.2% between 6 and 10, and 36.4% were older than 10. There was no association between the time of diagnosis and the presence of retinopathy (p &gt; 0.05). </p>
      <p>Staging of hypertension can be seen in <xref ref-type="table" rid="en_aop08110a02tab03m-body2">Table 3</xref>. </p>
      <p content-type="asset">
        <table-wrap id="en_aop08110a02tab03m-body2">
          <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt03-en.jpg"/></table-wrap>
      </p>
      <p>The frequency of target organ damages is shown in <xref ref-type="table" rid="en_aop08110a02tab04m-body2">Table 4</xref>.</p>
      <p content-type="asset">
        <table-wrap id="en_aop08110a02tab04m-body2">
          <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt04-en.jpg"/></table-wrap>
      </p>
      <p>The prevalence of HR using DO and digital angiography, as well as the consensus of angiography by both observers are shown in <xref ref-type="table" rid="en_aop08110a02tab05m-body2">Table 5</xref>.</p>
      <p content-type="asset">
        <table-wrap id="en_aop08110a02tab05m-body2">
          <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt05-en.jpg"/></table-wrap>
      </p>
      <p>The coefficient of agreement for the presence of HR with DO was poor, with Kappa equal to 0.22 CI 95% [0.38 to 0.83].</p>
      <p>However, there was a good coefficient of agreement for the presence of HR with digital angiography, with Kappa value equal to 0.66 CI 95% [0.00 to 1.37].</p>
      <p>When we evaluated observers' coefficient of agreement in distinguishing grade I or grade II retinopathy through DO, this proved to be poor, with Kappa equal to 0.33 CI 95% [0.13 to 0.52].</p>
      <p>In that same analysis of severity of HR between grades I and II, there was a good agreement when using the digital angiography, with Kappa equal to 0.70 CI 95% [0.55 to 0.84].</p>
      <p>No relationship was found between the severity of HR and the stages of hypertension on examiners' consensus through digital angiography (<xref ref-type="table" rid="en_aop08110a02tab06m-body2">Table 6</xref>).</p>
      <p content-type="asset">
        <table-wrap id="en_aop08110a02tab06m-body2">
          <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt06-en.jpg"/></table-wrap>
      </p>
      <p>Renal dysfunction was present in 20.2% of the patients. No relationship was found between the degree of retinopathy and the severity of renal dysfunction (<xref ref-type="table" rid="en_aop08110a02tab07m-body2">Table 7</xref>).</p>
      <p content-type="asset">
        <table-wrap id="en_aop08110a02tab07m-body2">
          <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt07-en.jpg"/></table-wrap>
      </p>
      <p>We analyzed the electrocardiograms of 90 patients and observed electrocardiographic abnormalities in 27.3% of them. No relationship was found between the degree of retinopathy and ECG abnormalities (<xref ref-type="table" rid="en_aop08110a02tab08m-body2">Table 8</xref>).</p>
      <p content-type="asset">
        <table-wrap id="en_aop08110a02tab08m-body2">
          <graphic xlink:href="1678-4170-abc-95-02-0215-00086-gt08-en.jpg"/></table-wrap>
      </p>
      <p>History of stroke was present in 10 patients in the sample. However, no relationship was established between positive history of stroke and severity of HR.</p>
      <p>There was no association between race and severity of HR.</p>
      <p>
        <bold>Discussion</bold>
      </p>
      <p>International guidelines consider the retinal findings differently. For the European Society of Hypertension and the European Society of Cardiology, grade III and IV HR as classified by Keith, Wagener and Barker, is regarded as an associated clinical condition<sup>6,20</sup>.The International Society of Hypertension of the World Health Organization and the Guidelines of the British Society of Hypertension consider grades III and IV of Keith, Wagener and Barker as target organ damage<sup>21,22</sup>.The National Committee on Prevention, Detection, Evaluation and Treatment of Hypertension in the United States and the V Brazilian Guidelines on Hypertension consider the presence of any sign of retinopathy as target organ damage<sup>4,5</sup>.</p>
      <p>In this study, using DO and considering the presence of any sign of retinopathy, we observed prevalence above 90.0%, with grade I abnormalities in 51.0% and grade II in 43%. One patient had grade III HR. No patient with grade IV was found. The most common findings were diffuse arteriolar narrowing and arteriolar wall opacification, and pathologic arteriovenous crossing. Considering only advanced damages (Grade III and IV), the prevalence of HR would be 1.0%. </p>
      <p>In the Framingham Eye Study, with DO, in a general population aged 52-85, the prevalence of retinopathy was 0.8%, excluding patients with diabetes. The concept of retinopathy included only advanced forms such as retinal hemorrhages and exudates, without considering arteriolar wall abnormalities<sup>18</sup>.</p>
      <p>McDonough, Garrison and Hames<sup>23</sup>, using DO, evaluating 2,210 people, found that 2.2% had retinopathy defined as the presence of microaneurysms, hemorrhages or exudates. On evaluation of earliest signs of retinopathy, 34.0% had generalized or focal arteriolar narrowing, and 13.2%, pathological AV crossings<sup>23</sup>.</p>
      <p>Besharati et al<sup>24</sup> studied 213 hypertensive patients with DO and found a prevalence of 39.9%, considering any sign of retinopathy. In those with mild hypertension, the prevalence was 25.3%; in patients with moderate hypertension, 34.5%; and those with severe hypertension, prevalence was 84.6%. The most common findings were arteriolar narrowing (35.13%), pathologic arteriovenous crossing (17.12%) and cotton wool spots (9.0%)<sup>24</sup>.</p>
      <p>In this study, the coefficient of agreement for the diagnosis and severity of HR showed a weak agreement, using DO. </p>
      <p>Using DO in assessing hypertensive patients results in imprecision and interobserver variability. It is particularly imprecise in people with mild to moderate hypertension<sup>2,8</sup>.</p>
      <p>In this study, the detection of HR using angiography was higher than 90.0%, with grade I abnormalities in 42.0% and grade II in 52.0%. Three patients with grade III HR were detected, two of which were not detected by DO. No patient with grade IV was observed. Considering only advanced damages (Grade III and IV), the prevalence of HR would be 3.0%.</p>
      <p>Using angiography and standardized methodology for documenting and defining the various signs of HR, epidemiological studies have shown a prevalence ranging from 2-15.0% in the general population<sup>10,12,25-27</sup>. </p>
      <p>The Beaver Dam Eye Study<sup>12</sup>, using angiography, evaluated 2,375 non-diabetics aged 43-86, finding a focal arteriolar narrowing in 14.0%, retinopathy in 8.0%, and pathological AV crossings in 2.0%. When hypertensives were excluded, there was focal arteriolar narrowing in 11.0%, retinopathy in 6.0% and pathological AV crossings in 2.0%. Therefore, it can be inferred that retinal microvascular abnormalities are common in nondiabetic populations, although they are more prevalent in patients with hypertension<sup>12</sup>.</p>
      <p>In the Blue Mountains Eye Study<sup>27</sup>, 3,275 non-diabetic individuals underwent angiography. The prevalence of retinopathy was 9.9%. The Atherosclerossis Risk in Communities (ARIC) Study<sup>25</sup> studied 9,300 individuals older than 49, without diabetes, using angiography. The prevalence of focal arteriolar narrowing was 6.0%, retinopathy of 3.0% and pathological AV crossing of 6.0%. </p>
      <p>The higher prevalence of retinopathy observed in these studies, compared to the Framingham study, may be due to the higher sensitivity of photographic assessment techniques against ophthalmoscopy. However, these studies did not include the earliest sign of HR, the generalized arteriolar narrowing<sup>13</sup>.</p>
      <p>In this study, the coefficient of agreement for the detection and assessment of the severity of HR using angiography was higher than that found using DO.</p>
      <p>Cuspidi et al<sup>28</sup> evaluated 197 patients with grade I and II hypertension (73.0%) without pretreatment, using digital angiography, with two independent observers. The overall prevalence of retinal changes was 84.3% and 84.7% respectively.</p>
      <p>In this study, there was no correlation of retinopathy with age, sex, time of diagnosis and stage of hypertension. Data from the Beaver Dam and ARIC study suggest that the prevalence of arteriolar narrowing and pathological AV crossing seem to be directly related with age. The prevalence of retinopathy was also age-dependent in the Blue Mountains study<sup>12,24,26</sup>.</p>
      <p>The prevalence of retinopathy was higher in males, when adjusted for age, both in the Beaver Dam and in the ARIC study. However, in the Blue Mountains, no difference was found<sup>11,25,27</sup>.</p>
      <p>In literature, it is reported that generalized arteriolar narrowing and pathologic arteriovenous crossings can be observed more commonly in patients with longer duration of diagnosed hypertension, representing signs of chronic vascular damage. On the other hand, focal arteriolar narrowing, retinal hemorrhages, microaneurysms and cotton wool spots are believed to be related to the current level of hypertension<sup>13,19</sup>.</p>
      <p>The distribution of the severity of HR in this study, according to the classification of Keith, Wagener and Barker was presented as follows: Grade I - 42 patients (42.4%), grade II - 52 patients (52.6%), grade III - 3 patients (3%) and grade IV - no patient. </p>
      <p>The high frequency of early signs of retinopathy, including grades I and II of Keith, Wagener, and Barker, and the low frequency of intense signs, grades III and IV, may be related to the duration of hypertension and treatment and regular control of blood pressure<sup>6</sup>.</p>
      <p>In this study, renal dysfunction was observed in 20.2% of patients. However, no association was established between renal dysfunction and the presence and severity of HR. In the ARIC study, individuals with retinopathy (odds ratio 2.0; confidence interval 95.0%, 1.4-2.8), microaneurysms (OR, 2.0, CI 95.0%, 1.3 - 3.1), retinal hemorrhages (OR, 2.6, CI 95.0%, 1.6-4.0), cotton wool spots (OR 2.7, CI 95.0%, 1.6-4.8) and pathologic arteriovenous crossings (OR 1.4, CI 95.0%, 1.0-1.9) were more likely to develop renal dysfunction than individuals without retinal abnormalities<sup>11</sup>.</p>
      <p>The study found electrocardiographic abnormalities consistent with left ventricular hypertrophy, presence of pathological Q waves and ventricular repolarization abnormalities in 27.0% of patients. Gillum<sup>29</sup> noted that retinal arteriolar narrowing detected by ophthalmoscopy determined two to six-fold increased likelihood of developing ischemic heart disease, after controlled analysis for hypertension, diabetes and hypercholesterolemia.</p>
      <p>Duncan et al<sup>30</sup> demonstrated that the presence of RH in men doubled the chance of ischemic heart disease (relative risk 2.1; confidence interval 95%, 1.0 - 4.2). On the other hand, the ARIC study<sup>31</sup> reported a correlation between generalized arteriolar narrowing and ischemic heart disease in women (relative risk 2.2, confidence interval 95%, from 1.0 to 4.6) but not in men (relative risk 1.1, confidence interval 95%, 0.7 - 1.8).</p>
      <p>The limitations of this study should be highlighted. The number of patients evaluated may have been insufficient to demonstrate the relationship between specific signs of HR and target organ damage. The prevalence of abnormalities was higher than usually reported in the literature, and may have resulted from bias, given the subjectivity of defining abnormality in vascular diameters. Accurate methods of measurement may change these estimates. Another aspect is that the population of patients studied was of a League of Hypertension under regular clinical treatment and monitoring, which could explain the low frequency of more severe signs of HR.</p>
      <p>The relevance of this study should also be emphasized. The scarcity of studies on the subject in our country and the region makes the familiarization of frequency of HR signs in the population studied to serve as a parameter for other studies. This study is also useful in showing the profile of fundus findings in patients under regular treatment, mostly classified in the early stages of HR. The high frequency signal casts doubt on its relevance in the risk stratification of hypertensive patients. These findings were not proportional to the frequency of other target organ damages. The work also is unique in comparing HR diagnosing techniques, once we do not find in literature and other studies comparing DO and angiography in detecting HR. Superior fundus findings open discussions on the role of this diagnostic technique in assessing hypertensive patients.</p>
      <p>
        <bold>Conclusion</bold>
      </p>
      <p>HR is frequent in hypertensive patients being treated in primary care programs. The diagnostic agreement among ophthalmologists is higher in the analysis of angiographies than on direct ophthalmoscopy. The lack of association between retinal abnormalities and other evidence of target organ damage may be related to the small sample size. </p>
      <p>
        <bold>Potential Conflict of Interest</bold>
      </p>
      <p>No potential conflict of interest relevant to this article was reported.</p>
      <p>
        <bold>Sources of Funding</bold>
      </p>
      <p>There were no external funding sources for this study.</p>
      <p>
        <bold>Study Association</bold>
      </p>
      <p>This article is part of the thesis of master submitted by Guilherme Lima Pal&#225;cio, from Universidade Federal do Maranh&#227;o.</p>
      <p>
        <bold>References</bold>
      </p>
    </body>
  </sub-article>
</article>
