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o cancro &#233; a segunda maior causa de morte em Portugal&#44; logo a seguir &#224;s doen&#231;as cardiovasculares<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#44; e o cancro colorretal a principal causa de morte oncol&#243;gica<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46; Durante v&#225;rias d&#233;cadas&#44; estas rea&#231;&#245;es cardiot&#243;xicas a tratamentos antineopl&#225;sicos eram quase exclusivamente associadas ao uso de antraciclinas&#46; Mais recentemente&#44; uma nova dimens&#227;o do problema surgiu quando foram reconhecidos clinicamente alguns efeitos indesej&#225;veis&#44; no sistema cardiovascular&#44; de drogas que interferem na atividade de certos recetores associados a c&#237;nases da tirosina ou recetores tumor &#40;recetores de estrog&#233;nios&#41;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;6</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Grande parte da literatura cient&#237;fica sobre a cardiotoxicidade da terap&#234;utica oncol&#243;gica incide unicamente sobre a ocorr&#234;ncia de cardiomiopatia&#59; no entanto&#44; esta &#233; apenas uma das v&#225;rias condi&#231;&#245;es que podem comprometer a fun&#231;&#227;o cardiovascular<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#46; Outros efeitos sobre a vasculatura resultam em isquemia ou altera&#231;&#245;es na press&#227;o arterial<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> e&#44; no peric&#225;rdio&#44; as terapias antineopl&#225;sicas podem causar o seu espessamento ou uma instabilidade no equil&#237;brio do fluido peric&#225;rdico&#44; levando a derrame<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46; Al&#233;m disso&#44; este tipo de tratamento aumenta o risco de arritmias em pacientes predispostos a ectopia card&#237;aca<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">A prote&#231;&#227;o da fun&#231;&#227;o card&#237;aca representa atualmente um desafio constante para a ind&#250;stria farmac&#234;utica&#44; as autoridades reguladoras e para os m&#233;dicos que enfrentam&#44; na pr&#225;tica cl&#237;nica&#44; rea&#231;&#245;es adversas a diversos agentes terap&#234;uticos<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; A avalia&#231;&#227;o de doentes expostos a f&#225;rmacos antineopl&#225;sicos&#44; a an&#225;lise do risco envolvido na utiliza&#231;&#227;o destes para qualquer indiv&#237;duo ou grupo de doentes com cancro&#44; a preven&#231;&#227;o ou redu&#231;&#227;o de les&#227;o card&#237;aca&#44; a monitoriza&#231;&#227;o da fun&#231;&#227;o card&#237;aca durante e ap&#243;s a terap&#234;utica&#44; e o tratamento da cardiotoxicidade relacionada com a quimioterapia tem gerado uma vasta &#225;rea de conhecimento cient&#237;fico que tem sido denominada de &#171;c&#225;rdio-oncologia&#187;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;11</span></a>&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Ao longo da presente revis&#227;o&#44; iremos abordar as diversas respostas cardiot&#243;xicas ao uso de tratamentos oncol&#243;gicos e a sua rela&#231;&#227;o com os principais f&#225;rmacos antineopl&#225;sicos usados na pr&#225;tica cl&#237;nica&#46; Al&#233;m disso&#44; ser&#227;o analisadas as &#250;ltimas linhas de orienta&#231;&#227;o no que respeita &#224;s estrat&#233;gias de dete&#231;&#227;o&#47;monitoriza&#231;&#227;o da cardiotoxicidade em indiv&#237;duos com cancro&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Defini&#231;&#227;o de cardiotoxicidade</span><p id="par0030" class="elsevierStylePara elsevierViewall">A exist&#234;ncia de uma descri&#231;&#227;o padronizada de cardiotoxicidade &#233; essencial para fins assistenciais e de investiga&#231;&#227;o na popula&#231;&#227;o doente<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; Uma das defini&#231;&#245;es cl&#237;nicas mais precisas foi formulada pelo Comit&#233; de Avalia&#231;&#227;o e Revis&#227;o Card&#237;aca &#40;CREC&#41; durante a supervis&#227;o de ensaios terap&#234;uticos com <span class="elsevierStyleItalic">trastuzumab</span> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Tabela 1</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>&#46; Estes crit&#233;rios n&#227;o incluem as les&#245;es cardiovasculares subcl&#237;nicas que podem ocorrer no in&#237;cio de resposta a alguns agentes quimioter&#225;picos<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">F&#225;rmacos antineopl&#225;sicos e cardiomiopatia</span><p id="par0035" class="elsevierStylePara elsevierViewall">O padr&#227;o de cardiotoxicidade das terap&#234;uticas oncol&#243;gicas &#233; a cardiomiopatia relacionada com as antraciclinas<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#46; As primeiras evid&#234;ncias indicaram que a disfun&#231;&#227;o sist&#243;lica do ventr&#237;culo esquerdo &#40;VE&#41; estava intimamente relacionada com o uso de doses cumulativas de antraciclinas&#46; Segundo Lefrak et al<span class="elsevierStyleItalic">&#46;</span>&#44; administra&#231;&#245;es repetidas podem resultar em les&#245;es permanentes a n&#237;vel celular e intersticial&#44; frequentemente associadas ao risco de ocorr&#234;ncia de insufici&#234;ncia card&#237;aca refrat&#225;ria<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#46; Mais recentemente&#44; o uso de novos agentes terap&#234;uticos&#44; como o anticorpo monoclonal <span class="elsevierStyleItalic">trastuzumab</span>&#44; embora tamb&#233;m possam causar cardiomiopatia&#44; induzem uma disfun&#231;&#227;o transit&#243;ria revers&#237;vel dos mi&#243;citos sem que haja rela&#231;&#227;o com a dose utilizada&#44; resultando num progn&#243;stico cl&#237;nico mais favor&#225;vel<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;15</span></a>&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Os f&#225;rmacos antineopl&#225;sicos&#44; como as antraciclinas&#44; que causam predominantemente les&#245;es irrevers&#237;veis t&#234;m sido classificados como agentes tipo <span class="elsevierStyleSmallCaps">i</span>&#44; sendo os agentes tipo <span class="elsevierStyleSmallCaps">ii</span> aqueles que n&#227;o acarretam uma destrui&#231;&#227;o celular irrevers&#237;vel<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Tabela 2</a>&#41;&#46; As caracter&#237;sticas dos agentes terap&#234;uticos tipo <span class="elsevierStyleSmallCaps">ii</span> t&#234;m permitido o seu uso durante anos at&#233; ao aparecimento de sinais de les&#227;o card&#237;aca e a sua reintrodu&#231;&#227;o&#44; com risco aceit&#225;vel&#44; ap&#243;s a recupera&#231;&#227;o card&#237;aca<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#46; No entanto&#44; alguns ensaios cl&#237;nicos t&#234;m posto em causa a reversibilidade dos efeitos cardiot&#243;xicos deste tipo de f&#225;rmacos&#46; De facto&#44; o uso de terapias combinadas &#40;agentes tipo <span class="elsevierStyleSmallCaps">i</span> e <span class="elsevierStyleSmallCaps">ii</span>&#41; induz uma elevada incid&#234;ncia de disfun&#231;&#227;o card&#237;aca&#44; acima do expect&#225;vel&#44; em doentes com cancro<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Tipo <span class="elsevierStyleSmallCaps">i</span> &#8211; Antraciclinas</span><p id="par0045" class="elsevierStylePara elsevierViewall">As antraciclinas&#44; como a doxorrubicina &#40;DOX&#41;&#44; epirrubicina &#40;EPI&#41; e daunorrubicina &#40;DNR&#41;&#44; permanecem entre os agentes antineopl&#225;sicos mais usados no tratamento de uma ampla variedade de tumores s&#243;lidos e neoplasias hematol&#243;gicas<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; Infelizmente&#44; a preocupa&#231;&#227;o gerada na comunidade m&#233;dica em torno da sua cardiotoxicidade ainda limita a sua utiliza&#231;&#227;o&#46; Apesar de mais de 40 anos de investiga&#231;&#227;o&#44; os mecanismos de a&#231;&#227;o respons&#225;veis pela toxicidade card&#237;aca inerente ao uso de doses cumulativas de antraciclinas ainda n&#227;o foram completamente elucidados<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;7</span></a>&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Efeitos cardiot&#243;xicos a curto e longo prazo</span><p id="par0050" class="elsevierStylePara elsevierViewall">A cardiotoxicidade pode ocorrer de forma aguda ou cr&#243;nica&#44; podendo surgir anos ap&#243;s a conclus&#227;o do tratamento&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">A cardiotoxicidade aguda induzida pelas antraciclinas &#233; rara&#44; transit&#243;ria e independente da dose utilizada&#46; Caracteriza-se por altera&#231;&#245;es s&#250;bitas da repolariza&#231;&#227;o ventricular&#44; altera&#231;&#245;es eletrocardiogr&#225;ficas no intervalo Q-T&#44; arritmias ventriculares e supraventriculares&#44; s&#237;ndromes coron&#225;rias agudas&#44; pericardite e miocardite&#46; Estas altera&#231;&#245;es s&#227;o geralmente observadas desde o in&#237;cio do tratamento at&#233; 14&#160;dias ap&#243;s o t&#233;rmino do mesmo&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Por outro lado&#44; a forma cr&#243;nica &#233; dependente da dose usada clinicamente e pode ser diferenciada em 2 tipos&#44; de acordo com o in&#237;cio dos sintomas cl&#237;nicos&#46; O primeiro tipo ocorre no in&#237;cio&#44; ao longo do primeiro ano ap&#243;s o t&#233;rmino da quimioterapia&#44; e o segundo tipo ocorre tardiamente&#44; mais de um ano depois do tratamento&#46; A manifesta&#231;&#227;o mais caracter&#237;stica de cardiotoxicidade cr&#243;nica &#233; a disfun&#231;&#227;o ventricular sist&#243;lica ou diast&#243;lica que pode levar a cardiomiopatia grave e&#44; em &#250;ltima inst&#226;ncia&#44; mesmo &#224; morte<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;13</span></a>&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Fatores de risco</span><p id="par0065" class="elsevierStylePara elsevierViewall">A progress&#227;o e o grau de cardiotoxicidade inerente ao uso deste tipo de f&#225;rmacos s&#227;o vari&#225;veis entre indiv&#237;duos&#46; Tal deve-se &#224; influ&#234;ncia de diversos fatores de risco &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Tabela 3</a>&#41;&#44; bem como &#224; pr&#243;pria predisposi&#231;&#227;o gen&#233;tica<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">A dose cumulativa total &#233; o principal fator de risco para a ocorr&#234;ncia de insufici&#234;ncia card&#237;aca congestiva relacionada com a utiliza&#231;&#227;o de antraciclinas<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#46; No entanto&#44; n&#227;o existe nenhuma dose absolutamente segura a n&#237;vel cardiot&#243;xico&#44; sendo que esta deve ser sempre equilibrada com o seu grau de efic&#225;cia antineopl&#225;sica<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a>&#46; Al&#233;m disso&#44; a dura&#231;&#227;o da administra&#231;&#227;o tamb&#233;m poder&#225; influenciar o risco relativo de desenvolver cardiotoxicidade durante ou ap&#243;s a terapia oncol&#243;gica&#46; De facto&#44; o uso de tratamentos de administra&#231;&#227;o prolongada tem reduzido o grau de les&#245;es card&#237;acas<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#46; Por outro lado&#44; indiv&#237;duos tratados numa idade mais jovem parecem ser mais vulner&#225;veis aos efeitos cardiot&#243;xicos induzidos por este tipo de f&#225;rmacos<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Todos os fatores de risco est&#227;o intimamente relacionados com a cardiotoxicidade precoce e tardia&#44; e n&#227;o com a que surge de forma aguda<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Mecanismos fisiopatol&#243;gicos</span><p id="par0085" class="elsevierStylePara elsevierViewall">V&#225;rios mecanismos t&#234;m sido sugeridos para explicar a fisiopatologia da cardiotoxicidade induzida pelas antraciclinas&#44; embora ainda sejam desconhecidas as raz&#245;es pelas quais estes afetam preferencialmente os cardiomi&#243;citos&#46; Os principais processos propostos envolvem a peroxida&#231;&#227;o lip&#237;dica e o <span class="elsevierStyleItalic">stress</span> oxidativo nos cardiomi&#243;citos<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#46; Como consequ&#234;ncia do pr&#243;prio mecanismo de a&#231;&#227;o das antraciclinas&#44; est&#225; comprometida a s&#237;ntese de DNA&#44; RNA e prote&#237;nas<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&#44; bem como de importantes fatores de transcri&#231;&#227;o envolvidos na regula&#231;&#227;o de genes cardioespec&#237;ficos<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;25</span></a>&#46; Esta diminui&#231;&#227;o na express&#227;o proteica acoplada a um aumento da degrada&#231;&#227;o de miofilamentos leva a um balan&#231;o negativo das prote&#237;nas sarcom&#233;ricas&#44; como a titina&#44; nas c&#233;lulas card&#237;acas &#40;sarcopenia card&#237;aca&#41;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&#46; Por outro lado&#44; a redu&#231;&#227;o miofilamentar pode ser potenciada com a utiliza&#231;&#227;o de terapias combinadas &#40;antraciclinas e o anticorpo monoclonal <span class="elsevierStyleItalic">trastuzumab</span>&#41;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#46; O uso desta terap&#234;utica tamb&#233;m poder&#225;&#44; a n&#237;vel mitocondrial&#44; afetar a bioenerg&#233;tica<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> e induzir les&#245;es no DNA<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&#46; Al&#233;m disso&#44; as antraciclinas causam um desequil&#237;brio na regula&#231;&#227;o din&#226;mica da fun&#231;&#227;o card&#237;aca&#44; promovendo altera&#231;&#245;es na atividade adren&#233;rgica&#44; na adenilato ciclase<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> e na homeostasia do c&#225;lcio<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;30</span></a>&#46; Dados cl&#237;nicos e experimentais sugerem como mecanismo alternativo de cardiotoxicidade a indu&#231;&#227;o de morte nas c&#233;lulas card&#237;acas&#44; por apoptose ou necrose&#44; ap&#243;s cada exposi&#231;&#227;o &#224;s antraciclinas&#46; Dada a capacidade limitada de regenera&#231;&#227;o do m&#250;sculo card&#237;aco&#44; a redu&#231;&#227;o cumulativa do n&#250;mero de cardiomi&#243;citos promove a remodelagem ventricular<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#46; Mais recentemente&#44; de Angelis et al<span class="elsevierStyleItalic">&#46;</span> demonstraram que a cardiomiopatia promovida pela DOX tamb&#233;m pode ser mediada pela redu&#231;&#227;o de c&#233;lulas estaminais card&#237;acas e revertida atrav&#233;s da recupera&#231;&#227;o funcional das c&#233;lulas progenitoras<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a>&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Estrat&#233;gias para limitar a cardiotoxicidade</span><p id="par0090" class="elsevierStylePara elsevierViewall">Embora n&#227;o exista nenhum m&#233;todo clinicamente aceite&#44; t&#234;m sido adotadas diversas estrat&#233;gias com o intuito de limitar ou prevenir a cardiotoxicidade das antraciclinas&#46; Entre elas&#44; destacam-se a s&#237;ntese de an&#225;logos de compostos naturais&#44; o desenvolvimento de formula&#231;&#245;es espec&#237;ficas para determinado tumor e o uso cl&#237;nico de agentes cardioprotetores<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a>&#46;</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">S&#237;ntese de an&#225;logos dos compostos naturais</span><p id="par0095" class="elsevierStylePara elsevierViewall">A altera&#231;&#227;o estrutural de antraciclinas tem resultado em compostos com baixos n&#237;veis de cardiotoxicidade&#44; permitindo a administra&#231;&#227;o de doses terap&#234;uticas mais elevadas<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#46; A EPI<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> e a idarrubicina &#40;IDA&#41;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> surgem atualmente&#44; na terap&#234;utica oncol&#243;gica&#44; como alternativas &#250;teis ao uso de DOX e DNR&#44; respetivamente&#46; Outras antraciclinas&#44; como a pirarrubicina e aclarrubicina&#44; embora j&#225; tenham sido registadas em alguns pa&#237;ses&#44; ainda n&#227;o desempenham um papel significativo em termos globais<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a>&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Epirrubicina&#46;</span> A EPI &#233; um ep&#237;mero semissint&#233;tico da DOX com um espectro oncol&#243;gico id&#234;ntico<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a>&#46; Embora possua um mecanismo de a&#231;&#227;o id&#234;ntico &#224; DOX&#44; algumas propriedades f&#237;sico-qu&#237;micas e farmacocin&#233;ticas est&#227;o alteradas<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a>&#46; Comparada com a DOX&#44; a cardiotoxicidade da EPI &#233; significativamente menor quando administrada em doses que resultam em n&#237;veis id&#234;nticos de mielossupress&#227;o<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a>&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Idarrubicina</span>&#46; A IDA &#233; um an&#225;logo estrutural da DNR&#44; que se intercala ao DNA&#44; interage com a topoisomerase <span class="elsevierStyleSmallCaps">ii</span> e tem um efeito inibidor sobre a s&#237;ntese do &#225;cido nucleico<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a>&#46; Este composto possui uma elevada lipofilicidade&#44; permitindo uma elevada absor&#231;&#227;o celular<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a>&#46; A IDA pode ser administrada por via intravenosa ou oralmente&#46; Contudo&#44; atualmente t&#234;m sido postas em causa as vantagens deste agente antineopl&#225;sico na diminui&#231;&#227;o dos efeitos cardiot&#243;xicos<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;37</span></a>&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Formula&#231;&#245;es espec&#237;ficas para determinado tumor</span><p id="par0110" class="elsevierStylePara elsevierViewall">De forma a limitar a absor&#231;&#227;o das antraciclinas no tecido card&#237;aco t&#234;m sido desenvolvidas novas t&#233;cnicas no transporte dos agentes antineopl&#225;sicos<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Atualmente&#44; a incorpora&#231;&#227;o liposs&#243;mica de DOX e DNR representa o principal m&#233;todo de condu&#231;&#227;o passiva das antraciclinas ao tumor alvo<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a>&#46; Este procedimento oferece uma cardioprote&#231;&#227;o substancial&#44; aumentando o tamanho molecular do f&#225;rmaco atrav&#233;s de encapsula&#231;&#227;o e prolongando o seu tempo de elimina&#231;&#227;o&#44; de modo a permanecer no organismo com menos efeitos adversos&#46; Al&#233;m disso&#44; a incorpora&#231;&#227;o liposs&#243;mica permite a fixa&#231;&#227;o da droga longe de &#243;rg&#227;os que possuem jun&#231;&#245;es capilares normais&#44; penetrando facilmente em locais com um sistema vascular imaturo&#44; como nas neoplasias<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Por outro lado&#44; as pr&#243;-drogas de antraciclinas&#44; ao contr&#225;rio dos compostos liposs&#243;micos&#44; conseguem atingir o tecido tumoral por uma via ativa&#46; V&#225;rias pr&#243;-drogas t&#234;m sido obtidas por um processo de conjuga&#231;&#227;o com p&#233;ptidos&#44; hidratos de carbono&#44; anticorpos&#44; prote&#237;nas s&#233;ricas ou pol&#237;meros sint&#233;ticos<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a>&#46; Estes conjugados s&#227;o incapazes de penetrar em c&#233;lulas normais&#44; sendo ativadas especificamente por c&#233;lulas neopl&#225;sicas<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;40</span></a>&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Agentes cardioprotetores</span><p id="par0125" class="elsevierStylePara elsevierViewall">Na comunidade m&#233;dica &#233; cada vez mais premente o estabelecimento de estrat&#233;gias farmacol&#243;gicas que protejam o sistema cardiovascular&#44; sem interferir com os mecanismos antineop&#225;sicos associados ao uso de antraciclinas<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;41</span></a>&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Atualmente&#44; tendo em conta o papel patog&#233;nico das esp&#233;cies reativas de oxig&#233;nio &#40;ERO&#41; e do <span class="elsevierStyleItalic">stress</span> oxidativo na cardiotoxicidade induzida pelas antraciclinas&#44; t&#234;m-se estudado drogas e compostos naturais capazes de melhorar as defesas antioxidantes dos cardiomi&#243;citos<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a>&#46; V&#225;rias classes de f&#225;rmacos&#44; incluindo antioxidantes&#44; agentes quelantes de ferro e drogas hipolipemiantes&#44; foram testadas&#44; tanto em modelos animais como em doentes humanos<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#8211;43</span></a>&#46; No entanto&#44; a efic&#225;cia cardioprotetora de alguns compostos &#233; bastante question&#225;vel<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;43</span></a>&#46; O <span class="elsevierStyleItalic">dexrazoxane</span> &#40;Cardioxane<span class="elsevierStyleSup">&#174;</span>&#41; &#233; a &#250;nica droga certificada para uso cl&#237;nico para a preven&#231;&#227;o dos efeitos cardiot&#243;xicos induzidos pelas antraciclinas<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a>&#46; Por&#233;m&#44; a sua utiliza&#231;&#227;o &#233; atualmente controversa&#44; tendo sido associada a um eventual comprometimento da efic&#225;cia oncol&#243;gica e a um poss&#237;vel aumento de neoplasias secund&#225;rias&#44; pelo que o seu uso foi restrito pela <span class="elsevierStyleItalic">U&#46;S&#46; Food and Drug Administration</span> &#40;FDA&#41; a doentes adultos<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a>&#46;</p></span></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Tipo <span class="elsevierStyleSmallCaps">ii</span> - <span class="elsevierStyleItalic">Trastuzumab</span></span><p id="par0135" class="elsevierStylePara elsevierViewall">Os anticorpos monoclonais s&#227;o um dos paradigmas da terapia-alvo oncol&#243;gica e s&#227;o amplamente utilizados no tratamento antineopl&#225;sico&#46; No cancro da mama&#44; aproximadamente 15 a 25&#37; dos pacientes apresentam amplifica&#231;&#227;o do gene HER2&#44; resultando na sobre-express&#227;o do recetor HER2 &#40;recetor-2 do fator de crescimento epid&#233;rmico humano&#41;&#46; O <span class="elsevierStyleItalic">trastuzumab</span> liga-se especificamente ao dom&#237;nio extracelular do HER2&#44; resultando na inibi&#231;&#227;o da respetiva transdu&#231;&#227;o do sinal<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#46; Regimes de quimioterapia sem antraciclinas apresentam taxas menores de disfun&#231;&#227;o card&#237;aca quando comparados com regimes de uso combinado de <span class="elsevierStyleItalic">trastuzumab</span> e antraciclinas&#46; Por outro lado&#44; a associa&#231;&#227;o de <span class="elsevierStyleItalic">trastuzumab</span> com vinorelbina&#44; gemcitabina ou DOX lipossomal n&#227;o demonstra um risco significativo de cardiotoxicidade<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a>&#46;</p><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Fatores de risco</span><p id="par0140" class="elsevierStylePara elsevierViewall">Um dos principais fatores de risco cardiot&#243;xicos associados ao uso antineopl&#225;sico de <span class="elsevierStyleItalic">trastuzumab</span> &#233; a utiliza&#231;&#227;o de elevadas doses cumulativas de antraciclinas &#40;&#62;&#160;300<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#41;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a>&#46; Outros importantes fatores de risco incluem a disfun&#231;&#227;o ventricular esquerda associada ou n&#227;o ao uso concomitante de antraciclinas&#44; a pr&#233;-exist&#234;ncia de hipertens&#227;o arterial sist&#233;mica&#44; um &#237;ndice de massa corporal superior a 25 e a idade avan&#231;ada dos doentes&#46; Por outro lado&#44; o uso terap&#234;utico simult&#226;neo de irradia&#231;&#227;o tor&#225;cica com <span class="elsevierStyleItalic">trastuzumab</span> &#233; clinicamente vi&#225;vel<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a>&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Al&#233;m disso&#44; dados recentes demonstraram que doentes oncol&#243;gicos idosos &#40;&#8805;&#160;70 anos&#41; com historial de doen&#231;a card&#237;aca e&#47;ou diabetes apresentam um aumento da incid&#234;ncia de efeitos cardiot&#243;xicos associados ao uso de <span class="elsevierStyleItalic">trastuzumab</span> no tratamento do cancro da mama&#46; Segundo Serrano et al&#46;&#44; deve-se manter uma monitoriza&#231;&#227;o cuidada e cont&#237;nua desta popula&#231;&#227;o<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a>&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Mecanismos fisiopatol&#243;gicos</span><p id="par0150" class="elsevierStylePara elsevierViewall">Embora ainda n&#227;o sejam conhecidos os mecanismos intracelulares exatos associados &#224; a&#231;&#227;o fisiopatol&#243;gica do <span class="elsevierStyleItalic">trastuzumab</span>&#44; acredita-se que estes estejam intimamente relacionados com a sua a&#231;&#227;o inibit&#243;ria sobre a sinaliza&#231;&#227;o card&#237;aca do HER2&#46; Diversos estudos evidenciaram o importante papel do HER2 na sobreviv&#234;ncia e no desenvolvimento dos cardiomi&#243;citos<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50&#44;51</span></a>&#46; De facto&#44; ratos manipulados geneticamente com n&#237;veis reduzidos de HER2 desenvolvem cardiomiopatia dilatada&#44; menor capacidade adaptativa a condi&#231;&#245;es de sobrecarga de press&#227;o e maior sensibilidade &#224; toxicidade associada ao uso de antraciclinas<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">52&#44;53</span></a>&#46; Por outro lado&#44; a sobre-express&#227;o de HER2 e&#47;ou ativa&#231;&#227;o da via de sinaliza&#231;&#227;o HER2&#47;HER4 promovida pela neuregulina &#40;NRG&#41; confere&#44; a n&#237;vel celular&#44; maior prote&#231;&#227;o face ao <span class="elsevierStyleItalic">stress</span> oxidativo e impede a ocorr&#234;ncia de apoptose<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a>&#46; Na verdade&#44; foram determinados elevados n&#237;veis s&#233;ricos de HER2 em indiv&#237;duos com insufici&#234;ncia card&#237;aca cr&#243;nica<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> e&#44; mais recentemente&#44; foi demonstrado em ensaios cl&#237;nicos que a administra&#231;&#227;o de NRG-1 recombinante humana no tratamento de IC cr&#243;nica est&#225;vel melhora a fun&#231;&#227;o card&#237;aca&#44; para al&#233;m de ser bem tolerada pelos doentes<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a>&#46; De acordo com estes dados&#44; se&#44; por um lado&#44; o <span class="elsevierStyleItalic">stress</span> card&#237;aco promove o aumento da express&#227;o de HER2 e a ativa&#231;&#227;o da via HER2&#47;HER4 pela NRG&#44; por outro&#44; a inibi&#231;&#227;o do HER2 pelo <span class="elsevierStyleItalic">trastuzumab</span> induz o desenvolvimento de disfun&#231;&#227;o ventricular<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figura 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">Contudo&#44; o mecanismo fisiopatol&#243;gico associado ao uso de <span class="elsevierStyleItalic">trastuzumab</span> &#233; provavelmente mais complexo&#44; n&#227;o envolvendo apenas a inibi&#231;&#227;o do HER2&#46; De facto&#44; dados recentes revelaram o aparecimento de n&#237;veis de toxicidade m&#237;nimos ap&#243;s o uso cl&#237;nico de <span class="elsevierStyleItalic">lapatinib</span>&#44; um inibidor da tirosina-c&#237;nase com dupla a&#231;&#227;o sobre a HER2 e o fator de crescimento epid&#233;rmico &#40;EGF&#41;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a>&#46; V&#225;rios fatores poder&#227;o contribuir para a ocorr&#234;ncia de diferentes perfis cardiot&#243;xicos entre estes dois f&#225;rmacos&#46; Estudos espec&#237;ficos analisaram o efeito das rea&#231;&#245;es imunit&#225;rias citot&#243;xicas promovidas pelo dom&#237;nio IgG1 do <span class="elsevierStyleItalic">trastuzumab</span> nas les&#245;es dos cardiomi&#243;citos&#46; Os dados mostraram que a indu&#231;&#227;o de citotoxicidade celular dependente de anticorpos &#40;ADCC&#41; em c&#233;lulas tumorais estava intimamente relacionada com a cardiotoxicidade<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a>&#46; Outro mecanismo proposto envolve uma resposta intracelular &#250;nica ap&#243;s ativa&#231;&#227;o do HER2 nos cardiomi&#243;citos&#46; Ap&#243;s ligar-se ao HER2&#44; o <span class="elsevierStyleItalic">trastuzumab</span> regula a integridade mitocondrial atrav&#233;s da fam&#237;lia de prote&#237;nas BCL-<span class="elsevierStyleSmallCaps">X</span>&#44; promovendo a deple&#231;&#227;o de ATP e a consequente disfun&#231;&#227;o contr&#225;til nos cardiomi&#243;citos&#46; Curiosamente&#44; alguns estudos indicam que o <span class="elsevierStyleItalic">lapatinib</span> promove o efeito oposto&#44; reduzindo a citotoxicidade do <span class="elsevierStyleItalic">trastuzumab</span> quando os dois f&#225;rmacos s&#227;o administrados concomitantemente<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#44;61</span></a>&#46; Isto deve-se &#224;s diferentes a&#231;&#245;es que as drogas t&#234;m sobre a funcionalidade da prote&#237;na c&#237;nase ativada pelo AMP &#40;AMPK&#41;&#58; enquanto o <span class="elsevierStyleItalic">trastuzumab</span> inibe a AMPK&#44; diminuindo a quantidade de ATP intracelular&#44; o <span class="elsevierStyleItalic">lapatinib</span>&#44; por sua vez&#44; promove a sua atividade&#44; aumentando a produ&#231;&#227;o de ATP por vias oxidativas<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a>&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Cardiotoxicidade <span class="elsevierStyleItalic">trastuzumab</span>-antraciclinas</span><p id="par0160" class="elsevierStylePara elsevierViewall">Atualmente&#44; os mecanismos cardiot&#243;xicos associados ao uso concomitante de <span class="elsevierStyleItalic">trastuzumab</span> e de antraciclinas s&#227;o de particular interesse&#44; dada a utiliza&#231;&#227;o frequente de terapias combinadas no tratamento do cancro da mama<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a>&#46; O uso deste tipo de terapia conduz a um aumento intracelular de ERO e a uma redu&#231;&#227;o de compostos antioxidantes&#44; promovendo a ocorr&#234;ncia de <span class="elsevierStyleItalic">stress</span> oxidativo que leva a disfun&#231;&#227;o card&#237;aca e consequente sobre-express&#227;o de angiontensina <span class="elsevierStyleSmallCaps">ii</span> &#40;Ang <span class="elsevierStyleSmallCaps">II</span>&#41;&#46; Os n&#237;veis elevados de Ang <span class="elsevierStyleSmallCaps">II</span> inibem a a&#231;&#227;o da NRG&#44; impedindo a sua liga&#231;&#227;o aos recetores HER e a posterior ativa&#231;&#227;o de vias de sinaliza&#231;&#227;o antiapopt&#243;ticas&#46; Al&#233;m disso&#44; a inibi&#231;&#227;o destes recetores pode contribuir para o aumento de produ&#231;&#227;o de ERO&#46; Outro efeito da Ang <span class="elsevierStyleSmallCaps">II</span> prende-se com a ativa&#231;&#227;o e&#47;ou regula&#231;&#227;o positiva de NADPH oxidase<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">63&#44;64</span></a>&#46; A Ang <span class="elsevierStyleSmallCaps">II</span> interage com o recetor AT1&#44; associado a prote&#237;nas G&#44; que ativam a NADPH oxidase atrav&#233;s da prote&#237;na c&#237;nase C &#40;PKC&#41;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a>&#46; A NADPH oxidase&#44; por sua vez&#44; produz radicais ani&#245;es super&#243;xidos que s&#227;o ERO potentes&#46; Finalmente&#44; a sinaliza&#231;&#227;o do recetor AT1 est&#225; relacionada com a ativa&#231;&#227;o da c&#237;nase 1 reguladora do sinal apopt&#243;tico &#40;ASK1&#41;&#44; membro da fam&#237;lia das MAPK&#44; conduzindo a morte celular e disfun&#231;&#227;o card&#237;aca<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a>&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Em suma&#44; a a&#231;&#227;o do <span class="elsevierStyleItalic">trastuzumab</span> pode inibir diretamente as vias de sinaliza&#231;&#227;o antiapopt&#243;ticas&#44; ou por outro lado&#44; estimular a sobre-express&#227;o de Ang <span class="elsevierStyleSmallCaps">II</span>&#44; que promove a produ&#231;&#227;o de ERO e a inibi&#231;&#227;o da a&#231;&#227;o da NRG<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figura 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Estrat&#233;gias para limitar a cardiotoxicidade</span><p id="par0170" class="elsevierStylePara elsevierViewall">V&#225;rias estrat&#233;gias cl&#237;nicas t&#234;m sido postas em pr&#225;tica com o objetivo de atenuar a cardiotoxicidade do <span class="elsevierStyleItalic">trastuzumab</span> sem comprometer significativamente a sua efic&#225;cia terap&#234;utica&#46; Estas incluem a utiliza&#231;&#227;o de combina&#231;&#245;es otimizadas de quimioterapia&#44; o encurtamento do tratamento e o acompanhamento rigoroso dos doentes tratados<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a>&#46;</p><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle"><span class="elsevierStyleItalic">Trastuzumab</span> sem antraciclinas</span><p id="par0175" class="elsevierStylePara elsevierViewall">O estudo <span class="elsevierStyleItalic">Breast Cancer International Research Group</span> &#40;BCIRG&#41; <span class="elsevierStyleItalic">006</span> foi o primeiro a testar um procedimento terap&#234;utico adjuvante sem o uso de antraciclinas&#46; Este ensaio comprovou que um regime quimioterap&#234;utico com <span class="elsevierStyleItalic">trastuzumab</span> e sem antraciclinas&#44; no tratamento do cancro da mama&#44; tem uma efic&#225;cia antineopl&#225;sica equivalente e com menor incid&#234;ncia de eventos cardiot&#243;xicos&#44; quando comparado com regimes terap&#234;uticos adjuvantes com <span class="elsevierStyleItalic">trastuzumab</span> e antraciclinas<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a>&#46; Embora outros ensaios confirmem a efic&#225;cia desta estrat&#233;gia terap&#234;utica<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a>&#44; atualmente&#44; ainda existem opini&#245;es controversas sobre o papel das antraciclinas no tratamento combinado antineopl&#225;sico<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a>&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conjugados <span class="elsevierStyleItalic">trastuzumab</span>-toxinas</span><p id="par0180" class="elsevierStylePara elsevierViewall">Os anticorpos podem ser utilizados de forma a dirigir os agentes citot&#243;xicos para antig&#233;nios espec&#237;ficos de tumores alvo&#46; Esta liga&#231;&#227;o qu&#237;mica confere um maior controlo apopt&#243;tico a anticorpos monoclonais que s&#227;o espec&#237;ficos do tumor&#44; mas n&#227;o suficientemente citot&#243;xicos&#44; para al&#233;m de promover maior seletividade na sua a&#231;&#227;o<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a>&#46; De facto&#44; Phillips et al<span class="elsevierStyleItalic">&#46;</span> demonstraram que o uso de <span class="elsevierStyleItalic">trastuzumab</span> associado &#224; toxina f&#250;ngica maitansina DM1 desenvolve baixos &#237;ndices de toxicidade<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a>&#46; Mais recentemente&#44; ensaios cl&#237;nicos t&#234;m comprovado a efic&#225;cia e toler&#226;ncia do uso terap&#234;utico do conjugado <span class="elsevierStyleItalic">trastuzumab</span>-DM1 em pacientes com cancro da mama<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a>&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Regimes de tratamento de curto prazo</span><p id="par0185" class="elsevierStylePara elsevierViewall">Este tipo de abordagem suscita grande interesse na comunidade m&#233;dica&#44; dado o perfil de seguran&#231;a do seu uso e a rela&#231;&#227;o custo-benef&#237;cio<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; O estudo FinHER <span class="elsevierStyleItalic">&#40;Finland Herceptin&#41;</span> comparou o uso de docetaxel com vinorelbina&#44; administrados com ou sem <span class="elsevierStyleItalic">trastuzumab</span>&#44; como tratamento adjuvante do cancro da mama precoce&#46; Neste estudo&#44; o <span class="elsevierStyleItalic">trastuzumab</span> foi administrado antes de outras terapias cardiot&#243;xicas e concomitantemente com docetaxel-vinorelbina durante apenas nove semanas para testar a hip&#243;tese de que este regime iria limitar a cardiotoxicidade e manter a efic&#225;cia antineopl&#225;sica&#46; A ocorr&#234;ncia de baixas taxas de cardiotoxicidade estava intimamente relacionada com o uso de regimes de tratamento curtos com <span class="elsevierStyleItalic">trastuzumab</span><a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a>&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Uso individualizado de antraciclinas</span><p id="par0190" class="elsevierStylePara elsevierViewall">A topoisomerase-<span class="elsevierStyleSmallCaps">ii</span>&#945; &#40;TOP2A&#41; &#233; um dos alvos moleculares da a&#231;&#227;o das antraciclinas e tem sido considerada como um poss&#237;vel marcador preditivo de resposta a estes agentes&#46; A amplifica&#231;&#227;o do gene TOP2A&#44; localizado pr&#243;ximo do gene HER2&#44; &#233; mais frequente em tumores com amplifica&#231;&#227;o do HER2 &#40;34-90&#37;&#41; do que em tumores sem amplifica&#231;&#227;o do HER2 &#40;5-10&#37;&#41;&#46; Diversos relat&#243;rios e investiga&#231;&#245;es cl&#237;nicas retrospetivas encontraram uma taxa de efic&#225;cia adicional ap&#243;s o uso de regimes terap&#234;uticos que cont&#233;m antraciclinas no tratamento do cancro da mama HER2 positivo&#44; propondo a redu&#231;&#227;o do uso de antraciclinas em doentes com tumores HER2 negativo<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">74&#8211;76</span></a>&#46; Por outro lado&#44; resultados opostos foram obtidos em diferentes ensaios cl&#237;nicos<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a>&#46; Assim sendo&#44; o uso de regimes adjuvantes com antraciclinas no tratamento de doentes com coamplifica&#231;&#227;o dos genes HER2 e TOP2A permanece controverso<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46;</p></span></span></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Outros efeitos cardiot&#243;xicos</span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Isquemia mioc&#225;rdica</span><p id="par0195" class="elsevierStylePara elsevierViewall">Os indiv&#237;duos com cancro apresentam&#44; atualmente&#44; uma taxa de sobrevida mais favor&#225;vel&#44; o que resulta numa maior exposi&#231;&#227;o a fatores de risco associados &#224; ocorr&#234;ncia de doen&#231;as ateroscler&#243;ticas<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a>&#46; O aparecimento de doen&#231;a coron&#225;ria em doentes oncol&#243;gicos tem sido associado ao uso terap&#234;utico de alguns f&#225;rmacos antineopl&#225;sicos&#44; particularmente a capecitabina&#44; 5-fluoracilo &#40;5-FU&#41; e <span class="elsevierStyleItalic">bevacizumab</span>&#46; No entanto&#44; outras drogas est&#227;o relacionadas com o aparecimento de eventos isqu&#233;micos como os agentes antimicrot&#250;bulos &#40;paclitaxel e docetaxel&#41;&#44; os inibidores da tirosina-c&#237;nase <span class="elsevierStyleItalic">&#40;sorafenib&#44; sunitinib&#41;</span> e os alcaloides da vinca &#40;vincristina&#44; vinorelbina&#41;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;79</span></a>&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">O vasoespasmo coron&#225;rio &#233; o mecanismo fisiopatol&#243;gico isqu&#233;mico relacionado com a administra&#231;&#227;o de 5-FU&#44; ou da sua pr&#243;-droga fluoropirimidina&#44; a capecitabina&#46; Muitos dos indiv&#237;duos afetados possuem doen&#231;a arterial coron&#225;ria pr&#233;via&#44; o que pode aumentar o potencial isqu&#233;mico de 5-FU&#46; Com o evento isqu&#233;mico controlado&#44; o tratamento deve ser realizado continuamente e com maior aten&#231;&#227;o na preven&#231;&#227;o de recidivas<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a>&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Al&#233;m disso&#44; o <span class="elsevierStyleItalic">bevacizumab</span> &#233; um anticorpo monoclonal contra o fator de crescimento vascular endotelial &#40;FCVE&#41; e demonstra uma atividade antitumoral significativa quando combinado com quimioterapia&#46; O uso deste agente terap&#234;utico est&#225; associado&#44; raramente&#44; a eventos tromb&#243;ticos arteriais&#44; incluindo a ocorr&#234;ncia de enfarte agudo do mioc&#225;rdio em 0&#44;6-1&#44;5&#37; dos doentes<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;81</span></a>&#46; Os mecanismos de a&#231;&#227;o respons&#225;veis pela sua cardiotoxicidade ainda n&#227;o foram completamente elucidados<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a>&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Arritmias</span><p id="par0210" class="elsevierStylePara elsevierViewall">A taxa de incid&#234;ncia de arritmias no doente oncol&#243;gico ainda n&#227;o est&#225; bem determinada e &#233; vari&#225;vel de acordo com o tratamento antineopl&#225;sico utilizado<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a>&#46; Fatores de risco preponderantes incluem a idade avan&#231;ada do doente&#44; o uso de radia&#231;&#227;o card&#237;aca&#44; a ocorr&#234;ncia de infiltra&#231;&#245;es amil&#243;ides e qualquer outra anomalia subjacente ao sistema de condu&#231;&#227;o<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46; Por outro lado&#44; o cancro gera por si s&#243; um ambiente pr&#243;-arritmog&#233;nico&#44; independentemente de outros fatores de risco<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a>&#46; A fibrila&#231;&#227;o auricular &#233; a arritmia mais prevalente em doentes com cancro&#46; Segundo Onaitis et al&#46;&#44; esta &#233; respons&#225;vel por significativa morbilidade ap&#243;s cirurgia oncol&#243;gica&#44; com uma taxa de incid&#234;ncia de at&#233; 12&#44;6&#37;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a>&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Atualmente&#44; existe uma grande dificuldade em determinar a rela&#231;&#227;o causal dos eventos arr&#237;tmicos com cada um dos f&#225;rmacos utilizados clinicamente&#46; Os quimioter&#225;picos mais conhecidos por causar arritmias s&#227;o as antraciclinas &#40;DOX&#44; EPI&#41;&#44; os agentes antimicrot&#250;bulos &#40;paclitaxel e docetaxel&#41;&#44; os antimetab&#243;litos &#40;capecitabina&#44; 5-fluoracilo&#44; e gemcitabina&#41;&#44; os agentes alquilantes &#40;cisplatina e ciclofosfamida&#41;&#44; os inibidores da tirosina-c&#237;nase &#40;<span class="elsevierStyleItalic">trastuzumab</span> e <span class="elsevierStyleItalic">cetuximab</span>&#41;&#44; o tri&#243;xido de ars&#233;nio&#44; a talidomida e a interleucina-2<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a>&#46;</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Hipertens&#227;o arterial sist&#233;mica</span><p id="par0220" class="elsevierStylePara elsevierViewall">Alguns agentes quimioter&#225;picos que inibem a angiog&#233;nese&#44; como o <span class="elsevierStyleItalic">bevacizumab</span>&#44; <span class="elsevierStyleItalic">sutinib</span> e <span class="elsevierStyleItalic">sorafenib</span>&#44; <span class="elsevierStyleItalic">vatalanib</span>&#44; <span class="elsevierStyleItalic">pazopanib</span>&#44; <span class="elsevierStyleItalic">mosetamib</span>&#44; <span class="elsevierStyleItalic">axitinib</span> e <span class="elsevierStyleItalic">aflibercept</span> agravam ou induzem o aumento da press&#227;o arterial sist&#233;mica<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">85&#44;86</span></a>&#46; Antes da introdu&#231;&#227;o deste tipo de f&#225;rmacos&#44; a preval&#234;ncia de hipertens&#227;o arterial nos doentes oncol&#243;gicos era semelhante &#224; da popula&#231;&#227;o adulta em geral<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a>&#46; No entanto&#44; com a maior sobrevida dos doentes e o aumento da utiliza&#231;&#227;o de quimioter&#225;picos que interferem com press&#227;o arterial sist&#233;mica&#44; a hipertens&#227;o arterial tem sido diagnosticada mais frequentemente nestes indiv&#237;duos<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">85&#44;86</span></a>&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Os agentes antineopl&#225;sicos inibidores da angiog&#233;nese diminuem a atividade da tirosina-c&#237;nase do recetor do fator de crescimento endotelial vascular&#44; que &#233; respons&#225;vel pela produ&#231;&#227;o de &#243;xido n&#237;trico&#44; aumento da permeabilidade capilar e prolifera&#231;&#227;o das c&#233;lulas endoteliais<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">85&#44;86</span></a>&#46; A hipertens&#227;o arterial preexistente nos doentes com cancro &#233; um importante fator de risco para a ocorr&#234;ncia&#44; mais tarde&#44; de graves sequelas hipertensivas&#46; Uma forte interven&#231;&#227;o anti-hipertensora&#44; antes e durante o uso de f&#225;rmacos antiangiog&#233;nicos&#44; &#233; um componente essencial no tratamento dos doentes<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46;</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Tromboembolismo</span><p id="par0230" class="elsevierStylePara elsevierViewall">O tromboembolismo venoso &#233; uma das principais causas de morte nos doentes oncol&#243;gicos&#46; A doen&#231;a tromboemb&#243;lica venosa tem sido associada ao uso de drogas antiangiog&#233;nicas&#44; talidomida&#44; lenalidomida&#44; <span class="elsevierStyleItalic">bevacizumab</span> e terapias hormonais &#40;tamoxifeno&#41;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a>&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">A talidomida &#233; o agente antineopl&#225;sico mais comummente relacionado com os eventos tromboemb&#243;licos<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46; O uso monoterap&#234;utico desta droga est&#225; associado a uma incid&#234;ncia de 5&#37; de fen&#243;menos tromb&#243;ticos<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">88</span></a>&#46; Por outro lado&#44; a lenalidomida &#233; um an&#225;logo da talidomida com um perfil de toxicidade geral favor&#225;vel&#46; Contudo&#44; o risco de eventos tromboemb&#243;licos relacionados com a sua utiliza&#231;&#227;o tamb&#233;m &#233; alto<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">89</span></a>&#46; O mecanismo trombog&#233;nico destas drogas envolve uma a&#231;&#227;o direta nas c&#233;lulas endoteliais e o aumento da agrega&#231;&#227;o plaquet&#225;ria<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">O tamoxifeno&#44; antagonista do recetor do estrog&#233;nio&#44; est&#225; associado a um aumento da incid&#234;ncia de complica&#231;&#245;es tromboemb&#243;licas<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">90</span></a>&#46; Por outro lado&#44; os inibidores da aromatase&#44; como o anastrozol e letrozol&#44; que bloqueiam a convers&#227;o de androg&#233;nios para estrog&#233;nio em mulheres na p&#243;s-menopausa&#44; foram associados a uma maior incid&#234;ncia de efeitos nefastos a n&#237;vel card&#237;aco<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Tabela 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span></span></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Cardiotoxicidade associada &#224; radioterapia</span><p id="par0245" class="elsevierStylePara elsevierViewall">Atualmente&#44; estima-se que mais de 50&#37; dos doentes oncol&#243;gicos sejam tratados com radioterapia&#46; Juntamente com o desenvolvimento de novos agentes quimioter&#225;picos&#44; a radioterapia tem revolucionado o progn&#243;stico de indiv&#237;duos com v&#225;rios tipos de cancro&#46; No entanto&#44; s&#227;o detetados frequentemente efeitos tardios a n&#237;vel cardiovascular ap&#243;s o uso deste m&#233;todo terap&#234;utico<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a>&#46; A maioria das informa&#231;&#245;es cl&#237;nicas obtidas sobre a cardiotoxicidade da irradia&#231;&#227;o tor&#225;cica &#233; baseada em estudos de indiv&#237;duos com cancro da mama ou doen&#231;a de Hodgkin&#44; que desenvolveram doen&#231;a sintom&#225;tica durante o tratamento ou monitoriza&#231;&#227;o<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">93</span></a>&#46; As doen&#231;as peric&#225;rdicas s&#227;o manifesta&#231;&#245;es patol&#243;gicas frequentemente associadas ao uso de radioterapia&#46; Contudo&#44; outras poder&#227;o surgir&#44; meses ou anos ap&#243;s a irradia&#231;&#227;o&#44; como a fibrose mioc&#225;rdica e a cardiomiopatia&#44; a doen&#231;a arterial coron&#225;ria acelerada&#44; as irregularidades no sistema de condu&#231;&#227;o e a disfun&#231;&#227;o valvular &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figura 3</a>&#41;&#46; A ocorr&#234;ncia e manifesta&#231;&#227;o dos fen&#243;menos cardiot&#243;xicos dependem essencialmente da dose de radia&#231;&#227;o utilizada&#44; da &#225;rea do cora&#231;&#227;o exposta e da t&#233;cnica espec&#237;fica de aplica&#231;&#227;o&#46; Outros fatores de risco&#44; tais como a idade do doente no momento da exposi&#231;&#227;o&#44; tamb&#233;m t&#234;m um papel fulcral neste contexto&#44; sendo os doentes jovens &#40;&#60;&#160;20 anos&#41; mais suscet&#237;veis a les&#245;es card&#237;acas<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a>&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Monitoriza&#231;&#227;o e dete&#231;&#227;o precoce</span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Durante o desenvolvimento de f&#225;rmacos</span><p id="par0250" class="elsevierStylePara elsevierViewall">Antes da autoriza&#231;&#227;o comercial de todos os compostos&#44; &#233; geralmente aceite pela comunidade m&#233;dica que os dados pr&#233;-cl&#237;nicos obtidos dever&#227;o orientar a monitoriza&#231;&#227;o card&#237;aca durante os estudos subsequentes em humanos<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; No entanto&#44; ainda n&#227;o se conhecem os mecanismos moleculares exatos associados &#224; cardiotoxicidade de certos f&#225;rmacos&#44; o que dificulta a sua previs&#227;o e dete&#231;&#227;o precoce durante a fase de pr&#233;-comercializa&#231;&#227;o&#46; As culturas prim&#225;rias de c&#233;lulas card&#237;acas s&#227;o frequentemente usadas como modelos em testes toxicol&#243;gicos&#46; Por outro lado&#44; os cardiomi&#243;citos derivados de c&#233;lulas estaminais embrion&#225;rias representam modelos promissores neste contexto&#44; que poder&#227;o ampliar recursos e melhorar a preditividade dos testes n&#227;o-cl&#237;nicos<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a>&#46; Embora tenham sido desenvolvidas v&#225;rias abordagens alternativas&#44; os modelos animais apenas esclarecem a base molecular inerente ao aparecimento de disfun&#231;&#227;o card&#237;aca&#44; n&#227;o prevendo resultados cl&#237;nicos<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">96</span></a>&#46;</p></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Durante a aplica&#231;&#227;o cl&#237;nica</span><p id="par0255" class="elsevierStylePara elsevierViewall">Em doentes tratados com um regime de antraciclinas&#44; a necessidade de monitoriza&#231;&#227;o&#44; mesmo ap&#243;s o t&#233;rmino da terapia&#44; depende de aspetos espec&#237;ficos que os m&#233;dicos possam enfrentar na pr&#225;tica cl&#237;nica&#44; como a idade do doente oncol&#243;gico&#44; a dose de radia&#231;&#227;o utilizada e a dose cumulativa de antraciclinas<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">97</span></a>&#46; Al&#233;m disso&#44; deve avaliar-se a suscetibilidade individual &#40;p&#46; ex&#46; <span class="elsevierStyleItalic">background</span> gen&#233;tico&#41; de forma a identificar os doentes oncol&#243;gicos mais vulner&#225;veis e usar um tratamento personalizado&#46; A identifica&#231;&#227;o de subgrupos de risco e a sua incorpora&#231;&#227;o nos sistemas de monitoriza&#231;&#227;o &#233; fortemente recomendada<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;98</span></a>&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Relativamente a f&#225;rmacos como o <span class="elsevierStyleItalic">trastuzumab</span>&#44; pouco se sabe sobre os seus efeitos card&#237;acos a longo prazo e a reversibilidade do fen&#243;meno cardiot&#243;xico&#46; A principal limita&#231;&#227;o est&#225; associada ao seguimento a m&#233;dio prazo &#40;2 a 3<span class="elsevierStyleHsp" style=""></span>anos para o <span class="elsevierStyleItalic">trastuzumab</span>&#41;&#44; em que n&#227;o existem dados que indiquem se o tratamento da insufici&#234;ncia card&#237;aca cr&#243;nica promove uma recupera&#231;&#227;o permanente do doente ou diminui o risco de disfun&#231;&#227;o card&#237;aca tardia&#46; Al&#233;m disso&#44; n&#227;o tem sido realizada uma an&#225;lise e identifica&#231;&#227;o sistem&#225;tica dos fatores de risco associados &#224; cardiotoxicidade deste tipo de compostos&#46; Contudo&#44; &#233; recomendada uma cuidadosa avalia&#231;&#227;o da fun&#231;&#227;o card&#237;aca em todos os doentes eleg&#237;veis&#44; especialmente em casos cl&#237;nicos de reserva mioc&#225;rdica reduzida<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">A FEVE&#44; avaliada por angiografia de radionucl&#237;deos ou ecocardiografia&#44; &#233; o &#237;ndice mais comummente utilizado para a monitoriza&#231;&#227;o da fun&#231;&#227;o card&#237;aca durante o tratamento oncol&#243;gico<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">99</span></a>&#46; No entanto&#44; esta pode subestimar a les&#227;o cardiot&#243;xica&#44; dada a capacidade adaptativa do mioc&#225;rdio&#44; que permite manter este par&#226;metro dentro dos limites da normalidade&#44; mesmo na presen&#231;a de disfun&#231;&#227;o mioc&#225;rdica<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">100</span></a>&#46; Assim sendo&#44; outros m&#233;todos de monitoriza&#231;&#227;o alternativos t&#234;m sido estudados para avaliar a fun&#231;&#227;o card&#237;aca durante a terap&#234;utica oncol&#243;gica&#46; A an&#225;lise pr&#233;via da suscetibilidade individual&#44; a dete&#231;&#227;o de eventos cardiot&#243;xicos tempor&#225;rios &#40;p&#46; ex&#46; liberta&#231;&#227;o de pept&#237;deos natriur&#233;ticos&#41; ou a identifica&#231;&#227;o de altera&#231;&#245;es subcl&#237;nicas&#44; tais como varia&#231;&#245;es nos par&#226;metros diast&#243;licos&#44; poder&#227;o ser &#250;teis na dete&#231;&#227;o precoce de cardiotoxicidade<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">99</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Tabela 5</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0270" class="elsevierStylePara elsevierViewall">Embora existam diretrizes dispon&#237;veis para a monitoriza&#231;&#227;o dos efeitos cardiot&#243;xicos&#44; o tempo necess&#225;rio para acompanhamento m&#233;dico&#44; ap&#243;s o t&#233;rmino da terapia&#44; permanece desconhecido<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">99</span></a>&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Assim sendo&#44; h&#225; uma necessidade cada vez mais premente na monitoriza&#231;&#227;o cardiovascular dos indiv&#237;duos com cancro&#44; a fim de detetar precocemente efeitos cardiot&#243;xicos da terap&#234;utica antineopl&#225;sica&#46;</p></span></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclus&#227;o</span><p id="par0280" class="elsevierStylePara elsevierViewall">O uso extensivo de agentes quimioter&#225;picos e radioterapia&#44; na pr&#225;tica cl&#237;nica&#44; tem vindo a gerar uma enorme controv&#233;rsia&#44; devido aos seus potenciais efeitos adversos a n&#237;vel cardiovascular nos doentes oncol&#243;gicos tratados que sobrevivem&#46; Estes efeitos incluem cardiomiopatia&#44; isquemia&#44; arritmias&#44; hipertens&#227;o arterial&#44; doen&#231;as peric&#225;rdicas e doen&#231;a tromboemb&#243;lica&#46; No entanto&#44; n&#227;o existe um consenso na comunidade m&#233;dica que permita padronizar a monitoriza&#231;&#227;o da fun&#231;&#227;o mioc&#225;rdica nesses doentes&#44; assim como ainda n&#227;o foram desenvolvidos modelos preditivos precisos que possibilitem estimar esse mesmo risco de toxicidade com maior efic&#225;cia&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">De uma perspetiva farmacol&#243;gica e conforme recomendado por muitos especialistas da &#225;rea&#44; h&#225; uma necessidade urgente em compreender os mecanismos respons&#225;veis pela cardiotoxicidade&#46; Uma boa gest&#227;o e avalia&#231;&#227;o do perfil de seguran&#231;a card&#237;aco destes doentes s&#227;o essenciais&#44; sendo necess&#225;rio um estudo mais rigoroso dos efeitos a longo prazo das v&#225;rias estrat&#233;gias terap&#234;uticas&#46; Neste contexto&#44; &#233; cada vez mais importante o estabelecimento de uma parceria din&#226;mica entre a &#225;rea da Oncologia e da Cardiologia&#44; de forma a reduzir o risco de mortalidade e melhorar a qualidade de vida destes indiv&#237;duos&#44; sem interferir&#44; se poss&#237;vel&#44; no tratamento espec&#237;fico antineopl&#225;sico&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">Em suma&#44; a cardiotoxicidade induzida por tratamentos antineopl&#225;sicos deve ser encarada como um problema multidisciplinar&#44; com uma abordagem que engloba a ci&#234;ncia b&#225;sica&#44; oncol&#243;gica e cardiovascular&#46;</p></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Responsabilidades &#233;ticas</span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Prote&#231;&#227;o de pessoas e animais</span><p id="par0295" class="elsevierStylePara elsevierViewall">Os autores declaram que para esta investiga&#231;&#227;o n&#227;o se realizaram experi&#234;ncias em seres humanos e&#47;ou animais&#46;</p></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Confidencialidade dos dados</span><p id="par0300" class="elsevierStylePara elsevierViewall">Os autores declaram que n&#227;o aparecem dados de pacientes neste artigo&#46;</p></span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Direito &#224; privacidade e consentimento escrito</span><p id="par0305" class="elsevierStylePara elsevierViewall">Os autores declaram que n&#227;o aparecem dados de pacientes neste artigo&#46;</p></span></span><span id="sec0175" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Financiamento</span><p id="par0310" class="elsevierStylePara elsevierViewall">Este trabalho foi financiado por Fundos FEDER atrav&#233;s do Programa Operacional Fatores de Competitividade &#8211; COMPETE e por Fundos Nacionais atrav&#233;s da FCT &#8211; Funda&#231;&#227;o para a Ci&#234;ncia e a Tecnologia no &#226;mbito do projeto &#171;n&#46;&#176; FCOMP-01-0124-FEDER-011051 &#40;Ref&#46; FCT PTDC&#47;SAU-FCF&#47;100442&#47;2008&#41;&#187;&#44; pela Bolsa de Estudo Jo&#227;o Porto 2008 e pelos Projetos Pluridisciplinares para Est&#237;mulo &#224; Inicia&#231;&#227;o &#224; Investiga&#231;&#227;o na Universidade do Porto&#47;Santander Totta&#44; edi&#231;&#245;es 2009 e 2010&#46; Carmen Br&#225;s-Silva &#233; investigadora ao abrigo Programa Ci&#234;ncia 2008&#46;</p></span><span id="sec0180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflito de interesses</span><p id="par0315" class="elsevierStylePara elsevierViewall">Os autores declaram n&#227;o haver conflito de interesses&#46;</p></span></span>"
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            1 => "Cardiomiopatia"
            2 => "Quimioterapia"
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            2 => "Chemotherapy"
            3 => "Anthracyclines"
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        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A cardiotoxicidade &#233; um dos efeitos adversos mais significativos do tratamento oncol&#243;gico&#44; respons&#225;vel por uma consider&#225;vel morbimortalidade&#46; Entre os eventos lesivos dos agentes&#47;f&#225;rmacos quimioter&#225;picos no sistema cardiovascular&#44; destaca-se&#44; pela sua maior frequ&#234;ncia e gravidade&#44; a ocorr&#234;ncia de insufici&#234;ncia card&#237;aca com disfun&#231;&#227;o ventricular sist&#243;lica&#46; Outros efeitos t&#243;xicos cardiovasculares incluem hipertens&#227;o arterial&#44; doen&#231;a tromboemb&#243;lica&#44; doen&#231;as peric&#225;rdicas&#44; arritmias e isquemia mioc&#225;rdica&#46; Durante v&#225;rias d&#233;cadas&#44; a cardiomiopatia induzida por terap&#234;utica oncol&#243;gica era quase exclusivamente associada ao uso de doses cumulativas de antraciclinas&#44; que promovem les&#245;es permanentes a n&#237;vel celular&#46; No entanto&#44; o uso de novos agentes terap&#234;uticos&#44; como o anticorpo monoclonal <span class="elsevierStyleItalic">trastuzumab</span>&#44; induz uma disfun&#231;&#227;o transit&#243;ria revers&#237;vel dos mi&#243;citos sem que haja rela&#231;&#227;o com a dose utilizada&#46; Atualmente&#44; &#233; essencial para os doentes com cancro a identifica&#231;&#227;o precoce da les&#227;o cardiovascular&#44; o diagn&#243;stico preciso de eventos cardiot&#243;xicos e a implementa&#231;&#227;o de planos de monitoriza&#231;&#227;o adequados&#46; Neste contexto&#44; &#233; fulcral na pr&#225;tica cl&#237;nica uma coopera&#231;&#227;o estreita entre cardiologistas e oncologistas&#44; de forma a equilibrar os riscos cardiot&#243;xicos com os benef&#237;cios da terapia antineopl&#225;sica em doentes oncol&#243;gicos&#46; Neste artigo revimos as diversas respostas cardiot&#243;xicas ao uso de tratamentos oncol&#243;gicos e a sua rela&#231;&#227;o com os principais f&#225;rmacos antineopl&#225;sicos usados na pr&#225;tica cl&#237;nica&#46; Al&#233;m disso&#44; ser&#227;o abordadas as principais linhas de orienta&#231;&#227;o no que respeita &#224;s estrat&#233;gias de dete&#231;&#227;o&#47;monitoriza&#231;&#227;o da cardiotoxicidade em indiv&#237;duos com cancro&#46;</p>"
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        "titulo" => "Abstract"
        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Cardiotoxicity is one of the most significant adverse effects of cancer treatment&#44; and is responsible for considerable morbidity and mortality&#46; Among the effects of chemotherapeutic agents on the cardiovascular system&#44; the most frequent and serious is heart failure with ventricular systolic dysfunction&#46; Other toxic effects include hypertension&#44; thromboembolic disease&#44; pericardial disease&#44; arrhythmias and myocardial ischemia&#46; For several decades&#44; cancer therapy-induced cardiomyopathy was almost exclusively associated with the use of cumulative doses of anthracyclines&#44; which cause permanent damage at the cellular level&#46; However&#44; new therapeutic agents&#44; such as the monoclonal antibody trastuzumab&#44; induce transient reversible myocyte dysfunction which is unrelated to the dose used&#46; Early identification of potential cardiovascular injury&#44; accurate diagnosis of cardiotoxic events and implementation of appropriate monitoring plans are essential in patients with cancer&#46; Close cooperation between cardiologists and oncologists is thus crucial&#44; in order to balance the risks and benefits of cardiotoxic anticancer therapy&#46; In this article we review the various responses to cardiotoxic cancer treatments and their relationship with the main antineoplastic drugs used in clinical practice&#46; In addition&#44; we discuss the main guidelines on detection and monitoring of cardiotoxicity in patients with cancer&#46;</p>"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Adaptado de&#58; Seidman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">FEVE&#58; fra&#231;&#227;o de eje&#231;&#227;o do ventr&#237;culo esquerdo&#59; IC&#58; insufici&#234;ncia card&#237;aca&#46;</p>"
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                  \t\t\t\t"><span class="elsevierStyleSmallCaps">i</span>&#41; Cardiomiopatia caracterizada por uma diminui&#231;&#227;o da FEVE&#44; global ou mais grave no septo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Cardiotoxicidade&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Rela&#231;&#227;o dose-cumulativa&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Doxorrubicina&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Sim&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ciclofosfamida&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tipo <span class="elsevierStyleSmallCaps">ii</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Trastuzumab</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sim &#40;na maioria de casos&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Sunitinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Sorafenib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab354984.png"
              ]
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        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Classifica&#231;&#227;o proposta para a cardiomiopatia associada ao uso de quimioter&#225;picos</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl0015"
        "etiqueta" => "Tabela 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Fatores de risco&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Risco aumentado&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Idade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Menor idade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G&#233;nero&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Feminino&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Modo de administra&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inje&#231;&#227;o intravenosa r&#225;pida&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dose cumulativa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Excedendo a dose cumulativa de&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Daunorrubicina 550-800&#160;mg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doxorrubicina 400-550&#160;mg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epirrubicina 900-1000&#160;mg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Idarrubicina 150-225&#160;mg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Amsacrina 580&#160;mg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mitoxantrona &#62;&#160;100-140&#160;mg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Irradia&#231;&#227;o mediast&#237;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Irradia&#231;&#227;o mediast&#237;nica precoce ou concomitante excedendo a dose cumulativa de&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doxorrubicina 450&#160;mg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;as cardiovasculares pr&#233;vias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipertens&#227;o arterial&#44; doen&#231;a coron&#225;ria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dist&#250;rbios eletrol&#237;ticos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipocalcemia&#44; hipomagnesemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab354987.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Fatores de risco associados &#224; cardiotoxidade das antraciclinas</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "tbl0020"
        "etiqueta" => "Tabela 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">ERO&#58; esp&#233;cies reativas de oxig&#233;nio&#59; FCVE&#58; fator de crescimento vascular endotelial&#59; HER2&#58; recetor-2 do fator de crescimento epid&#233;rmico humano&#59; IC&#58; insufici&#234;ncia card&#237;aca&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Classe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Exemplos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Tratamento oncol&#243;gico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Toxicidade cardiovascular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Mecanismo de a&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Antraciclinas</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doxorrubicina&#44; epirrubicina&#44; daunorrubicina&#44; idarrubicina&#44; mitoxantrone</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leucemias agudas&#44; linfomas Hodgkin e n&#227;o Hodgkin e cancro da mama</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aguda&#58; IC&#44; arritmias&#44; altera&#231;&#245;es no intervalo Q-T&#44; altera&#231;&#227;o na repolariza&#231;&#227;o ventricular</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Les&#245;es nos cardiomi&#243;citos&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- <span class="elsevierStyleItalic">Stress</span> oxidativo &#40;Produ&#231;&#227;o de ERO&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- Apoptose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cr&#243;nica &#40;dose-dependente&#41;&#58; Disfun&#231;&#227;o ventricular esquerda &#40;n&#227;o revers&#237;vel&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Agentes alquilantes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ciclofosfamida&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro da bexiga&#44; endom&#233;trio&#44; mama&#44; ov&#225;rio&#44; pulm&#227;o e neoplasias hematol&#243;gicas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IC aguda &#40;geralmente revers&#237;vel&#41;&#44; derrame peric&#225;rdico&#44; arritmias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Produ&#231;&#227;o de ERO&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cisplatina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Isquemia mioc&#225;rdica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Antimetabolitos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5-fluoracilo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tumores s&#243;lidos&#44; como pulm&#227;o&#44; c&#243;lon e mama&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Isquemia mioc&#225;rdica&#44; Enfarte agudo do mioc&#225;rdio&#44; arritmias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Espasmo coron&#225;rio&#44; toxicidade mioc&#225;rdica celular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Capecitabina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Agentes antimicrot&#250;bulos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Paclitaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro do ov&#225;rio&#44; mama&#44; sarcoma de Kaposi e cancro do pulm&#227;o de n&#227;o-pequenas c&#233;lulas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bradicardia&#44; s&#237;ncope&#44; disfun&#231;&#227;o ventricular esquerda&#44; arritmias ventriculares&#44; isquemia mioc&#225;rdica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Les&#245;es nos cardiomi&#243;citos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Docetaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro da mama&#44; cancro do pulm&#227;o de n&#227;o-pequenas c&#233;lulas&#44; da pr&#243;stata&#44; da cabe&#231;a&#44; pesco&#231;o&#44; bexiga&#44; ov&#225;rio e adenocarcinoma g&#225;strico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alcal&#243;ides de vinca&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vincristina&#44; vinblastina e&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leucemias e linfomas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Isquemia mioc&#225;rdica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vinorelbina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anticorpos inibidores da tirosina-c&#237;nase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Trastuzumab</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro da mama&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disfun&#231;&#227;o ventricular esquerda &#40;revers&#237;vel&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibi&#231;&#227;o dos recetores HER2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Bevacizumab</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro colorretal metast&#225;tico e cancro do pulm&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipertens&#227;o arterial sist&#233;mica&#44; tromboembolismo venoso&#44; disfun&#231;&#227;o ventricular esquerda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibi&#231;&#227;o do VEGF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Rituximab</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Linfomas&#44; leucemias&#44; rejei&#231;&#245;es a transplantes e algumas desordens autoimunes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipotens&#227;o ortost&#225;tica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Associado a alergia&#44; angioedema&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Alemtuzumab</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leucemia linfoc&#237;tica cr&#243;nica&#44; linfomas cut&#226;neos de c&#233;lulas T e linfomas de c&#233;lulas T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipotens&#227;o&#44; isquemia mioc&#225;rdica&#44; disfun&#231;&#227;o ventricular esquerda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pequenas mol&#233;culas inibidoras da tirosina-c&#237;nase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Imatinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leucemia mieloide cr&#243;nica&#44; Leucemia linfobl&#225;stica&#44; tumores do estroma gastrointestinal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disfun&#231;&#227;o ventricular esquerda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibi&#231;&#227;o das vias protetoras mitocondriais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Sunitinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carcinoma de c&#233;lulas renais&#44; tumores do estroma gastrointestinal resistente ao imatinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disfun&#231;&#227;o ventricular esquerda&#44; IC&#44; isquemia mioc&#225;rdica&#44; hipertens&#227;o&#44; altera&#231;&#245;es eletrocardiogr&#225;ficas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Les&#227;o mitocondrial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Sorafenib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carcinoma hepatocelular e carcinoma de c&#233;lulas renais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disfun&#231;&#227;o ventricular esquerda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Erlotinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro do pulm&#227;o e do p&#226;ncreas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Isquemia mioc&#225;rdica&#44; Enfarte agudo do mioc&#225;rdio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Lapatinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro da mama&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disfun&#231;&#227;o ventricular esquerda&#44; IC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Dasatinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leucemia miel&#243;ide cr&#243;nica ap&#243;s tratamento com <span class="elsevierStyleItalic">imatinib</span> e leucemia linfobl&#225;stica aguda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disfun&#231;&#227;o ventricular esquerda&#44; IC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sem classifica&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gemcitabina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro do pulm&#227;o de n&#227;o-pequenas c&#233;lulas&#44; cancro do p&#226;ncreas&#44; cancro da mama e cancro da bexiga&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Derrame peric&#225;rdico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#193;cido retinoico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leucemia promieloc&#237;tica aguda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Derrame peric&#225;rdico&#44; disfun&#231;&#227;o ventricular esquerda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S&#237;ndrome retin&#243;ico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tri&#243;xido de ars&#233;nio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Reca&#237;das ou recidivas de Leucemia promieloc&#237;tica aguda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prolongamento do intervalo Q-T&#44; <span class="elsevierStyleItalic">torsades de pointes</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intera&#231;&#227;o com os canais i&#243;nicos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tamoxifeno&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro da mama&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Trombose venosa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">profunda&#44; embolia pulmonar e acidente vascular cerebral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Talidomida e lenalidomida&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mieloma m&#250;ltiplo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Edema e bradicardia sinusal&#44; trombose venosa profunda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Interleucina-2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Melanoma e carcinoma metast&#225;tico de c&#233;lulas renais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipotens&#227;o&#44; arritmias card&#237;acas&#44; isquemia mioc&#225;rdica&#44; cardiomiopatia e miocardite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#171;Choque s&#233;tico&#187;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab354985.png"
              ]
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        "descripcion" => array:1 [
          "pt" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Toxicidade cardiovascular das principais classes de f&#225;rmacos antineopl&#225;sicos aplicados na pr&#225;tica cl&#237;nica</p>"
        ]
      ]
      7 => array:7 [
        "identificador" => "tbl0025"
        "etiqueta" => "Tabela 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Adaptado de&#58; Raschi et al&#46;<span class="elsevierStyleSup">3</span></p><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">cTnT&#58; troponina T card&#237;aca&#59; FEVE&#58; fra&#231;&#227;o de eje&#231;&#227;o do ventr&#237;culo esquerdo&#59; PNC&#58; pept&#237;deo natriur&#233;tico cerebral&#59; RM&#58; resson&#226;ncia magn&#233;tica&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">T&#233;cnica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Vantagens&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Desvantagens&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">N&#227;o usado atualmente</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Bi&#243;psia endomioc&#225;rdica</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tradicionalmente aceite como m&#233;todo padr&#227;o &#40;embora erradamente&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Invasivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evid&#234;ncias histol&#243;gicas de les&#227;o card&#237;aca&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Requer especialista para realizar e interpretar resultados&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pequena quantidade de amostra mioc&#225;rdica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o fornece informa&#231;&#227;o funcional&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Padr&#227;o atual</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Ecocardiografia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inofensivo e de baixo custo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dependente do operador &#40;variabilidade intra-observador e inter-observador&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avalia&#231;&#227;o morfol&#243;gica e funcional&#58; par&#226;metros sist&#243;licos &#40;FEVE&#44; fra&#231;&#227;o de encurtamento do VE&#44; espessamento da parede em s&#237;stole&#41; e diast&#243;licos &#40;raz&#227;o E&#47;A&#44; tempo de relaxamento isovolum&#233;trico&#44; padr&#227;o do fluxo venoso pulmonar&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A avalia&#231;&#227;o da FEVE &#233; dependente da qualidade da imagem e sujeito a variabilidade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dados sobre a estrutura valvular e do peric&#225;rdio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Valor preditivo pouco claro na dete&#231;&#227;o precoce de les&#245;es subcl&#237;nicas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Angiografia de radionucl&#237;deos</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bem validada na determina&#231;&#227;o da fra&#231;&#227;o de eje&#231;&#227;o</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subestima volumes ventriculares&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sobrestima a fra&#231;&#227;o de eje&#231;&#227;o em ventr&#237;culos mais pequenos &#40;crian&#231;as e mulheres&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alta reprodutibilidade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Exposi&#231;&#227;o a radia&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Variabilidade inter- e intra-observador baixa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baixa resolu&#231;&#227;o temporal e espacial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o fornece informa&#231;&#227;o sobre a fun&#231;&#227;o valvular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Poucas informa&#231;&#245;es sobre a fun&#231;&#227;o diast&#243;lica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Valor preditivo limitado na dete&#231;&#227;o precoce de les&#245;es subcl&#237;nicas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Eletrocardiografia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inofensivo e de baixo custo no rastreio de arritmias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nenhuma informa&#231;&#227;o sobre a FEVE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prolongamento do intervalo QT &#233; reconhecido como marcador de cardiotoxicidade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Variabilidade intra- e inter-sujeito em valores QT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Problemas na medi&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o do intervalo QT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">T&#233;cnicas promissoras</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Doppler tecidular</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Permite detetar disfun&#231;&#227;o diast&#243;lica isolada&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Experi&#234;ncia limitada&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dete&#231;&#227;o precoce de les&#245;es subcl&#237;nicas &#40;combinado com marcadores inflamat&#243;rios&#47;<span class="elsevierStyleItalic">stress</span> oxidativo&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">An&#225;lise mais demorada&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Excelente resolu&#231;&#227;o temporal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avalia&#231;&#227;o funcional&#58; press&#245;es de enchimento &#40;raz&#227;o E&#47;A&#41; velocidades&#44; deforma&#231;&#227;o <span class="elsevierStyleItalic">&#40;strain&#41;</span> e taxas de deforma&#231;&#227;o <span class="elsevierStyleItalic">&#40;strain rate&#41;</span> sist&#243;lica e diast&#243;lica das paredes ventriculares&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Ecocardiograma de stress</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avalia&#231;&#227;o da reserva contr&#225;til do mioc&#225;rdio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dados limitados e controversos na dete&#231;&#227;o precoce de cardiotoxicidade em doentes oncol&#243;gicos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Natureza semi-invasiva&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Resson&#226;ncia magn&#233;tica</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Altamente reprodut&#237;vel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baixa resolu&#231;&#227;o temporal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avalia&#231;&#227;o funcional e da perfus&#227;o mioc&#225;rdica&#58; identifica&#231;&#227;o de cicatrizes p&#243;s-enfarte e de mioc&#225;rdio vi&#225;vel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Custo elevado&#44; principalmente pela necessidade de exames repetidos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Caracteriza&#231;&#227;o tecidular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disponibilidade limitada&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#218;til em pacientes com janela ecocardiogr&#225;fica limitada&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evid&#234;ncias ainda preliminares sobre o valor preditivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Tomografia computadorizada</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Boa qualidade de imagem &#40;semelhante &#224; RM&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alta dose de radia&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disponibilidade limitada&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baixa resolu&#231;&#227;o temporal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Cintigrafia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Natureza n&#227;o invasiva&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dados limitados&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avalia&#231;&#227;o estrutural e funcional&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o usado rotineiramente na pr&#225;tica cl&#237;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Radia&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Biomarcadores</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o invasivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Valor preditivo indefinido&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baixa variabilidade interobservador&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o usado rotineiramente na pr&#225;tica cl&#237;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avalia&#231;&#227;o da fun&#231;&#227;o cardiovascular e de potenciais sinais de les&#227;o card&#237;aca&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">cTnT&#44; PNC e glicog&#233;nio fosforilase<span class="elsevierStyleItalic">-</span>BB s&#227;o promissores marcadores na dete&#231;&#227;o precoce de les&#227;o mioc&#225;rdica &#40;alta sensibilidade e especificidade&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Les&#227;o endotelial</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">As citocinas&#44; mol&#233;culas de ades&#227;o e a rela&#231;&#227;o &#237;ntima&#47;m&#233;dia da art&#233;ria car&#243;tida s&#227;o potenciais par&#226;metros alternativos na avalia&#231;&#227;o da toxicidade cardiovascular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Valor preditivo desconhecido&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">An&#225;lise gen&#233;tica</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Minimamente invasivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Valor preditivo desconhecido&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avalia&#231;&#227;o da suscetibilidade individual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "imagenFichero" => array:1 [
                0 => "xTab354983.png"
              ]
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        "descripcion" => array:1 [
          "pt" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Principais t&#233;cnicas usadas na monitoriza&#231;&#227;o da cardiotoxicidade na pr&#225;tica cl&#237;nica&#58; vantagens e desvantagens</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "Bibliografia"
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        0 => array:2 [
          "identificador" => "bibs0005"
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            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cardiovascular side-effects of modern cancer therapy"
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                        0 => array:2 [ …2]
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Circ J"
                        "fecha" => "2010"
                        "volumen" => "74"
                        "paginaInicial" => "1779"
                        "paginaFinal" => "1786"
                        "link" => array:1 [ …1]
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              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cardiovascular complications of cancer therapy&#58; Incidence&#44; pathogenesis&#44; diagnosis&#44; and management"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jacc.2009.02.050"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Coll Cardiol"
                        "fecha" => "2009"
                        "volumen" => "53"
                        "paginaInicial" => "2231"
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                        "link" => array:1 [ …1]
                      ]
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              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anticancer drugs and cardiotoxicity&#58; Insights and perspectives in the era of targeted therapy"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.pharmthera.2009.10.002"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pharmacol Ther"
                        "fecha" => "2010"
                        "volumen" => "125"
                        "paginaInicial" => "196"
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                        "link" => array:1 [ …1]
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            3 => array:3 [
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              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cost of cancer care in Portugal"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Acta Med Port"
                        "fecha" => "2009"
                        "volumen" => "22"
                        "paginaInicial" => "525"
                        "paginaFinal" => "536"
                        "link" => array:1 [ …1]
                      ]
                    ]
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            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Estimates of cancer incidence and mortality in Europe in 2008"
                      "autores" => array:1 [
                        0 => array:2 [ …2]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ejca.2009.12.014"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Cancer"
                        "fecha" => "2010"
                        "volumen" => "46"
                        "paginaInicial" => "765"
                        "paginaFinal" => "781"
                        "link" => array:1 [ …1]
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              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cardiovascular toxicity associated with cancer treatment"
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                        0 => array:2 [ …2]
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                    0 => array:2 [
                      "doi" => "10.1188/08.CJON.627-638"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin J Oncol Nurs"
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Artigo de revisão
Cardiotoxicidade associada à terapêutica oncológica: mecanismos fisiopatológicos e estratégias de prevenção
Cardiotoxicity associated with cancer therapy: Pathophysiology and prevention strategies
Rui Adãoa, Gilles de Keulenaerb, Adelino Leite-Moreiraa, Carmen Brás-Silvaa,
Autor para correspondência
carmensb@med.up.pt

Autor para correspondência.
a Departamento de Fisiologia e Cirurgia Cardiotorácica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
b Laboratory of Physiology, University of Antwerp, Antuérpia, Bélgica
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introdu&#231;&#227;o</span><p id="par0005" class="elsevierStylePara elsevierViewall">Ao longo dos &#250;ltimos anos&#44; a terap&#234;utica oncol&#243;gica tem evolu&#237;do drasticamente&#46; O desenvolvimento e a implementa&#231;&#227;o de intensivos tratamentos antineopl&#225;sicos melhoraram substancialmente o progn&#243;stico dos doentes oncol&#243;gicos<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46; No entanto&#44; apesar do benef&#237;cio cl&#237;nico inquestion&#225;vel deste tipo de terapia&#44; n&#227;o se deve subestimar o perfil de seguran&#231;a no seu uso&#46; De facto&#44; devido aos seus mecanismos de a&#231;&#227;o&#44; muitos destes f&#225;rmacos podem causar efeitos nefastos no sistema cardiovascular<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Atualmente&#44; o cancro &#233; a segunda maior causa de morte em Portugal&#44; logo a seguir &#224;s doen&#231;as cardiovasculares<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#44; e o cancro colorretal a principal causa de morte oncol&#243;gica<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46; Durante v&#225;rias d&#233;cadas&#44; estas rea&#231;&#245;es cardiot&#243;xicas a tratamentos antineopl&#225;sicos eram quase exclusivamente associadas ao uso de antraciclinas&#46; Mais recentemente&#44; uma nova dimens&#227;o do problema surgiu quando foram reconhecidos clinicamente alguns efeitos indesej&#225;veis&#44; no sistema cardiovascular&#44; de drogas que interferem na atividade de certos recetores associados a c&#237;nases da tirosina ou recetores tumor &#40;recetores de estrog&#233;nios&#41;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;6</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Grande parte da literatura cient&#237;fica sobre a cardiotoxicidade da terap&#234;utica oncol&#243;gica incide unicamente sobre a ocorr&#234;ncia de cardiomiopatia&#59; no entanto&#44; esta &#233; apenas uma das v&#225;rias condi&#231;&#245;es que podem comprometer a fun&#231;&#227;o cardiovascular<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#46; Outros efeitos sobre a vasculatura resultam em isquemia ou altera&#231;&#245;es na press&#227;o arterial<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> e&#44; no peric&#225;rdio&#44; as terapias antineopl&#225;sicas podem causar o seu espessamento ou uma instabilidade no equil&#237;brio do fluido peric&#225;rdico&#44; levando a derrame<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46; Al&#233;m disso&#44; este tipo de tratamento aumenta o risco de arritmias em pacientes predispostos a ectopia card&#237;aca<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">A prote&#231;&#227;o da fun&#231;&#227;o card&#237;aca representa atualmente um desafio constante para a ind&#250;stria farmac&#234;utica&#44; as autoridades reguladoras e para os m&#233;dicos que enfrentam&#44; na pr&#225;tica cl&#237;nica&#44; rea&#231;&#245;es adversas a diversos agentes terap&#234;uticos<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; A avalia&#231;&#227;o de doentes expostos a f&#225;rmacos antineopl&#225;sicos&#44; a an&#225;lise do risco envolvido na utiliza&#231;&#227;o destes para qualquer indiv&#237;duo ou grupo de doentes com cancro&#44; a preven&#231;&#227;o ou redu&#231;&#227;o de les&#227;o card&#237;aca&#44; a monitoriza&#231;&#227;o da fun&#231;&#227;o card&#237;aca durante e ap&#243;s a terap&#234;utica&#44; e o tratamento da cardiotoxicidade relacionada com a quimioterapia tem gerado uma vasta &#225;rea de conhecimento cient&#237;fico que tem sido denominada de &#171;c&#225;rdio-oncologia&#187;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;11</span></a>&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Ao longo da presente revis&#227;o&#44; iremos abordar as diversas respostas cardiot&#243;xicas ao uso de tratamentos oncol&#243;gicos e a sua rela&#231;&#227;o com os principais f&#225;rmacos antineopl&#225;sicos usados na pr&#225;tica cl&#237;nica&#46; Al&#233;m disso&#44; ser&#227;o analisadas as &#250;ltimas linhas de orienta&#231;&#227;o no que respeita &#224;s estrat&#233;gias de dete&#231;&#227;o&#47;monitoriza&#231;&#227;o da cardiotoxicidade em indiv&#237;duos com cancro&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Defini&#231;&#227;o de cardiotoxicidade</span><p id="par0030" class="elsevierStylePara elsevierViewall">A exist&#234;ncia de uma descri&#231;&#227;o padronizada de cardiotoxicidade &#233; essencial para fins assistenciais e de investiga&#231;&#227;o na popula&#231;&#227;o doente<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; Uma das defini&#231;&#245;es cl&#237;nicas mais precisas foi formulada pelo Comit&#233; de Avalia&#231;&#227;o e Revis&#227;o Card&#237;aca &#40;CREC&#41; durante a supervis&#227;o de ensaios terap&#234;uticos com <span class="elsevierStyleItalic">trastuzumab</span> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Tabela 1</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>&#46; Estes crit&#233;rios n&#227;o incluem as les&#245;es cardiovasculares subcl&#237;nicas que podem ocorrer no in&#237;cio de resposta a alguns agentes quimioter&#225;picos<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">F&#225;rmacos antineopl&#225;sicos e cardiomiopatia</span><p id="par0035" class="elsevierStylePara elsevierViewall">O padr&#227;o de cardiotoxicidade das terap&#234;uticas oncol&#243;gicas &#233; a cardiomiopatia relacionada com as antraciclinas<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#46; As primeiras evid&#234;ncias indicaram que a disfun&#231;&#227;o sist&#243;lica do ventr&#237;culo esquerdo &#40;VE&#41; estava intimamente relacionada com o uso de doses cumulativas de antraciclinas&#46; Segundo Lefrak et al<span class="elsevierStyleItalic">&#46;</span>&#44; administra&#231;&#245;es repetidas podem resultar em les&#245;es permanentes a n&#237;vel celular e intersticial&#44; frequentemente associadas ao risco de ocorr&#234;ncia de insufici&#234;ncia card&#237;aca refrat&#225;ria<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#46; Mais recentemente&#44; o uso de novos agentes terap&#234;uticos&#44; como o anticorpo monoclonal <span class="elsevierStyleItalic">trastuzumab</span>&#44; embora tamb&#233;m possam causar cardiomiopatia&#44; induzem uma disfun&#231;&#227;o transit&#243;ria revers&#237;vel dos mi&#243;citos sem que haja rela&#231;&#227;o com a dose utilizada&#44; resultando num progn&#243;stico cl&#237;nico mais favor&#225;vel<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;15</span></a>&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Os f&#225;rmacos antineopl&#225;sicos&#44; como as antraciclinas&#44; que causam predominantemente les&#245;es irrevers&#237;veis t&#234;m sido classificados como agentes tipo <span class="elsevierStyleSmallCaps">i</span>&#44; sendo os agentes tipo <span class="elsevierStyleSmallCaps">ii</span> aqueles que n&#227;o acarretam uma destrui&#231;&#227;o celular irrevers&#237;vel<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Tabela 2</a>&#41;&#46; As caracter&#237;sticas dos agentes terap&#234;uticos tipo <span class="elsevierStyleSmallCaps">ii</span> t&#234;m permitido o seu uso durante anos at&#233; ao aparecimento de sinais de les&#227;o card&#237;aca e a sua reintrodu&#231;&#227;o&#44; com risco aceit&#225;vel&#44; ap&#243;s a recupera&#231;&#227;o card&#237;aca<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#46; No entanto&#44; alguns ensaios cl&#237;nicos t&#234;m posto em causa a reversibilidade dos efeitos cardiot&#243;xicos deste tipo de f&#225;rmacos&#46; De facto&#44; o uso de terapias combinadas &#40;agentes tipo <span class="elsevierStyleSmallCaps">i</span> e <span class="elsevierStyleSmallCaps">ii</span>&#41; induz uma elevada incid&#234;ncia de disfun&#231;&#227;o card&#237;aca&#44; acima do expect&#225;vel&#44; em doentes com cancro<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Tipo <span class="elsevierStyleSmallCaps">i</span> &#8211; Antraciclinas</span><p id="par0045" class="elsevierStylePara elsevierViewall">As antraciclinas&#44; como a doxorrubicina &#40;DOX&#41;&#44; epirrubicina &#40;EPI&#41; e daunorrubicina &#40;DNR&#41;&#44; permanecem entre os agentes antineopl&#225;sicos mais usados no tratamento de uma ampla variedade de tumores s&#243;lidos e neoplasias hematol&#243;gicas<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; Infelizmente&#44; a preocupa&#231;&#227;o gerada na comunidade m&#233;dica em torno da sua cardiotoxicidade ainda limita a sua utiliza&#231;&#227;o&#46; Apesar de mais de 40 anos de investiga&#231;&#227;o&#44; os mecanismos de a&#231;&#227;o respons&#225;veis pela toxicidade card&#237;aca inerente ao uso de doses cumulativas de antraciclinas ainda n&#227;o foram completamente elucidados<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;7</span></a>&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Efeitos cardiot&#243;xicos a curto e longo prazo</span><p id="par0050" class="elsevierStylePara elsevierViewall">A cardiotoxicidade pode ocorrer de forma aguda ou cr&#243;nica&#44; podendo surgir anos ap&#243;s a conclus&#227;o do tratamento&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">A cardiotoxicidade aguda induzida pelas antraciclinas &#233; rara&#44; transit&#243;ria e independente da dose utilizada&#46; Caracteriza-se por altera&#231;&#245;es s&#250;bitas da repolariza&#231;&#227;o ventricular&#44; altera&#231;&#245;es eletrocardiogr&#225;ficas no intervalo Q-T&#44; arritmias ventriculares e supraventriculares&#44; s&#237;ndromes coron&#225;rias agudas&#44; pericardite e miocardite&#46; Estas altera&#231;&#245;es s&#227;o geralmente observadas desde o in&#237;cio do tratamento at&#233; 14&#160;dias ap&#243;s o t&#233;rmino do mesmo&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Por outro lado&#44; a forma cr&#243;nica &#233; dependente da dose usada clinicamente e pode ser diferenciada em 2 tipos&#44; de acordo com o in&#237;cio dos sintomas cl&#237;nicos&#46; O primeiro tipo ocorre no in&#237;cio&#44; ao longo do primeiro ano ap&#243;s o t&#233;rmino da quimioterapia&#44; e o segundo tipo ocorre tardiamente&#44; mais de um ano depois do tratamento&#46; A manifesta&#231;&#227;o mais caracter&#237;stica de cardiotoxicidade cr&#243;nica &#233; a disfun&#231;&#227;o ventricular sist&#243;lica ou diast&#243;lica que pode levar a cardiomiopatia grave e&#44; em &#250;ltima inst&#226;ncia&#44; mesmo &#224; morte<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;13</span></a>&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Fatores de risco</span><p id="par0065" class="elsevierStylePara elsevierViewall">A progress&#227;o e o grau de cardiotoxicidade inerente ao uso deste tipo de f&#225;rmacos s&#227;o vari&#225;veis entre indiv&#237;duos&#46; Tal deve-se &#224; influ&#234;ncia de diversos fatores de risco &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Tabela 3</a>&#41;&#44; bem como &#224; pr&#243;pria predisposi&#231;&#227;o gen&#233;tica<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">A dose cumulativa total &#233; o principal fator de risco para a ocorr&#234;ncia de insufici&#234;ncia card&#237;aca congestiva relacionada com a utiliza&#231;&#227;o de antraciclinas<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#46; No entanto&#44; n&#227;o existe nenhuma dose absolutamente segura a n&#237;vel cardiot&#243;xico&#44; sendo que esta deve ser sempre equilibrada com o seu grau de efic&#225;cia antineopl&#225;sica<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a>&#46; Al&#233;m disso&#44; a dura&#231;&#227;o da administra&#231;&#227;o tamb&#233;m poder&#225; influenciar o risco relativo de desenvolver cardiotoxicidade durante ou ap&#243;s a terapia oncol&#243;gica&#46; De facto&#44; o uso de tratamentos de administra&#231;&#227;o prolongada tem reduzido o grau de les&#245;es card&#237;acas<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#46; Por outro lado&#44; indiv&#237;duos tratados numa idade mais jovem parecem ser mais vulner&#225;veis aos efeitos cardiot&#243;xicos induzidos por este tipo de f&#225;rmacos<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Todos os fatores de risco est&#227;o intimamente relacionados com a cardiotoxicidade precoce e tardia&#44; e n&#227;o com a que surge de forma aguda<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Mecanismos fisiopatol&#243;gicos</span><p id="par0085" class="elsevierStylePara elsevierViewall">V&#225;rios mecanismos t&#234;m sido sugeridos para explicar a fisiopatologia da cardiotoxicidade induzida pelas antraciclinas&#44; embora ainda sejam desconhecidas as raz&#245;es pelas quais estes afetam preferencialmente os cardiomi&#243;citos&#46; Os principais processos propostos envolvem a peroxida&#231;&#227;o lip&#237;dica e o <span class="elsevierStyleItalic">stress</span> oxidativo nos cardiomi&#243;citos<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#46; Como consequ&#234;ncia do pr&#243;prio mecanismo de a&#231;&#227;o das antraciclinas&#44; est&#225; comprometida a s&#237;ntese de DNA&#44; RNA e prote&#237;nas<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&#44; bem como de importantes fatores de transcri&#231;&#227;o envolvidos na regula&#231;&#227;o de genes cardioespec&#237;ficos<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;25</span></a>&#46; Esta diminui&#231;&#227;o na express&#227;o proteica acoplada a um aumento da degrada&#231;&#227;o de miofilamentos leva a um balan&#231;o negativo das prote&#237;nas sarcom&#233;ricas&#44; como a titina&#44; nas c&#233;lulas card&#237;acas &#40;sarcopenia card&#237;aca&#41;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&#46; Por outro lado&#44; a redu&#231;&#227;o miofilamentar pode ser potenciada com a utiliza&#231;&#227;o de terapias combinadas &#40;antraciclinas e o anticorpo monoclonal <span class="elsevierStyleItalic">trastuzumab</span>&#41;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#46; O uso desta terap&#234;utica tamb&#233;m poder&#225;&#44; a n&#237;vel mitocondrial&#44; afetar a bioenerg&#233;tica<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> e induzir les&#245;es no DNA<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&#46; Al&#233;m disso&#44; as antraciclinas causam um desequil&#237;brio na regula&#231;&#227;o din&#226;mica da fun&#231;&#227;o card&#237;aca&#44; promovendo altera&#231;&#245;es na atividade adren&#233;rgica&#44; na adenilato ciclase<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> e na homeostasia do c&#225;lcio<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;30</span></a>&#46; Dados cl&#237;nicos e experimentais sugerem como mecanismo alternativo de cardiotoxicidade a indu&#231;&#227;o de morte nas c&#233;lulas card&#237;acas&#44; por apoptose ou necrose&#44; ap&#243;s cada exposi&#231;&#227;o &#224;s antraciclinas&#46; Dada a capacidade limitada de regenera&#231;&#227;o do m&#250;sculo card&#237;aco&#44; a redu&#231;&#227;o cumulativa do n&#250;mero de cardiomi&#243;citos promove a remodelagem ventricular<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#46; Mais recentemente&#44; de Angelis et al<span class="elsevierStyleItalic">&#46;</span> demonstraram que a cardiomiopatia promovida pela DOX tamb&#233;m pode ser mediada pela redu&#231;&#227;o de c&#233;lulas estaminais card&#237;acas e revertida atrav&#233;s da recupera&#231;&#227;o funcional das c&#233;lulas progenitoras<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a>&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Estrat&#233;gias para limitar a cardiotoxicidade</span><p id="par0090" class="elsevierStylePara elsevierViewall">Embora n&#227;o exista nenhum m&#233;todo clinicamente aceite&#44; t&#234;m sido adotadas diversas estrat&#233;gias com o intuito de limitar ou prevenir a cardiotoxicidade das antraciclinas&#46; Entre elas&#44; destacam-se a s&#237;ntese de an&#225;logos de compostos naturais&#44; o desenvolvimento de formula&#231;&#245;es espec&#237;ficas para determinado tumor e o uso cl&#237;nico de agentes cardioprotetores<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a>&#46;</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">S&#237;ntese de an&#225;logos dos compostos naturais</span><p id="par0095" class="elsevierStylePara elsevierViewall">A altera&#231;&#227;o estrutural de antraciclinas tem resultado em compostos com baixos n&#237;veis de cardiotoxicidade&#44; permitindo a administra&#231;&#227;o de doses terap&#234;uticas mais elevadas<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#46; A EPI<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> e a idarrubicina &#40;IDA&#41;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> surgem atualmente&#44; na terap&#234;utica oncol&#243;gica&#44; como alternativas &#250;teis ao uso de DOX e DNR&#44; respetivamente&#46; Outras antraciclinas&#44; como a pirarrubicina e aclarrubicina&#44; embora j&#225; tenham sido registadas em alguns pa&#237;ses&#44; ainda n&#227;o desempenham um papel significativo em termos globais<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a>&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Epirrubicina&#46;</span> A EPI &#233; um ep&#237;mero semissint&#233;tico da DOX com um espectro oncol&#243;gico id&#234;ntico<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a>&#46; Embora possua um mecanismo de a&#231;&#227;o id&#234;ntico &#224; DOX&#44; algumas propriedades f&#237;sico-qu&#237;micas e farmacocin&#233;ticas est&#227;o alteradas<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a>&#46; Comparada com a DOX&#44; a cardiotoxicidade da EPI &#233; significativamente menor quando administrada em doses que resultam em n&#237;veis id&#234;nticos de mielossupress&#227;o<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a>&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Idarrubicina</span>&#46; A IDA &#233; um an&#225;logo estrutural da DNR&#44; que se intercala ao DNA&#44; interage com a topoisomerase <span class="elsevierStyleSmallCaps">ii</span> e tem um efeito inibidor sobre a s&#237;ntese do &#225;cido nucleico<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a>&#46; Este composto possui uma elevada lipofilicidade&#44; permitindo uma elevada absor&#231;&#227;o celular<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a>&#46; A IDA pode ser administrada por via intravenosa ou oralmente&#46; Contudo&#44; atualmente t&#234;m sido postas em causa as vantagens deste agente antineopl&#225;sico na diminui&#231;&#227;o dos efeitos cardiot&#243;xicos<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;37</span></a>&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Formula&#231;&#245;es espec&#237;ficas para determinado tumor</span><p id="par0110" class="elsevierStylePara elsevierViewall">De forma a limitar a absor&#231;&#227;o das antraciclinas no tecido card&#237;aco t&#234;m sido desenvolvidas novas t&#233;cnicas no transporte dos agentes antineopl&#225;sicos<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Atualmente&#44; a incorpora&#231;&#227;o liposs&#243;mica de DOX e DNR representa o principal m&#233;todo de condu&#231;&#227;o passiva das antraciclinas ao tumor alvo<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a>&#46; Este procedimento oferece uma cardioprote&#231;&#227;o substancial&#44; aumentando o tamanho molecular do f&#225;rmaco atrav&#233;s de encapsula&#231;&#227;o e prolongando o seu tempo de elimina&#231;&#227;o&#44; de modo a permanecer no organismo com menos efeitos adversos&#46; Al&#233;m disso&#44; a incorpora&#231;&#227;o liposs&#243;mica permite a fixa&#231;&#227;o da droga longe de &#243;rg&#227;os que possuem jun&#231;&#245;es capilares normais&#44; penetrando facilmente em locais com um sistema vascular imaturo&#44; como nas neoplasias<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Por outro lado&#44; as pr&#243;-drogas de antraciclinas&#44; ao contr&#225;rio dos compostos liposs&#243;micos&#44; conseguem atingir o tecido tumoral por uma via ativa&#46; V&#225;rias pr&#243;-drogas t&#234;m sido obtidas por um processo de conjuga&#231;&#227;o com p&#233;ptidos&#44; hidratos de carbono&#44; anticorpos&#44; prote&#237;nas s&#233;ricas ou pol&#237;meros sint&#233;ticos<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a>&#46; Estes conjugados s&#227;o incapazes de penetrar em c&#233;lulas normais&#44; sendo ativadas especificamente por c&#233;lulas neopl&#225;sicas<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;40</span></a>&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Agentes cardioprotetores</span><p id="par0125" class="elsevierStylePara elsevierViewall">Na comunidade m&#233;dica &#233; cada vez mais premente o estabelecimento de estrat&#233;gias farmacol&#243;gicas que protejam o sistema cardiovascular&#44; sem interferir com os mecanismos antineop&#225;sicos associados ao uso de antraciclinas<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;41</span></a>&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Atualmente&#44; tendo em conta o papel patog&#233;nico das esp&#233;cies reativas de oxig&#233;nio &#40;ERO&#41; e do <span class="elsevierStyleItalic">stress</span> oxidativo na cardiotoxicidade induzida pelas antraciclinas&#44; t&#234;m-se estudado drogas e compostos naturais capazes de melhorar as defesas antioxidantes dos cardiomi&#243;citos<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a>&#46; V&#225;rias classes de f&#225;rmacos&#44; incluindo antioxidantes&#44; agentes quelantes de ferro e drogas hipolipemiantes&#44; foram testadas&#44; tanto em modelos animais como em doentes humanos<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#8211;43</span></a>&#46; No entanto&#44; a efic&#225;cia cardioprotetora de alguns compostos &#233; bastante question&#225;vel<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;43</span></a>&#46; O <span class="elsevierStyleItalic">dexrazoxane</span> &#40;Cardioxane<span class="elsevierStyleSup">&#174;</span>&#41; &#233; a &#250;nica droga certificada para uso cl&#237;nico para a preven&#231;&#227;o dos efeitos cardiot&#243;xicos induzidos pelas antraciclinas<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a>&#46; Por&#233;m&#44; a sua utiliza&#231;&#227;o &#233; atualmente controversa&#44; tendo sido associada a um eventual comprometimento da efic&#225;cia oncol&#243;gica e a um poss&#237;vel aumento de neoplasias secund&#225;rias&#44; pelo que o seu uso foi restrito pela <span class="elsevierStyleItalic">U&#46;S&#46; Food and Drug Administration</span> &#40;FDA&#41; a doentes adultos<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a>&#46;</p></span></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Tipo <span class="elsevierStyleSmallCaps">ii</span> - <span class="elsevierStyleItalic">Trastuzumab</span></span><p id="par0135" class="elsevierStylePara elsevierViewall">Os anticorpos monoclonais s&#227;o um dos paradigmas da terapia-alvo oncol&#243;gica e s&#227;o amplamente utilizados no tratamento antineopl&#225;sico&#46; No cancro da mama&#44; aproximadamente 15 a 25&#37; dos pacientes apresentam amplifica&#231;&#227;o do gene HER2&#44; resultando na sobre-express&#227;o do recetor HER2 &#40;recetor-2 do fator de crescimento epid&#233;rmico humano&#41;&#46; O <span class="elsevierStyleItalic">trastuzumab</span> liga-se especificamente ao dom&#237;nio extracelular do HER2&#44; resultando na inibi&#231;&#227;o da respetiva transdu&#231;&#227;o do sinal<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#46; Regimes de quimioterapia sem antraciclinas apresentam taxas menores de disfun&#231;&#227;o card&#237;aca quando comparados com regimes de uso combinado de <span class="elsevierStyleItalic">trastuzumab</span> e antraciclinas&#46; Por outro lado&#44; a associa&#231;&#227;o de <span class="elsevierStyleItalic">trastuzumab</span> com vinorelbina&#44; gemcitabina ou DOX lipossomal n&#227;o demonstra um risco significativo de cardiotoxicidade<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a>&#46;</p><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Fatores de risco</span><p id="par0140" class="elsevierStylePara elsevierViewall">Um dos principais fatores de risco cardiot&#243;xicos associados ao uso antineopl&#225;sico de <span class="elsevierStyleItalic">trastuzumab</span> &#233; a utiliza&#231;&#227;o de elevadas doses cumulativas de antraciclinas &#40;&#62;&#160;300<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#41;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a>&#46; Outros importantes fatores de risco incluem a disfun&#231;&#227;o ventricular esquerda associada ou n&#227;o ao uso concomitante de antraciclinas&#44; a pr&#233;-exist&#234;ncia de hipertens&#227;o arterial sist&#233;mica&#44; um &#237;ndice de massa corporal superior a 25 e a idade avan&#231;ada dos doentes&#46; Por outro lado&#44; o uso terap&#234;utico simult&#226;neo de irradia&#231;&#227;o tor&#225;cica com <span class="elsevierStyleItalic">trastuzumab</span> &#233; clinicamente vi&#225;vel<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a>&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Al&#233;m disso&#44; dados recentes demonstraram que doentes oncol&#243;gicos idosos &#40;&#8805;&#160;70 anos&#41; com historial de doen&#231;a card&#237;aca e&#47;ou diabetes apresentam um aumento da incid&#234;ncia de efeitos cardiot&#243;xicos associados ao uso de <span class="elsevierStyleItalic">trastuzumab</span> no tratamento do cancro da mama&#46; Segundo Serrano et al&#46;&#44; deve-se manter uma monitoriza&#231;&#227;o cuidada e cont&#237;nua desta popula&#231;&#227;o<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a>&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Mecanismos fisiopatol&#243;gicos</span><p id="par0150" class="elsevierStylePara elsevierViewall">Embora ainda n&#227;o sejam conhecidos os mecanismos intracelulares exatos associados &#224; a&#231;&#227;o fisiopatol&#243;gica do <span class="elsevierStyleItalic">trastuzumab</span>&#44; acredita-se que estes estejam intimamente relacionados com a sua a&#231;&#227;o inibit&#243;ria sobre a sinaliza&#231;&#227;o card&#237;aca do HER2&#46; Diversos estudos evidenciaram o importante papel do HER2 na sobreviv&#234;ncia e no desenvolvimento dos cardiomi&#243;citos<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50&#44;51</span></a>&#46; De facto&#44; ratos manipulados geneticamente com n&#237;veis reduzidos de HER2 desenvolvem cardiomiopatia dilatada&#44; menor capacidade adaptativa a condi&#231;&#245;es de sobrecarga de press&#227;o e maior sensibilidade &#224; toxicidade associada ao uso de antraciclinas<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">52&#44;53</span></a>&#46; Por outro lado&#44; a sobre-express&#227;o de HER2 e&#47;ou ativa&#231;&#227;o da via de sinaliza&#231;&#227;o HER2&#47;HER4 promovida pela neuregulina &#40;NRG&#41; confere&#44; a n&#237;vel celular&#44; maior prote&#231;&#227;o face ao <span class="elsevierStyleItalic">stress</span> oxidativo e impede a ocorr&#234;ncia de apoptose<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a>&#46; Na verdade&#44; foram determinados elevados n&#237;veis s&#233;ricos de HER2 em indiv&#237;duos com insufici&#234;ncia card&#237;aca cr&#243;nica<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> e&#44; mais recentemente&#44; foi demonstrado em ensaios cl&#237;nicos que a administra&#231;&#227;o de NRG-1 recombinante humana no tratamento de IC cr&#243;nica est&#225;vel melhora a fun&#231;&#227;o card&#237;aca&#44; para al&#233;m de ser bem tolerada pelos doentes<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a>&#46; De acordo com estes dados&#44; se&#44; por um lado&#44; o <span class="elsevierStyleItalic">stress</span> card&#237;aco promove o aumento da express&#227;o de HER2 e a ativa&#231;&#227;o da via HER2&#47;HER4 pela NRG&#44; por outro&#44; a inibi&#231;&#227;o do HER2 pelo <span class="elsevierStyleItalic">trastuzumab</span> induz o desenvolvimento de disfun&#231;&#227;o ventricular<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figura 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">Contudo&#44; o mecanismo fisiopatol&#243;gico associado ao uso de <span class="elsevierStyleItalic">trastuzumab</span> &#233; provavelmente mais complexo&#44; n&#227;o envolvendo apenas a inibi&#231;&#227;o do HER2&#46; De facto&#44; dados recentes revelaram o aparecimento de n&#237;veis de toxicidade m&#237;nimos ap&#243;s o uso cl&#237;nico de <span class="elsevierStyleItalic">lapatinib</span>&#44; um inibidor da tirosina-c&#237;nase com dupla a&#231;&#227;o sobre a HER2 e o fator de crescimento epid&#233;rmico &#40;EGF&#41;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a>&#46; V&#225;rios fatores poder&#227;o contribuir para a ocorr&#234;ncia de diferentes perfis cardiot&#243;xicos entre estes dois f&#225;rmacos&#46; Estudos espec&#237;ficos analisaram o efeito das rea&#231;&#245;es imunit&#225;rias citot&#243;xicas promovidas pelo dom&#237;nio IgG1 do <span class="elsevierStyleItalic">trastuzumab</span> nas les&#245;es dos cardiomi&#243;citos&#46; Os dados mostraram que a indu&#231;&#227;o de citotoxicidade celular dependente de anticorpos &#40;ADCC&#41; em c&#233;lulas tumorais estava intimamente relacionada com a cardiotoxicidade<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a>&#46; Outro mecanismo proposto envolve uma resposta intracelular &#250;nica ap&#243;s ativa&#231;&#227;o do HER2 nos cardiomi&#243;citos&#46; Ap&#243;s ligar-se ao HER2&#44; o <span class="elsevierStyleItalic">trastuzumab</span> regula a integridade mitocondrial atrav&#233;s da fam&#237;lia de prote&#237;nas BCL-<span class="elsevierStyleSmallCaps">X</span>&#44; promovendo a deple&#231;&#227;o de ATP e a consequente disfun&#231;&#227;o contr&#225;til nos cardiomi&#243;citos&#46; Curiosamente&#44; alguns estudos indicam que o <span class="elsevierStyleItalic">lapatinib</span> promove o efeito oposto&#44; reduzindo a citotoxicidade do <span class="elsevierStyleItalic">trastuzumab</span> quando os dois f&#225;rmacos s&#227;o administrados concomitantemente<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#44;61</span></a>&#46; Isto deve-se &#224;s diferentes a&#231;&#245;es que as drogas t&#234;m sobre a funcionalidade da prote&#237;na c&#237;nase ativada pelo AMP &#40;AMPK&#41;&#58; enquanto o <span class="elsevierStyleItalic">trastuzumab</span> inibe a AMPK&#44; diminuindo a quantidade de ATP intracelular&#44; o <span class="elsevierStyleItalic">lapatinib</span>&#44; por sua vez&#44; promove a sua atividade&#44; aumentando a produ&#231;&#227;o de ATP por vias oxidativas<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a>&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Cardiotoxicidade <span class="elsevierStyleItalic">trastuzumab</span>-antraciclinas</span><p id="par0160" class="elsevierStylePara elsevierViewall">Atualmente&#44; os mecanismos cardiot&#243;xicos associados ao uso concomitante de <span class="elsevierStyleItalic">trastuzumab</span> e de antraciclinas s&#227;o de particular interesse&#44; dada a utiliza&#231;&#227;o frequente de terapias combinadas no tratamento do cancro da mama<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a>&#46; O uso deste tipo de terapia conduz a um aumento intracelular de ERO e a uma redu&#231;&#227;o de compostos antioxidantes&#44; promovendo a ocorr&#234;ncia de <span class="elsevierStyleItalic">stress</span> oxidativo que leva a disfun&#231;&#227;o card&#237;aca e consequente sobre-express&#227;o de angiontensina <span class="elsevierStyleSmallCaps">ii</span> &#40;Ang <span class="elsevierStyleSmallCaps">II</span>&#41;&#46; Os n&#237;veis elevados de Ang <span class="elsevierStyleSmallCaps">II</span> inibem a a&#231;&#227;o da NRG&#44; impedindo a sua liga&#231;&#227;o aos recetores HER e a posterior ativa&#231;&#227;o de vias de sinaliza&#231;&#227;o antiapopt&#243;ticas&#46; Al&#233;m disso&#44; a inibi&#231;&#227;o destes recetores pode contribuir para o aumento de produ&#231;&#227;o de ERO&#46; Outro efeito da Ang <span class="elsevierStyleSmallCaps">II</span> prende-se com a ativa&#231;&#227;o e&#47;ou regula&#231;&#227;o positiva de NADPH oxidase<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">63&#44;64</span></a>&#46; A Ang <span class="elsevierStyleSmallCaps">II</span> interage com o recetor AT1&#44; associado a prote&#237;nas G&#44; que ativam a NADPH oxidase atrav&#233;s da prote&#237;na c&#237;nase C &#40;PKC&#41;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a>&#46; A NADPH oxidase&#44; por sua vez&#44; produz radicais ani&#245;es super&#243;xidos que s&#227;o ERO potentes&#46; Finalmente&#44; a sinaliza&#231;&#227;o do recetor AT1 est&#225; relacionada com a ativa&#231;&#227;o da c&#237;nase 1 reguladora do sinal apopt&#243;tico &#40;ASK1&#41;&#44; membro da fam&#237;lia das MAPK&#44; conduzindo a morte celular e disfun&#231;&#227;o card&#237;aca<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a>&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Em suma&#44; a a&#231;&#227;o do <span class="elsevierStyleItalic">trastuzumab</span> pode inibir diretamente as vias de sinaliza&#231;&#227;o antiapopt&#243;ticas&#44; ou por outro lado&#44; estimular a sobre-express&#227;o de Ang <span class="elsevierStyleSmallCaps">II</span>&#44; que promove a produ&#231;&#227;o de ERO e a inibi&#231;&#227;o da a&#231;&#227;o da NRG<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figura 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Estrat&#233;gias para limitar a cardiotoxicidade</span><p id="par0170" class="elsevierStylePara elsevierViewall">V&#225;rias estrat&#233;gias cl&#237;nicas t&#234;m sido postas em pr&#225;tica com o objetivo de atenuar a cardiotoxicidade do <span class="elsevierStyleItalic">trastuzumab</span> sem comprometer significativamente a sua efic&#225;cia terap&#234;utica&#46; Estas incluem a utiliza&#231;&#227;o de combina&#231;&#245;es otimizadas de quimioterapia&#44; o encurtamento do tratamento e o acompanhamento rigoroso dos doentes tratados<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a>&#46;</p><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle"><span class="elsevierStyleItalic">Trastuzumab</span> sem antraciclinas</span><p id="par0175" class="elsevierStylePara elsevierViewall">O estudo <span class="elsevierStyleItalic">Breast Cancer International Research Group</span> &#40;BCIRG&#41; <span class="elsevierStyleItalic">006</span> foi o primeiro a testar um procedimento terap&#234;utico adjuvante sem o uso de antraciclinas&#46; Este ensaio comprovou que um regime quimioterap&#234;utico com <span class="elsevierStyleItalic">trastuzumab</span> e sem antraciclinas&#44; no tratamento do cancro da mama&#44; tem uma efic&#225;cia antineopl&#225;sica equivalente e com menor incid&#234;ncia de eventos cardiot&#243;xicos&#44; quando comparado com regimes terap&#234;uticos adjuvantes com <span class="elsevierStyleItalic">trastuzumab</span> e antraciclinas<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a>&#46; Embora outros ensaios confirmem a efic&#225;cia desta estrat&#233;gia terap&#234;utica<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a>&#44; atualmente&#44; ainda existem opini&#245;es controversas sobre o papel das antraciclinas no tratamento combinado antineopl&#225;sico<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a>&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conjugados <span class="elsevierStyleItalic">trastuzumab</span>-toxinas</span><p id="par0180" class="elsevierStylePara elsevierViewall">Os anticorpos podem ser utilizados de forma a dirigir os agentes citot&#243;xicos para antig&#233;nios espec&#237;ficos de tumores alvo&#46; Esta liga&#231;&#227;o qu&#237;mica confere um maior controlo apopt&#243;tico a anticorpos monoclonais que s&#227;o espec&#237;ficos do tumor&#44; mas n&#227;o suficientemente citot&#243;xicos&#44; para al&#233;m de promover maior seletividade na sua a&#231;&#227;o<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a>&#46; De facto&#44; Phillips et al<span class="elsevierStyleItalic">&#46;</span> demonstraram que o uso de <span class="elsevierStyleItalic">trastuzumab</span> associado &#224; toxina f&#250;ngica maitansina DM1 desenvolve baixos &#237;ndices de toxicidade<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a>&#46; Mais recentemente&#44; ensaios cl&#237;nicos t&#234;m comprovado a efic&#225;cia e toler&#226;ncia do uso terap&#234;utico do conjugado <span class="elsevierStyleItalic">trastuzumab</span>-DM1 em pacientes com cancro da mama<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a>&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Regimes de tratamento de curto prazo</span><p id="par0185" class="elsevierStylePara elsevierViewall">Este tipo de abordagem suscita grande interesse na comunidade m&#233;dica&#44; dado o perfil de seguran&#231;a do seu uso e a rela&#231;&#227;o custo-benef&#237;cio<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; O estudo FinHER <span class="elsevierStyleItalic">&#40;Finland Herceptin&#41;</span> comparou o uso de docetaxel com vinorelbina&#44; administrados com ou sem <span class="elsevierStyleItalic">trastuzumab</span>&#44; como tratamento adjuvante do cancro da mama precoce&#46; Neste estudo&#44; o <span class="elsevierStyleItalic">trastuzumab</span> foi administrado antes de outras terapias cardiot&#243;xicas e concomitantemente com docetaxel-vinorelbina durante apenas nove semanas para testar a hip&#243;tese de que este regime iria limitar a cardiotoxicidade e manter a efic&#225;cia antineopl&#225;sica&#46; A ocorr&#234;ncia de baixas taxas de cardiotoxicidade estava intimamente relacionada com o uso de regimes de tratamento curtos com <span class="elsevierStyleItalic">trastuzumab</span><a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a>&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Uso individualizado de antraciclinas</span><p id="par0190" class="elsevierStylePara elsevierViewall">A topoisomerase-<span class="elsevierStyleSmallCaps">ii</span>&#945; &#40;TOP2A&#41; &#233; um dos alvos moleculares da a&#231;&#227;o das antraciclinas e tem sido considerada como um poss&#237;vel marcador preditivo de resposta a estes agentes&#46; A amplifica&#231;&#227;o do gene TOP2A&#44; localizado pr&#243;ximo do gene HER2&#44; &#233; mais frequente em tumores com amplifica&#231;&#227;o do HER2 &#40;34-90&#37;&#41; do que em tumores sem amplifica&#231;&#227;o do HER2 &#40;5-10&#37;&#41;&#46; Diversos relat&#243;rios e investiga&#231;&#245;es cl&#237;nicas retrospetivas encontraram uma taxa de efic&#225;cia adicional ap&#243;s o uso de regimes terap&#234;uticos que cont&#233;m antraciclinas no tratamento do cancro da mama HER2 positivo&#44; propondo a redu&#231;&#227;o do uso de antraciclinas em doentes com tumores HER2 negativo<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">74&#8211;76</span></a>&#46; Por outro lado&#44; resultados opostos foram obtidos em diferentes ensaios cl&#237;nicos<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a>&#46; Assim sendo&#44; o uso de regimes adjuvantes com antraciclinas no tratamento de doentes com coamplifica&#231;&#227;o dos genes HER2 e TOP2A permanece controverso<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46;</p></span></span></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Outros efeitos cardiot&#243;xicos</span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Isquemia mioc&#225;rdica</span><p id="par0195" class="elsevierStylePara elsevierViewall">Os indiv&#237;duos com cancro apresentam&#44; atualmente&#44; uma taxa de sobrevida mais favor&#225;vel&#44; o que resulta numa maior exposi&#231;&#227;o a fatores de risco associados &#224; ocorr&#234;ncia de doen&#231;as ateroscler&#243;ticas<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a>&#46; O aparecimento de doen&#231;a coron&#225;ria em doentes oncol&#243;gicos tem sido associado ao uso terap&#234;utico de alguns f&#225;rmacos antineopl&#225;sicos&#44; particularmente a capecitabina&#44; 5-fluoracilo &#40;5-FU&#41; e <span class="elsevierStyleItalic">bevacizumab</span>&#46; No entanto&#44; outras drogas est&#227;o relacionadas com o aparecimento de eventos isqu&#233;micos como os agentes antimicrot&#250;bulos &#40;paclitaxel e docetaxel&#41;&#44; os inibidores da tirosina-c&#237;nase <span class="elsevierStyleItalic">&#40;sorafenib&#44; sunitinib&#41;</span> e os alcaloides da vinca &#40;vincristina&#44; vinorelbina&#41;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;79</span></a>&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">O vasoespasmo coron&#225;rio &#233; o mecanismo fisiopatol&#243;gico isqu&#233;mico relacionado com a administra&#231;&#227;o de 5-FU&#44; ou da sua pr&#243;-droga fluoropirimidina&#44; a capecitabina&#46; Muitos dos indiv&#237;duos afetados possuem doen&#231;a arterial coron&#225;ria pr&#233;via&#44; o que pode aumentar o potencial isqu&#233;mico de 5-FU&#46; Com o evento isqu&#233;mico controlado&#44; o tratamento deve ser realizado continuamente e com maior aten&#231;&#227;o na preven&#231;&#227;o de recidivas<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a>&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Al&#233;m disso&#44; o <span class="elsevierStyleItalic">bevacizumab</span> &#233; um anticorpo monoclonal contra o fator de crescimento vascular endotelial &#40;FCVE&#41; e demonstra uma atividade antitumoral significativa quando combinado com quimioterapia&#46; O uso deste agente terap&#234;utico est&#225; associado&#44; raramente&#44; a eventos tromb&#243;ticos arteriais&#44; incluindo a ocorr&#234;ncia de enfarte agudo do mioc&#225;rdio em 0&#44;6-1&#44;5&#37; dos doentes<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;81</span></a>&#46; Os mecanismos de a&#231;&#227;o respons&#225;veis pela sua cardiotoxicidade ainda n&#227;o foram completamente elucidados<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a>&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Arritmias</span><p id="par0210" class="elsevierStylePara elsevierViewall">A taxa de incid&#234;ncia de arritmias no doente oncol&#243;gico ainda n&#227;o est&#225; bem determinada e &#233; vari&#225;vel de acordo com o tratamento antineopl&#225;sico utilizado<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a>&#46; Fatores de risco preponderantes incluem a idade avan&#231;ada do doente&#44; o uso de radia&#231;&#227;o card&#237;aca&#44; a ocorr&#234;ncia de infiltra&#231;&#245;es amil&#243;ides e qualquer outra anomalia subjacente ao sistema de condu&#231;&#227;o<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46; Por outro lado&#44; o cancro gera por si s&#243; um ambiente pr&#243;-arritmog&#233;nico&#44; independentemente de outros fatores de risco<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a>&#46; A fibrila&#231;&#227;o auricular &#233; a arritmia mais prevalente em doentes com cancro&#46; Segundo Onaitis et al&#46;&#44; esta &#233; respons&#225;vel por significativa morbilidade ap&#243;s cirurgia oncol&#243;gica&#44; com uma taxa de incid&#234;ncia de at&#233; 12&#44;6&#37;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a>&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Atualmente&#44; existe uma grande dificuldade em determinar a rela&#231;&#227;o causal dos eventos arr&#237;tmicos com cada um dos f&#225;rmacos utilizados clinicamente&#46; Os quimioter&#225;picos mais conhecidos por causar arritmias s&#227;o as antraciclinas &#40;DOX&#44; EPI&#41;&#44; os agentes antimicrot&#250;bulos &#40;paclitaxel e docetaxel&#41;&#44; os antimetab&#243;litos &#40;capecitabina&#44; 5-fluoracilo&#44; e gemcitabina&#41;&#44; os agentes alquilantes &#40;cisplatina e ciclofosfamida&#41;&#44; os inibidores da tirosina-c&#237;nase &#40;<span class="elsevierStyleItalic">trastuzumab</span> e <span class="elsevierStyleItalic">cetuximab</span>&#41;&#44; o tri&#243;xido de ars&#233;nio&#44; a talidomida e a interleucina-2<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a>&#46;</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Hipertens&#227;o arterial sist&#233;mica</span><p id="par0220" class="elsevierStylePara elsevierViewall">Alguns agentes quimioter&#225;picos que inibem a angiog&#233;nese&#44; como o <span class="elsevierStyleItalic">bevacizumab</span>&#44; <span class="elsevierStyleItalic">sutinib</span> e <span class="elsevierStyleItalic">sorafenib</span>&#44; <span class="elsevierStyleItalic">vatalanib</span>&#44; <span class="elsevierStyleItalic">pazopanib</span>&#44; <span class="elsevierStyleItalic">mosetamib</span>&#44; <span class="elsevierStyleItalic">axitinib</span> e <span class="elsevierStyleItalic">aflibercept</span> agravam ou induzem o aumento da press&#227;o arterial sist&#233;mica<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">85&#44;86</span></a>&#46; Antes da introdu&#231;&#227;o deste tipo de f&#225;rmacos&#44; a preval&#234;ncia de hipertens&#227;o arterial nos doentes oncol&#243;gicos era semelhante &#224; da popula&#231;&#227;o adulta em geral<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a>&#46; No entanto&#44; com a maior sobrevida dos doentes e o aumento da utiliza&#231;&#227;o de quimioter&#225;picos que interferem com press&#227;o arterial sist&#233;mica&#44; a hipertens&#227;o arterial tem sido diagnosticada mais frequentemente nestes indiv&#237;duos<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">85&#44;86</span></a>&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Os agentes antineopl&#225;sicos inibidores da angiog&#233;nese diminuem a atividade da tirosina-c&#237;nase do recetor do fator de crescimento endotelial vascular&#44; que &#233; respons&#225;vel pela produ&#231;&#227;o de &#243;xido n&#237;trico&#44; aumento da permeabilidade capilar e prolifera&#231;&#227;o das c&#233;lulas endoteliais<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">85&#44;86</span></a>&#46; A hipertens&#227;o arterial preexistente nos doentes com cancro &#233; um importante fator de risco para a ocorr&#234;ncia&#44; mais tarde&#44; de graves sequelas hipertensivas&#46; Uma forte interven&#231;&#227;o anti-hipertensora&#44; antes e durante o uso de f&#225;rmacos antiangiog&#233;nicos&#44; &#233; um componente essencial no tratamento dos doentes<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46;</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Tromboembolismo</span><p id="par0230" class="elsevierStylePara elsevierViewall">O tromboembolismo venoso &#233; uma das principais causas de morte nos doentes oncol&#243;gicos&#46; A doen&#231;a tromboemb&#243;lica venosa tem sido associada ao uso de drogas antiangiog&#233;nicas&#44; talidomida&#44; lenalidomida&#44; <span class="elsevierStyleItalic">bevacizumab</span> e terapias hormonais &#40;tamoxifeno&#41;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a>&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">A talidomida &#233; o agente antineopl&#225;sico mais comummente relacionado com os eventos tromboemb&#243;licos<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46; O uso monoterap&#234;utico desta droga est&#225; associado a uma incid&#234;ncia de 5&#37; de fen&#243;menos tromb&#243;ticos<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">88</span></a>&#46; Por outro lado&#44; a lenalidomida &#233; um an&#225;logo da talidomida com um perfil de toxicidade geral favor&#225;vel&#46; Contudo&#44; o risco de eventos tromboemb&#243;licos relacionados com a sua utiliza&#231;&#227;o tamb&#233;m &#233; alto<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">89</span></a>&#46; O mecanismo trombog&#233;nico destas drogas envolve uma a&#231;&#227;o direta nas c&#233;lulas endoteliais e o aumento da agrega&#231;&#227;o plaquet&#225;ria<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">O tamoxifeno&#44; antagonista do recetor do estrog&#233;nio&#44; est&#225; associado a um aumento da incid&#234;ncia de complica&#231;&#245;es tromboemb&#243;licas<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">90</span></a>&#46; Por outro lado&#44; os inibidores da aromatase&#44; como o anastrozol e letrozol&#44; que bloqueiam a convers&#227;o de androg&#233;nios para estrog&#233;nio em mulheres na p&#243;s-menopausa&#44; foram associados a uma maior incid&#234;ncia de efeitos nefastos a n&#237;vel card&#237;aco<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Tabela 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span></span></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Cardiotoxicidade associada &#224; radioterapia</span><p id="par0245" class="elsevierStylePara elsevierViewall">Atualmente&#44; estima-se que mais de 50&#37; dos doentes oncol&#243;gicos sejam tratados com radioterapia&#46; Juntamente com o desenvolvimento de novos agentes quimioter&#225;picos&#44; a radioterapia tem revolucionado o progn&#243;stico de indiv&#237;duos com v&#225;rios tipos de cancro&#46; No entanto&#44; s&#227;o detetados frequentemente efeitos tardios a n&#237;vel cardiovascular ap&#243;s o uso deste m&#233;todo terap&#234;utico<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a>&#46; A maioria das informa&#231;&#245;es cl&#237;nicas obtidas sobre a cardiotoxicidade da irradia&#231;&#227;o tor&#225;cica &#233; baseada em estudos de indiv&#237;duos com cancro da mama ou doen&#231;a de Hodgkin&#44; que desenvolveram doen&#231;a sintom&#225;tica durante o tratamento ou monitoriza&#231;&#227;o<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">93</span></a>&#46; As doen&#231;as peric&#225;rdicas s&#227;o manifesta&#231;&#245;es patol&#243;gicas frequentemente associadas ao uso de radioterapia&#46; Contudo&#44; outras poder&#227;o surgir&#44; meses ou anos ap&#243;s a irradia&#231;&#227;o&#44; como a fibrose mioc&#225;rdica e a cardiomiopatia&#44; a doen&#231;a arterial coron&#225;ria acelerada&#44; as irregularidades no sistema de condu&#231;&#227;o e a disfun&#231;&#227;o valvular &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figura 3</a>&#41;&#46; A ocorr&#234;ncia e manifesta&#231;&#227;o dos fen&#243;menos cardiot&#243;xicos dependem essencialmente da dose de radia&#231;&#227;o utilizada&#44; da &#225;rea do cora&#231;&#227;o exposta e da t&#233;cnica espec&#237;fica de aplica&#231;&#227;o&#46; Outros fatores de risco&#44; tais como a idade do doente no momento da exposi&#231;&#227;o&#44; tamb&#233;m t&#234;m um papel fulcral neste contexto&#44; sendo os doentes jovens &#40;&#60;&#160;20 anos&#41; mais suscet&#237;veis a les&#245;es card&#237;acas<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a>&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Monitoriza&#231;&#227;o e dete&#231;&#227;o precoce</span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Durante o desenvolvimento de f&#225;rmacos</span><p id="par0250" class="elsevierStylePara elsevierViewall">Antes da autoriza&#231;&#227;o comercial de todos os compostos&#44; &#233; geralmente aceite pela comunidade m&#233;dica que os dados pr&#233;-cl&#237;nicos obtidos dever&#227;o orientar a monitoriza&#231;&#227;o card&#237;aca durante os estudos subsequentes em humanos<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; No entanto&#44; ainda n&#227;o se conhecem os mecanismos moleculares exatos associados &#224; cardiotoxicidade de certos f&#225;rmacos&#44; o que dificulta a sua previs&#227;o e dete&#231;&#227;o precoce durante a fase de pr&#233;-comercializa&#231;&#227;o&#46; As culturas prim&#225;rias de c&#233;lulas card&#237;acas s&#227;o frequentemente usadas como modelos em testes toxicol&#243;gicos&#46; Por outro lado&#44; os cardiomi&#243;citos derivados de c&#233;lulas estaminais embrion&#225;rias representam modelos promissores neste contexto&#44; que poder&#227;o ampliar recursos e melhorar a preditividade dos testes n&#227;o-cl&#237;nicos<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a>&#46; Embora tenham sido desenvolvidas v&#225;rias abordagens alternativas&#44; os modelos animais apenas esclarecem a base molecular inerente ao aparecimento de disfun&#231;&#227;o card&#237;aca&#44; n&#227;o prevendo resultados cl&#237;nicos<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">96</span></a>&#46;</p></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Durante a aplica&#231;&#227;o cl&#237;nica</span><p id="par0255" class="elsevierStylePara elsevierViewall">Em doentes tratados com um regime de antraciclinas&#44; a necessidade de monitoriza&#231;&#227;o&#44; mesmo ap&#243;s o t&#233;rmino da terapia&#44; depende de aspetos espec&#237;ficos que os m&#233;dicos possam enfrentar na pr&#225;tica cl&#237;nica&#44; como a idade do doente oncol&#243;gico&#44; a dose de radia&#231;&#227;o utilizada e a dose cumulativa de antraciclinas<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">97</span></a>&#46; Al&#233;m disso&#44; deve avaliar-se a suscetibilidade individual &#40;p&#46; ex&#46; <span class="elsevierStyleItalic">background</span> gen&#233;tico&#41; de forma a identificar os doentes oncol&#243;gicos mais vulner&#225;veis e usar um tratamento personalizado&#46; A identifica&#231;&#227;o de subgrupos de risco e a sua incorpora&#231;&#227;o nos sistemas de monitoriza&#231;&#227;o &#233; fortemente recomendada<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;98</span></a>&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Relativamente a f&#225;rmacos como o <span class="elsevierStyleItalic">trastuzumab</span>&#44; pouco se sabe sobre os seus efeitos card&#237;acos a longo prazo e a reversibilidade do fen&#243;meno cardiot&#243;xico&#46; A principal limita&#231;&#227;o est&#225; associada ao seguimento a m&#233;dio prazo &#40;2 a 3<span class="elsevierStyleHsp" style=""></span>anos para o <span class="elsevierStyleItalic">trastuzumab</span>&#41;&#44; em que n&#227;o existem dados que indiquem se o tratamento da insufici&#234;ncia card&#237;aca cr&#243;nica promove uma recupera&#231;&#227;o permanente do doente ou diminui o risco de disfun&#231;&#227;o card&#237;aca tardia&#46; Al&#233;m disso&#44; n&#227;o tem sido realizada uma an&#225;lise e identifica&#231;&#227;o sistem&#225;tica dos fatores de risco associados &#224; cardiotoxicidade deste tipo de compostos&#46; Contudo&#44; &#233; recomendada uma cuidadosa avalia&#231;&#227;o da fun&#231;&#227;o card&#237;aca em todos os doentes eleg&#237;veis&#44; especialmente em casos cl&#237;nicos de reserva mioc&#225;rdica reduzida<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">A FEVE&#44; avaliada por angiografia de radionucl&#237;deos ou ecocardiografia&#44; &#233; o &#237;ndice mais comummente utilizado para a monitoriza&#231;&#227;o da fun&#231;&#227;o card&#237;aca durante o tratamento oncol&#243;gico<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">99</span></a>&#46; No entanto&#44; esta pode subestimar a les&#227;o cardiot&#243;xica&#44; dada a capacidade adaptativa do mioc&#225;rdio&#44; que permite manter este par&#226;metro dentro dos limites da normalidade&#44; mesmo na presen&#231;a de disfun&#231;&#227;o mioc&#225;rdica<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">100</span></a>&#46; Assim sendo&#44; outros m&#233;todos de monitoriza&#231;&#227;o alternativos t&#234;m sido estudados para avaliar a fun&#231;&#227;o card&#237;aca durante a terap&#234;utica oncol&#243;gica&#46; A an&#225;lise pr&#233;via da suscetibilidade individual&#44; a dete&#231;&#227;o de eventos cardiot&#243;xicos tempor&#225;rios &#40;p&#46; ex&#46; liberta&#231;&#227;o de pept&#237;deos natriur&#233;ticos&#41; ou a identifica&#231;&#227;o de altera&#231;&#245;es subcl&#237;nicas&#44; tais como varia&#231;&#245;es nos par&#226;metros diast&#243;licos&#44; poder&#227;o ser &#250;teis na dete&#231;&#227;o precoce de cardiotoxicidade<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">99</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Tabela 5</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0270" class="elsevierStylePara elsevierViewall">Embora existam diretrizes dispon&#237;veis para a monitoriza&#231;&#227;o dos efeitos cardiot&#243;xicos&#44; o tempo necess&#225;rio para acompanhamento m&#233;dico&#44; ap&#243;s o t&#233;rmino da terapia&#44; permanece desconhecido<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">99</span></a>&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Assim sendo&#44; h&#225; uma necessidade cada vez mais premente na monitoriza&#231;&#227;o cardiovascular dos indiv&#237;duos com cancro&#44; a fim de detetar precocemente efeitos cardiot&#243;xicos da terap&#234;utica antineopl&#225;sica&#46;</p></span></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclus&#227;o</span><p id="par0280" class="elsevierStylePara elsevierViewall">O uso extensivo de agentes quimioter&#225;picos e radioterapia&#44; na pr&#225;tica cl&#237;nica&#44; tem vindo a gerar uma enorme controv&#233;rsia&#44; devido aos seus potenciais efeitos adversos a n&#237;vel cardiovascular nos doentes oncol&#243;gicos tratados que sobrevivem&#46; Estes efeitos incluem cardiomiopatia&#44; isquemia&#44; arritmias&#44; hipertens&#227;o arterial&#44; doen&#231;as peric&#225;rdicas e doen&#231;a tromboemb&#243;lica&#46; No entanto&#44; n&#227;o existe um consenso na comunidade m&#233;dica que permita padronizar a monitoriza&#231;&#227;o da fun&#231;&#227;o mioc&#225;rdica nesses doentes&#44; assim como ainda n&#227;o foram desenvolvidos modelos preditivos precisos que possibilitem estimar esse mesmo risco de toxicidade com maior efic&#225;cia&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">De uma perspetiva farmacol&#243;gica e conforme recomendado por muitos especialistas da &#225;rea&#44; h&#225; uma necessidade urgente em compreender os mecanismos respons&#225;veis pela cardiotoxicidade&#46; Uma boa gest&#227;o e avalia&#231;&#227;o do perfil de seguran&#231;a card&#237;aco destes doentes s&#227;o essenciais&#44; sendo necess&#225;rio um estudo mais rigoroso dos efeitos a longo prazo das v&#225;rias estrat&#233;gias terap&#234;uticas&#46; Neste contexto&#44; &#233; cada vez mais importante o estabelecimento de uma parceria din&#226;mica entre a &#225;rea da Oncologia e da Cardiologia&#44; de forma a reduzir o risco de mortalidade e melhorar a qualidade de vida destes indiv&#237;duos&#44; sem interferir&#44; se poss&#237;vel&#44; no tratamento espec&#237;fico antineopl&#225;sico&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">Em suma&#44; a cardiotoxicidade induzida por tratamentos antineopl&#225;sicos deve ser encarada como um problema multidisciplinar&#44; com uma abordagem que engloba a ci&#234;ncia b&#225;sica&#44; oncol&#243;gica e cardiovascular&#46;</p></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Responsabilidades &#233;ticas</span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Prote&#231;&#227;o de pessoas e animais</span><p id="par0295" class="elsevierStylePara elsevierViewall">Os autores declaram que para esta investiga&#231;&#227;o n&#227;o se realizaram experi&#234;ncias em seres humanos e&#47;ou animais&#46;</p></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Confidencialidade dos dados</span><p id="par0300" class="elsevierStylePara elsevierViewall">Os autores declaram que n&#227;o aparecem dados de pacientes neste artigo&#46;</p></span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Direito &#224; privacidade e consentimento escrito</span><p id="par0305" class="elsevierStylePara elsevierViewall">Os autores declaram que n&#227;o aparecem dados de pacientes neste artigo&#46;</p></span></span><span id="sec0175" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Financiamento</span><p id="par0310" class="elsevierStylePara elsevierViewall">Este trabalho foi financiado por Fundos FEDER atrav&#233;s do Programa Operacional Fatores de Competitividade &#8211; COMPETE e por Fundos Nacionais atrav&#233;s da FCT &#8211; Funda&#231;&#227;o para a Ci&#234;ncia e a Tecnologia no &#226;mbito do projeto &#171;n&#46;&#176; FCOMP-01-0124-FEDER-011051 &#40;Ref&#46; FCT PTDC&#47;SAU-FCF&#47;100442&#47;2008&#41;&#187;&#44; pela Bolsa de Estudo Jo&#227;o Porto 2008 e pelos Projetos Pluridisciplinares para Est&#237;mulo &#224; Inicia&#231;&#227;o &#224; Investiga&#231;&#227;o na Universidade do Porto&#47;Santander Totta&#44; edi&#231;&#245;es 2009 e 2010&#46; Carmen Br&#225;s-Silva &#233; investigadora ao abrigo Programa Ci&#234;ncia 2008&#46;</p></span><span id="sec0180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflito de interesses</span><p id="par0315" class="elsevierStylePara elsevierViewall">Os autores declaram n&#227;o haver conflito de interesses&#46;</p></span></span>"
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        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A cardiotoxicidade &#233; um dos efeitos adversos mais significativos do tratamento oncol&#243;gico&#44; respons&#225;vel por uma consider&#225;vel morbimortalidade&#46; Entre os eventos lesivos dos agentes&#47;f&#225;rmacos quimioter&#225;picos no sistema cardiovascular&#44; destaca-se&#44; pela sua maior frequ&#234;ncia e gravidade&#44; a ocorr&#234;ncia de insufici&#234;ncia card&#237;aca com disfun&#231;&#227;o ventricular sist&#243;lica&#46; Outros efeitos t&#243;xicos cardiovasculares incluem hipertens&#227;o arterial&#44; doen&#231;a tromboemb&#243;lica&#44; doen&#231;as peric&#225;rdicas&#44; arritmias e isquemia mioc&#225;rdica&#46; Durante v&#225;rias d&#233;cadas&#44; a cardiomiopatia induzida por terap&#234;utica oncol&#243;gica era quase exclusivamente associada ao uso de doses cumulativas de antraciclinas&#44; que promovem les&#245;es permanentes a n&#237;vel celular&#46; No entanto&#44; o uso de novos agentes terap&#234;uticos&#44; como o anticorpo monoclonal <span class="elsevierStyleItalic">trastuzumab</span>&#44; induz uma disfun&#231;&#227;o transit&#243;ria revers&#237;vel dos mi&#243;citos sem que haja rela&#231;&#227;o com a dose utilizada&#46; Atualmente&#44; &#233; essencial para os doentes com cancro a identifica&#231;&#227;o precoce da les&#227;o cardiovascular&#44; o diagn&#243;stico preciso de eventos cardiot&#243;xicos e a implementa&#231;&#227;o de planos de monitoriza&#231;&#227;o adequados&#46; Neste contexto&#44; &#233; fulcral na pr&#225;tica cl&#237;nica uma coopera&#231;&#227;o estreita entre cardiologistas e oncologistas&#44; de forma a equilibrar os riscos cardiot&#243;xicos com os benef&#237;cios da terapia antineopl&#225;sica em doentes oncol&#243;gicos&#46; Neste artigo revimos as diversas respostas cardiot&#243;xicas ao uso de tratamentos oncol&#243;gicos e a sua rela&#231;&#227;o com os principais f&#225;rmacos antineopl&#225;sicos usados na pr&#225;tica cl&#237;nica&#46; Al&#233;m disso&#44; ser&#227;o abordadas as principais linhas de orienta&#231;&#227;o no que respeita &#224;s estrat&#233;gias de dete&#231;&#227;o&#47;monitoriza&#231;&#227;o da cardiotoxicidade em indiv&#237;duos com cancro&#46;</p>"
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        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Cardiotoxicity is one of the most significant adverse effects of cancer treatment&#44; and is responsible for considerable morbidity and mortality&#46; Among the effects of chemotherapeutic agents on the cardiovascular system&#44; the most frequent and serious is heart failure with ventricular systolic dysfunction&#46; Other toxic effects include hypertension&#44; thromboembolic disease&#44; pericardial disease&#44; arrhythmias and myocardial ischemia&#46; For several decades&#44; cancer therapy-induced cardiomyopathy was almost exclusively associated with the use of cumulative doses of anthracyclines&#44; which cause permanent damage at the cellular level&#46; However&#44; new therapeutic agents&#44; such as the monoclonal antibody trastuzumab&#44; induce transient reversible myocyte dysfunction which is unrelated to the dose used&#46; Early identification of potential cardiovascular injury&#44; accurate diagnosis of cardiotoxic events and implementation of appropriate monitoring plans are essential in patients with cancer&#46; Close cooperation between cardiologists and oncologists is thus crucial&#44; in order to balance the risks and benefits of cardiotoxic anticancer therapy&#46; In this article we review the various responses to cardiotoxic cancer treatments and their relationship with the main antineoplastic drugs used in clinical practice&#46; In addition&#44; we discuss the main guidelines on detection and monitoring of cardiotoxicity in patients with cancer&#46;</p>"
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSmallCaps">iii</span>&#41; Sinais associados a IC&#44; como o galope S3&#44; taquicardia&#44; ou ambos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSmallCaps">iv</span>&#41; Redu&#231;&#227;o da FEVE de pelo menos 5 para menos de 55&#37; com sinais ou sintomas de IC&#44; ou uma queda na FEVE de pelo menos 10 para menos de 55&#37;&#44; sem sinais ou sintomas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab354986.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Crit&#233;rios para confirmar ou classificar um diagn&#243;stico preliminar de disfun&#231;&#227;o card&#237;aca</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Tabela 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Cardiotoxicidade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Prot&#243;tipo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Rela&#231;&#227;o dose-cumulativa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Reversibilidade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tipo <span class="elsevierStyleSmallCaps">i</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doxorrubicina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sim&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ciclofosfamida&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tipo <span class="elsevierStyleSmallCaps">ii</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Trastuzumab</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sim &#40;na maioria de casos&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Sunitinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Sorafenib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "pt" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Classifica&#231;&#227;o proposta para a cardiomiopatia associada ao uso de quimioter&#225;picos</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl0015"
        "etiqueta" => "Tabela 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Fatores de risco&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Risco aumentado&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Idade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Menor idade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">G&#233;nero&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Feminino&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Modo de administra&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inje&#231;&#227;o intravenosa r&#225;pida&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dose cumulativa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Excedendo a dose cumulativa de&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Daunorrubicina 550-800&#160;mg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doxorrubicina 400-550&#160;mg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epirrubicina 900-1000&#160;mg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Idarrubicina 150-225&#160;mg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Amsacrina 580&#160;mg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mitoxantrona &#62;&#160;100-140&#160;mg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Irradia&#231;&#227;o mediast&#237;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Irradia&#231;&#227;o mediast&#237;nica precoce ou concomitante excedendo a dose cumulativa de&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doxorrubicina 450&#160;mg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doen&#231;as cardiovasculares pr&#233;vias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipertens&#227;o arterial&#44; doen&#231;a coron&#225;ria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dist&#250;rbios eletrol&#237;ticos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipocalcemia&#44; hipomagnesemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab354987.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Fatores de risco associados &#224; cardiotoxidade das antraciclinas</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "tbl0020"
        "etiqueta" => "Tabela 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">ERO&#58; esp&#233;cies reativas de oxig&#233;nio&#59; FCVE&#58; fator de crescimento vascular endotelial&#59; HER2&#58; recetor-2 do fator de crescimento epid&#233;rmico humano&#59; IC&#58; insufici&#234;ncia card&#237;aca&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Classe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Exemplos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Tratamento oncol&#243;gico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Toxicidade cardiovascular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Mecanismo de a&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Antraciclinas</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doxorrubicina&#44; epirrubicina&#44; daunorrubicina&#44; idarrubicina&#44; mitoxantrone</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leucemias agudas&#44; linfomas Hodgkin e n&#227;o Hodgkin e cancro da mama</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aguda&#58; IC&#44; arritmias&#44; altera&#231;&#245;es no intervalo Q-T&#44; altera&#231;&#227;o na repolariza&#231;&#227;o ventricular</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Les&#245;es nos cardiomi&#243;citos&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- <span class="elsevierStyleItalic">Stress</span> oxidativo &#40;Produ&#231;&#227;o de ERO&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- Apoptose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cr&#243;nica &#40;dose-dependente&#41;&#58; Disfun&#231;&#227;o ventricular esquerda &#40;n&#227;o revers&#237;vel&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Agentes alquilantes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ciclofosfamida&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro da bexiga&#44; endom&#233;trio&#44; mama&#44; ov&#225;rio&#44; pulm&#227;o e neoplasias hematol&#243;gicas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IC aguda &#40;geralmente revers&#237;vel&#41;&#44; derrame peric&#225;rdico&#44; arritmias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Produ&#231;&#227;o de ERO&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cisplatina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Isquemia mioc&#225;rdica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Antimetabolitos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5-fluoracilo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tumores s&#243;lidos&#44; como pulm&#227;o&#44; c&#243;lon e mama&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Isquemia mioc&#225;rdica&#44; Enfarte agudo do mioc&#225;rdio&#44; arritmias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Espasmo coron&#225;rio&#44; toxicidade mioc&#225;rdica celular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Capecitabina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Agentes antimicrot&#250;bulos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Paclitaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro do ov&#225;rio&#44; mama&#44; sarcoma de Kaposi e cancro do pulm&#227;o de n&#227;o-pequenas c&#233;lulas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bradicardia&#44; s&#237;ncope&#44; disfun&#231;&#227;o ventricular esquerda&#44; arritmias ventriculares&#44; isquemia mioc&#225;rdica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Les&#245;es nos cardiomi&#243;citos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Docetaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro da mama&#44; cancro do pulm&#227;o de n&#227;o-pequenas c&#233;lulas&#44; da pr&#243;stata&#44; da cabe&#231;a&#44; pesco&#231;o&#44; bexiga&#44; ov&#225;rio e adenocarcinoma g&#225;strico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alcal&#243;ides de vinca&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vincristina&#44; vinblastina e&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leucemias e linfomas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Isquemia mioc&#225;rdica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vinorelbina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anticorpos inibidores da tirosina-c&#237;nase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Trastuzumab</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro da mama&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disfun&#231;&#227;o ventricular esquerda &#40;revers&#237;vel&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibi&#231;&#227;o dos recetores HER2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Bevacizumab</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro colorretal metast&#225;tico e cancro do pulm&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipertens&#227;o arterial sist&#233;mica&#44; tromboembolismo venoso&#44; disfun&#231;&#227;o ventricular esquerda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibi&#231;&#227;o do VEGF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Rituximab</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Linfomas&#44; leucemias&#44; rejei&#231;&#245;es a transplantes e algumas desordens autoimunes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipotens&#227;o ortost&#225;tica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Associado a alergia&#44; angioedema&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Alemtuzumab</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leucemia linfoc&#237;tica cr&#243;nica&#44; linfomas cut&#226;neos de c&#233;lulas T e linfomas de c&#233;lulas T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipotens&#227;o&#44; isquemia mioc&#225;rdica&#44; disfun&#231;&#227;o ventricular esquerda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pequenas mol&#233;culas inibidoras da tirosina-c&#237;nase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Imatinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leucemia mieloide cr&#243;nica&#44; Leucemia linfobl&#225;stica&#44; tumores do estroma gastrointestinal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disfun&#231;&#227;o ventricular esquerda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibi&#231;&#227;o das vias protetoras mitocondriais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Sunitinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carcinoma de c&#233;lulas renais&#44; tumores do estroma gastrointestinal resistente ao imatinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disfun&#231;&#227;o ventricular esquerda&#44; IC&#44; isquemia mioc&#225;rdica&#44; hipertens&#227;o&#44; altera&#231;&#245;es eletrocardiogr&#225;ficas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Les&#227;o mitocondrial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Sorafenib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carcinoma hepatocelular e carcinoma de c&#233;lulas renais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disfun&#231;&#227;o ventricular esquerda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Erlotinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro do pulm&#227;o e do p&#226;ncreas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Isquemia mioc&#225;rdica&#44; Enfarte agudo do mioc&#225;rdio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Lapatinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro da mama&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disfun&#231;&#227;o ventricular esquerda&#44; IC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Dasatinib</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leucemia miel&#243;ide cr&#243;nica ap&#243;s tratamento com <span class="elsevierStyleItalic">imatinib</span> e leucemia linfobl&#225;stica aguda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disfun&#231;&#227;o ventricular esquerda&#44; IC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sem classifica&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gemcitabina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro do pulm&#227;o de n&#227;o-pequenas c&#233;lulas&#44; cancro do p&#226;ncreas&#44; cancro da mama e cancro da bexiga&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Derrame peric&#225;rdico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#193;cido retinoico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leucemia promieloc&#237;tica aguda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Derrame peric&#225;rdico&#44; disfun&#231;&#227;o ventricular esquerda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S&#237;ndrome retin&#243;ico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tri&#243;xido de ars&#233;nio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Reca&#237;das ou recidivas de Leucemia promieloc&#237;tica aguda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prolongamento do intervalo Q-T&#44; <span class="elsevierStyleItalic">torsades de pointes</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intera&#231;&#227;o com os canais i&#243;nicos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tamoxifeno&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancro da mama&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Trombose venosa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">profunda&#44; embolia pulmonar e acidente vascular cerebral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Talidomida e lenalidomida&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mieloma m&#250;ltiplo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Edema e bradicardia sinusal&#44; trombose venosa profunda&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Interleucina-2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Melanoma e carcinoma metast&#225;tico de c&#233;lulas renais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hipotens&#227;o&#44; arritmias card&#237;acas&#44; isquemia mioc&#225;rdica&#44; cardiomiopatia e miocardite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#171;Choque s&#233;tico&#187;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "pt" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Toxicidade cardiovascular das principais classes de f&#225;rmacos antineopl&#225;sicos aplicados na pr&#225;tica cl&#237;nica</p>"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Adaptado de&#58; Raschi et al&#46;<span class="elsevierStyleSup">3</span></p><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">cTnT&#58; troponina T card&#237;aca&#59; FEVE&#58; fra&#231;&#227;o de eje&#231;&#227;o do ventr&#237;culo esquerdo&#59; PNC&#58; pept&#237;deo natriur&#233;tico cerebral&#59; RM&#58; resson&#226;ncia magn&#233;tica&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">T&#233;cnica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Vantagens&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Desvantagens&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">N&#227;o usado atualmente</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Bi&#243;psia endomioc&#225;rdica</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tradicionalmente aceite como m&#233;todo padr&#227;o &#40;embora erradamente&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Invasivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evid&#234;ncias histol&#243;gicas de les&#227;o card&#237;aca&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Requer especialista para realizar e interpretar resultados&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pequena quantidade de amostra mioc&#225;rdica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o fornece informa&#231;&#227;o funcional&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Padr&#227;o atual</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Ecocardiografia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inofensivo e de baixo custo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dependente do operador &#40;variabilidade intra-observador e inter-observador&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avalia&#231;&#227;o morfol&#243;gica e funcional&#58; par&#226;metros sist&#243;licos &#40;FEVE&#44; fra&#231;&#227;o de encurtamento do VE&#44; espessamento da parede em s&#237;stole&#41; e diast&#243;licos &#40;raz&#227;o E&#47;A&#44; tempo de relaxamento isovolum&#233;trico&#44; padr&#227;o do fluxo venoso pulmonar&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A avalia&#231;&#227;o da FEVE &#233; dependente da qualidade da imagem e sujeito a variabilidade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dados sobre a estrutura valvular e do peric&#225;rdio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Valor preditivo pouco claro na dete&#231;&#227;o precoce de les&#245;es subcl&#237;nicas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Angiografia de radionucl&#237;deos</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bem validada na determina&#231;&#227;o da fra&#231;&#227;o de eje&#231;&#227;o</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subestima volumes ventriculares&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sobrestima a fra&#231;&#227;o de eje&#231;&#227;o em ventr&#237;culos mais pequenos &#40;crian&#231;as e mulheres&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alta reprodutibilidade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Exposi&#231;&#227;o a radia&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Variabilidade inter- e intra-observador baixa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baixa resolu&#231;&#227;o temporal e espacial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o fornece informa&#231;&#227;o sobre a fun&#231;&#227;o valvular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Poucas informa&#231;&#245;es sobre a fun&#231;&#227;o diast&#243;lica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Valor preditivo limitado na dete&#231;&#227;o precoce de les&#245;es subcl&#237;nicas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Eletrocardiografia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inofensivo e de baixo custo no rastreio de arritmias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nenhuma informa&#231;&#227;o sobre a FEVE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prolongamento do intervalo QT &#233; reconhecido como marcador de cardiotoxicidade&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Variabilidade intra- e inter-sujeito em valores QT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Problemas na medi&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o do intervalo QT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">T&#233;cnicas promissoras</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Doppler tecidular</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Permite detetar disfun&#231;&#227;o diast&#243;lica isolada&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Experi&#234;ncia limitada&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dete&#231;&#227;o precoce de les&#245;es subcl&#237;nicas &#40;combinado com marcadores inflamat&#243;rios&#47;<span class="elsevierStyleItalic">stress</span> oxidativo&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">An&#225;lise mais demorada&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Excelente resolu&#231;&#227;o temporal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avalia&#231;&#227;o funcional&#58; press&#245;es de enchimento &#40;raz&#227;o E&#47;A&#41; velocidades&#44; deforma&#231;&#227;o <span class="elsevierStyleItalic">&#40;strain&#41;</span> e taxas de deforma&#231;&#227;o <span class="elsevierStyleItalic">&#40;strain rate&#41;</span> sist&#243;lica e diast&#243;lica das paredes ventriculares&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Ecocardiograma de stress</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avalia&#231;&#227;o da reserva contr&#225;til do mioc&#225;rdio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dados limitados e controversos na dete&#231;&#227;o precoce de cardiotoxicidade em doentes oncol&#243;gicos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Natureza semi-invasiva&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Resson&#226;ncia magn&#233;tica</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Altamente reprodut&#237;vel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baixa resolu&#231;&#227;o temporal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avalia&#231;&#227;o funcional e da perfus&#227;o mioc&#225;rdica&#58; identifica&#231;&#227;o de cicatrizes p&#243;s-enfarte e de mioc&#225;rdio vi&#225;vel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Custo elevado&#44; principalmente pela necessidade de exames repetidos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Caracteriza&#231;&#227;o tecidular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disponibilidade limitada&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#218;til em pacientes com janela ecocardiogr&#225;fica limitada&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evid&#234;ncias ainda preliminares sobre o valor preditivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Tomografia computadorizada</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Boa qualidade de imagem &#40;semelhante &#224; RM&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alta dose de radia&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disponibilidade limitada&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baixa resolu&#231;&#227;o temporal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Cintigrafia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Natureza n&#227;o invasiva&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dados limitados&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avalia&#231;&#227;o estrutural e funcional&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o usado rotineiramente na pr&#225;tica cl&#237;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Radia&#231;&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Biomarcadores</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o invasivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Valor preditivo indefinido&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baixa variabilidade interobservador&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o usado rotineiramente na pr&#225;tica cl&#237;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avalia&#231;&#227;o da fun&#231;&#227;o cardiovascular e de potenciais sinais de les&#227;o card&#237;aca&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">cTnT&#44; PNC e glicog&#233;nio fosforilase<span class="elsevierStyleItalic">-</span>BB s&#227;o promissores marcadores na dete&#231;&#227;o precoce de les&#227;o mioc&#225;rdica &#40;alta sensibilidade e especificidade&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Les&#227;o endotelial</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">As citocinas&#44; mol&#233;culas de ades&#227;o e a rela&#231;&#227;o &#237;ntima&#47;m&#233;dia da art&#233;ria car&#243;tida s&#227;o potenciais par&#226;metros alternativos na avalia&#231;&#227;o da toxicidade cardiovascular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Valor preditivo desconhecido&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">An&#225;lise gen&#233;tica</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Minimamente invasivo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Valor preditivo desconhecido&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avalia&#231;&#227;o da suscetibilidade individual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab354983.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Principais t&#233;cnicas usadas na monitoriza&#231;&#227;o da cardiotoxicidade na pr&#225;tica cl&#237;nica&#58; vantagens e desvantagens</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "Bibliografia"
      "seccion" => array:1 [
        0 => array:2 [
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Informação do artigo
ISSN: 08702551
Idioma original: Português
DOI:10.1016/j.repc.2012.11.002
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