Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC thBgLzL4FnwYFJ773JmyMcz S0066-782X2020000600817 abc.20200273 10.36660/abc.20200273 Artigo de Revisão O Efeito da Doença de Coronavírus 2019 nas Doenças Cardiovasculares 0000-0001-7768-2562 Askin Lutfu 1 Tanrıverdi Okan 1 Askin Husna Sengul 2 Adiyaman Universitesi Egitim ve Arastirma Hastanesi Adıyaman Centry Turquia Adiyaman Universitesi Egitim ve Arastirma Hastanesi – Cardiology,Adıyaman, Centry – Turquia Adiyaman Universitesi Egitim ve Arastirma Hastanesi Adıyaman Centry Turquia Adiyaman Universitesi Egitim ve Arastirma Hastanesi - Infectious Disease,Adıyaman, Centry – Turquia Correspondência: Lutfu Askin • Adiyaman Universitesi Egitim ve Arastirma Hastanesi – Cardiology – Adıyaman Eğitim Ve Araştırma Hastanesi Kardiyoloji Bölümü Adıyaman Centry 2230 – Turquia. E-mail: lutfuaskin23@gmail.com

Contribuição dos autores

Concepção e desenho da pesquisa, Obtenção de dados, Análise e interpretação dos dados, Análise estatística, Obtenção de financiamento, Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Askin L, Tanrıverdi O, Askin HS.

Potencial conflito de interesses

Declaro não haver conflito de interesses pertinentes.

 01 06 2020 05 2020 114 5 817 822 02 04 2020 06 04 2020 08 04 2020 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Resumo

A doença de coronavírus 2019 (COVID-19) é uma pandemia global afetando o mundo, estando presente em mais de 1.300.000 pacientes. O COVID-19 age pelo receptor da enzima conversora de angiotensina 2 (ECA2). As comorbidades cardiovasculares são mais frequentes com COVID-19, e cerca 10% de casos desenvolvem miocardite (22% de pacientes críticas). Mais pesquisas serão necessárias para continuar ou descontinuar inibidores de ECA e bloqueadores dos receptores da angiotensina, que são essenciais para hipertensão e insuficiência cardíaca em COVID-19. Pesquisa intensiva é promissora para o tratamento e a prevenção da COVID-19.

 Coronavirus COVID-19 Doenças Cardiovasculares/complicações Comorbidade Hipertensão Insuficiência Cardíaca Miocardite Síndrome Respiratória Aguda Pandemias Mortalidade Hospitalização Cuidados Críticos Introdução

A doença de coronavírus 2019 (COVID-19) tem sido caracterizada como uma pandemia global. Em 28 março 2020, havia pacientes infectados em 167 países ao redor do mundo e mais de 1.300.000 casos com aproximadamente 69.780 mortes.1 O surto originou na China, e o número de casos fora da China já excedeu o número de casos na China. Estava difundido de modo constante em 28 de março 2020. Além disso, o número de mortes na Itália agora excede três vezes o número total na China. O COVID-19 interage com o sistema cardiovascular e aumenta morbidade e mortalidade, causando disfunção miocardial em pacientes com comorbidades cardiovasculares prévias.

A COVID-19 causa síndrome respiratória aguda grave coronavírus-2 (SARS-CoV-2). Tendo estrutura de envelope em cadeia única, o vírus de RNA é o sétimo coronavírus humano conhecido. O SARS-CoV-2 difere dos coronavírus que causaram síndrome respiratória aguda grave (SARS-CoV) zoonótico2 em 2002 e síndrome respiratória do Oriente Médio (MERS-CoV)3 em 2012. Acredita-se que o SARS-CoV-2 tenha 89% a 96% similaridade de nucleotídeos com coronavíroses de morcego e seja causado por morcegos, semelhante a outros coronavírus.4 Como SARS-CoV-1 e MERS, SARS-CoV-2 pode passar de morcegos para um hospedeiro intermediário (possivelmente um pangolim malaio com 91% de identidade nucleotídica) e depois para humanos.5

O SARS-CoV-2 se liga ao receptor da enzima conversora de angiotensina 2 (ECA2) humana (Figura 1) após a ativação da proteína pelo protease transmembranar, serina 2 (TMPRSS2).6 A ECA2 é principalmente expressa no pulmão (células alveolares tipo II),7 que parece ser o local de acesso dominante. A ECA2 é altamente liberada no coração em casos de ativação excessiva do sistema renina-angiotensina, como em hipertensão (HT), insuficiência cardíaca congestiva (ICC) e aterosclerose.8 Além dos seus efeitos cardíacos, ECA2 é expressa nos pulmões, epitélio intestinal, endotélio vascular e rins, sendo uma das causas de falência de múltiplos órgãos em infecção pelo SARS-CoV-2.8,9A evidência para a associação da COVID-19 com morbididade e mortalidade está crescendo em doenças cardiovasculares (DCV). Nesta revisão, objetivamos compartilhar dados atualizados sobre a COVID-19, que se difunde muito rapidamente.

– <italic>Interação dos receptores de SARS-CoV-2. ECA2: enzima conversora de angiotensina 2; TMPRSS2: protease transmembranar, serina 2</italic>

COVID-19 em DCV

DCV foi uma comorbidade comum em infecções por SARS e MERS antes da COVID-19. A prevalência de diabetes mellitus (DM) e DCV em SARS foi de 11% e 8%, respectivamente, e a presença das duas comorbidades estava associada a um risco doze vezes mais alto de morte.10 DM e HT eram frequentes em aproximadamente 50% de casos de MERS.11 A presença de comorbidades cardiovasculares também se aplica à COVID-19, e a sua importância aumenta nos casos mais severos. Em Wuhan, 30% dos pacientes infectados (48% dos que sobreviveram) tinham HT; 19% tinham DM (31% dos que sobreviveram), e 8% tinham DCV (13% dos que sobreviveram).12 Em uma coorte de 138 pacientes com COVID-19, as comorbidades cardiovasculares foram similarmente frequentes (46% geral, 72% em pacientes em terapia intensiva). Destes, 31% tinham HT (58% em pacientes em terapia intensiva); 15% tinham DCV (25% em pacientes em terapia intensiva), e 10% tinham DM (22% em pacientes em terapia intensiva).13

Em uma análise de coorte de 1.099 pacientes ambulatoriais e internados, 24% apresentaram alguma comorbidade (58% entre os com intubação ou óbito); 15% tinham HT (36% entre os com intubação ou óbito); 7.4% tinham DM (27% entre os com intubação ou óbito), e 2,5% tinham DCV (9% entre os com intubação ou óbito).14 A Comissão Nacional de Saúde da China relatou que 35% dos pacientes diagnosticados com COVID-19 apresentavam HT e 17% apresentavam doença cardíaca coronariana.15 Uma meta-análise na China mostrou que a comorbidade mais comum entre 46.248 pacientes infectados foi a HT.16 O possível mecanismo dessas associações é considerado ser mais comum em indivíduos com idade avançada, sistema imunológico comprometido, níveis altos de ECA2 ou predisposição a DCV. Outro estudo realizado na China indicou que a comorbidade mais frequentemente observada em pacientes que evoluíram para óbito de COVID-19 foi DCV, observada em 10,5% (Figura 2).17

– <italic>Taxas de comorbidades em pacientes com óbito por COVID-19 na China.</italic>

COVID-19 e dano miocárdico

Dano miocárdico, com biomarcadores cardíacos aumentados, estava presente entre os primeiros casos na China. Em um estudo com 138 pacientes com COVID-19 em Wuhan, dano cardíaco com troponina I de alta sensibilidade (hs-cTnI) e abnormalidades no ECG ou ecocardiográficos foram geralmente presentes em 7,2% de pacientes e em 22% de pacientes necessitando terapia intensiva.13 O relato nacional chinês da saúde relatou que aproximadamente 12% dos pacientes sem DCV têm níveis aumentados de troponina ou taxas de parada durante a internação hospitalar.15 A hs-cTnI, em particular, estava acima do limite de referência superior ao percentil 99 em 46% dos sobreviventes.12

Resultados iniciais indicam que há dois padrões de dano miocardial em COVID-19. Um estudo mostrou que, no quarto dia após começo dos sintomas, o nível médio de hs-cTnI nos sobreviventes foi de 8,8 pg/mL e de 2,5 pg/mL nos que evoluíram para óbito. Durante acompanhamento, hs-cTnI média entre sobrevivente não alterou significantemente (2,5 – 4,4 pg/mL), mas no sétimo dia, valores de hs-cTnI estavam de 24,7 pg/mL; no 13º dia, de 55,7 pg/mL; no 19º dia, de 134,5 pg/mL; e no 22º dia, de 290,6 pg/mL. Em particular, o tempo médio entre o começo dos sintomas e o óbito foi de 18,5 dias (IQR 15 – 20 dias).12

Os níveis aumentados de hs-cTnI foram associados a outros biomarcadores inflamatórios (dímero D, ferritina, interleucina-6 [IL-6], lactato desidrogenase). Isto foi o motivo da tempestade de citokinas ou da hemofagocitose secundária. A miocardite viral ou a a cardiomiopatia por estresse é mais relatada nos casos que apresentam principalmente sintomas cardíacos. Recentemente, foi relatado um caso de dor no peito com supradesnivelamento do segmento ST no ECG, porém com coronárias normais. O paciente apresentava fração de ejeção (FE) reduzida (27%), aumento dos diâmetros do ventrículo esquerdo e altos biomarcadores cardíacos (troponina T > 10 ng/mL, NT-proBNP > 21.000 pg/mL).18 Imunoglobulina e esteróides intravenosos melhoraram a sua capacidade cardíaca em três semanas.

Em outro relato da China, um homem de 63 anos sem história cardíaca prévia apresentava sintomas respiratórios graves, ventrículo esquerdo aumentado (DDVE 6,1 cm) e miocardite fulminante com FE reduzida. Ele apresentava níveis mais altos de troponina-I (> 11 ng/mL) e NT-proBNP (> 22.000 pg/ml). Foram aplicados oxigenação por membrana extracorpórea e regimes de imunoglobulina intravenosa, esteróides e antivirais devido à situação de choque cardiogênico. A função ventricular melhorou significativamente em duas semanas.19

A terapia glicocorticóide não é recomendada pela Organização Mundial da Saúde, porque o efeito dessa terapia ainda é incerto.20,21O relato nacional chinês também relatou que os síntomas podem ser palpitações e dor no peito, raramente.15 Dados limitados mostraram uma incidência menor de miocardite fulminante e de choque cardiogênico. No entanto, a taxa de recuperação e tratamento ainda não encontra-se em um nível sistemático.

O mecanismo exato do envolvimento cardíaco de COVID-19 ainda está sob investigação. Um mecanismo potencial é o envolvimento miocárdico direto mediado por ECA2. Observou-se que uma infecção miocárdica por ECA2 também foi desencadeada por infecção pulmonar por SARS-CoV desenvolvida em um modelo murino.22 Durante a epidemia de SARS em Toronto, o RNA viral de SARS-CoV foi detectado em 35% das autópsias.23 Outros possíveis mecanismos do envolvimento cardíaco relacionado à COVID-19 são a tempestade de citocinas induzida por uma resposta desequilibrada entre subtipos de células T auxiliares e o excesso de cálcio intracelular induzindo apoptose de cardiomiócitos hipóxicos.12

 O papel dos inibidores da enzima de conversão da angiotensina e dos bloqueadores dos receptores da angiotensina

A ECA2 é um homólogo de ECA que converte a angiotensina II em angiotensina 1-7, assim reduzindo a vasoconstrição mediada pelo sistema renina-angiotensina. O uso de inibidores da ECA (IECA) e bloqueadores dos receptores da angiotensina (BRA) é comum em DCV (HT, doença arterial coronariana, CHF e DM). Existem dados conflitantes de estudos que mostram que esses medicamentos aumentam os níveis de ECA2.24-25 O SARS-CoV-2 se liga à ECA2 para entrar nas células, porém, a ECA2 tem um papel de proteção contra lesão pulmonar aguda.

Em um modelo murino, a ligação da proteína spike do SARS-CoV à ECA2 foi o motivo para a regulação negativa da ECA2, aumento dos níveis de angiotensina II, permeabilidade vascular pulmonar, edema pulmonar e função pulmonar comprometida. Contudo, o tratamento com ECA2 recombinante26 e losartana27 reduziu o grau de lesão pulmonar. Atualmente, estudos estão em andamento em pacientes com COVID-19 devido ao potencial de reduzir danos pulmonares com losartana.28 Atualmente, não foram publicadas recomendações sobre a continuação ou descontinuação de IECA, BRA ou outros antagonistas do sistema renina-angiotensina-aldosterona (SRAA). Devido à falta de evidências sobre os efeitos negativos dos antagonistas do SRAA, a terapia com o SRAA continuará no COVID-19.29

Peng et al.,30 relataram que pacientes com COVID-19 e DCV tinham um risco mais alto de mortalidade. Pacientes críticos também tinham baixa contagem de linfócitos e alto índice de massa corpórea (IMC). Uso de IECA/ARB não afeta morbidade e mortalidade em pacientes com COVID-19 e DCV. As causas agravantes da morte incluem inflamação fulminante, acúmulo de ácido lático e eventos trombóticos.

A COVID-19 tem causado grandes danos à saúde e à situação econômica da China. Lidar com as doenças da aorta tornou-se um problema sério nessa situação. Diagnóstico rápido, transporte seguro e eficaz, implementação do procedimento intervencionista, proteção da equipe de cirurgia vascular, manejo pós-operatório e acompanhamento desses pacientes são problemas urgentes para os pacientes. Mais estudos serão necessários para minimizar as complicações em doenças vasculares, emergências críticas em cirurgia vascular e até gerenciar doenças vasculares na rotina com o COVID-19.31

 Terapia farmacológica e COVID-19: Efeitos Cardiovasculares Terapia Antiviral

Ribavirina e remdesivir são dois agentes que se ligam ao sítio ativo da RNA polimerase dependente de RNA no SARS-CoV2.32 Porém, lopinavir/ritonavir inibe a replicação do vírus de RNA e demonstra ter um efeito sinérgico com a ribavirina.33 Ensaios clínicos atuais estão pesquisando a ribavirina e lopinavir/ritonavir para COVID19, e esses antivirais foram usados como componentes do tratamento da hepatite C e HIV durante anos.34,35

A ribavirina, caracteristicamente, não apresenta toxicidade cardiovascular direta. No entanto, lopinavir/ritonavir pode causar prolongamento do intervalo QT em pacientes com intervalo QT longo.35 Tanto ribavirina quanto lopinavir/ritonavir têm o potencial de afetar a dose de anticoagulante.36 A ribavirina afeta as doses de varfarina. Pode ser necessário evitar medicamentos mediados pelo CYP3A, como rivaroxaban e apixaban, durante tratamento com lopinavir/ritonavir.37,38

Lopinavir/ritonavir também podem influenciar a atividade de inibidores de P2P12 por meio da inibição de CYP3A4, levar a concentrações séricas diminuídas dos metabólitos ativos de clopidogrel e prasugrel e aumentar as concentrações séricas de ticagrelor. Nos Estados Unidos e no Canadá, não é recomendado o uso desses medicamentos com ticagrelor devido ao risco excessivo de sangramento.39,40

Pelo contrário, o clopidogrel pode não sempre proporcionar inibição plaquetária adequada na administração simultânea de lopinavir/ritonavir.41,42 Prasugrel pode ser preferível a outras inibidores de P2Y12 durante a terapia com lopinavir/ritonavir. Contudo, é contraindicado em casos como histórico de acidente vascular cerebral ou ataque isquêmico transitório, IMC baixo ou sangramento patológico ativo. Uma abordagem guiada por testes com agentes antiplaquetários alternativos pode ser considerada. Detalhes sobre a troca de inibidores de P2Y12 já foram determinados.43 O metabolismo de cangrelor é independente da função hepática, portanto, interação não é esperada.44

Os inibidores da HMG-CoA redutase (estatinas) também têm potencial para interagir em combinação com lopinavir/ritonavir. A administração concomitante pode causar miopatia devido aos altos níveis de estatina. Lovastatina e sinvastatina são contraindicadas para a administração concomitante com lopinavir/ritonavir devido ao risco de rabdomiólise. Outras estatinas, incluindo atorvastatina e rosuvastatina, devem ser administradas na dose mais baixa possível e não devem exceder a dose máxima indicada com lopinavir/ritonavir.35

O remdesivir é um medicamento de pesquisa previamente avaliado durante a epidemia de Ebola e atualmente estudado em pacientes com COVID-19. Embora ainda não tenham sido relatadas toxicidades cardiovasculares extensas e interações medicamentosas, a avaliação preliminar desse medicamento durante a epidemia de Ebola observou o desenvolvimento de hipotensão e subsequente parada cardíaca em um paciente (de um total de 175 pacientes).45

 Outras terapias

Além dos medicamentos antivirais, um grande número de imunomoduladores e medicamentos secundários estão sendo investigados para prevenir complicações do COVID-19. A cloroquina, usada como agente antimalárico, bloqueia a infecção pelo vírus aumentando o pH endossômico necessário para a fusão vírus/célula e interrompe a atividade do SARS-CoV2 in vitro.46,47 A cloroquina e a hidroxicloroquina agem como tóxicas para os miócitos cardíacos. Os fatores de risco incluem exposição prolongada (> 3 meses), maior dose baseada em peso, doença cardíaca pré-existente e insuficiência renal. A toxicidade cardíaca da cloroquina ocorre como cardiomiopatia restritiva ou dilatada ou anormalidades de condução que se acredita serem devidas à inibição intracelular de enzimas lisossômicas nos miócitos.48

Além disso, devido aos efeitos da cloroquina na inibição do CYP2D6, os betabloqueadores (como metoprolol, carvedilol, propranolol ou labetalol) metabolizados via CYP2D6 podem causar aumento da concentração do fármaco que requer monitoramento cuidadoso das alterações da frequência cardíaca e da pressão arterial. Finalmente, ambos os agentes estão associados ao risco de torsade de pointes condicional em pacientes com anormalidades eletrolíticas ou em combinação com agentes que prolongam o QT. A exposição a curto prazo a esses agentes, como esperado no tratamento de COVID-19, representa um risco menor para esses efeitos colaterais dependentes da dose.49

Casos de COVID-19 complicados pela síndrome do desconforto respiratório agudo grave (SDRA) são atualmente tratados com metilprednisolona.50 Este esteróide causa retenção de líquidos, irregularidade eletrolítica e hipertensão, além de interagir com a varfarina através de um mecanismo desconhecido. Os médicos aconselham a observação dessas interações medicamentosas. Finalmente, o COVID-19 grave pode criar dificuldades na aplicação de medicamentos cardiovasculares de rotina; por esse motivo, os pacientes com risco de doença cardíaca isquêmica ou insuficiência cardíaca podem piorar.47

 Outros estudos publicados recentemente

Estudos recentes fornecem informações promissoras para o tratamento e acompanhamento do COVID-19. Diaz et al.,51 mostraram que a terapia com IECA e ARB aumentou o número de receptores ECA2 em animais experimentais. Os receptores ECA2 servem como locais de ligação para o vírus SARS-CoV-2 nos pulmões. Esse aumento pode produzir resultados sérios da doença. O COVID-19 pode suprimir as funções cardíacas e causar danos ao miocárdio. A história de doença cardíaca coronariana e o aumento dos níveis de cTnI são dois marcadores independentes principais que afetam a evolução clínica dos pacientes com COVID-19.52

Em HT e DM, os medicamentos que aumentam a ECA2 representam um risco de infecção grave por COVID-19; portanto, a terapia com IECA e ARB exige monitoramento rigoroso. Como os bloqueadores dos canais de cálcio (BCC) não demonstraram afetar a expressão ou atividade da ECA2, eles podem ser uma terapia alternativa em pacientes com COVID-19.53 A idade, a presença de doenças subjacentes, a infecção secundária e altos indicadores inflamatórios no sangue são determinantes da mortalidade no COVID-19. A mortalidade por COVID-19 se desenvolve devido à “síndrome da tempestade de citocinas” ativada por vírus ou miocardite fulminante.54

A história metabólica cardiovascular prévia pode aumentar ainda mais a gravidade do COVID-19 e afetar o prognóstico do COVID-19 de modo significativo. Por outro lado, é observado um aumento acentuado do dano miocárdico em pacientes com COVID-19.55 Estudos recentes concentraram-se no efeito benéfico da cloroquina, um medicamento antimalárico, eficaz no tratamento de pacientes com SARS-CoV-2. Devido a experiências anteriores com cloroquina no campo da pesquisa antiviral, a comunidade científica está mais preocupada com o tratamento da cloroquina.56 Entre casos de COVID-19, os pacientes com comorbidades apresentam piores resultados clínicos do que aqueles sem comorbidades. Mais comorbidade está associada a piores desfechos clínicos.57

O reconhecimento da miocardite aguda como uma complicação associada à COVID-19 é importante para o acompanhamento mais próximo dos pacientes afetados pelo COVID-19 e para o aumento do conhecimento das autoridades de saúde pública sobre esse tipo de complicação. A vigilância clínica e os exames laboratoriais, incluindo os níveis de troponina, são essenciais para a identificação adequada do COVID-19 e a redução da transmissão. Mais estudos serão necessários para determinar a eficácia dos corticosteróides na supressão da resposta inflamatória do miocárdio. Não se pode negar que fármacos antivirais ou cloroquina possam contribuir para a recuperação de pacientes com COVID-19.58

A lesão do miocárdio tem consequências fatais para o COVID-19. Pacientes com histórico de doença arterial coronariana sem lesão miocárdica apresentam prognóstico relativamente melhor. O dano miocárdico desencadeia disfunção cardíaca e arritmias. A inflamação é uma das possíveis causas de lesão do miocárdio. Um acompanhamento mais próximo e regimes de tratamento múltiplos devem ser considerados para pacientes com alto risco de lesão do miocárdio.59 O dano cardíaco tem sido comum entre pacientes internados com COVID-19 e está intimamente relacionado ao risco de mortalidade hospitalar. Mais pesquisas serão necessárias para esclarecer o mecanismo da lesão cardíaca, e as complicações devem ser cuidadosamente monitoradas no tratamento com COVID-19.60

Chen et al.,61 observaram que idosos, pacientes do sexo masculino e/ou pacientes com doenças relacionadas à expressão de ECA2 elevada apresentaram pior prognóstico quando expostos à COVID-19. Baseada em evidências pré-clínicas, pensava-se que o bloqueio do sistema renina-angiotensina aliviasse a COVID-19. Estudos multicêntricos serão necessários para testar a hipótese antes de fazer recomendações sobre medicamentos potencialmente essenciais.62

 Conclusão

O SARS-CoV-2 que causa o COVID-19 é um problema global de pandemia. DCV é mais frequente em pacientes com COVID-19. A taxa de morbimortalidade é alta nesses pacientes. Ainda não foi esclarecido se o DCV é um risco independente ou se é mediado por outros fatores (e.g., idade). O dano miocárdico ocorreu em mais de um quarto dos casos críticos. Os medicamentos clínicos IECA e BRA não apresentam problemas de acordo com as evidências atuais. Atualmente, a pesquisa é promissora em termos de tratamento.

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Clin Pharmacol Ther. 2019;105(1):219-28. Itkonen MK Tornio A Lapatto-Reiniluoto O Neuvonen M Neuvonen PJ Niemi M et al Clopidogrel increases dasabuvir exposure with or without ritonavir, and ritonavir inhibits the bioactivation of clopidogrel Clin Pharmacol Ther 2019 105 1 219 228 42. Marsousi N, Daali Y, Fontana P, Reny JL, Ancrenaz-Sirot V, Calmy A, et al. Impact of boosted antiretroviral therapy on the pharmacokinetics and efficacy of clopidogrel and prasugrel active metabolites. Clin Pharmacokinet. 2018;57(10):1347-54. Marsousi N Daali Y Fontana P Reny JL Ancrenaz-Sirot V Calmy A et al Impact of boosted antiretroviral therapy on the pharmacokinetics and efficacy of clopidogrel and prasugrel active metabolites Clin Pharmacokinet 2018 57 10 1347 1354 43. Angiolillo DJ, Rollini F, Storey RF, Bhatt DL, James S, Schneider DJ, et al. International expert consensus on switching platelet P2Y12 receptor-inhibiting therapies. Circulation. 2017;136(20):1955-75. Angiolillo DJ Rollini F Storey RF Bhatt DL James S Schneider DJ et al International expert consensus on switching platelet P2Y12 receptor-inhibiting therapies Circulation 2017 136 20 1955 1975 44. Kengreal [package insert]. Cary, NC: Chiesi USA, INC; 2015. Kengreal package insert Cary, NC Chiesi USA, INC 2015 45. Mulangu S, Dodd LE, Davey RT Jr, Tshiani Mbaya O, Proschan M, Mukadi D, et al. A randomized, controlled trial of ebola virus disease therapeutics. N Engl J Med. 2019;381(24):2293-303. Mulangu S Dodd LE Davey RT Jr Tshiani Mbaya O Proschan M Mukadi D et al A randomized, controlled trial of ebola virus disease therapeutics N Engl J Med 2019 381 24 2293 2303 46. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavíirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-71. Wang M Cao R Zhang L Yang X Liu J Xu M et al Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavíirus (2019-nCoV) in vitro Cell Res 2020 30 3 269 271 47. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14(1):72-3. Gao J Tian Z Yang X Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies Biosci Trends 2020 14 1 72 73 48. Tonnesmann E, Kandolf R, Lewalter T. Chloroquine cardiomyopathy - a review of the literature. Immunopharmacol Immunotoxicol. 2013;35(3):434-42. Tonnesmann E Kandolf R Lewalter T Chloroquine cardiomyopathy - a review of the literature Immunopharmacol Immunotoxicol 2013 35 3 434 442 49. Driggin E, Madhavan MV, Bikdeli B, Chuich T, Laracy J, Bondi-Zoccai G, et al. Cardiovascular Considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic. J Am Coll Cardiol. 2020 Mar 18:pii:S0735-1097(20)34637-4. Driggin E Madhavan MV Bikdeli B Chuich T Laracy J Bondi-Zoccai G et al Cardiovascular Considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic J Am Coll Cardiol 2020 03 18 pii:S0735-1097(20)34637-4 50. Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020;63(3):364-74. Liu Y Yang Y Zhang C Huang F Wang F Yuan J et al Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury Sci China Life Sci 2020 63 3 364 374 51. Diaz JH. 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Fang L Karakiulakis G Roth M Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020 8 4 e21 54. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 Mar 3. [Epub ahead of print]. Ruan Q Yang K Wang W Jiang L Song J Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China Intensive Care Med 2020 03 3 Epub ahead of print 55. Li B, Yang J, Zhao F, Zhi L, Wang X, Liu L, et al. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol. 2020 Mar 11. [Epub ahead of print]. Li B Yang J Zhao F Zhi L Wang X Liu L et al Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China Clin Res Cardiol 2020 03 11 Epub ahead of print 56. Touret F, de Lamballerie X. Of chloroquine and COVID-19. 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 Review Article The Effect of Coronavirus Disease 2019 on Cardiovascular Diseases 0000-0001-7768-2562 Askin Lutfu 1 Tanrıverdi Okan 1 Askin Husna Sengul 2 Turkey Adiyaman Universitesi Egitim ve Arastirma Hastanesi – Cardiology, Adıyaman, Centry – Turkey Turkey Adiyaman Universitesi Egitim ve Arastirma Hastanesi – Infectious Disease, Adıyaman, Centry – Turkey Mailing Address: Lutfu Askin • Adiyaman Universitesi Egitim ve Arastirma Hastanesi – Cardiology - Adıyaman Eğitim Ve Araştırma Hastanesi Kardiyoloji Bölümü Adıyaman Centry 2230 – Turkey. E-mail: lutfuaskin23@gmail.com

Author contributions

Conception and design of the research: L.A., O.T., H.S.A. ; Acquisition of data: L.A., O.T., H.S.A. ; Analysis and interpretation of the data: L.A., O.T., H.S.A. ; Writing of the manuscript: L.A., O.T., H.S.A. ; Critical revision of the manuscript for intellectual content: L.A., O.T., H.S.A.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 Abstract

Coronavirus disease 2019 (COVID-19) is a global pandemic affecting the world, seen in more than 1,300,000 patients. COVID-19 acts through the angiotensin-converting enzyme 2 (ACE2) receptor. Cardiovascular comorbidities are more common with COVID-19, and nearly 10% of cases develop myocarditis (22% of critical patients). Further research is needed to continue or discontinue ACE inhibitors and angiotensin receptor blockers, which are essential in hypertension and heart failure in COVID-19. Intensive research is promising for the treatment and prevention of COVID-19.

 Coronavirus COVID 19 Cardiovascular Diseases/complications Comorbidity Hypertension Heart Failure Myocarditis Acute Respiratory Syndrome Pandemic Mortality Hospitalization Critical Care Introduction

Coronavirus disease 2019 (COVID-19) has been characterized as a global pandemic. As of March 28, 2020, there were infected patients in 167 countries worldwide and more than 1,300,000 cases with approximately 69,780 deaths.1 The outbreak originated in China, and the number of cases outside China has exceeded the number of cases in China. It is increasing steadily as of March 28, 2020. Furthermore, the number of deaths in Italy now exceeds three times the total number in China. COVID-19 interacts with the cardiovascular system and increases morbidity and mortality by causing myocardial dysfunction in patients with previous cardiovascular comorbidities.

COVID-19 causes severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In its single-chain envelope structure, the RNA virus is the seventh known human coronavirus. SARS-CoV-2 differs from the coronaviruses that caused zoonotic severe acute respiratory syndrome coronavirus (SARS-CoV)2 in 2002 and middle east respiratory syndrome coronavirus (MERS-CoV)3 in 2012. SARS-CoV-2 is thought to have 89% to 96% nucleotide similarity with bat coronaviruses and to be caused by bats, similar to other coronaviruses.4 Like SARS-CoV-1 and MERS, SARS-CoV-2 can pass from bats to an intermediate host (possibly a Malayan pangolin sharing 91% nucleotide identity) and then to humans.5

SARS-CoV-2 binds to the human angiotensin-converting enzyme 2 (ACE2) receptor (Figure 1) after activation of the spike protein by transmembrane protease, serine 2 (TMPRSS2).6 ACE2 is mainly expressed in the lung (type II alveolar cells),7 and this appears to be the dominant access site. ACE2 is highly released in the heart in cases of excessive activation of the renin-angiotensin system, such as hypertension (HT), congestive heart failure (CHF), and atherosclerosis.8 In addition to its cardiac effects, ACE2 is expressed in the lung, intestinal epithelium, vascular endothelium, and kidneys, which is one of the causes of multiple organ failure in SARS-CoV-2 infection.8,9 Evidence for the association of COVID-19 with morbidity and mortality is growing in cardiovascular diseases (CVD). In this review, we aimed to share up-to-date data on COVID-19, which spreads very rapidly.

– <italic>SARS-CoV-2 receptor interaction.</italic>

COVID-19 in CVD

CVD was a common comorbidity in SARS and MERS infections before COVID-19. The prevalence of diabetes mellitus (DM) and CVD in SARS was 11% and 8%, respectively, and the presence of both comorbidities had a twelve-fold risk of death.10 DM and HT were common in approximately 50% of MERS cases.11 The presence of cardiovascular comorbidities also applies to COVID-19, and its importance increases in more severe cases. In Wuhan, 30% of infected patients (48% of survivors) had HT; 19% had DM (31% of survivors), and 8% had KVH (13% of survivors).12 In a cohort of 138 patients with COVID-19, cardiovascular comorbidities were similarly common (46% overall, 72% in intensive care patients). Of these, 31% had HT (58% in intensive care patients); 15% had CVD (25% in intensive care patients), and 10% had DM (22% intensive care patients).13

In a cohort analysis of 1,099 outpatients and inpatients, 24% had some comorbidity (58% among intubation or death); 15% had HT (36% among intubation or death); 7.4% had DM (27% among intubation or death), and 2.5% had KVH (9% among those with intubation or death).14 The Chinese National Health Commission reported that 35% of patients diagnosed with COVID-19 had HT, and 17% had coronary heart disease.15 A metaanalysis in China showed that, in 46,248 infected patients, the most common comorbidity was HT.16 The possible mechanism of these associations is considered to be more common in people with advanced age, impaired immune system, high ACE2 levels, or predisposition to CVD. Another study conducted in China indicated that the most common comorbidity seen in patients who died from COVID-19 was CVD with 10.5% (Figure 2).17

– <italic>Comorbidity rates in patients who died from COVID-19 in China.</italic>

COVID-19 and myocardial damage

Myocardial damage, with increased cardiac biomarkers, was among the first cases in China. In a study with 138 patients with COVID-19 in Wuhan, cardiac damage with high sensitivity Troponin I (hs-cTnI) and ECG or echocardiographic abnormalities were generally present in 7.2% of patients and 22% of patients in need of intensive care.13 The Chinese national health report stated that approximately 12% of patients without CVD have increased troponin levels or arrest rates during hospitalization.15 Hs-cTnI, in particular, was above the 99th percentile upper reference limit in 46% of survivors.12

Initial results show that there are two myocardial damage patterns with COVID-19. One study showed that on the fourth day following the onset of symptoms, the median hs-cTnI level in survivors was 8.8 pg/mL and 2.5 pg/mL in those who died. During follow-up, mean hs-cTnI between survivors did not change significantly (2.5 – 4.4 pg/mL), but on the seventh day, hs-cTnI values were 24.7 pg/mL; 55.7 pg/mL on the 13th day; 134.5 pg/mL on the 19th day, and 290.6 pg/mL on the 22nd day. In particular, average time from onset of symptoms to death was 18.5 days (IQR 15 – 20 days).12

The increased hs-cTnI level was associated with other inflammatory biomarkers (D-dimer, ferritin, interleukin-6 [IL-6], lactate dehydrogenase). This was the reason for the cytokine storm or secondary hemophagocytosis. Viral myocarditis or stress cardiomyopathy is mostly reported in the cases who mostly present with cardiac symptoms. Recently, a case with chest pain with ST-segment elevation on ECG but normal coronaries was reported. The patient had reduced ejection fraction (EF) (27%), increased left ventricular diameters, and high cardiac biomarkers (troponin T > 10 ng/mL, NT-proBNP > 21,000 pg/mL).18 Intravenous immunoglobulin and steroids improved his cardiac capacity within three weeks.

In another report from China, a 63-year-old male with no cardiac history had severe respiratory symptoms, enlarged left ventricle (LVEDD 6.1 cm), and fulminant myocarditis with reduced EF. He had higher troponin-I (> 11 ng/mL) and NT-proBNP (> 22,000 pg/ml) levels. Extracorporeal membrane oxygenation and intravenous immunoglobulin, steroids, antiviral treatment regimens were applied because of the cardiogenic shock situation. Ventricular function improved significantly within 2 weeks.19

Glucocorticoid therapy is not recommended by the world health organization because the effect of this therapy is still uncertain.20,21 China’s national report also reported that symptoms might be palpitations and chest pain rarely.15 Limited data showed a lower incidence of fulminant myocarditis and cardiogenic shock. However, the rate of recovery and treatment is not yet at a systematic level.

The exact mechanism of COVID-19’s cardiac involvement is still under investigation. A potential mechanism is ACE2-mediated direct myocardial involvement. It was observed that a myocardial infection due to ACE2 was also triggered by SARS-CoV pulmonary infection developed by in murine model.22 During the Toronto SARS epidemic, SARS-CoV viral RNA was detected in 35% of autopsies.23 Other possible mechanisms of cardiac involvement related to21 COVID-19 are cytokine storm induced by an imbalanced response between T helper cell subtypes and excess intracellular calcium inducing hypoxic cardiomyocyte apoptosis.12

 The role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers

ACE2 is an ACE homolog that converts angiotensin II to angiotensin 1-7, thereby reducing vasoconstriction mediated by the renin-angiotensin system. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) use is common in CVD (HT, coronary artery disease [CAD], CHF, and DM). There are conflicting data from studies showing that these drugs increase ACE2 levels.24,25 SARS-CoV-2 binds to ACE2 in order to gain entry into cells. However, ACE2 has a protective role against acute lung injury.

In a murine model, binding of the SARS-CoV spike protein to ACE2 is the reason for ACE2 downregulation, increased angiotensin II levels, pulmonary vascular permeability, pulmonary edema, and impaired lung function. However, treatment with recombinant ACE226 and losartan27 reduced the degree of lung injury. Studies are currently underway in patients with COVID-19 due to the potential to reduce lung damage with losartan.28 Currently, no recommendations have been reported on the continuation or discontinuation of ACEi, ARB or other renin-angiotensin-aldosterone system (RAAS) antagonists. Due to the lack of evidence about the harms of RAAS antagonists, RAAS therapy will continue in COVID-19.29

Peng et al.30 reported that patients with COVID-19 and CVD had a higher risk of mortality. Critical patients also had low lymphocyte counts and high body mass index (BMI). ACEI/ARB usage does not affect morbidity and mortality in COVID-19 patients with CVD. Aggravating causes of death include fulminant inflammation, lactic acid accumulation, and thrombotic events.

COVID-19 has caused great damage to the health and economic situation of China. How to deal with aortic diseases has become a serious problem in this situation. Rapid diagnosis, safe and effective transportation, implementation of the interventional procedure, protection of the vascular surgery team, postoperative management, and follow-up of such patients are urgent problems for patients. More studies are needed to minimize complications in vascular diseases, critical emergencies in vascular surgery and even manage routine vascular diseases with COVID-19. 31

 Drug Therapy and COVID-19: Cardiovascular Effects Antiviral Therapy

Ribavirin and remdesivir are two agents that bind to the active site on RNA-dependent RNA polymerases on SARS-CoV2.32 However, lopinavir/ritonavir inhibits the replication of the RNA virus and proves to have a synergistic effect with ribavirin.33 Clinical trials are currently researching ribavirin and lopinavir/ritonavir for COVID19, and these antivirals were used as components of hepatitis C and HIV treatment for years.34,35

Ribavirin does not characteristically have direct cardiovascular toxicity. However, lopinavir/ritonavir may cause QT prolongation in patients with long QT.35 Both ribavirin and lopinavir/ritonavir have the potential to affect the anticoagulant dose.36 Ribavirin affects warfarin doses. It may be necessary to avoid CYP3A-mediated drugs such as rivaroxaban and apixaban with lopinavir/ritonavir treatment.37,38

Lopinavir/ritonavir may also influence the activity of P2P12 inhibitors through CYP3A4 inhibition, lead to decreased serum concentrations of clopidogrel and prasugrel active metabolites, and increase serum concentrations of ticagrelor. In the United States and Canada, it is not recommended to use such drugs with ticagrelor due to the excessive risk of bleeding.39,40

On the contrary, clopidogrel may not always provide adequate platelet inhibition in the simultaneous administration of lopinavir/ritonavir.41,42 Prasugrel may be preferable to other P2Y12 inhibitors during lopinavir/ritonavir therapy. However, it is contraindicated in cases such as a history of stroke or TIA, low BMI, or active pathological bleeding. A test-guided approach with alternative antiplatelet agents may be considered. Details about switching P2Y12 inhibitors have already been determined.43 cangrelor metabolism is independent of hepatic function, so drug interaction is not expected.44 HMG-CoA reductase inhibitors (statins) also have the potential to interact with the lopinavir/ritonavir combination. Co-administration may cause myopathy due to high statin levels. Lovastatin and simvastatin are contraindicated for co-administration with lopinavir/ritonavir due to the risk of rhabdomyolysis. Other statins, including atorvastatin and rosuvastatin, should be administered in the lowest possible dose, and they should not exceed the maximum dose indicated with lopinavir/ritonavir.35

Remdesivir is a research drug previously evaluated during the Ebola epidemic and currently studied in patients with COVID-19. Although extensive cardiovascular toxicities and drug interactions have not yet been reported, preliminary assessment of this drug during the Ebola epidemic noted the development of hypotension and subsequent cardiac arrest in one patient (out of a total of 175 patients).45

 Other therapies

In addition to antiviral drugs, a large number of immunomodulators and secondary drugs are being investigated to prevent complications from COVID-19. Chloroquine, used as an antimalarial agent, blocks virus infection by increasing the endosomal pH required for virus/cell fusion and stops SARS-CoV2 activity in vitro.46,47 Chloroquine and hydroxychloroquine act toxic to cardiac myocytes. Risk factors include prolonged exposure (> 3 months), higher weight-based dose, pre-existing heart disease, and kidney failure. Chloroquine cardiac toxicity occurs as restrictive or dilated cardiomyopathy or conduction abnormalities that are thought to be due to intracellular inhibition of lysosomal enzymes in myocytes.48

Furthermore, due to the effects of chloroquine on CYP2D6 inhibition, beta-blockers (such as metoprolol, carvedilol, propranolol, or labetalol) metabolized via CYP2D6 may cause increased drug concentration that requires careful monitoring of heart rate and blood pressure changes. Finally, both agents are associated with the risk of conditional torsade de pointes in patients with electrolyte abnormalities or in combination with agents that prolong QT. Short-term exposure to these agents as expected in the treatment of COVID-19 poses a lower risk for these dose-dependent side effects.49

COVID-19 cases complicated by severe acute respiratory distress syndrome (ARDS) are currently treated by methylprednisolone.50 This steroid cause fluid retention, electrolyte irregularity, and hypertension, and it also interacts with warfarin through an unknown mechanism. Clinicians advise observing these drug interactions. Finally, severe COVID-19 may create difficulties in the application of routine cardiovascular medications; for this reason, patients at a risk of ischemic heart disease or heart failure may worsen.47

 Other recently published studies

Recent studies provide promising information for treatment and follow-up of COVID-19. Diaz et al.51 showed that ACEi and ARB therapy increased the number of ACE2 receptors in experimental animals. ACE2 receptors serve as binding sites for SARS-CoV-2 virions in the lungs. This increase can produce serious disease outcomes. COVID-19 can suppress cardiac functions and cause myocardial damage. History of CAD and increased levels of cTnI are two major independent markers that affect clinical evolution of patients with COVID-19.52

In HT and DM, ACE2 enhancing drugs pose a risk for serious COVID-19 infection, so ACEi and ARB therapy require close monitoring. As calcium channel blockers (CCBs) have not been shown to affect ACE2 expression or activity, they may be an alternative therapy in COVID-19 patients.53 Age, presence of underlying diseases, secondary infection, and high inflammatory indicators in the blood are determinants of mortality in COVID-19. COVID-19 mortality develops due to virus-activated “cytokine storm syndrome” or fulminant myocarditis.54

Previous cardiovascular metabolic history may further increase the severity of COVID-19 and greatly affect the prognosis of COVID-19. On the other hand, a marked increase in myocardial damage is observed in patients with COVID-19.55 Recent studies have focused on the beneficial effect of chloroquine, an antimalarial drug, which is effective on the treatment of patients with SARS-CoV-2. Due to previous experiments with chloroquine in the field of antiviral research, the scientific community is more concerned with the treatment of chloroquine56 Among cases of COVID-19, patients with comorbidities have worse clinical results than those without comorbidities. More comorbidity is associated with worse clinical outcomes.57

Recognizing acute myocarditis as a complication associated with COVID-19 is important for close follow-up of patients affected by COVID-19 and increased knowledge of public health officials about this type of complication. Clinical surveillance and laboratory tests, including troponin levels, are essential for proper identification of COVID-19 and reduction of transmission. More studies are needed to determine the effectiveness of corticosteroids in suppressing the myocardial inflammatory response. It cannot be denied that antiviral drugs or chloroquine can contribute to the recovery of patients with COVID-19.58

Myocardial injury has fatal consequences for COVID-19. Patients with a history of CAD without myocardial damage have relatively better prognosis. Myocardial damage triggers cardiac dysfunction and arrhythmias. Inflammation is one of the possible causes of myocardial injury. Closer follow-up and multiple treatment regimens should be considered for patients with a high risk of myocardial injury.59 Cardiac damage has been common among patients hospitalized with COVID-19, and it is closely related to the risk of in-hospital mortality. More research is needed to clarify the mechanism of cardiac injury, and complications should be carefully monitored in COVID-19 management.60

Chen et al.61 observed that the elderly, male patients, and/or patients with high ACE2 expression-related diseases had worse prognosis when exposed to COVID-19. With preclinical evidence, renin-angiotension system blockade was thought to alleviate COVID-19. Multicentre studies are needed to test the hypothesis before making recommendations on potentially essential drugs.62

 Conclusion

SARS-CoV-2 causing COVID-19 is a global pandemic problem. KVH is more common in COVID-19 patients. Morbidity and mortality rate is high in these patients. Whether CVD is an independent risk or whether it is mediated by other factors (e.g. age) has not been clarified yet. Myocardial damage occurred in more than a quarter of critical cases. Clinical ACEi and ARB medications do not present problems according to the current evidence. Research is currently promising in terms of treatment.

Study Association

This article is not related to any study association

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

Sources of Funding

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