Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC j7WqKyygcHW6LJKTZ4LVcTw S0066-782X2020000701051 abc.20200373 10.36660/abc.20200373 Artigo de Revisão Doença de Coronavírus-19 e o Miocárdio 0000-0003-3739-7702 Figueiredo José Albuquerque de Neto 1 Marcondes-Braga Fabiana G. 2 Moura Lidia Zytinski 3 0000-0001-6486-8317 Figueiredo André Melo e Silva de 1 0000-0002-2532-1607 Figueiredo Viviane Melo e Silva de 1 Mourilhe-Rocha Ricardo 4 Mesquita Evandro Tinoco 5 Universidade Federal do Maranhão São Luis MA Brasil Universidade Federal do Maranhão, São Luis, MA - Brasil Hospital das Clínicas Faculdade de Medicina Universidade de São Paulo São Paulo SP Brasil Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo,São Paulo, SP - Brasil Pontifícia Universidade Católica do Paraná Curitiba PR Brasil Pontifícia Universidade Católica do Paraná, Curitiba, PR - Brasil Universidade do Estado do Rio de Janeiro Hospital Pró-cardíaco Brasil Universidade do Estado do Rio de Janeiro e Hospital Pró-cardíaco. Brasil C.T.E.B UHG Brazil Educador C.T.E.B./UHG.Brazil Correspondência: José Albuquerque de Figueiredo Neto • Avenida dos Holandeses, 1B, ap. 1202, Ponta D’Areia, São Luís - MA – Brasil E-mail: jafneto@terra.com.br

Contribuição dos autores

Concepção e desenho da pesquisa, Análise e interpretação dos dados, Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Figueiredo Neto JA, Marcondes F, Moura L, Rocha RM, Mesquita ET; Obtenção de dados: Figueiredo Neto JA, Marcondes F, Moura L, Figueiredo AMS, Figueiredo VMS, Rocha RM, Mesquita ET.

Potencial conflito de interesses

Os autores declaram não haver conflito de interesses pertinentes.

 03 07 2020 06 2020 114 6 1051 1057 23 04 2020 04 05 2020 06 05 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 infecção pelo coronavírus denominada COVID-19 promoveu crescente interesse de cardiologistas, emergencistas, intensivistas e pesquisadores, pelo estudo do acometimento miocárdico partindo de diferentes formas clínicas decorrentes de desmodulação imunoinflamatória e neuro-humoral.O acometimento miocárdico pode ser mínimo e apenas identificado a partir de alterações eletrocardiográficas, principalmente por aumento de troponinas cardíacas, ou no outro lado do espectro pelas formas de miocardite fulminante e síndrome de takotsubo.A descrição de provável miocardite aguda tem sido comumente apoiada pela observação da troponina elevada em associação com disfunção. A clássica definição de miocardite, respaldada pela biópsia endomiocárdica de infiltrado inflamatório é rara, e foi observada em um único relato de caso até o momento, não se identificando o vírus no interior dos cardiomiócitos.Assim, o fenômeno que se tem documentado é de injúria miocárdica aguda, sendo obrigatório afastar doença coronária obstrutiva a partir da elevação de marcadores de necrose miocárdica, associada ou não à disfunção ventricular, provavelmente associada à tempestade de citoquinas e outros fatores que podem sinergicamente promover lesão miocárdica, tais como hiperativação simpática, hipoxemia, hipotensão arterial e fenômenos trombóticos microvasculares.Fenômenos inflamatórios sistêmicos e miocárdicos após infecção viral estão bem documentados, podendo evoluir para remodelamento cardíaco e disfunção miocárdica. Portanto, será importante a cardiovigilância desses indivíduos para monitorar o desenvolvimento do fenótipo de miocardiopatia dilatada.A presente revisão apresenta os principais achados etiofisiopatológicos, descrição da taxonomia desses tipos de acometimento cardíaco e sua correlação com as principais formas clínicas do componente miocárdico presente nos pacientes na fase aguda de COVID-19.

 Miocárdio/lesões Troponina Doenças Inflamatórias Miocardite Síndrome de Takotsubo Biomarcadores Coronavirus COVID-19 Pandemia Cardiomiopatia Dilatada Microangiopatias Trombóticas Introdução

A lesão miocárdica, evidenciada por biomarcadores cardíacos elevados, foi reconhecida entre os primeiros casos de COVID-19, na China. O relatório do Conselho Nacional de Saúde da China relatou que quase 12% dos pacientes sem doença cardiovascular (DCV) conhecida apresentaram níveis elevados de troponina ou parada cardíaca durante a hospitalização.1

Estes achados estimularam a pesquisa e o interesse por parte de cardiologistas, intensivistas e pesquisadores clínicos, pelo reconhecimento precoce destas anormalidades, bem como a busca dos mecanismos fisiopatológicos e o seu real impacto prognóstico.

Ao lado disso, foi identificado que indivíduos portadores de DCVs prévias, apresentavam maior risco para o desenvolvimento das formas graves e maior mortalidade.

Desta forma, entender o espectro do acometimento miocárdico, primário ou secundário, bem como os mecanismos etiofisiopatológicos envolvidos, são de fundamental importância para o desenvolvimento de estratégias terapêuticas, que possam prevenir e atenuar a agressão miocárdica presente na fase aguda.

 SARS-CoV-2 e o mecanismo de agressão celular direta

A infecção por SARS-CoV-2 é causada pela ligação da proteína spike da superfície viral ao receptor da enzima conversora de angiotensina 2 (ECA-2) humana após a ativação da proteína spike pela protease serina 2 transmembrana (TMPRSS2).

A ECA-2 é expressa no pulmão, principalmente nas células alveolares do tipo II, e parece ser o portal de entrada predominante.2 - 4 Ao se ligar à ECA-2, SARS-CoV-2 gera downregulation desta enzima e determina aumento dos níveis de angiotensina II, o que pode levar aos efeitos deletérios da ativação do sistema renina-angiotensina-aldosterona, tais como vaso constrição, alteração de permeabilidade vascular, remodelamento miocárdico e injúria pulmonar aguda; isto pode justificar, em parte, os sintomas pulmonares frequentes na síndrome5 ( Figura 1 ).6

– <italic>O SARS-CoV-2 liga-se por meio da proteína spike da superfície viral ao receptor da ECA-2 humana após a ativação da proteína spike pela TMPRSS2. SARS-CoV: coronavírus da síndrome respiratória aguda grave; SARS-COV-2: coronavírus da síndrome respiratória aguda grave 2; COVID-19: doença do coronavírus 2019; ECA-2: enzima conversora de angiotensina-2; TMPRSS2: serina protease transmembrana-2. Fonte: Costa IBSS, Brittar CS, Rizk SI, et al., 2020.</italic>

A ECA-2 também é altamente expressa no coração, neutralizando os efeitos da angiotensina II em estados com ativação excessiva do sistema renina-angiotensina, como hipertensão arterial sistêmica (HAS), insuficiência cardíaca (IC) e aterosclerose, por converter angiotensina II em angiotensina I-VII, que tem efeito cardioprotetor.

Além do coração e do pulmão, a ECA-2 é expressa no epitélio intestinal, endotélio vascular e rins, fornecendo um mecanismo para a disfunção de múltiplos órgãos que pode ser observada na infecção por SARS-CoV-2.

 COVID-19 e Lesão Miocárdica

A presença de troponina elevada na admissão hospitalar esteve associada com maior mortalidade em dois estudos envolvendo pacientes internados com COVID-19.7 - 8

Um destes estudos, desenvolvido em um hospital da Universidade de Wuhan, avaliou uma coorte de 416 pacientes hospitalizados por COVID-19 em que a média de idade foi 64 anos, 50% do sexo feminino e a DCV mais frequente foi HAS (30,5%). Dentre os pacientes incluídos, 82 (19,7%) tiveram injúria miocárdica, definida através da troponina I de alta sensibilidade acima do percentil 99. Pacientes hipertensos tiveram mais injúria miocárdica que aqueles sem hipertensão (59% x 23%); assim como pacientes com doença arterial coronária (DAC) (29,3% x 6,0%); doença cerebrovascular (15,9% x 2,7%) e IC (14,6% x 1,5%) (p < 0,001 para todas as variáveis). Os autores observaram maior frequência de síndrome da angústia respiratória aguda (58,5% x 14,7%, p < 0,001) assim como maior mortalidade entre os pacientes com injúria miocárdica (51% x 4,5%, p < 0,001).7

O outro estudo trata-se de uma coorte retrospectiva unicêntrica que avaliou 187 pacientes com COVID-19. A média de idade foi de 58 anos; 35% apresentavam alguma DCV (HAS, DAC ou cardiomiopatia) e 43 pacientes evoluíram a óbito (23%). Os autores observaram troponina T elevada em 27,8% dos casos. A taxa de mortalidade foi em torno de 7% para pacientes sem DCV e troponina T negativa, porém este valor foi 10 vezes maior quando a presença de DCV associou-se à presença de injúria cardíaca.7 Vale destacar que os pacientes com DCV que apresentavam troponina T negativa durante a infecção não tiveram mortalidade tão expressiva (13,3%) quanto aqueles que apresentaram elevação de troponina.8

Pacientes com troponina elevada eram mais idosos; tinham mais comorbidades e níveis mais elevados de leucócitos, NT-pró-BNP, proteína C-reativa e procalcitonina, mas com contagem mais baixa de linfócitos.

Um estudo demonstrou que, no quarto dia após o início dos sintomas, os níveis médios de troponina foram de 8,8 pg/mL em não sobreviventes vs. 2,5 pg/mL em sobreviventes. Durante o acompanhamento, a mediana de troponina entre os sobreviventes não mudou significativamente (2,5 – 4,4 pg/mL), enquanto subiu para 24,7 pg/mL no sétimo dia, 55,7 pg/mL no décimo terceiro dia, 134,5 pg/mL no décimo nono dia e 290,6 pg/mL no vigésimo segundo dia entre os não sobreviventes. O tempo médio até a morte desde o início dos sintomas foi de 18,5 dias (IQR 15 – 20 dias).9

O aumento da troponina foi acompanhado pela elevação de outros biomarcadores inflamatórios (dímero D, ferritina, interleucina-6 [IL-6], desidrogenase lactato), aumentando a possibilidade de que isso reflita mais a tempestade de citocinas ou a linfohistiocitose hematofagocítica secundária do que lesão miocárdica isolada.

 Mecanismos da lesão miocárdica e COVID-19

Os mecanismos da lesão miocárdica não estão bem estabelecidos, mas provavelmente envolvem aumento do estresse cardíaco devido à insuficiência respiratória e hipoxemia, síndrome coronariana aguda (SCA), lesão indireta da resposta inflamatória sistêmica, infecção miocárdica direta por SARS-CoV-2, entre outros fatores ( Figura 2 ).10

<italic>Mecanismos potenciais de lesão miocárdica na COVID-19. IM: infarto do miocárdio; CID: coagulação intravascular disseminada. Fonte: Figura adaptada de Atri D, Siddidi HK, Lang J, et al. COVID-19 for the Cardiologist: A Current Review of the Virology, Clinical Epidemiology, Cardiac and Other Clinical Manifestations and Potential Therapeutic Strategies. JACC Basic Transl Sci. 2020 Apr 10. doi: 10.1016/j.jacbts.2020.04.002. [Epub ahead of print]</italic>

Lesão miocárdica secundária ao desequilíbrio entre oferta e demanda de oxigênio

Situações de grave estresse fisiológico como sepse e insuficiência respiratória presentes em pacientes com COVID-19 estão associadas a elevações de biomarcadores de lesão miocárdica, determinando pior prognostico em alguns pacientes.11

O mecanismo mais provável é um desequilíbrio entre oferta e demanda de oxigênio, sem ruptura da placa ateromatosa e consistente com o diagnóstico de infarto do miocárdio tipo 2.12 , 13

Estes pacientes têm taxas de mortalidade mais altas, quando comparados com os que apresentam infarto do miocárdio tipo 1, provavelmente decorrente de um maior número de comorbidades.14

Devido à idade e ao perfil de comorbidades dos pacientes hospitalizados com COVID-19 grave, pode-se supor que essa população tenha um maior risco de DAC não obstrutiva subjacente e que a ocorrência de infarto do miocárdio tipo 2 contribui para a elevação da troponina e para piores desfechos.7

 Lesão microvascular

O provável mecanismo da lesão miocárdica decorre da formação de microtrombos na vasculatura do miocárdio, na presença de um estado de hipercoagulabilidade como na coagulação intravascular disseminada (CIVD). Alterações nos sistemas de coagulação e fibrinolítico estão presentes de maneira importante em pacientes com COVID-19, observando-se CIVD na maioria dos pacientes que faleceram.15

Os mecanismos da CIVD no contexto de sepse e síndrome do desconforto respiratório agudo presente nestes pacientes são complexos, mas acredita-se que esteja relacionado a uma exaustão dos sistemas de coagulação e fibrinolítico determinando sangramento e trombose no mesmo paciente.16

O aumento das citocinas inflamatórias, como IL-6 e fator de necrose tumoral-alfa (TNF-α), bem como a lesão endotelial, aumentam a expressão do fator tecidual, determinado um estado pró-trombótico.17

Por outro lado, a desregulação da antitrombina III, do inibidor do ativador do plasminogênio tipo 1 (PAI-1) e da proteína C em situações de inflamação e sepse significativas promove um estado de anticoagulação.18

Além disso, a ativação plaquetária também ocorre no contexto de sepse e inflamação, alterando o delicado equilíbrio do sistema de coagulação.19

Desta forma, a presença de inflamação e da ativação imune presentes na infecção grave por COVID-19 podem determinar CIVD, disfunção microvascular e lesão miocárdica.

 Resposta inflamatória sistêmica

Um dos prováveis mecanismos relacionados à lesão cardíaca em pacientes com COVID-19 grave envolve a intensa resposta inflamatória sistêmica. Relatos iniciais demonstraram que níveis extremamente elevados de biomarcadores inflamatórios e citocinas, incluindo IL-6, proteína C-reativa , TNF-α, interleucina-2R (IL-2R) e ferritina estiveram associados a manifestações mais graves de COVID-19 e a piores desfechos.20

Vários estudos já demonstraram que a cardiomiopatia na sepse é parcialmente mediada por citocinas inflamatórias como TNF-α, IL-6, IL-1β, INF-γ e IL-2.21 , 22

Cardiomiócitos de ratos cultivados demonstraram contratilidade reduzida quando expostos a IL-6. O mecanismo pode ser através da modulação da atividade do canal de cálcio com disfunção miocárdica resultante.23

Além disso, acredita-se que o óxido nítrico seja um mediador da depressão do miocárdio em estados de intensa inflamação, como a sepse.24

Mais recentemente, a observação do papel da disfunção mitocondrial nos estados sépticos levantou questões sobre o papel dessa entidade na cardiomiopatia associada à sepse.25

Pacientes com as formas mais graves de COVID-19 apresentam disfunção multiorgânica com tempestade de citocinas e desregulação imunológica, sendo estes prováveis mecanismos envolvidos na lesão miocárdica observada nestes pacientes.26

 Cardiomiopatia por estresse

O papel da cardiomiopatia por estresse (takotsubo) na lesão cardíaca relacionada à COVID-19 ainda não é bem conhecido, com poucos relatos até o momento.27 - 29

No entanto, acredita-se que vários dos mecanismos propostos para lesão cardíaca relacionada à COVID-19, detalhados nesta revisão, estejam implicados na fisiopatologia da cardiomiopatia por estresse, particularmente os de disfunção microvascular, tempestade de citocinas e aumento simpático.30

O intenso estresse emocional e as infecções respiratórias causadas pela COVID-19 podem representar potenciais gatilhos nesse contexto. É possível que cardiomiopatia por estresse também possa desempenhar um papel significativo na pandemia da COVID-19.

 Síndrome coronariana aguda não obstrutiva

Pacientes com COVID-19 podem apresentar sinais e sintomas clássicos para SCA, tais como dor torácica, alterações eletrocardiográficas sugestivas de isquemia miocárdica ou infarto agudo do miocárdio, tornando difícil este diagnostico diferencial.31

Os dados publicados até agora não explicitam a incidência de SCA por ruptura da placa epicárdica, como mecanismo para a lesão cardíaca observada na COVID-19.

Contudo, já existe um conhecimento adquirido, que demonstra a associação entre infecção e um risco elevado de SCA. Estudos epidemiológicos demonstraram que a hospitalização por pneumonia está associada a um maior risco de eventos ateroscleróticos.32

Estudos avaliando a infecção por influenza demonstraram associação temporal entre complicações cardiovasculares e SCA, e a vacinação anual contra influenza esteve associada à redução de 36% de eventos cardiovasculares adversos maiores, em metanálise de ensaios clínicos que avaliaram essa questão.33 , 34

Desta forma, a infecção viral está associada a um risco aumentado de eventos coronarianos e a prevenção está associada com uma redução desse risco. Portanto, é plausível que a SCA também seja uma causa importante de lesão cardíaca aguda em pacientes com COVID-19. Existem vários possíveis mecanismos fisiopatológicos, pelos quais a infecção viral sistêmica (por influenza ou SARS-CoV-2, por exemplo) pode levar a um maior risco de desestabilização da placa e SCA. Entre eles, o papel da inflamação no desenvolvimento e progressão da aterosclerose está bem estabelecido.35 - 38

A resposta imune à infecção viral aguda e o aumento concomitante de citocinas e mediadores inflamatórios presentes na COVID-19 podem levar à inflamação arterial localizada, que pode ser mais pronunciada nas placas coronárias.39

A entrada de produtos virais na circulação sistêmica, também conhecidos como padrões moleculares associados a patógenos (PMAP), pode causar a ativação inata do receptor imune, levando à ativação de células imunes residentes em ateroma preexistente, podendo determinar ruptura da placa; além do fato de que os PMAP virais podem ativar o inflamassoma, promovendo a conversão de pró-citocinas nas citocinas biologicamente ativas.40 , 41

Por fim, a disfunção endotelial decorrente da infecção e inflamação pode determinar vasoconstricção, com diminuição do fluxo coronariano.42

Todas estas alterações fisiopatológicas presentes na COVID-19 podem determinar à desestabilização de placa aterosclerótica pré-existente deflagrando um evento coronariano agudo.

 Lesão miocárdica viral direta

Relatos de casos de miocardite na COVID-19 fornecem evidências de inflamação cardíaca, mas não determinam o mecanismo.

Um dos mecanismos propostos para a lesão miocárdica observada na COVID-19 seria a infecção viral direta do coração, com miocardite resultante.

De fato, o miocárdio humano expressa o receptor utilizado pela COVID-19 para infectar as células hospedeiras, a ECA-2. Assim, sem dúvida, em alguns casos, uma miocardite viral devido a esse agente pode ocorrer.

No entanto, o aumento da troponina parece quase onipresente em pacientes que necessitam de tratamento intensivo, uma indicação de envolvimento cardíaco, que em muitos casos é um marcador de mau prognóstico, como em muitas outras circunstâncias.41

Um modelo murino de infecção pulmonar, demonstrada com SARS-CoV-1 também precipitou infecção miocárdica dependente de ECA-242 - 43 . Entre os seres humanos, durante o surto de SARS de Toronto, o RNA do vírus SARS-CoV-1 foi detectado em 35% dos corações autopsiados.1 Isso aumenta a possibilidade de danos diretos de cardiomiócitos pelo vírus.44

À luz do receptor de entrada da célula hospedeira compartilhado entre SARS-CoV-1 e SARS-CoV-2, uma entrada miocárdica viral direta e a lesão resultante são plausíveis também com SARS-CoV-2. O SARS-CoV-2 pode compartilhar o mesmo mecanismo com o SARS-CoV-1, porque os dois vírus são altamente homólogos no genoma.45 , 46

Temos até o momento apenas um relato de miocardite viral por SARS-CoV-2 comprovada por biópsia com inclusões virais ou DNA viral detectado no tecido do miocárdio.46 Porem não havia a presença de partículas virais no cardiomiócito, apenas no interior dos macrófagos no interstício cardíaco.

Outro mecanismo hipotético de lesão viral direta ao miocárdio é através de uma vasculite mediada por infecção. O receptor ECA-2 é altamente expresso em artérias e veias endoteliais.47

Existem dados patológicos do SARS-CoV-1, mostrando evidências de vasculite com infiltração de monócitos e linfócitos e lesão de células endoteliais no coração.48

A entrada viral direta nas células endoteliais do miocárdio pode desencadear uma vasculite, ou a presença do vírus pode levar a uma resposta imunológica indireta e consequente reação de hipersensibilidade.49 , 50 Esse insulto estaria associado à lesão miocárdica e talvez até à disfunção miocárdica evidente na COVID-19.

Embora a ECA-2 seja apenas levemente expressa no cardiomiócito, ela é altamente expressa nos pericitos. A COVID-19 pode atacar pericitos essenciais para a estabilidade endotelial, causando disfunção endotelial, que leva a distúrbios microcirculatórios. Isso explica por que, embora a ECA-2 seja apenas ligeiramente expresso nos cardiomiócitos, COVID-19 pode causar lesão cardíaca.51

As autópsias mostram infiltrados inflamatórios compostos por macrófagos e, em menor grau, por células T e CD4+.52 , 53

Esses infiltrados mononucleares estão associados a regiões de necrose de cardiomiócitos que, pelos critérios de Dallas, definem miocardite.54

As análises de PCR em tempo real de tecido cardíaco post mortem da epidemia de SARS detectaram o genoma viral em 35% dos pacientes que morreram de SARS. É importante notar que esses corações também apresentaram níveis diminuídos de ECA-2 e aumento da hipertrofia.44

Observados estes dados em conjunto, ainda não está claro quanto da lesão cardíaca é atribuível à infecção viral direta versus toxicidade indireta pela infecção sistêmica. Além disso, não estão definidas quais populações celulares no miocárdio são mais vulneráveis a infecções e/ou inflamação sistêmica. Os níveis de expressão da ECA-2 podem ser importantes, mas novamente as implicações de tais diferenças são discutíveis.

Inciardi et al.,55 descrevem uma paciente com COVID-19, que se apresentou com fadiga, aumento da troponina, elevação de peptídeo natriurético tipo B (BNP), alterações eletrocardiográficas, alterações de contração segmentar, derrame pericárdico e disfunção ventricular esquerda ao ecocardiograma com angiotomografia das artérias coronárias normal aproximadamente uma semana após ter apresentado quadro de febre e tosse seca; a ressonância magnética demonstrou acentuado edema intersticial miocárdico biventricular e o padrão de realce tardio do gadolínio sugerindo o diagnóstico de miocardite. A paciente necessitou suporte inotrópico e apresentou melhora clínica e laboratorial a partir de uma semana de tratamento.

Hu et al.,56 descreveram um paciente com quadro de dor torácica e dispneia durante três dias, elevação da troponina e BNP; alterações eletrocardiográficas; alterações de contração segmentar; derrame pericárdico e disfunção ventricular esquerda ao ecocardiograma com angiotomografia das artérias coronárias normal. À admissão, apresentava-se hipotenso com quadro sugestivo de miocardite fulminante. Foi tratado com suporte hemodinâmico (drogas vasopressoras e inotrópicas) e metilprednisolona associada à imunoglobulina humana. Após três semanas de tratamento evoluiu com recuperação completa da função ventricular e normalização dos marcadores de lesão miocárdica.

Em suma, nos parece clara a associação entre a presença de injúria miocárdica, identificado através da elevação de troponina, e pior prognóstico em pacientes com COVID-19. Em relação ao diagnóstico de miocardite, definido pela elevação de marcadores, associada a quadro clínico sugestivo, com alterações compatíveis em exames de cardioimagem, foram descritos alguns relatos de casos em pacientes com COVID-19, porém sem dados de biopsia comprovando a causa da miocardite.

Desta forma, considerando que SARS-CoV-1 e SARS-CoV-2 infectam as células através da ECA-2, proteína de membrana presente em células miocárdicas, é possível que esse mecanismo seja responsável também por miocardite em pacientes com diagnóstico de COVID-19. No entanto, maiores evidências são necessárias para comprovar tal associação.

 Conclusão

O envolvimento miocárdico e pericárdico (derrames/pericardite) é comum nas fases graves na doença causada pela COVID-19. O acometimento agudo do miocárdio tem sido descrito como uma injúria cardíaca aguda, induzida por uma possível “tempestade de citoquinas inflamatórias”, podendo ou não ocasionar necrose do cardiomiócito.

Raros casos de infiltrado inflamatório leve e a presença do vírus nas células inflamatórias do interstício cardíaco e nas células endoteliais da microcirculação coronária foram precisamente descritos, confirmando a real presença histológica de miocardite viral, porém até o momento não se descreveu o coronavírus no interior do cardiomiócito. O estado de resposta adrenérgica e inflamação miocárdica pode explicar a ocorrência do padrão fenotípico de síndrome de takotsubo.

Em resumo, o elevado grau de suspeita clínica com dor torácica, alteração hemodinâmica e/ou alterações do ST e/ou arritmias no ECG, associadas a anormalidades morfofuncionais nos métodos de cardioimagem e elevação da troponina cardíaca, representam os pilares do raciocínio clínico para a presença da agressão miocárdica aguda na atual pandemia por coronavírus.

Adicionalmente, torna-se necessário a cardiovigilância destes pacientes, posto que, à luz dos conhecimentos atuais, não sabemos se eles poderão ou não evoluir com disfunção miocárdica tardia.

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Lancet. 2004;363(9404):203-9. Pathan N Hemingway CA Alizadeh AA Stephens AC Boldrick JC Oragui EE et al Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock Lancet 2004 363 9404 203 209 24. Hobai IA, Edgecomb J, LaBarge K, Colucci WS. Dysregulation of intracellular calcium transportes in animal models of sepsis-induced cardiomyopathy. Shock. 2015;43(1):3-15. Hobai IA Edgecomb J LaBarge K Colucci WS Dysregulation of intracellular calcium transportes in animal models of sepsis-induced cardiomyopathy Shock 2015 43 1 3 15 25. Balligand JL, Ungureanu D, Kelly RA, Kobzik L, Pimental D, Michel T, et al. Abnormal contractile function due to induction ofnitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage conditioned medium. J Clin Invest. 1993;91(5):2314-9. Balligand JL Ungureanu D Kelly RA Kobzik L Pimental D Michel T et al Abnormal contractile function due to induction ofnitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage conditioned medium J Clin Invest 1993 91 5 2314 2319 26. Stanzani G, Duchen MR, Singer M. The role of mitochondria in sepsis-induced cardiomyopathy. Biochim Biophys Acta Mol Basis Dis. 2019;1865(4):759-73. Stanzani G Duchen MR Singer M The role of mitochondria in sepsis-induced cardiomyopathy Biochim Biophys Acta Mol Basis Dis 2019 1865 4 759 773 27. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall S, Manson JJ, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4. Mehta P McAuley DF Brown M Sanchez E Tattersall S Manson JJ et al COVID-19: consider cytokine storm syndromes and immunosuppression Lancet 2020 395 10229 1033 1034 28. Meyer P, Degrauwe S, Van Delden C, Ghadri JR, Templin C. Typical takotsubo syndrome triggered by SARS-CoV-2 infection. Eur Heart J. 2020;41(19):1860. Meyer P Degrauwe S Van Delden C Ghadri JR Templin C Typical takotsubo syndrome triggered by SARS-CoV-2 infection Eur Heart J 2020 41 19 1860 29. Sala S, Peretto G, Gramegna M, Palmisano A, Villatore A, Vignale D, et al. Acute myocarditis presenting as a reverse TakoTsubo syndrome in a patient with SARS-CoV-2 respiratory infection. Eur Heart J. 2020;41(19):1861-2. Sala S Peretto G Gramegna M Palmisano A Villatore A Vignale D et al Acute myocarditis presenting as a reverse TakoTsubo syndrome in a patient with SARS-CoV-2 respiratory infection Eur Heart J 2020 41 19 1861 1862 30. Chazal HM, Del Buono MG, Keyser-Marcus L, Ma L, Moeller FG, Berrocal D, et al. Stress cardiomyopathy diagnosis and treatment: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72(16):1955-71. Chazal HM Del Buono MG Keyser-Marcus L Ma L Moeller FG Berrocal D et al Stress cardiomyopathy diagnosis and treatment: JACC state-of-the-art review J Am Coll Cardiol 2018 72 16 1955 1971 31. Bangalore S, Sharma A, Slotwiner A, Yatskar L, Harari R, Shah B, et al. ST-segment elevation in patients with Covid-19 — a case series. N Engl J Med. 2020 Apr 17. [Epub ahead of print]. Bangalore S Sharma A Slotwiner A Yatskar L Harari R Shah B et al ST-segment elevation in patients with Covid-19 — a case series N Engl J Med 2020 04 17 Epub ahead of print 32. Corrales-Medina VF, Alvarez KN, Weissfeld LA, Angus DC, Chirinos JA, Chang CCH, et al. Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease. JAMA. 2015;313(3):264-74. Corrales-Medina VF Alvarez KN Weissfeld LA Angus DC Chirinos JA Chang CCH et al Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease JAMA 2015 313 3 264 274 33. Udell JA, Zawi R, Bhatt DL, Keshtkar-Jahromi M, Gaughran F, Phrommintikul A, et al. Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis. JAMA. 2013;310(16):1711-20. Udell JA Zawi R Bhatt DL Keshtkar-Jahromi M Gaughran F Phrommintikul A et al Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis JAMA 2013 310 16 1711 1720 34. Nguyen JL, Yang W, Ito K, Matte TD, Shaman J, Kinney PL. Seasonal influenza infections and cardiovascular disease mortality. JAMA Cardiol. 2016;1(3):274-81. Nguyen JL Yang W Ito K Matte TD Shaman J Kinney PL Seasonal influenza infections and cardiovascular disease mortality JAMA Cardiol 2016 1 3 274 281 35. Libby P, Loscalzo J, Ridker PM, Farkouh ME, Hsue PY, Fuster V, et al. Inflammation, immunity, and infection in atherothrombosis:JACC review topic of the week. J Am Coll Cardiol. 2018;72(17):2071-81. Libby P Loscalzo J Ridker PM Farkouh ME Hsue PY Fuster V et al Inflammation, immunity, and infection in atherothrombosis:JACC review topic of the week J Am Coll Cardiol 2018 72 17 2071 2081 36. Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32(9):2045-51. Libby P Inflammation in atherosclerosis Arterioscler Thromb Vasc Biol 2012 32 9 2045 2051 37. Violi F, Cangemi R, Calvieri C. Pneumonia, thrombosis and vascular disease. J Thromb Haemost. 2014;12(9):1391-400. Violi F Cangemi R Calvieri C Pneumonia, thrombosis and vascular disease J Thromb Haemost 2014 12 9 1391 1400 38. Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev. 2009;22(2):240-73. Mogensen TH Pathogen recognition and inflammatory signaling in innate immune defenses Clin Microbiol Rev 2009 22 2 240 273 39. Van de Veerdonk FL, Netea MG, Dinarello CA, Joosten LAB. Inflammasome activation and IL-1beta and IL-18 processing during infection. Trends Immunol. 2011;32(3):110-6. Van de Veerdonk FL Netea MG Dinarello CA Joosten LAB Inflammasome activation and IL-1beta and IL-18 processing during infection Trends Immunol 2011 32 3 110 116 40. Vallance P, Collier J, Bhagat K. Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link? Lancet. 1997;349(9062):1391-2. Vallance P Collier J Bhagat K Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link? Lancet 1997 349 9062 1391 1392 41. Libby P. The Heart in COVID19: primary target or secondary bystander? JACC Basic Transl Sci. 2020;5(5):537-42. Libby P The Heart in COVID19: primary target or secondary bystander? JACC Basic Transl Sci 2020 5 5 537 542 42. Ding Y, He L, Zhang Q, Huang Z, Che X, Hou J, et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways. J Pathol. 2004;203(2):622-30. Ding Y He L Zhang Q Huang Z Che X Hou J et al Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways J Pathol 2004 203 2 622 630 43. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-33. Zhu N Zhang D Wang W Li X Yang B Song J et al A novel coronavirus from patients with pneumonia in China, 2019 N Engl J Med 2020 382 8 727 733 44. Oudit GY, Kassiri Z, Jiang C, Liu PP, Poutanen SM, Penninger JM, et al. SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest. 2009;39(7):618-25. Oudit GY Kassiri Z Jiang C Liu PP Poutanen SM Penninger JM et al SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS Eur J Clin Invest 2009 39 7 618 625 45. Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci. 2020;63(3):457-60. Xu X Chen P Wang J Feng J Zhou H Li X et al Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission Sci China Life Sci 2020 63 3 457 460 46. Tavazzi G, Pellegrini C, Maurelli M, Belliato M, Sciutti F, Bottazzi A, et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail. 2020 Apr 10. [Epub ahead of print]. Tavazzi G Pellegrini C Maurelli M Belliato M Sciutti F Bottazzi A et al Myocardial localization of coronavirus in COVID-19 cardiogenic shock Eur J Heart Fail 2020 04 10 Epub ahead of print 47. Ding Y, Wang H, Shen H, Li Z, Geng J, Han H, et al. The clinical pathology of severe acute respiratory syndrome(SARS): a report from China. J Pathol. 2003;200(3):282-9. Ding Y Wang H Shen H Li Z Geng J Han H et al The clinical pathology of severe acute respiratory syndrome(SARS): a report from China J Pathol 2003 200 3 282 289 48. Hamming I, Timens W, Bulthuis MLC, Lely AT, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631-7. Hamming I Timens W Bulthuis MLC Lely AT van Goor H Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis J Pathol 2004 203 2 631 637 49. Pagnoux C, Cohen P, Guillevin L. Vasculitides secondary to infections. Clin Exp Rheumatol. 2006;24(2 Suppl 41):S71-81. Pagnoux C Cohen P Guillevin L Vasculitides secondary to infections Clin Exp Rheumatol 2006 24 2 Suppl 41 S71 S81 50. Guillevin L. Virus-induced systemic vasculitides: new therapeutic approaches. Clin Dev Immunol. 2004;11(3-4):227–31. Guillevin L Virus-induced systemic vasculitides: new therapeutic approaches Clin Dev Immunol 2004 11 3-4 227 231 51. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res.2020;116(6):1097–1100. Chen L Li X Chen M Feng Y Xiong C The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2 Cardiovasc Res 2020 116 6 1097 1100 52. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8(4),420-2.. Xu Z Shi L Wang Y Zhang J Huang L Zhang C et al Pathological findings of COVID-19 associated with acute respiratory distress syndrome Lancet Respir Med 2020 8 4 420 422 53. Yao XH, Li TY, He ZC, Ping YF, Liu HW, Yu SC, et al. A pathological report of three covid-19 cases by minimally invasive autopsies. Zhonghua Bing Li Xue Za Zhi. 2020;49(5):411-7. Yao XH Li TY He ZC Ping YF Liu HW Yu SC et al A pathological report of three covid-19 cases by minimally invasive autopsies Zhonghua Bing Li Xue Za Zhi 2020 49 5 411 417 54. Fung G, Luo H, Qiu Y, Yang D, McManus B. Myocarditis. Circ Res. 2016;118(3):496-514. Fung G Luo H Qiu Y Yang D McManus B Myocarditis Circ Res 2016 118 3 496 514 55. Inciardi RM, Lupi L, Zaccone G, Italia L, Raffo M, Tomasoni D, et al. Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020 Mar 27. Inciardi RM Lupi L Zaccone G Italia L Raffo M Tomasoni D et al Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19) JAMA Cardiol 2020 03 27 56. Hu H, Ma F, Wei X, Fang Y. Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin. Eur Heart J. 2020 Mar 16. [Epub ahead of print]. Hu H Ma F Wei X Fang Y Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin Eur Heart J 2020 03 16 Epub ahead of print

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 Review Article Coronavirus Disease 2019 and the Myocardium 0000-0003-3739-7702 Figueiredo José Albuquerque de Neto 1 Marcondes-Braga Fabiana G. 2 Moura Lidia Zytinski 3 0000-0001-6486-8317 Figueiredo André Melo e Silva de 1 0000-0002-2532-1607 Figueiredo Viviane Melo e Silva de 1 Mourilhe-Rocha Ricardo 4 Mesquita Evandro Tinoco 5 Brazil Universidade Federal do Maranhão, São Luis, MA - Brazil Brazil Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP - Brazil Brazil Pontifícia Universidade Católica do Paraná, Curitiba, PR - Brazil Brazil Universidade do Estado do Rio de Janeiro e Hospital Pró-cardíaco. Brazil Brazil Educador C.T.E.B./UHG.Brazil Mailing Address: José Albuquerque de Figueiredo Neto • Avenida dos Holandeses, 1B, ap. 1202, Ponta D’Areia, São Luís - MA – Brazil E-mail: jafneto@terra.com.br

Author contributions

Conception and design of the research, Analysis and interpretation of the data, Writing of the manuscript and Critical revision of the manuscript for intellectual content: Figueiredo Neto JA, Marcondes F, Moura L, Rocha RM, Mesquita ET; Data acquisition: Figueiredo Neto JA, Marcondes F, Moura L, Figueiredo AMS, Figueiredo VMS, Rocha RM, Mesquita ET.

Potential Conflict of Interest

The authors report no conflict of interest concerning the materials and methods used in this study or the findings specified in this paper.

 Abstract

Infection with the coronavirus known as COVID-19 has promoted growing interest on the part of cardiologists, emergency care specialists, intensive care specialists, and researchers, due to the study of myocardial involvement based on different clinical forms resulting from immunoinflammatory and neurohumoral demodulation.Myocardial involvement may be minimal and identifiable only by electrocardiographic changes, mainly increased cardiac troponins, or, on the other side of the spectrum, by forms of fulminant myocarditis and takotsubo syndrome.The description of probable acute myocarditis has been widely supported by the observation of increased troponin in association with dysfunction. Classical definition of myocarditis, supported by endomyocardial biopsy of inflammatory infiltrate, is rare; it has been observed in only one case report to date, and the virus has not been identified inside cardiomyocytes.Thus, the phenomenon that has been documented is acute myocardial injury, making it necessary to rule our obstructive coronary disease based on increased markers of myocardial necrosis, whether or not they are associated with ventricular dysfunction, likely associated with cytokine storms and other factors that may synergistically promote myocardial injury, such as sympathetic hyperactivation, hypoxemia, arterial hypotension, and microvascular thrombotic phenomena.Systemic inflammatory and myocardial phenomena following viral infection have been well documented, and they may progress to cardiac remodeling and myocardial dysfunction. Cardiac monitoring of these patients is, therefore, important in order to monitor the development of the phenotype of dilated myocardiopathy.This review presents the main etiological and physiopathological findings, a description of the taxonomy of these types of cardiac involvement, and their correlation with the main clinical forms of the myocardial component present in patients in the acute phase of COVID-19.

 Myocardium/injuries Troponin Inflammatory Diseases Myocarditis Takotsubo Syndrome Biomarkers Coronavirus COVID-19 Pandemics Cardiomyopathy, Dilated Thrombotic Microangiopathies Introduction

Myocardial injury, as shown by increased cardiac biomarkers, was identified among the first cases of COVID-19 in China. The National Health Council of China reported that almost 12% of patients without known cardiovascular disease (CVD) showed elevated levels of troponin or cardiac arrest during hospitalization.1

These findings have stimulated research and interest on the part of cardiologists, intensive care specialists, and clinical researchers, due to early recognition of these abnormalities, as well as the search for physiopathological mechanisms and their real impacts on prognosis.

In addition to this, individuals with previous CVD have been shown to be at a higher risk of developing severe forms and higher mortality.

Accordingly, it is of fundamental importance to understand the spectrum of myocardial involvement, whether primary or secondary, in addition to the etiological and physiopathological mechanisms involved, in order to promote the development of therapeutic strategies that can prevent and diminish myocardial aggression during the acute phase.

 SARS-CoV-2 and the mechanism of direct cellular aggression

SARS-CoV-2 infection is caused by binding of the spike protein on the surface of the virus to the human angiotensin converting enzyme 2 (ACE-2) receptor after activation of the spike protein by transmembrane protease, serine 2 (TMPRSS2).

ACE-2 is expressed in the lungs, mainly in the type-II alveolar cells, and it seems to be the predominant means of entry.2 - 4 SARS-CoV-2, in binding to ACE-2, causes downregulation of this enzyme, determining an increase in levels of angiotensin II, which may lead to deleterious effects in the activation of the renin-angiotensin-aldosterone system, such as vessel constriction, changes in vascular permeability, myocardial remodeling, and acute pulmonary injury, which may partially justify the frequent pulmonary symptoms in this syndrome5 ( Figure 1 ).6

– <italic>By means of its surface spike protein, SARS-CoV-2 binds to the human ACE-2 receptor following activation of the spike protein by TMPRSS2. SARS-CoV: severe acute respiratory syndrome coronavirus; SARS-COV-2: severe acute respiratory syndrome coronavirus 2; COVID-19: coronavirus disease 2019; ACE-2: angiotensin-converting enzyme-2; TMPRSS2: transmembrane protease, serine 2. Source: Costa IBSS, Brittar CS, Rizk SI, et al., 2020.</italic>

ACE-2 is also highly expressed in the heart, neutralizing the effects of angiotensin II in states with excessive activation of the renin-angiotensin system, such as systemic arterial hypertension (SAH), heart failure (HF), and atherosclerosis, by converting angiotensin II into angiotensin I-VII, which has a cardioprotective effect.

In addition to the heart and lungs, ACE-2 is expressed in the intestinal epithelium, vascular endothelium, and kidneys, providing a mechanism for multiple organ dysfunction, which can be observed in SARS-CoV-2 infection.

 3- COVID-19 and Myocardial Injury

Increased troponin upon admission to the hospital has been associated with higher mortality in two studies involving patients hospitalized with COVID-19.7 - 8

One of these studies, which was conducted in a hospital at Wuhan University, evaluated a cohort of 416 patients hospitalized for COVID-19, with a mean age of 64 years, 50% of whom were female; the most frequent CVD was SAH (30.5%). Of the patients included, 82 (19.7%) had myocardial injury, defined as high-sensitivity troponin I above the 99th percentile. Patients with hypertension had more myocardial injury than those without hypertension (59% vs. 23%). The same was the case patients for patients with coronary artery disease (CAD) (29.3% vs. 6.0%); cerebrovascular disease (15.9% vs. 2.7%), and HF (14.6% vs. 1.5%) (p < 0.001 for all variables). The authors observed greater frequency of acute respiratory distress syndrome (58.5% vs. 14.7%, p < 0.001) and greater mortality among patients with myocardial injury (51% x 4.5%, p < 0.001).7

The second, a single-center retrospective study, evaluated a cohort of 187 patients with COVID-19. Mean age was 58 years; 35% had some CVD (SAH, CAD, or cardiomyopathy), and 43 patients progressed to death (23%). The authors observed increased troponin T in 27.8% of cases. Mortality rate was around 7% for patients without CVD and negative troponin T; this value was ten-fold when the presence of CVD was associated with the presence of cardiac injury.7 It is worth underscoring that mortality in patients with CVD, who nonetheless had negative troponin T during infection, was not as expressive (13.3%) as mortality in those with increased troponin.8

Patients with increased troponin were more elderly. They had more comorbidities; higher levels of leukocytes, NT-pro-BNP, C-reactive protein, and procalcitonin; and lower lymphocyte counts.

Another study demonstrated that, on the fourth day after onset of symptoms, mean troponin levels were 8.8 pg/mL in patients who did not survive, in comparison with 2.5 pg/mL in those who survived. During follow-up, median troponin among survivors did not change significantly (2.5 – 4.4 pg/mL), while it rose to 24.7 pg/mL on the seventh day, 55.7 pg/mL on the thirteenth day, 134.5 pg/mL on the nineteenth day, and 290.6 pg/mL on the twenty-second day among patients who did not survive. Average time to death after onset of symptoms was 18.5 days (IQR 15 - 20 days).9

The increase in troponin was accompanied by an increase in other inflammatory biomarkers (D dimer, ferritin, interleukin-6 (IL-6), and lactate dehydrogenase), thus increasing the chance that this reflects a cytokine storm or secondary hemophagocytic lymphohistiocytosis, rather than isolated myocardial injury.

 Mechanisms of myocardial injury and COVID -19

The mechanisms of myocardial injury are not well established, but they probably involve an increase in cardiac stress due to respiratory failure and hypoxemia, acute coronary syndrome (ACS), indirect lesion from the systemic inflammatory response, direct myocardial infection by SARS-CoV-2, and other factors ( Figure 2 ).10

– <italic>Potential mechanisms of myocardial injury in COVID-19. DIC: disseminated intravascular coagulation; MI: myocardial infarction. Source: Atri D, Siddidi HK, Lang J, et al. COVID-19 for the Cardiologist: A Current Review of the Virology, Clinical Epidemiology, Cardiac and Other Clinical Manifestations and Potential Therapeutic Strategies. JACC Basic Transl Sci. 2020 Apr 10. doi: 10.1016/j.jacbts.2020.04.002. [Epub ahead of print]</italic>

Myocardial injury secondary to imbalance between oxygen supply and demand

Situations of severe physiological stress, such as sepsis and respiratory failure, which are present in patients with COVID-19, are associated with increased biomarkers of myocardial injury, leading to worse prognosis in some patients.11

The most likely mechanism is an imbalance between oxygen supply and demand, without rupture of the atheromatous plaque, consistent with diagnosis of type 2 myocardial infarction.12 , 13

These patients have higher rates of mortality when compared to those with type 1 myocardial infarction, likely as a result of a greater number of comorbities.14

Due to age and the comorbidity profile of patients hospitalized with severe COVID-19, it may be inferred that this population has a higher risk of underlying non-obstructive CAD and that the occurrence of type 2 myocardial contributes to increased troponin and worse outcomes.7

 Microvascular injury

The likely mechanism of myocardial injury results from the formation of microthrombi in the myocardial vasculature, in the presence of a state of hypercoagulability as in disseminated intravascular coagulation (DIC). Changes in the coagulation and fibrinolytic systems are important in patients with COVID-19, and DIC has been observed in the majority patients who died.15

The mechanisms of DIC in the context of sepsis and acute respiratory distress syndrome present in these patients are complex; it is believed to be related to an exhaustion of the coagulation and fibrinolytic systems causing both bleeding and thrombosis.16

The increase in inflammatory cytokines, such as IL-6 and tumor necrosing factor-alpha (TNF-α), as well as endothelial injury, increase the expression of tissue factor, leading to a pro-thrombotic state.17

On the other hand, dysregulation of antithrombin III, plasminogen activator inhibitor type 1 (PAI-1), and protein C in significant situations of inflammation and sepsis promotes a state of anticoagulation.18

Furthermore, platelet activation also occurs in the context of sepsis and inflammation, changing the delicate balance of the coagulation system.19

In this manner, the presence of inflammation and the immune activation present in severe COVID-19 infection may lead to DIC, microvascular dysfunction, and myocardial injury.

 Systemic inflammatory response

One of the likely mechanisms related to cardiac injury in patients with severe COVID-19 involves the intense systemic inflammatory response. Initial reports demonstrate that extremely high levels of inflammatory biomarkers and cytokines, IL-6, C-reactive protein, TNF-α, interleukin-2R (IL-2R), and ferritin were associated with more severe manifestations of COVID-19 and worst outcomes.20

Several studies have demonstrated that cardiomyopathy in sepsis is partially mediated by inflammatory cytokines such as TNF-α, IL-6, IL-1β, INF-γ, and IL-2.21 , 22

Cultivated rat cardiomyocytes demonstrated reduced contractility when exposed to IL-6. The mechanism may be through modulated calcium channel activity with resulting myocardial dysfunction.23

It is furthermore believed that nitric oxide is a mediator of myocardial depression in states of intense inflammation, such as sepsis.24

More recently, observation of the role of mitochondrial dysfunction in septic states raised questions concerning the role of this entity in cardiomyopathy associated with sepsis.25

Patients with more severe forms of COVID-19 have multiple organ dysfunction with cytokine storms and immune dysregulation, which are likely mechanisms involved in the myocardial injury observed in these patients.26

 Stress cardiomyopathy

The role of stress cardiomyopathy (takotsubo syndrome) in cardiac injury related to COVID-19 is still not well known, and there are few reports to date.27 - 29

It is, however, believed that several of the proposed mechanisms for cardiac injury related to COVID-19 that are detailed in this review are implicated in the pathophysiology of stress cardiomyopathy, especially microvascular dysfunction, cytokine storm, and sympathetic increase.30

The intense emotional stress and the respiratory infections caused by COVID-19 may represent potential triggers in this context. It is possible that stress cardiomyopathy may also play a significant role in the COVID-19 pandemic.

 Non-obstructive acute coronary syndrome

Patients with COVID-19 may have more classical signs and symptoms of ACS, such as chest pain and electrocardiographic changes suggestive of myocardial ischemia or acute myocardial infarction, making this differential diagnosis difficult.31

The data published to date do not explain the incidence of ACS due to epicardial plaque rupture, as a mechanism for the cardiac injury observed in COVID-19.

Nonetheless, existing acquired knowledge demonstrates the association between infection and increased risk of ACS. Epidemiological studies have demonstrated that hospitalization due to pneumonia is associated with increased risk of atherosclerotic events.32

Studies evaluating influenza infection have demonstrated a temporal association between cardiovascular complications and ACS, and annual vaccination against influenza was associated with a 36% decrease in major adverse cardiovascular events in a meta-analysis of clinical trials evaluating this question.33 , 34

In this manner, viral infection is associated with an increased risk of coronary events, and prevention is associated with reduced risk. It is, therefore, plausible that ACS is also an important cause of acute cardiac injury in patients with COVID-19. There are several possible pathophysiological mechanisms whereby systemic viral infection (by influenza or SARS-CoV-2, for example) can lead to an increased risk of plaque destabilization and ACS. The role of inflammation in the development and progression of atherosclerosis is well established.35 - 38

The immune response to acute viral infection and the concomitant increase in cytokines and inflammatory mediators present in COVID-19 can lead to localized arterial inflammation, which may be more pronounced in coronary plaque.39

The entrance of viral products into systemic circulation, also known as pathogen-associated molecular patterns (PAMP), can lead to innate activation of the immune receptor, in turn leading to activation of immune cells residing in pre-existing atheroma, which may cause plaque rupture; furthermore, viral PAMP can activate the inflammasome, promoting conversion of pro-cytokines to biologically active cytokines.40 , 41

Finally, endothelial dysfunction resulting from infection and inflammation may lead to vessel constriction, with decreased coronary flow.42

All of these physiopathological alterations present in COVID-19 can lead to destabilization of pre-existing atherosclerotic plaque, thus triggering an acute coronary event.

 Direct viral myocardial injury

Reports of cases of myocarditis in COVID-19 provide evidence of cardiac inflammation, but they do not determine the mechanism.

One of the proposed mechanisms behind the myocardial injury observed in COVID-19 is direct viral infection of the heart, with resulting myocarditis.

In fact, the human myocardium expresses the receptor used by COVID-19 to infect host cells, namely, ACE-2. Thus, without a doubt, in some cases, viral myocarditis may occur due to this agent.

The increase in troponin, however, appears to be omnipresent in patients who require intensive care, an indication of cardiac involvement, which is a marker of poor prognosis in many cases, as in many other circumstances.41

A murine model of lung infection, demonstrated with SARS-CoV-1, also precipitated myocardial infection dependent on ACE-242 - 43 . In human beings, during the SARS outbreak in Toronto, RNA of the SARS-CoV-1 virus was detected in 35% of autopsied hearts.1 This increases the likelihood of direct viral damage to cardiomyocytes.44

In view of the host cell input receptor shared by SARS-CoV-1 and SARS-CoV-2, direct viral myocardial entry and the resulting injury is also plausible with SARS-CoV-2. SARS-CoV-2 may share the same mechanism with SARS-CoV-1, given that the two viruses have highly homologous genomes.45 , 46

To date, we have only one report of viral myocarditis due to SARS-CoV-2 confirmed by biopsy, with viral inclusions of viral DNA detected in myocardial tissue.46 Viral particles, however, were not present in cardiomyocytes, but only inside macrophages in the cardiac interstice.

Another hypothetical mechanism behind direct viral myocardial injury is due to infection-mediated vasculitis. The ACE-2 receptor is highly expressed in arteries and endothelial veins.47

There are pathological data on SARS-CoV-1, showing evidence of vasculitis with the infiltration of monocytes and lymphocytes, as well as endothelial cell injury in the heart.48

Direct viral entry in endothelial cells of the myocardium can trigger vasculitis, or the presence of the virus can lead to an indirect immunological response and consequent reaction of hypersensitivity.49 , 50 This injury would be associated with myocardial injury and perhaps also with the myocardial dysfunction that is evident in COVID-19.

Even though ACE-2 is only slightly expressed in cardiomyocytes, it is highly expressed in pericytes. COVID-19 may attack pericytes, which are essential to endothelial stability, thus causing endotelial dysfunction, which leads to microcirculatory disorders. This explains why COVID-19 may cause cardiac injury, even though ACE-2 is only slightly expressed in cardiomyocytes.51

Autopsies have shown inflammatory infiltrates composed of macrophages and, to a lesser extent, T and CD4 + cells.52 , 53

These mononuclear infiltrates are associated with areas of cardiomyocyte necrosis, which, according to the Dallas criteria, define myocarditis.54

Real-time PCR analyses of post-mortem cardiac tissue from the SARS-CoV-1 epidemic detected the viral genome in 35% of patients who died of SARS-CoV-1. It is important to note that these hearts also showed decreased levels of ACE-2 and increased hypertrophy.44

Observing these data together, it is still not clear to what extent cardiac injury is attributable to direct viral infection versus indirect toxicity due to systemic infection. Furthermore, it has yet to be defined which cell populations in the myocardium are most vulnerable to infections and/or systemic inflammation. Levels of expression of ACE-2 may be important, but the implications of such differences are still debatable.

Inciardi et al.55 described a patient with COVID-19 who presented with fatigue, increased troponin, increased BNP, electrocardiographic changes, changes in segmental contraction, pericardial effusion, and left ventricular dysfunction on echocardiogram, with normal coronary angiography approximately one week after having presented fever and dry cough; magnetic resonance demonstrated biventricular myocardial interstitial edema, and diffuse late gadolinium enhancement suggesting diagnosis of myocarditis. The patient required inotropic support, and she showed clinical and laboratorial improvement after one week after treatment.

Hu et al.56 described a patient with chest pain and dyspnea for three days, as well as increased troponin and BNP, electrocardiographic changes, changes in segmental contraction, pericardial effusion, and left ventricular dysfunction, with normal coronary angiography. Upon admission, he had hypotension with clinical picture suggestive of fulminant myocarditis. He was treated with hemodynamic support (vasopressor and inotropic drugs) and methylprednisolone associated with human immunoglobulin. After three weeks of treatment, the patient evolved with complete recovery of ventricular function and normalized markers of myocardial injury.

In short, it seems clear that there is an association between the presence of myocardial injury, identified by increased troponin, and worse prognosis in patients with COVID-19. In relation to diagnosis of myocarditis, as defined by elevated markers, associated with a suggestive clinical picture and compatible alterations on cardiac imaging exams, some case reports have been described in patients with COVID-19, but without biopsy data confirming the cause of myocarditis.

In this manner, considering that SARS-CoV-1 and SARS-CoV-2 infect cells through ACE-2, a membrane protein present in myocardial cells, it is possible that this mechanism is also responsible for myocarditis in patients diagnosed with COVID-19. However, more evidence is needed to prove this association.

 Conclusion

Myocardial and pericardial involvement (strokes/pericarditis) is common in severe phases of COVID-19. Acute myocardial involvement has been described as acute cardiac injury, induced by a possible “inflammatory cytokine storm,” which may or may not cause cardiomyocyte necrosis.

Rare cases of mild inflammatory infiltrate and the presence of the virus in inflammatory cells of the cardiac interstice and the endothelial cells of coronary microcirculation have been precisely described, confirming the real histological presence of viral myocarditis, but, to date, the coronavirus has not been described inside the cardiomyocyte. The state of adrenergic response and myocardial inflammation may explain the occurrence of the phenotypic pattern of takotsubo syndrome.

In summary, high degree of clinical suspicion, characterized by chest pain, hemodynamic changes and/or changes in ST/Te arrhythmias (ECG), associated with morphofunctional abnormalities in cardiac imaging methods, and increased cardiac troponin, represent the pillars of clinical reasoning for the presence of acute myocardial aggression in the current coronavirus pandemic.

Furthermore, cardiac monitoring has become necessary for these patients, given that, in light of the current knowledge, we do not know whether or not they may progress with late myocardial dysfunction.

Study Association

This study is not associated with any thesis or dissertation.

Sources of Funding

There was no external funding source for this study.