ABC HFABC: Heart Failure & CardiomyopathyABC Heart Fail Cardiomyop2764-3107Sociedade Brasileira de Cardiologia - SBCabchf.2023001510.36660/abchf.20230015ViewpointPost-COVID-19 Cardiomyopathy in Children and Adults: Fact or Fiction?SilvaAnna Esther Araujo e12Conceptiondesign of the researchWriting of the manuscriptAcquisition of dataAnalysis and interpretation of the dataCritical revision of the manuscript for important intellectual content0000-0001-7935-7966TorbeyAna Flavia Malheiros1Analysis and interpretation of the dataCritical revision of the manuscript for important intellectual content0000-0002-5969-8226SouzaAurea Lucia Alves de Azevedo Grippa de1Acquisition of dataCritical revision of the manuscript for important intellectual contentUniversidade Federal FluminenseHospital Universitário Antônio PedroNiteróiRJBrazilUniversidade Federal Fluminense Hospital Universitário Antônio Pedro, Niterói, RJ – BrazilHospital Getúlio Vargas FilhoNiteróiRJBrazilHospital Getúlio Vargas Filho, Niterói, RJ – BrazilMailing Address: Anna Esther Araujo e Silva • Universidade Federal Fluminense Hospital Universitário Antônio Pedro – Rua Marquês do Paraná, 303. Postal Code 24033-900, Niterói, RJ – Brazil. E-mail: annaesther.silva@gmail.com
Potential conflict of interest
No potential conflict of interest relevant to this article was reported.
17082023202331e20230015240320231106202320062023This is an open-access article distributed under the terms of the Creative Commons Attribution LicenseKeywordsCardiomyopathiesCOVID-19ChildAdult
Since the emergence of the novel coronavirus 2019 disease (COVID-19), cardiovascular impairment and alterations in cardiology laboratory tests suggestive of myocardial injury, even in patients without cardiovascular symptoms, have been observed in hospitalized children and adults.1–4
Epidemiological data from China have suggested that cardiac injury may occur in 19% to 28% of hospitalized patients with COVID-19.5 Several factors seem to contribute to myocardial damage, and potential mechanisms of injury include: hypoxic injury, stress cardiomyopathy, ischemic lesion caused by cardiac microvascular dysfunction, small vessel cardiac vasculitis, endotheliitis, epicardial coronary artery disease, right heart distention (acute cor pulmonale with pulmonary embolism), myocarditis, systemic inflammatory response syndrome (cytokine storm), and others 3,4 (Figure 1).
Potential mechanisms of myocardial injury in COVID-19. DIC: disseminated intravascular coagulation; MI: myocardial infarction. Source: Figure adapted from Atri D, Siddiqi HK, Lang J et al. COVID-19 for the Cardiologist: Basic Virology, Epidemiology, Cardiac Manifestations, and Potential Therapeutic Strategies. JACC Basic Transl Sci. 2020;5(5):518–536. <ext-link ext-link-type="uri" xlink:href="https://doi:10.1016/j.jacbts.2020.04.002">https://doi:10.1016/j.jacbts.2020.04.002</ext-link>.
Cases of myocarditis after infection with the SARS-CoV-2 virus have been reported in the literature, including cases of fulminant myocarditis, and their true incidence is still difficult to establish. The main theories indicate direct action of the virus or hyperimmune response. The first endomyocardial biopsy-proven case that satisfied the Dallas criteria for myocarditis was consistent with virus-negative lymphocytic myocarditis, suggestive of immune-mediated pathogenesis. On the other hand, the first report of myocarditis due to COVID-19 corroborated by histological evidence of direct infection of the cardiomyocyte by SARS-CoV-2 was associated with limited myocyte necrosis, supporting the hypothesis of a hyperinflammatory response involving the myocardium, rather than direct loss of cardiomyocytes due to viral infection.5–7
Although it is considered a separate entity from post-COVID-19 myocarditis, it is important to note the occurrence of myopericarditis following COVID-19 messenger RNA (mRNA) vaccination. Cases are rare, occurring more frequently in male adolescents and young adults within 7 days after receiving the second dose of the vaccine.8 Most patients evolve favorably, with signs of clinical and laboratory improvement, with or without treatment. A meta-analysis published in 2022 showed that the risk of myocarditis is 7 times greater in people infected with SARS-CoV-2 than in those who have received the vaccine, demonstrating that it is recommendable to use mRNA vaccines in people who are eligible, according to current recommendations.9
Adults, children, and adolescents can also develop a late form of multisystem inflammatory disease temporally related to prior exposure to SARS-CoV-2, which can lead to severe cardiac impairment, including fulminant myocarditis. This situation, known as multisystem inflammatory syndrome in children (MIS-C) or multisystem inflammatory syndrome in adults (MIS-A), occurs days to weeks after a patient becomes ill with COVID-19.7,10–13
MIS-C is considered a rare, albeit severe post-inflammatory complication that can cause acute myocardial dysfunction, arrhythmias, conduction abnormalities, and coronary artery dilation. The outcome of MIS-C is generally very favorable, with resolution of inflammation and cardiovascular abnormalities within 1 to 4 weeks of diagnosis. Mortality is also rare, with an estimated occurrence in 1.4% to 1.9% of cases. However, some series have reported the progression of coronary artery aneurysms after discharge and the potential for long-term complications.12
MIS-A is less common than MIS-C and more difficult to distinguish from acute COVID-19. However, as in MIS-C, adults with MIS-A seem to recover quickly from severe cardiac complications.13
The long-term cardiovascular effects of patients affected by COVID-19 are still not very well defined, and studies in this regard have appeared in the literature. Some patients infected with SARS-CoV-2 experience cardiac symptoms such as chest pain, dyspnea, fatigue, and palpitations that persist for months after the onset of the illness.14,15
Two studies were published in 2022 with large cohorts of adult patients who had acute COVID-19, with a follow-up of up to 1 year after the illness. Both studies included patients who were hospitalized, patients with outpatient follow-up only, and control groups.16,17
The first study, by Yan Xie et al.,16 used national healthcare databases from the United States Department of Veterans Affairs and demonstrated that the risk and increase in cases of cardiovascular disease at 1 year are high in hospitalized and non-hospitalized patients who survived COVID-19. The cardiovascular diseases found in the study encompass several categories, such as ischemic and non-ischemic heart disease, cardiac arrhythmias, and others. Probable mechanisms of cardiovascular sequelae include direct viral invasion of cardiomyocytes, endothelial cell infection and endotheliitis, transcriptional alteration of multiple cell types in cardiac tissue, complement activation, complement-mediated coagulopathy and microangiopathy, dysregulation of the renin-angiotensin-aldosterone system, persistent hyperactive immune response, autoimmunity, or persistence of the virus in immune-privileged sites, among others. The study provides robust evidence, but it is worth emphasizing that the majority of the study population was composed of White men.
A subsequent publication, by Weijie Wang et al.17 used data from 48 health care institutions in the United States contained in the TriNetX platform (a global platform for collaborative clinical research in health, which collects electronic medical data in real time from several health organizations worldwide). TriNetX currently holds the largest global COVID-19 dataset. The institutions involved in the study were hospitals, primary health care units, or specialists. COVID-19 survivors had a higher risk of cardiovascular complications (cerebrovascular complications, arrhythmias, inflammatory or ischemic heart disease, and thromboembolic disorders) than those in the control group. The risks of two composite endpoints, major adverse cardiac events and any cardiovascular complication, were also higher in COVID-19 survivors. The risks of cardiovascular complications were evident in both the male and the female sex. These findings could be justified by irreversible damage previously caused to the cardiovascular or cerebrovascular system during SARS-CoV-2 infection; damage to the respiratory system with impaired lung function and systemic hypoxia, causing ischemic heart disease, acute coronary syndrome, and ischemic stroke; hyper-coagulopathy status caused by COVID-19 persisting after recovery from COVID-19, increasing the risks of thromboembolic events and embolism; cytokine storm with damage to various organs, among others. Finally, some drugs eventually used by some individuals with COVID-19, such as hydroxychloroquine and azithromycin, have adverse effects on the cardiovascular system. The authors conclude that the risk of 1-year burden of cardiovascular disease is substantially higher in COVID-19 survivors than in controls and that patients with a history of COVID-19 should be mindful of their long-term cardiovascular health.
In the absence of robust data from clinical trials, with the intention of providing practical guidance related to the evaluation and management of patients whose cardiac symptoms persist after the acute phase of COVID-19, in May 2022, the American College of Cardiology published an Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults.18 The publication aims to serve as a resource for doctors who care for this group of patients, mainly in the outpatient setting, also addressing the return of athletes to physical activities and the management of patients with myopericarditis following COVID-19 mRNA vaccination. As the recommendations reflect current knowledge up to early 2022, the authors recognize that the guidance provided will change over time as understanding of COVID-19 evolves.
It is a fact that COVID-19 is related to myocardial impairment, both in the acute phase and in later periods of the disease, in adults and children. More long-term studies are needed, however. Up to this moment, it seems to be important to include cardiovascular health in the line of care for patients with acute COVID-19 or patients who have survived this condition.
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There were no external funding sources for this study.
Study association
This study is not associated with any thesis or dissertation work.
Ethics approval and consent to participate
This article does not contain any studies with human participants or animals performed by any of the authors.
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Lancet. 2021;397(10270):220-32. doi: 10.1016/S0140-6736(20)32656-8.XieYXuEBoweBAl-AlyZLong-Term Cardiovascular Outcomes of COVID-19Nat Med202228358359010.1038/s41591-022-01689-3Xie Y, Xu E, Bowe B, Al-Aly Z. Long-Term Cardiovascular Outcomes of COVID-19. Nat Med. 2022;28(3):583-90. doi: 10.1038/s41591-022-01689-3.WangWWangCYWangSIWeiJCLong-Term Cardiovascular Outcomes in COVID-19 Survivors Among Non-Vaccinated Population: A Retrospective Cohort Study from the TriNetX US Collaborative NetworksEClinicalMedicine20225310161910161910.1016/j.eclinm.2022.101619Wang W, Wang CY, Wang SI, Wei JC. Long-Term Cardiovascular Outcomes in COVID-19 Survivors Among Non-Vaccinated Population: A Retrospective Cohort Study from the TriNetX US Collaborative Networks. EClinicalMedicine. 2022;53:101619. doi: 10.1016/j.eclinm.2022.101619.GluckmanTJBhaveNMAllenLAChungEHSpatzESAmmiratiE2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and Other Myocardial Involvement, Post-Acute Sequelae of SARS-CoV-2 Infection, and Return to Play: A Report of the American College of Cardiology Solution Set Oversight CommitteeJ Am Coll Cardiol202279171717175610.1016/j.jacc.2022.02.003Gluckman TJ, Bhave NM, Allen LA, Chung EH, Spatz ES, Ammirati E, et al. 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and Other Myocardial Involvement, Post-Acute Sequelae of SARS-CoV-2 Infection, and Return to Play: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022;79(17):1717-56. doi: 10.1016/j.jacc.2022.02.003.Ponto de VistaMiocardiopatia Pós-COVID-19 em Crianças e Adultos - Fato ou Ficção?SilvaAnna Esther Araujo e12Concepçãodesenho da pesquisaRedação do manuscritoObtenção de dadosAnálise e interpretação dos dadosRevisão crítica do manuscrito quanto ao conteúdo intelectual importante0000-0001-7935-7966TorbeyAna Flavia Malheiros1Análise e interpretação dos dadosRevisão crítica do manuscrito quanto ao conteúdo intelectual importante0000-0002-5969-8226SouzaAurea Lucia Alves de Azevedo Grippa de1Obtenção de dadosRevisão crítica do manuscrito quanto ao conteúdo intelectual importanteNiteróiRJBrasilUniversidade Federal Fluminense Hospital Universitário Antônio Pedro, Niterói, RJ – BrasilNiteróiRJBrasilHospital Getúlio Vargas Filho, Niterói, RJ – BrasilCorrespondência: Anna Esther Araujo e Silva • Universidade Federal Fluminense Hospital Universitário Antônio Pedro – Rua Marquês do Paraná, 303. CEP 24033-900, Niterói, RJ – Brasil. E-mail: annaesther.silva@gmail.com
Desde o surgimento da doença pelo novo coronavírus 2019 (COVID-19), comprometimento cardiovascular e alterações em exames laboratoriais cardiológicos sugestivos de injúria miocárdica, mesmo em pacientes sem sintomatologia cardiovascular, têm sido observados em crianças e adultos hospitalizados.1–4
Dados epidemiológicos chineses sugerem que a injúria cardíaca pode ocorrer em 19% a 28% dos pacientes hospitalizados com COVID-19.5 Vários fatores parecem contribuir para o dano miocárdico e os potenciais mecanismos de injúria incluem: lesão hipóxica, cardiomiopatia por estresse, lesão isquêmica causada por disfunção microvascular cardíaca, vasculite cardíaca de pequenos vasos, endotelite ou doença arterial coronariana epicárdica, distensão do coração direito (cor pulmonale agudo com embolia pulmonar), miocardite, síndrome da resposta inflamatória sistêmica (tempestade de citocinas), entre outras 3,4 (Figura 1).
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: basic virology, epidemiology, cardiac manifestations, and potential therapeutic strategies. JACC Basic Transl. Sci. 2020;5 (5):518-536. <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.jacbts.2020.04.002">https://doi.org/10.1016/j.jacbts.2020.04.002</ext-link>.
Casos de miocardite após infecção pelo vírus SARS-CoV-2, incluindo casos de miocardite fulminante, são relatados na literatura, sendo sua incidência verdadeira ainda difícil de estabelecer. As principais teorias indicam uma ação direta do vírus ou resposta hiperimune. O primeiro caso comprovado por biópsia endomiocárdica, que preenchia os critérios de Dallas para miocardite, foi consistente com miocardite linfocítica vírus-negativa, sugestiva de patogênese imunomediada. Por outro lado, o primeiro relato de miocardite por COVID-19 corroborado por evidência histológica de infecção direta do cardiomiócito pelo SARS-CoV-2 foi associada à necrose limitada de miócitos, apoiando a hipótese de resposta hiper-inflamatória envolvendo o miocárdio, em vez da perda direta de cardiomiócitos por infecção viral.5–7
Apesar de ser considerada uma entidade separada da miocardite pós COVID-19, é importante ressaltar a ocorrência de miopericardite pós vacina de COVID-19 com RNA mensageiro (mRNA). Os casos são raros, ocorrendo com mais frequência em adolescentes e adultos jovens do sexo masculino dentro de 7 dias após receber a segunda dose da vacina.8 A maioria dos pacientes tem boa evolução, com sinais de melhora clínica e laboratorial com ou sem tratamento. Metanálise publicada em 2022 mostrou que o risco de miocardite é 7 vezes maior em pessoas infectadas com o SARS-CoV-2 do que naqueles que receberam a vacina, demonstrando ser recomendável o uso das vacinas mRNA em pessoas elegíveis de acordo com as recomendações vigentes.9
Adultos, crianças e adolescentes também podem desenvolver uma forma tardia de doença inflamatória multissistêmica relacionada temporalmente à exposição prévia ao SARS-CoV-2, que pode levar a comprometimento cardiológico grave, incluindo miocardite fulminante. Esta situação, conhecida como síndrome inflamatória multissistêmica pediátrica (SIM-P) ou síndrome inflamatória multissistêmica do adulto (SIM-A), ocorre dias a semanas após o indivíduo adoecer com COVID-19.7,10–13
A SIM-P é considerada uma complicação pós-inflamatória rara, mas grave, que pode causar disfunção miocárdica aguda, arritmias ou anormalidades de condução e dilatação da artéria coronária. O desfecho da SIM-P é geralmente muito bom, com resolução da inflamação e anormalidades cardiovasculares dentro de 1 a 4 semanas após o diagnóstico. A mortalidade também é rara, com ocorrência estimada em 1,4% a 1,9% dos casos. No entanto, algumas séries relatam a progressão dos aneurismas da artéria coronária após a alta e o potencial de complicações a longo prazo.12
A SIM-A é menos comum que a SIM-P e mais difícil de distinguir do COVID-19 agudo. No entanto, assim como em crianças com SIM-P, adultos com SIM-A parecem se recuperar rapidamente das complicações cardíacas graves.13
Os efeitos cardiovasculares a longo prazo de pacientes acometidos por COVID-19 ainda não estão muito bem definidos e estudos a este respeito têm surgido na literatura. Alguns pacientes infectados com SARS-CoV-2 apresentam sintomas cardíacos como dor torácica, dispneia, fadiga e palpitações que persistem por meses após o início da doença.14,15
Em 2022, foram publicados dois estudos com grande coorte de pacientes adultos que tiveram COVID-19 aguda, com acompanhamento de até 1 ano após a doença. Os dois estudos incluíram pacientes que foram hospitalizados e aqueles que fizeram apenas acompanhamento ambulatorial e grupos controle.16,17
O primeiro estudo (Yan Xie et al.)16 utilizou o Banco de Dados Nacionais de Saúde do Departamento de Assuntos de Veteranos dos Estados Unidos e demonstrou que o risco e o aumento de casos de doença cardiovascular em 1 ano são altos em sobreviventes hospitalizados e não hospitalizados por COVID-19. As doenças cardiovasculares encontradas no estudo abrangem várias categorias, como doença cardíaca isquêmica e não isquêmica, arritmias cardíacas, entre outras. Mecanismos prováveis para a sequela cardiovascular incluem invasão viral direta de cardiomiócitos, infecção de células endoteliais e endotelite, alteração transcricional de vários tipos de células no tecido cardíaco, ativação do complemento, coagulopatia e microangiopatia mediada pelo complemento, desregulação do sistema renina-angiotensina-aldosterona, resposta imune hiperativa persistente, autoimunidade ou persistência do vírus em locais imunoprivilegiados, entre outros. O estudo provê evidências robustas, mas vale enfatizar que a população estudada foi majoritariamente de homens brancos.
Uma publicação posterior, de Weijie Wang et al.17 utilizou dados de 48 instituições prestadoras de cuidados em saúde dos Estados Unidos contidas na plataforma TriNetX (plataforma global de pesquisa clínica colaborativa em saúde, que coleta dados médicos eletrônicos, em tempo real, de várias organizações de saúde no mundo). Atualmente a TriNetX detém o maior conjunto de dados globais de COVID-19. As instituições envolvidas no estudo foram hospitais, unidades de cuidados primários em saúde ou especialistas. Sobreviventes da COVID-19 tiveram maior risco de complicações cardiovasculares (complicações cerebrovasculares, arritmias, doença cardíaca inflamatória ou isquêmica e distúrbios tromboembólicos) do que os do grupo controle. Os riscos de dois desfechos compostos, eventos cardíacos adversos maiores e qualquer complicação cardiovascular, também foram maiores nos sobreviventes da COVID-19. Os riscos de complicações cardiovasculares foram evidentes tanto no sexo masculino quanto no feminino. Esses achados poderiam ser justificados por danos irreversíveis causados previamente ao sistema cardiovascular ou cerebrovascular durante a infecção pelo SARS-CoV-2; danos ao sistema respiratório com prejuízo da função pulmonar e hipóxia sistêmica, provocando doença isquêmica do coração, síndrome coronariana aguda, e acidente vascular cerebral isquêmico; estado de hipercoagulopatia causado pelo COVID-19 mantido após a recuperação do COVID-19, aumentando os riscos de eventos tromboembólicos e embolia; tempestade de citocinas com danos a vários órgãos, entre outros. Finalmente, alguns medicamentos eventualmente utilizados por alguns indivíduos com COVID-19, como hidroxicloroquina e azitromicina, têm efeitos adversos no sistema cardiovascular. Os autores concluem que o risco de incidência de doenças cardiovasculares em 1 ano é substancialmente maior nos sobreviventes da COVID-19 do que nos controles e que pacientes com histórico de COVID-19 devem estar atentos à sua saúde cardiovascular a longo prazo.
Na ausência de dados robustos de ensaios clínicos e com a intenção de fornecer orientações práticas relacionadas à avaliação e manejo de pacientes que permanecem com sintomatologia cardiológica após a fase aguda da COVID-19, em maio de 2022, o Colégio Americano de Cardiologia publicou um Consenso de Especialistas sobre o Caminho de Decisão em Sequelas Cardiovasculares de COVID-19 em Adultos.18 Essa publicação objetiva servir como recurso para médicos que cuidam desse grupo de pacientes, principalmente no contexto ambulatorial, abordando também a volta de atletas a atividades físicas e o manejo de indivíduos com miopericardite pós-vacina contra COVID-19 de mRNA. Como as recomendações refletem conhecimentos vigentes até o início de 2022, os autores reconhecem que tais orientações mudarão com o tempo, à medida que o entendimento sobre a COVID-19 evoluir.
É fato que a COVID-19 está relacionada ao comprometimento miocárdico, tanto na fase aguda como em períodos mais tardios da doença, em adultos e crianças. Porém, mais estudos de longo prazo são necessários. Até o momento parece ser importante incluir na linha de cuidado dos pacientes com COVID-19 aguda, ou que sobreviveram a esta condição, a atenção à saúde cardiovascular.
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