Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC n4QkFjtFmRgJpCmvzhxbX9k S0066-782X2022005010202 S0066-782X2022000800267 abc.20210485 10.36660/abc.20210485 Artigo Original Achados Ecocardiográficos Anormais em Pacientes Internados com Covid-19: Uma Revisão Sistemática e Metanálise 0000-0002-0711-7995 Barberato Silvio Henrique 1 2 Bruneto Eduardo G. 3 Reis Gabriel S. 4 0000-0001-5947-7880 Oliveira Paula Rauen Franco de 5 Possamai Alexandre F. 5 Silvestre Odilson 3 Silva Miguel M. Fernandes 4 Centro de Diagnóstico Cardiovascular Curitiba PR Brasil CardioEco Centro de Diagnóstico Cardiovascular, Curitiba, PR – Brasil Quanta Diagnóstico, Ecocardiografia Curitiba PR Brasil Quanta Diagnóstico, Ecocardiografia,Curitiba, PR – Brasil Universidade Federal do Acre Rio Branco AC Brasil Universidade Federal do Acre, Rio Branco, AC – Brasil Universidade Federal do Paraná Curitiba PR Brasil Universidade Federal do Paraná, Curitiba, PR – Brasil Pontifícia Universidade Católica do Paraná Curitiba PR Brasil Pontifícia Universidade Católica do Paraná, Curitiba, PR – Brasil Correspondência: Silvio Henrique Barberato • CardioEco Centro de Diagnóstico Cardiovascular – Avenida República Argentina, 1336, conj 215. CEP 80620-010, Curitiba, PR – Brasil E-mail: silviohb@cardiol.br

Contribuição dos autores

Concepção e desenho da pesquisa: Silvio Henrique Barberato, Eduardo G. Bruneto, Odilson Silvestre, Miguel M. Fernandes Silva; Obtenção de dados e Redação do manuscrito: Silvio Henrique Barberato, Eduardo G. Bruneto, Gabriel S. Reis, Paula Rauen Franco de Oliveira, Alexandre F. Possamai, Miguel M. Fernandes Silva; Análise e interpretação dos dados: Silvio Henrique Barberato, Eduardo G. Bruneto, Gabriel S. Reis, Paula Rauen Franco de Oliveira, Alexandre F. Possamai, Odilson Silvestre, Miguel M. Fernandes Silva; Análise estatística: Silvio Henrique Barberato, Eduardo G. Bruneto, Miguel M. Fernandes Silva; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Silvio Henrique Barberato, Odilson Silvestre, Miguel M. Fernandes Silva.

Potencial Conflito de Interesse

Declaro não haver conflito de interesses pertinentes.

 11 07 2022 08 2022 119 2 267 279 08 06 2021 12 10 2021 08 12 2021 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Resumo Fundamentos

A doença do coronavírus 2019 (Covid-19) pode levar à insuficiência respiratória grave e lesão cardíaca aguda, mas não está claro com que frequência ela pode causar disfunção cardíaca.

 Objetivos

Nesta revisão sistemática, nosso objetivo foi resumir os principais achados ecocardiográficos em pacientes com Covid-19.

 Métodos

Conduzimos uma busca sistemática nos bancos de dados PUBMED, EMBASE, LILACS e Cochrane, além de artigos não pulicados ( preprints ) no MedRxiv e Scielo desde o início até 21 de julho de 2021. Foram incluídos estudos que apresentaram dados ecocardiográficos de pacientes com Covid-19. Características demográficas, doença cardiovascular (DCV) prévia, e achados ecocardiográficos foram extraídos dos estudos. Realizamos uma metanálise de proporções para estimar os principais achados ecocardiográficos. O nível de significância foi p<0,05.

 Resultados

Do total de 11 233 estudos, 38 preencheram os critérios de inclusão e foram incluídos na metanálise. A proporção estimada de disfunção sistólica do ventrículo esquerdo (VE) foi 25% (IC95%: 19, 31; I2 93%), strain longitudinal global anormal 34% (IC95% 23, 45; I2 90%), disfunção sistólica do ventrículo direito (VD) 17% (IC95% 13, 21; I2 90%), derrame pericárdico 17% (IC95%: 9, 26; I2 97%), e hipertensão pulmonar 23% (IC95%: 15, 33, I2 96%). Disfunção sistólica do VE foi diretamente associada com prevalência de ecocardiograma anormal prévio nos estudos (p<0,001). A proporção de pacientes em ventilação mecânica, indicando gravidade da doença, não explicou a heterogeneidade nas proporções de disfunção do VE (p=0,37).

 Conclusão

Entre os pacientes internados com Covid-19, a disfunção ventricular esquerda foi descrita em um quarto dos pacientes, com menores proporções de disfunção do ventrículo direito, derrame pericárdico e hipertensão pulmonar. No entanto, houve uma proporção mais alta de disfunção do VE nos estudos que relataram presença de doença cardíaca prévia, sugerindo que a disfunção cardíaca era predominantemente pré-existente.

 Ecocardiografia Covid-19 Miocardite Função Ventricular Esquerda Introdução

A Doença do Coronavírus 2019 (Covid-19), causada pelo novo coronavírus da síndrome respiratória aguda grave (SARS-CoV-2), pode resultar em insuficiência respiratória grave e lesão cardíaca aguda. Níveis elevados de troponina e exames de imagem mostrando uma função cardíaca anormal foram associados a um pior prognóstico em pacientes com Covid-19 aguda.1 O pior prognóstico pode resultar de uma combinação de fatores relacionados à doença, tais como virulência e resposta inflamatória, e fatores relacionados ao paciente, como fatores de risco cardiovascular e doença cardiovascular (DCV) pré-existentes. Por isso, tem-se recomendado avaliar a função cardíaca por ecocardiografia transtorácica (ETT) para o direcionamento no manejo dos pacientes com sintomas cardiovasculares novos ou progressivos, instabilidade hemodinâmica, e níveis elevados de biomarcadores.2

No início da pandemia, existiram relatos infundados da ocorrência de insuficiência cardíaca (IC) e miocardite fulminante em pacientes com Covid-19.3 , 4 Estudos utilizando ressonância magnética cardíaca mostraram que evidência de inflamação do miocárdio em atletas de elite, que recentemente se recuperaram de Covid-19 era comum, porém sem significância clínica.5 Contudo, estudos mais recentes mostraram que a ocorrência de miocardite é bem menos comum (menos que 2%) que a sugerido anteriormente, mesmo em pacientes com níveis elevados de troponina.6 , 7 Também não se sabe com que frequência a Covid-19 afeta a função cardíaca, seja por lesão direta no miocárdio ou por aumento da resistência pulmonar quando os pulmões estão gravemente comprometidos. Estudos ecocardiográficos têm apresentado achados variáveis de disfunção ventricular direita e esquerda; por exemplo, a disfunção sistólica do ventrículo esquerdo (VE) tem sido identificada em menos de 10% dos pacientes em alguns estudos, e em quase 40% em outros.8 , 9 Ainda faltam estudos amplos, mostrando estimativas precisas da incidência de disfunção cardíaca significativa, sua importância clínica, e fatores de risco associados. Dado o risco de contaminação dos profissionais de saúde, o uso de ecocardiografia deve ser criticamente baseado nos benefícios para o paciente.10 Portanto, nosso objetivo foi resumir os principais achados ecocardiográficos de pacientes com Covid-19 por meio de uma revisão sistemática e metanálise.

 Métodos Delineamento do estudo e critérios de elegibilidade

Nós conduzimos uma revisão sistemática, seleção de estudos e metanálise de proporções de acordo com as recomendações PRISMA para metanálise.11 Incluímos todos os estudos com pelo menos 10 participantes, descrevendo os achados ecocardiográficos em pacientes hospitalizados por Covid-19, publicados em inglês, português ou espanhol, até 21 de julho de 2021. Estudos que não apresentaram achados ecocardiográficos foram excluídos. Também excluímos resumos não publicados, estudos faltando informações clínicas basais dos pacientes, ou dados ecocardiográficos insuficientes para se obter o número de participantes com função ou estrutura cardíaca anormal.

 Fontes e busca de informações

Realizamos uma busca sistemática nos bancos de dados PUBMED, EMBASE, LILACS e Cochrane (CENTRAL). Também buscamos artigos no repositório de artigos não publicados ( preprints ) nos bancos de dados do MedRxiv (https://www.medrxiv.org/) e Scielo. Para a busca, usamos os termos “Covid-19”, “SARS CoV 2”, “Coronavirus infection”, “Heart Diseases” e “Echocardiography” como descritores (Medical Subject Headings – MeSH) ou conceito suplementar ( supplementary concept ) e sinônimos como texto livre nos títulos e resumos para aumentar a sensibilidade. A estratégia de busca de artigos completos está descrita no material suplementar (Tabela Suplementar 3).

 Seleção de estudos e extração de dados

Combinamos os resultados de busca de cada banco de dados usando o programa EndNote, removendo os estudos duplicados. Quatro autores (EB, GR, PO, AP) avaliaram independentemente títulos e resumos para excluir artigos sem relevância. Os textos completos de artigos potencialmente relevantes foram examinados e os estudos que preencheram os critérios de elegibilidade foram selecionados. Artigos diferentes, derivados dos mesmos estudos foram associados, e aquele com a maior amostra foi selecionado. Discrepâncias foram solucionadas por consenso. As referências dos artigos de revisão foram examinadas quanto a outros estudos, e aqueles considerados elegíveis foram incorporados na metanálise.

Os seguintes dados foram extraídos dos estudos: nomes dos autores, mês de publicação, ecocardiograma anormal dos pacientes, tamanho amostral dos pacientes submetidos à ecocardiografia, e número de indivíduos com disfunção sistólica no VE, disfunção sistólica no ventrículo direito (VD), hipertensão pulmonar, e derrame pericárdico. As definições de cada estudo para cada anormalidade ecocardiográfica encontram-se detalhadas na Tabela Suplementar 2. Quando a disfunção sistólica não foi claramente definida pelos autores, nós adotamos uma fração de ejeção do VE (FEVE) inferior a 50%. Strain longitudinal global (GLS) anormal foi definido como inferior a 18%. Disfunção ventricular direita foi determinada conforme definição usada em cada estudo e, em sua ausência, adotamos a excursão sistólica do plano anular tricúspide (TAPSE) inferior a 17 mm e/ou Doppler tecidual da parede livre do VD (S’) menor que 9,5 cm/s. Hipertensão pulmonar foi definida por velocidade de regurgitação tricúspide acima de 2,8 cm/s, tempo de aceleração pulmonar abaixo de 100 ms e/ou pressão sistólica na artéria pulmonar (PSAP) acima de 35mmHg. (Tabela Suplementar 2). Somente dois estudos definiram hipertensão pulmonar por diferentes pontos de cortes para PSAP: um acima de 40 mmHg,12 e um acima de 45 mmHg.13 O número de pacientes com disfunção ventricular esquerda ou direita foi estimado usando a FEVE média e desvio padrão respectivo (ou intervalo de confiança de 95%), conforme recomendado previamente para extração de dados nas revisões sistemáticas. Todos os dados foram organizados em uma tabela usando o programa Excel.

 Fontes hipotéticas de heterogeneidade

Devido à variação das características dos pacientes entre os estudos, esperamos uma heterogeneidade importante entre eles. Decidimos avaliar a gravidade da doença usando a proporção de indivíduos em ventilação mecânica e história de DCV (IC ou doença arterial coronariana). Utilizamos a estatística I 2 para identificar heterogeneidade, e meta-regressão, adotando essas características como potenciais modificadores dos achados ecocardiográficos anormais.

 Avaliação de qualidade

Usamos uma ferramenta descrita anteriormente para avaliar a qualidade metodológica de estudos observacionais, adaptada para relatos de caso e séries de casos.14 Para cada estudo, os revisores responderam as seguintes questões para avaliar se preenchiam os critérios de qualidade:

- Seleção: Os pacientes representam toda a experiência do investigador (centro) ou o método de seleção não é suficientemente claro, de modo que outros pacientes com apresentação similar podem não ter sido estudados?

- Determinação da exposição: A exposição foi definida adequadamente?

- Exclusão das causas alternativas: Outras causas alternativas que poderiam explicar a observação foram excluídas?

- Seguimento adequado: A ecocardiografia foi realizada no momento mais crítico do paciente durante sua internação?

- Detalhamento suficiente: O caso é descrito com detalhamento suficiente para que outros investigadores possam replicar a pesquisa ou outros profissionais possam fazer inferências em suas práticas?

Foram utilizados gráficos de funil para avaliar viés de publicação, uma vez que publicações de relatos de casos de achados cardíacos anormais são mais comuns. Os gráficos foram construídos traçando tamanho da amostra versus log odds ratio de cada desfecho, conforme proposto anteriormente na avaliação de viés de publicação de estudos não comparativos de proporções.15

 Análise estatística

Conduzimos uma metanálise de proporções para estimar a proporção de disfunção sistólica do VE, disfunção sistólica do VD, hipertensão pulmonar e efusão pericárdica em pacientes com Covid-19 aguda. Para avaliar se DCV prévia e a gravidade da doença influenciaram a proporção de achados ecocardiográficos anormais, realizamos uma meta-regressão usando a prevalência de DCV e a proporção de pacientes em ventilação mecânica em cada estudo. O nível de significância adotado foi p<0,05.

Dada a variabilidade esperada nos estudos selecionados, realizamos uma metanálise de efeitos aleatórios com transformação do arco seno duplo de Freeman-Tukey para detectar qualquer violação da presunção de normalidade nessa variável. A heterogeneidade foi avaliada pela estatística I2. A metanálise foi realizada usando o programa Stata ( StataCorp . College Station, Texas) versão 15.0.

 Resultados Resultados da busca

A busca inicial resultou em 11 233 títulos, e o número final após exclusão dos artigos duplicados foi 7550 ( Figura 1 ). Desses, 318 eram estudos potencialmente relevantes e os respectivos textos completos foram analisados quanto à elegibilidade, e 38 estudos foram considerados elegíveis e incluídos na metanálise ( Tabela 1 ).

Fluxograma da seleção dos estudos para a metanálise.

Características dos estudos incluídos na metanálise
Primeiro autor (Mês Ano) País Características da população Amostra com ecocardiograma Idade média Homens, % Obesidade % Hipertensão % Diabetes, % DCV prévia, % IC prévia,% ECO anormal prévio,% % Ventilação mecânica%
Deng (Março2020) 8 China Pacientes internados com Covid-19 112 65 51 37 32 17 13 4 4 25
Li (Abril2020) 16 China Pacientes com Covid-19 com ecocardiograma 120 61 48 18 40 12 9 0 0 13
Bangalore (Abril2020) 29 EUA Pacientes com Covid-19 com ecocardiograma 17 63 83 NR 61 33 17 NR 50 67
Rath (Maio2020) 18 Alemanha Pacientes internados com Covid-19 98 68 63 20 70 24 23 NR NR 40
Ge (Maio2020) 30 China Pacientes com Covid-19 na UTI 51 70 73 NR 43 31 31 8 NR 41
Evrard (Maio2020) 31 França Pacientes com Covid-19 em ventilação mecânica 18 70 67 NR 61 22 NR NR NR 100
Szekely (Maio2020) 19 Israel Pacientes internados com Covid-19 100 66,1 63 29 57 29 16 7 2 10
Stefanini (Junho2020) 32 Itália Pacientes com Covid-19 com STEMI 28 68 71 4 71 32 21 NR NR 0
Dweck (Junho2020) 9 69 países Pacientes com Covid-19 com ecocardiograma 1216 62 69 NR 37 19 20 9 NR 0
Vasudev (Junho2020) 33 EUA Pacientes com Covid-19 com ecocardiograma 45 61,4 51 NR 64 56 27 24 9 NR
Lazzeri (Julho2020) 13 Itália Pacientes internados com Covid-19 28 61 79 61 89 39 29 NR NR 86
Rodríguez-Santamarta (Julho2020) 34 Espanha Pacientes com Covid-19 na UTI 37 67,6 92 NR NR NR 5 0 NR NR
van den Heuvel (Julho2020) 17 Holanda Pacientes internados com Covid-19 51 63 80 0 41 18 22 0 18 33
Stöbe (Agosto2020) 35 Alemanha Pacientes com Covid-19 com ecocardiograma 18 64 78 NR 72 28 11 NR NR 78
Giustino (Agosto2020) 36 EUA Pacientes internados com Covid-19 118 66 100 NR NR NR NR NR NR NR
Krishnamoorthy (Agosto2020) 37 EUA Pacientes com Covid-19 com ecocardiograma 12 57 42 42 58 33 17 NR NR 42
Schott (Agosto2020) 38 EUA Pacientes com Covid-19 com ecocardiograma 66 60 58 86 58 35 NR 11 6 35
Sud (Agosto2020) 22 EUA Pacientes com Covid-19 com ecocardigrama 24 64,5 54 NR NR NR NR 8 8 42
Duerr (Setembro2020) 39 Alemanha Pacientes internados com Covid-19 19 69 47 NR 63 26 37 NR NR NR
Kunal (Outubro2020) 40 Índia Pacientes com Covid-19 sintomáticos 28 51 65 NR 38 32 13 1 NR 23
Lassen (Outubro2020) 26 Dinamarca Pacientes com Covid-19 com ecocardiograma 214 69 55 18 57 24 16 10 NR 0
Jain (Outubro2020) 20 EUA Pacientes com Covid-19 com ecocardiograma 77 61 7 5 6 4 2 2 NR 5
Lairez (Outubro2020) 41 França Pacientes internados com Covid-19 31 57 87 23 48 32 NR NR NR 68
Weckbach (Novembro2020) 42 Alemanha Pacientes internados com Covid-19 e lesão no miocárdio 18 70 89 NR 78 39 39 6 NR 50
Argulian (Novembro2020) 43 EUA Pacientes internados com Covid-19 105 66 61 NR NR NR NR NR NR 28
Gonzalez (Dezembro2020) 44 Portugal Covid-19 Pacientes na UTI com Covid-19 30 61 NR 53 73 30 NR NR NR 23
Ferrante (Dezembro2020) 45 Itália Pacientes com Covid-19 com TC de tórax 21 67 71 NR 54 21 15 NR NR 20
Bagate (Dezembro2020) 12 França Pacientes na UTI com Covid-19 67 61 82 31 54 36 NR 10 NR 99
Shmueli (Janeiro2021) 46 EUA Pacientes com Covid-19 com ecocardiograma 60 66,2 65 17 47 27 17 13 NR 32
Moody (Janeiro2021) 47 Reino Unido Pacientes com Covid-19 com ecocardiograma 164 61 78 NR 41 32 13 NR NR 73
Pishgahi (Fevereiro2021) 48 Irã Pacientes com Covid-19 com ecocardiograma 680 55 63 NR 44 25 16 NR NR NR
Morin (Março2021) 49 EUA Pacientes com Covid-19 com ecocardiograma 396 67 48 NR 58 31 NR NR NR 21
Norderfeldt (Março2021) 50 Suécia Pacientes com Covid-19 na UTI 67 58 94 NR NR NR NR NR NR 100
Li (Março2021) 51 China Pacientes internados com Covid-19 157 62 50 15 45 15 17 3 NR 24
Liaqat (Março2021) 52 Paquistão Pacientes internados com Covid-19 181 44 59 5 17 17 NR NR NR 28
Mercedes (Abril2021) 53 República Dominicana Gestantes com Covid-19 15 29 0 33 0 NR 0 0 NR 0
Karagodin (Maio2021) 54 10 países Pacientes internados com Covid-19 870 60 56 NR 43 20 14 7 NR 27
Barberato (Julho2021) 23 Brasil Pacientes internados com Covid-19 223 61,4 59 27 52 35 13 7 NR NR

Todos os estudos adotaram um nível de significância de 5% para teste de hipóteses. UTI: Unidade de Terapia Intensiva.

Achados ecocardiográficos nos pacientes com Covid-19

No geral, a proporção de disfunção sistólica do VE foi 25% (IC95%: 19, 31; I293%; Figura 2 ), embora a heterogeneidade entre os estudos tenha sido alta. Tal heterogeneidade não pôde ser explicada nem pela prevalência de DCV prévia de cada estudo ( Figura 2 , p para interação = 0,16), nem pela proporção de cada estudo dos pacientes em ventilação mecânica (Figura Suplementar 1, p para interação = 0,37). Entre os estudos que apresentaram dados ecocardiográficos antes da infecção por SARS-CoV2, encontramos uma relação direta entre ecocardiograma anormal prévio e proporções de disfunção do VE (Figura Suplementar 3, p para interação < 0,001).

Proporção de disfunção ventricular esquerda em pacientes com Covid-19 nos estudos, de acordo com a prevalência de doenças cardiovasculares. DCV: doenças cardiovasculares. * Os estudos foram divididos de acordo com a porcentagem de pacientes com DCV: tercil mais alto (menos que 15%), tercil médio (15-21%) e tercil superior (>21%).

Disfunção sistólica do VD esteve presente em 17% (IC95% 13, 21; I290%; Figura 3 ) dos pacientes com Covid-19. Contudo, apesar da alta heterogeneidade, DCV prévia (p=0,53), hipertensão pulmonar (p=0,96) e ventilação mecânica (p=0,65) não explicaram a variação na proporção de disfunção do VD entre os estudos ( Figura 3 , Figuras Suplementares 2 e 4).

Proporção de disfunção ventricular direita em pacientes com Covid-19 nos estudos, de acordo com a prevalência de doenças cardiovasculares. DCV: doenças cardiovasculares. * Os estudos foram divididos de acordo com a porcentagem de pacientes com DCV: tercil mais alto (menos que 15%), tercil médio (15-21%) e tercil superior (>21%).

Hipertensão pulmonar foi observada em 23% (IC95%: 15, 33, I2 96%; Figura 4 ) e derrame pericárdico em 17% (IC95%: 9, 26; I297%; Figura 5 ) dos pacientes com Covid-19. Contratilidade segmentar anormal da parede do VE foi relatado em 23% (IC95% 12, 38; I2 96%; Figura 6 ) em pacientes com Covid-19. O GLS foi anormal em 34% (IC95% 23, 45; I290%) dos pacientes com Covid-19 (Figura 7 ).

Proporção de hipertensão pulmonar em pacientes com Covid-19.

Proporção de derrame pericárdico em pacientes com Covid-19.

Proporção de anormalidade na motilidade regional do ventrículo esquerdo em pacientes com Covid-19.

Proporção de strain longitudinal global do ventrículo esquerdo anormal em pacientes com Covid-19.

Viés de publicação

Avaliamos potencial viés de publicação de estudos relatando disfunção sistólica do VE, disfunção sistólica do VD, derrame pericárdico, e hipertensão pulmonar. A análise visual do gráfico de funil sugere viés de publicação dos estudos relatando disfunção sistólica do VD, com uma maior probabilidade de estudos pequenos relatarem uma maior proporção do desfecho (Figura Suplementar 5).

 Discussão

Nesta revisão sistemática de achados ecocardiográficos em pacientes com Covid-19, encontramos que as proporções estimadas de disfunção sistólica do VE foram 25%, disfunção sistólica do VD 17%, hipertensão pulmonar 23%, e derrame pericárdico 17%. GLS, que é mais sensível para detectar disfunção ventricular esquerda subclínica, foi anormal em 34% dos pacientes com Covid-19. Independente do método, os achados da disfunção sistólica variaram consideravelmente, com menores proporções em estudos relatando proporcionalmente menos indivíduos com ecocardiograma anormal prévio.

Os achados ecocardiográficos em pacientes com Covid-19 têm sido bem heterogêneos. A prevalência de disfunção sistólica do VE, disfunção do VD, e dilatação do VD variou de 5,48 a 37,4%,9 3,68 a 33%,16 e 017 a 46.9%,18 respectivamente. Enquanto a maioria dos estudos destacaram a disfunção e/ou dilatação do VD como a alteração ecocardiográfica mais frequente,19 outros relataram a disfunção sistólica do VE como a alteração mais prevalente.8 , 9 Os resultados contraditórios acerca da prevalência e das consequências das alterações ecocardiográficas em pacientes com Covid-19 podem ser explicados por vários fatores. Amostras relativamente pequenas, viés de referência, protocolos diferentes de ETE, definições imprecisas das anormalidades ecocardiográficas, e diferenças nas características das populações, tais como proporção de pacientes em ventilação mecânica, e/ou DCV prévia, podem ter levado às conclusões amplamente variadas a respeito das manifestações cardíacas da Covid-19. Na busca por fontes de heterogeneidade, alguns pontos interessantes devem ser mencionados em nosso estudo. Quando separamos os estudos pela proporção de pacientes em ventilação mecânica (como um indicador de gravidade da doença), as proporções de disfunção do VE e do VD não mudaram. Quando analisamos uma população composta por indivíduos mais sadios (o tercil mais baixo de prevalência de DCV prévia), a proporção de pacientes com disfunção do VE tendeu a ser menor, mas essa diferença não foi estatisticamente significativa. Por outro lado, é possível que elevadas proporções de achados ecocardiográficos anormais no início da pandemia reflitam disfunção do VE prévia, uma vez que encontramos uma proporção mais alta de disfunção do VE nos estudos descrevendo proporcionalmente mais indivíduos com ecocardiograma prévio anormal. Uma análise do Registro Brasileiro de Ecocardiografia mostrou que os pacientes com Covid-19 sem DCV prévia tinham menor probabilidade de apresentar disfunção sistólica do VE que pacientes sem DCV prévia (13 vs. 34%, p <0,001).23

O estudo de Dweck et al.9 foi o primeiro (e o maior) a mostrar que anormalidades ecocardiográficas eram muito comuns em pacientes internados com Covid-19. Utilizando um inquérito online que coletou dados de 1216 pacientes (26% com DCV pré-existente) de 69 países, os autores encontraram que mais da metade dos pacientes (55%) apresentaram um ETE anormal. Os indivíduos com achados ecocardiográficos anormais eram mais velhos, e tinham uma maior prevalência de DCV pré-existente, IC ou doença valvular cardíaca. Disfunção sistólica do VE, de qualquer grau, foi diagnosticado em 37,4% dos indivíduos, e disfunção biventricular em 14,3%. Por outro lado, somente 3% tinham evidência de um novo infarto do miocárdio, 3% de miocardite, e 2% de achados sugestivos de síndrome de Takotsubo. O estudo foi limitado por viés de seleção, o que pode ter levado à superestimação dos achados cardíacos.

A fim de minimizar os vieses de referência, Szekely et al.19 realizaram sistematicamente ETE em 100 pacientes consecutivos internado por Covid-19, 43% deles com DCV prévia. Os autores encontraram que a disfunção/dilatação do VD foi a anormalidade mais frequente (39%), enquanto uma minoria (10%) apresentou disfunção sistólica do VE.19 Ainda, pacientes com Covid-19 com injúria miocárdica ou uma pior condição clínica não apresentaram diferença significativa na função sistólica do VE, mas apresentaram pior função do VD em comparação a pacientes sem injúria miocárdica ou com melhor condição clínica. A maior prevalência de disfunção do VD e pequena proporção de disfunção do VE também foram encontradas em outros estudos menores.20 , 21 , 24 Apesar de a maioria dos estudos desta metanálise não ter claramente identificado a presença de alterações ecocardiográficas pré-existentes, é possível que, em uma pequena parcela dos pacientes, a disfunção sistólica do VE reflita disfunção ventricular esquerda ”nova”, relacionada à Covid-19, particularmente naqueles pacientes sem DCV prévia. Além disso, anormalidades ecocardiográficas podem indicar a presença de doença cardíaca estável pré-existente que tenha piorado por causa de uma infecção por SARS-CoV. Assim, parece que a prevalência de disfunção cardíaca seja mais baixa que a sugerida no início da pandemia. Dados acerca do uso de ecocardiografia em pacientes internados com Covid-19, obtidos de estudos com delineamento, tamanho amostral e escore de gravidade variáveis, mostraram que achados ecocardiográficos normais foram relatados em 50% dos indivíduos, com menor alteração da FEVE.25 De fato, um estudo recente apresentou que disfunção do VE persistente não é comum após Covid-19: em pacientes com níveis elevados de troponina, ressonância magnética cardíaca realizada dois meses após infecção revelou disfunção sistólica do VE em somente 11% dos pacientes, embora um terço deles apresentasse achados sugestivos de miocardite.6

Uma vez que os principais esforços da comunidade científica visam prevenir as consequências graves à saúde da pandemia da Covid-19, tem sido um desafio equilibrar o uso de ecocardiografia a fim de prover cuidado médico de alta qualidade sem aumento no risco de transmissão cruzada entre profissionais da saúde e pacientes. Por outro lado, é importante enfatizar que a presença de disfunção cardíaca associa-se independentemente com um pior prognóstico em pacientes com Covid-19 grave.26 , 27 Parâmetros ecocardiográficos que identificam dano no miocárdio de modo mais precoce e preciso que parâmetros convencionais, tais como GLS bidimensional do VE ou VD, têm sido menos utilizados no contexto da Covid-19 devido às recomendações para se utilizar protocolos direcionados, que reduzem a exposição de profissionais da saúde à infecção. Nossa metanálise mostrou que estudos que avaliaram a função sistólica do VE com GLS detectaram uma maior proporção de pacientes com disfunção do VE em comparação a outros estudos que usaram a FEVE. Uma metanálise publicada recentemente mostrou que um GLS do VE e do VD mais baixos se associaram independentemente com pior desfecho na Covid-19.28

Nosso estudo tem limitações que merecem atenção. A maioria dos estudos estão sujeitos a viés de referência porque os ecocardiogramas foram realizados a critério do médico assistente, que pode ter superestimado a ocorrência de achados ecocardiográficos anormais. A maioria dos estudos teve um delineamento retrospectivo, exceto por um estudo prospectivo no qual ETT foi realizada em pacientes consecutivos internados por Covid-19, independentemente da indicação clínica.19 Ainda, as características dos pacientes e a apresentação da Covid-19 variaram entre os estudos, resultando em uma heterogeneidade considerável. Embora tenhamos avaliado algumas fontes de heterogeneidade, essa manteve-se elevada em alguns subgrupos. Aspectos técnicos relacionados à ecocardiografia, que potencialmente levam a um viés de classificação, e diferentes definições de anormalidades cardíacas podem ser fontes de heterogeneidade. Por exemplo, a avaliação à beira do leito da função do VD e hipertensão pulmonar pode ser limitada em pacientes críticos. Além disso, a maioria dos estudos não relataram a presença de anormalidades cardíacas prévias nem se os achados ecocardiográficos eram novos ou não. Por fim, devido à restrição de idioma em nossa pesquisa, uma possível exclusão de artigos importantes que não foram publicados em português, inglês ou espanhol não pode ser afastada.

 Conclusão

Em pacientes internados com Covid-19, achados ecocardiográficos anormais indicando disfunção do VE foram relatados em um em cada quatro pacientes. Foram detectadas prevalências mais baixas de disfunção do VD e efusão pericárdica, embora a disfunção sistólica do VE possa estar relacionada à doença cardíaca prévia. De fato, encontramos uma associação direta entre ecocardiograma anormal prévio e as frequências de disfunção do VE no subgrupo de estudos que relataram resultados de ecocardiografia prévios, o que fornece insights que podem ajudar no planejamento de estudos ecocardiográficos na Covid-19.

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Giustino G Croft LB Oates CP Rahman K Lerakis S Reddy VY et al Takotsubo Cardiomyopathy in Covid-19 J Am Coll Cardiol 2020 76 5 628 629 10.1016/j.jacc.2020.05.068 37. Krishnamoorthy P, Croft LB, Ro R, Anastasius M, Zhao W, Giustino G, et al. Biventricular Strain by Speckle Tracking Echocardiography in Covid-19: Findings and Possible Prognostic Implications. Future Cardiol. 2021;17(4):663–7. Krishnamoorthy P Croft LB Ro R Anastasius M Zhao W Giustino G et al Biventricular Strain by Speckle Tracking Echocardiography in Covid-19: Findings and Possible Prognostic Implications Future Cardiol 2021 17 4 663 667 38. Schott JP, Mertens AN, Bloomingdale R, O’Connell TF, Gallagher MJ, Dixon S, et al. Transthoracic Echocardiographic Findings in Patients Admitted with SARS-CoV-2 Infection. Echocardiography. 2020;37(10):1551-6. doi: 10.1111/echo.14835. Schott JP Mertens AN Bloomingdale R O’Connell TF Gallagher MJ Dixon S et al Transthoracic Echocardiographic Findings in Patients Admitted with SARS-CoV-2 Infection Echocardiography 2020 37 10 1551 1556 10.1111/echo.14835 39. Duerr GD, Heine A, Hamiko M, Zimmer S, Luetkens JA, Nattermann J, et al. Parameters Predicting Covid-19-induced Myocardial Injury and Mortality. Life Sci. 2020;260:118400. doi: 10.1016/j.lfs.2020.118400. Duerr GD Heine A Hamiko M Zimmer S Luetkens JA Nattermann J et al Parameters Predicting Covid-19-induced Myocardial Injury and Mortality Life Sci 2020 260 118400 10.1016/j.lfs.2020.118400 40. Showkathali R, Yalamanchi R, Sankeerthana MP, Kumaran SN, Shree S, Nayak R, et al. Acute Coronary Syndrome admissions and Outcome during Covid-19 Pandemic-Report from Large Tertiary Centre in India. Indian Heart J. 2020;72(6):599-602. doi: 10.1016/j.ihj.2020.09.005. Showkathali R Yalamanchi R Sankeerthana MP Kumaran SN Shree S Nayak R et al Acute Coronary Syndrome admissions and Outcome during Covid-19 Pandemic-Report from Large Tertiary Centre in India Indian Heart J 2020 72 6 599 602 10.1016/j.ihj.2020.09.005 41. Lairez O, Blanchard V, Houard V, Vardon-Bounes F, Lemasle M, Cariou E, et al. Cardiac Imaging Phenotype in Patients with Coronavirus Disease 2019 (Covid-19): Results of the Cocarde Study. Int J Cardiovasc Imaging. 2021;37(2):449-57. doi: 10.1007/s10554-020-02010-4. Lairez O Blanchard V Houard V Vardon-Bounes F Lemasle M Cariou E et al Cardiac Imaging Phenotype in Patients with Coronavirus Disease 2019 (Covid-19): Results of the Cocarde Study Int J Cardiovasc Imaging 2021 37 2 449 457 10.1007/s10554-020-02010-4 42. Weckbach LT, Curta A, Bieber S, Kraechan A, Brado J, Hellmuth JC, et al. Myocardial Inflammation and Dysfunction in Covid-19-Associated Myocardial Injury. Circ Cardiovasc Imaging. 2021;14(1):e012220. doi: 10.1161/CIRCIMAGING.120.011713. Weckbach LT Curta A Bieber S Kraechan A Brado J Hellmuth JC et al Myocardial Inflammation and Dysfunction in Covid-19-Associated Myocardial Injury Circ Cardiovasc Imaging 2021 14 1 e012220 10.1161/CIRCIMAGING.120.011713 43. Argulian E, Sud K, Vogel B, Bohra C, Garg VP, Talebi S, et al. Right Ventricular Dilation in Hospitalized Patients With Covid-19 Infection. JACC Cardiovasc Imaging. 2020;13(11):2459-61. doi: 10.1016/j.jcmg.2020.05.010. Argulian E Sud K Vogel B Bohra C Garg VP Talebi S et al Right Ventricular Dilation in Hospitalized Patients With Covid-19 Infection JACC Cardiovasc Imaging 2020 13 11 2459 2461 10.1016/j.jcmg.2020.05.010 44. Gonzalez F, Gomes R, Bacariza J, Michard F. Could Strain Echocardiography Help to Assess Systolic Function in Critically ill Covid-19 Patients? J Clin Monit Comput. 2021;35(5):1229-34. doi: 10.1007/s10877-021-00677-1. Gonzalez F Gomes R Bacariza J Michard F Could Strain Echocardiography Help to Assess Systolic Function in Critically ill Covid-19 Patients? J Clin Monit Comput 2021 35 5 1229 1234 10.1007/s10877-021-00677-1 45. Ferrante G, Fazzari F, Cozzi O, Maurina M, Bragato R, D’Orazio F, et al. Risk Factors for Myocardial Injury and Death in Patients with Covid-19: Insights from a Cohort Study with Chest Computed Tomography. Cardiovasc Res. 2020;116(14):2239-46. doi: 10.1093/cvr/cvaa193. Ferrante G Fazzari F Cozzi O Maurina M Bragato R D’Orazio F et al Risk Factors for Myocardial Injury and Death in Patients with Covid-19: Insights from a Cohort Study with Chest Computed Tomography Cardiovasc Res 2020 116 14 2239 2246 10.1093/cvr/cvaa193 46. Shmueli H, Shah M, Ebinger JE, Nguyen LC, Chernomordik F, Flint N, et al. Left Ventricular Global Longitudinal Strain in Identifying Subclinical Myocardial Dysfunction Among Patients Hospitalized with Covid-19. Int J Cardiol Heart Vasc. 2021;32:100719. doi: 10.1016/j.ijcha.2021.100719. Shmueli H Shah M Ebinger JE Nguyen LC Chernomordik F Flint N et al Left Ventricular Global Longitudinal Strain in Identifying Subclinical Myocardial Dysfunction Among Patients Hospitalized with Covid-19 Int J Cardiol Heart Vasc 2021 32 100719 10.1016/j.ijcha.2021.100719 47. Moody WE, Mahmoud-Elsayed HM, Senior J, Gul U, Khan-Kheil AM, Horne S, et al. Impact of Right Ventricular Dysfunction on Mortality in Patients Hospitalized With Covid-19, According to Race. CJC Open. 2021;3(1):91-100. doi: 10.1016/j.cjco.2020.09.016. Moody WE Mahmoud-Elsayed HM Senior J Gul U Khan-Kheil AM Horne S et al Impact of Right Ventricular Dysfunction on Mortality in Patients Hospitalized With Covid-19, According to Race CJC Open 2021 3 1 91 100 10.1016/j.cjco.2020.09.016 48. Pishgahi M, Toudeshki KK, Safari S, Yousefifard M. Echocardiographic Abnormalities as Independent Prognostic Factors of In-Hospital Mortality among Covid-19 Patients. Arch Acad Emerg Med. 2021;9(1):e21. doi: 10.22037/aaem.v9i1.1155. Pishgahi M Toudeshki KK Safari S Yousefifard M Echocardiographic Abnormalities as Independent Prognostic Factors of In-Hospital Mortality among Covid-19 Patients Arch Acad Emerg Med 2021 9 1 e21 10.22037/aaem.v9i1.1155 49. Morin DP, Manzo MA, Pantlin PG, Verma R, Bober RM, Krim SR, et al. Impact of Preinfection Left Ventricular Ejection Fraction on Outcomes in Covid-19 Infection. Curr Probl Cardiol. 2021;46(10):100845. doi: 10.1016/j.cpcardiol.2021.100845. Morin DP Manzo MA Pantlin PG Verma R Bober RM Krim SR et al Impact of Preinfection Left Ventricular Ejection Fraction on Outcomes in Covid-19 Infection Curr Probl Cardiol 2021 46 10 100845 10.1016/j.cpcardiol.2021.100845 50. Norderfeldt J, Liliequist A, Frostell C, Adding C, Agvald P, Eriksson M, et al. Acute Pulmonary Hypertension and Short-term Outcomes in Severe Covid-19 Patients Needing Intensive Care. Acta Anaesthesiol Scand. 2021;65(6):761-9. doi: 10.1111/aas.13819. Norderfeldt J Liliequist A Frostell C Adding C Agvald P Eriksson M et al Acute Pulmonary Hypertension and Short-term Outcomes in Severe Covid-19 Patients Needing Intensive Care Acta Anaesthesiol Scand 2021 65 6 761 769 10.1111/aas.13819 51. Li Y, Fang L, Zhu S, Xie Y, Wang B, He L, et al. Echocardiographic Characteristics and Outcome in Patients With Covid-19 Infection and Underlying Cardiovascular Disease. Front Cardiovasc Med. 2021;8:642973. doi: 10.3389/fcvm.2021.642973. Li Y Fang L Zhu S Xie Y Wang B He L et al Echocardiographic Characteristics and Outcome in Patients With Covid-19 Infection and Underlying Cardiovascular Disease Front Cardiovasc Med 2021 8 642973 10.3389/fcvm.2021.642973 52. Liaqat A, Ali-Khan RS, Asad M, Rafique Z. Evaluation of Myocardial Injury Patterns and ST Changes Among Critical and Non-critical Patients with Coronavirus-19 Disease. Sci Rep. 2021;11(1):4828. doi: 10.1038/s41598-021-84467-4. Liaqat A Ali-Khan RS Asad M Rafique Z Evaluation of Myocardial Injury Patterns and ST Changes Among Critical and Non-critical Patients with Coronavirus-19 Disease Sci Rep 2021 11 1 4828 10.1038/s41598-021-84467-4 53. Mercedes BR, Serwat A, Naffaa L, Ramirez N, Khalid F, Steward SB, et al. New-onset Myocardial Injury in Pregnant Patients with Coronavirus Disease 2019: A Case Series of 15 Patients. Am J Obstet Gynecol. 2021;224(4):387. doi: 10.1016/j.ajog.2020.10.031. Mercedes BR Serwat A Naffaa L Ramirez N Khalid F Steward SB et al New-onset Myocardial Injury in Pregnant Patients with Coronavirus Disease 2019: A Case Series of 15 Patients Am J Obstet Gynecol 2021 224 4 387 10.1016/j.ajog.2020.10.031 54. Karagodin I, Singulane CC, Woodward GM, Xie M, Tucay ES, Rodrigues ACT, et al. Echocardiographic Correlates of In-Hospital Death in Patients with Acute Covid-19 Infection: The World Alliance Societies of Echocardiography (WASE-COVID) Study. J Am Soc Echocardiogr. 2021;34(8):819-30. doi: 10.1016/j.echo.2021.05.010. Karagodin I Singulane CC Woodward GM Xie M Tucay ES Rodrigues ACT et al Echocardiographic Correlates of In-Hospital Death in Patients with Acute Covid-19 Infection: The World Alliance Societies of Echocardiography (WASE-COVID) Study J Am Soc Echocardiogr 2021 34 8 819 830 10.1016/j.echo.2021.05.010

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 Original Article Abnormal Echocardiographic Findings in Hospitalized Patients with Covid-19: A Systematic Review and Meta-analysis 0000-0002-0711-7995 Barberato Silvio Henrique 1 2 Bruneto Eduardo G. 3 Reis Gabriel S. 4 0000-0001-5947-7880 Oliveira Paula Rauen Franco de 5 Possamai Alexandre F. 5 Silvestre Odilson 3 Silva Miguel M. Fernandes 4 Brazil CardioEco Centro de Diagnóstico Cardiovascular, Curitiba, PR – Brazil Brazil Quanta Diagnóstico, Ecocardiografia,Curitiba, PR – Brazil Brazil Universidade Federal do Acre, Rio Branco, AC – Brazil Brazil Universidade Federal do Paraná, Curitiba, PR – Brazil Brazil Pontifícia Universidade Católica do Paraná, Curitiba, PR – Brazil Mailing Address: Silvio Henrique Barberato • CardioEco Centro de Diagnóstico Cardiovascular – Avenida República Argentina, 1336, conj 215. Postal Code 80620-010, Curitiba, PR – Brazil E-mail: silviohb@cardiol.br

Author contributions

Conception and design of the research: Silvio Henrique Barberato, Eduardo G. Bruneto, Odilson Silvestre, Miguel M. Fernandes Silva; Acquisition of data and Writing of the manuscript: Silvio Henrique Barberato, Eduardo G. Bruneto, Gabriel S. Reis, Paula Rauen Franco de Oliveira, Alexandre F. Possamai, Miguel M. Fernandes Silva; Analysis and interpretation of the data: Silvio Henrique Barberato, Eduardo G. Bruneto, Gabriel S. Reis, Paula Rauen Franco de Oliveira, Alexandre F. Possamai, Odilson Silvestre, Miguel M. Fernandes Silva; Statistical analysis: Silvio Henrique Barberato, Eduardo G. Bruneto, Miguel M. Fernandes Silva; Critical revision of the manuscript for intellectual content: Silvio Henrique Barberato, Odilson Silvestre, Miguel M. Fernandes Silva.

Potential Conflict of Interest

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

 Abstract Background

Coronavirus disease 2019 (Covid-19) can lead to severe respiratory distress and acute cardiac injury, but it is unclear how often it can cause cardiac dysfunction.

 Objective

In this systematic review, we aimed to summarize the main echocardiographic findings in patients with Covid-19.

 Methods

We systematically searched in PUBMED, EMBASE, LILACS and Cochrane databases, in addition MedRxiv and Scielo preprints from inception to July 21st, 2021. Studies reporting echocardiographic data in patients with Covid-19 were included. Demographic characteristics, previous cardiovascular disease (CVD), and echocardiographic findings were extracted. We performed a meta-analysis of proportions to estimate the main echocardiographic findings. The level of significance was p < 0.05.

 Results

From 11,233 studies, 38 fulfilled inclusion criteria and were included in the meta-analysis. The estimated proportions of left ventricular (LV) systolic dysfunction were 25% (95%CI: 19, 31; I293%), abnormal global longitudinal strain 34% (95% CI 23, 45; I290%), righ ventricular (RV) systolic dysfunction 17% (95%CI 13, 21; I290%), pericardial effusion 17% (95%CI: 9, 26; I297%), and pulmonary hypertension 23% (95%CI: 15, 33, I2 96%). LV systolic dysfunction was directly associated with study-specific prevalence of previous abnormal echocardiogram (p<0.001). The proportion of patients in mechanical ventilation, indicating severity of disease, did not explain the heterogeneity in the proportions of LV dysfunction (p=0.37).

 Conclusion

Among hospitalized patients with Covid-19, LV dysfunction has been reported in one quarter, with smaller proportions of right ventricular dysfunction, pericardial effusion and pulmonary hypertension. However, there was a higher proportion of LV dysfunction among studies reporting the presence of prior heart disease, which suggests that cardiac dysfunction was mostly pre-existing.

 Echocardiography Covid-19 Ventricular Function, Left Introduction

Coronavirus disease 2019 (Covid-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may result in severe respiratory distress and acute cardiac injury. Elevated troponin blood levels and imaging showing abnormal cardiac function have been associated with worse prognosis in patients with acute Covid-19.1 The worse prognosis may result from a combination of disease-related factors, such as virulence and inflammatory response, and patient-related factors, such as pre-existent cardiovascular risk factors and established cardiovascular disease (CVD). For this reason, it has been recommended to assess cardiac function using transthoracic echocardiography (TTE) to guide the management of patients with new or worsening cardiovascular symptoms, hemodynamic instability, and increased biomarkers levels.2

At the beginning of the pandemic, there have been anecdotal reports of new-onset heart failure (HF) and fulminant myocarditis in patients with Covid-19.3 , 4 Studies using cardiovascular magnetic resonance have shown that evidence of myocardial inflammation in elite athletes who had recently recovered from Covid-19 was common, but with uncertain clinical significance.5 Nevertheless, more recent reports have shown that myocarditis is far less common (less than 2%) than earlier suggested, even among patients with elevated circulating troponin levels.6 , 7 It is also unclear how often Covid-19 affects cardiac function, either due to direct myocardial injury or through increasing pulmonary resistance when the lungs are severely damaged. Echocardiographic studies have shown varied findings of left and right ventricular dysfunction; for instance, left ventricular (LV) systolic dysfunction has been found in less than 10% of patients in some studies and almost 40% in others.8 , 9 Large-scale studies showing accurate estimates of the incidence of major cardiac dysfunction, its clinical significance, and associated risk factors are lacking. Because of the risk of contamination of healthcare workers, the use of echocardiography should be based on critical consideration of the benefits for the patient.10 Therefore, we aimed to summarize the main echocardiographic findings of patients with Covid-19 through a systematic review and meta-analysis.

 Methods Study design and eligibility criteria

We performed a systematic review, study selection and meta-analysis of proportions according with the PRISMA statement for meta-analysis.11 We included all studies with at least 10 participants describing echocardiogram findings in hospitalized patients with Covid-19, published in English, Portuguese, and Spanish languages, from inception to July 21, 2021. Studies that did not report any echocardiogram findings were excluded. We also excluded unpublished abstracts, studies lacking baseline clinical information of participants or insufficient echocardiographic data to obtain the number of participants with abnormal cardiac function or structure.

 Information sources and search

We systematically searched in PUBMED, EMBASE, LILACS and Cochrane (CENTRAL) databases. We also searched articles in the repository of unpublished (preprints) manuscripts in MedRxiv (https://www.medrxiv.org/) and Scielo preprint databases. Our search used the terms “Covid-19”, “SARS CoV 2”, “Coronavirus infection”, “Heart Diseases” and “Echocardiography” as descriptors (Medical Subject Headings – MeSH) or supplementary concept, and synonyms as free text in title and abstract to increase sensitivity. The full search strategy was displayed in the supplemental material (Supplemental table 3).

 Study selection and data extraction

We merged the search results from each database using the EndNote software and removed duplicated studies. Four authors (EB, GR, PO, AP) independently examined titles and abstracts to remove irrelevant reports. Then, the full texts of potentially relevant reports were examined and the studies that fulfilled the eligibility criteria were selected. Different reports from the same study were linked and the study with the largest sample size was selected. Discrepancies were resolved by consensus. References of review articles were examined for additional studies, and those considered eligible were further incorporated into the meta-analysis.

The following data were extracted from the studies: authors’ names, month of publication, previous abnormal echocardiogram of patients, sample size of patients undergoing echocardiogram, and the number of individuals with LV systolic dysfunction, right ventricular (RV) systolic dysfunction, pulmonary hypertension, and pericardial effusion. The study-specific definitions for each echocardiographic abnormality were detailed in the supplemental table 2. When LV systolic dysfunction was not clearly defined by the authors, we adopted a LV ejection fraction (LVEF) below 50%. Abnormal global longitudinal strain (GLS) was defined as below 18%. Similarly, RV dysfunction was determined by study specific definition; otherwise, it was defined as tricuspid annular plane systolic excursion (TAPSE) below 17 mm and/or tissue Doppler of the free lateral wall of the right ventricle (S’) below 9.5 cm/s. Pulmonary hypertension was defined by tricuspid regurgitation velocity above 2.8 m/s, pulmonary acceleration time below 100 ms and/or pulmonary artery systolic pressure (PASP) above 35 mmHg (Supplemental Table 2). Only two studies defined pulmonary hypertension by different cut off values of PASP: one above 40mmHg,12 and one above 45mmHg.13 The number of patients with LV or RV dysfunction was estimated using the mean LVEF and the respective standard deviation (or 95% confidence interval) as previously recommended for data extraction in systematic reviews.14

Population characteristics, including mean age, proportion of men, prevalence of obesity, hypertension, diabetes, previous coronary heart disease and heart failure were also extracted. All data were entered in a table using Excel software.

 Hypothesized sources of heterogeneity

Since patient characteristics varied among the studies, we expected a significant heterogeneity across them. We decided to evaluate severity of disease using the proportion of individuals under mechanical ventilation and history of previous CVD (either HF or coronary heart disease). We used I2statistics to identify heterogeneity and meta-regression using these characteristics as potential modifiers of abnormal echocardiographic findings.

 Quality assessment

We used a previously reported tool for evaluating methodological quality of observational studies, adapted for case reports and case series.14 For each study, the reviewers answered the following questions to evaluate whether they fulfilled the quality criteria:

- Selection: Does the patient(s) represent(s) the whole experience of the investigator (center) or is the selection method unclear to the extent that other patients with similar presentation may not have been reported?

- Exposure ascertainment: Was the exposure adequately ascertained?

- Alternative cause ruled out: Were other alternative causes that may explain the observation ruled out?

- Enough follow-up: The echocardiography was performed in the most critical moment during the patient hospitalization?

- Sufficient detail: Is the case described with sufficient details to allow other investigators to replicate the research or to allow practitioners make inferences to their own practice?

Funnel plots were used to assess for publication bias, as case reports of abnormal cardiac findings might be more likely to be published. Funnel plots were constructing by plotting sample size against log odds ratio of each outcome, as previously proposed to assess publication bias in meta-analysis of non-comparative proportion studies.15

 Statistical analysis

We performed a meta-analysis of proportions to estimate the proportion of LV systolic dysfunction, RV systolic dysfunction, pulmonary hypertension and pericardial effusion among patients with acute Covid-19. To assess whether previous CVD and severity of disease influenced the proportion of abnormal echo findings, we performed a meta-regression using the prevalence of CVD and the proportion of participants under mechanical ventilation in each study. The level of significance was p < 0.05.

Due to expected variability in the selected studies, we performed a random-effects meta-analysis with Freeman-Tukey double arc-sine transformation to account for any violation of the assumption of normality in this variable. Heterogeneity was assessed with the I2statistic. The meta-analysis was performed using Stata ( StataCorp . College Station, Texas) version 15.0.

 Results Search Results

The initial search yielded 11,233 titles, and the final number after exclusion of duplicates was 7,550 ( Figure 1 ). From these, 318 were potentially relevant studies and the respective full texts were assessed for eligibility. Finally, 38 studies met the eligibility criteria and were included in the meta-analysis ( Table 1).

Flow-chart of study selection for the meta-analysis.

Characteristics of studies included in the meta-analysis
First author (Month Year) Country Population characteristics Sample with echo Mean age Men, % Obesity, % Hypertension, % Diabetes, % Previous CVD, % Previous HF, % Previous Abnormal Echo, % Mechanical ventilation, %
Deng (Mar2020) 8 China hospitalized patients with Covid-19 112 65 51 37 32 17 13 4 4 25
Li (Apr2020) 16 China Covid-19 patients with echocardiogram 120 61 48 18 40 12 9 0 0 13
Bangalore (Apr2020) 29 USA Covid-19 patients with electrocardiogram 17 63 83 NR 61 33 17 NR 50 67
Rath (May2020) 18 Germany hospitalized patients with Covid-19 98 68 63 20 70 24 23 NR NR 40
Ge (May2020) 30 China Covid-19 patients in the ICU 51 70 73 NR 43 31 31 8 NR 41
Evrard (May2020) 31 France Covid-19 patients in mechanical ventilation 18 70 67 NR 61 22 NR NR NR 100
Szekely (May2020) 19 Israel hospitalized patients with Covid-19 100 66.1 63 29 57 29 16 7 2 10
Stefanini (Jun2020) 32 Italy Covid-19 patients with STEMI 28 68 71 4 71 32 21 NR NR 0
Dweck (Jun2020) 9 69 countries Presumed Covid-19 patients with echocardiogram 1216 62 69 NR 37 19 20 9 NR 0
Vasudev (Jun2020) 33 USA Covid-19 patients with echocardiogram 45 61.4 51 NR 64 56 27 24 9 NR
Lazzeri (Jul2020) 13 Italy hospitalized patients with Covid-19 28 61 79 61 89 39 29 NR NR 86
Rodríguez-Santamarta (Jul2020) 34 Spain Covid-19 patients in the ICU 37 67.6 92 NR NR NR 5 0 NR NR
van den Heuvel (Jul2020) 17 Netherlands hospitalized patients with Covid-19 51 63 80 0 41 18 22 0 18 33
Stöbe (Aug2020) 35 Germany Covid-19 patients with echocardiogram 18 64 78 NR 72 28 11 NR NR 78
Giustino (Aug2020) 36 USA hospitalized patients with Covid-19 118 66 100 NR NR NR NR NR NR NR
Krishnamoorthy (Aug2020) 37 EUA Covid-19 patients with echocardiogram 12 57 42 42 58 33 17 NR NR 42
Schott (Aug2020) 38 USA Covid-19 patients with echocardiogram 66 60 58 86 58 35 NR 11 6 35
Sud (Aug2020) 22 USA Covid-19 patients with echocardiogram 24 64.5 54 NR NR NR NR 8 8 42
Duerr (Sep2020) 39 Germany hospitalized patients with Covid-19 19 69 47 NR 63 26 37 NR NR NR
Kunal (Oct2020) 40 India symptomatic Covid-19 patients 28 51 65 NR 38 32 13 1 NR 23
Lassen (Oct2020) 26 Denmark Covid-19 patients with echocardiogram 214 69 55 18 57 24 16 10 NR 0
Jain (Oct2020) 20 USA Covid-19 patients with echocardiogram 77 61 7 5 6 4 2 2 NR 5
Lairez (Oct2020) 41 France hospitalized patients with Covid-19 31 57 87 23 48 32 NR NR NR 68
Weckbach (Nov2020) 42 Germany Covid-19 and myocardial injury 18 70 89 NR 78 39 39 6 NR 50
Argulian (Nov2020) 43 USA hospitalized patients with Covid-19 105 66 61 NR NR NR NR NR NR 28
Gonzales (Dec2020) 44 Portugal Covid-19 patients in the ICU 30 61 NR 53 73 30 NR NR NR 23
Ferrante (Dec2020) 45 Italy Covid-19 patients with chest-CT 21 67 71 NR 54 21 15 NR NR 20
Bagate (Dec2020) 12 France Covid-19 patients in the ICU 67 61 82 31 54 36 NR 10 NR 99
Shmueli (Jan2021) 46 USA Covid-19 patients with echocardiogram 60 66.2 65 17 47 27 17 13 NR 32
Moody (Jan2021) 47 United Kingdom Covid-19 patients with echocardiogram 164 61 78 NR 41 32 13 NR NR 73
Pishgahi (Feb2021) 48 Iran Covid-19 patients with echocardiogram 680 55 63 NR 44 25 16 NR NR NR
Morin (Mar2021) 49 USA Covid-19 patients with echocardiogram 396 67 48 NR 58 31 NR NR NR 21
Norderfeldt (Mar2021) 50 Sweden Covid-19 patients in the ICU 67 58 94 NR NR NR NR NR NR 100
Li (Mar2021) 51 China hospitalized patients with Covid-19 157 62 50 15 45 15 17 3 NR 24
Liaqat (Mar2021) 52 Pakistan hospitalized patients with Covid-19 181 44 59 5 17 17 NR NR NR 28
Mercedes (Apr2021) 53 Dominican Republic Covid-19 pregnant patients 15 29 0 33 0 NR 0 0 NR 0
Karagodin (May2021) 54 10 countries hospitalized patients with Covid-19 870 60 56 NR 43 20 14 7 NR 27
Barberato (Jul2021) 23 Brazil hospitalized patients with Covid-19 223 61.4 59 27 52 35 13 7 NR NR

All studies adopted a 5% level of statistical significance for hypothesis testing. ICU: intensive care unit; NR: not reported.

 Echocardiographic findings in Covid-19 patients

Overall, we found that the proportion of LV systolic dysfunction was 25% (95%CI: 19, 31; I293%; Figure 2 ), but heterogeneity was high across the studies. This heterogeneity was neither explained by study-specific prevalence of previous CVD ( Figure 2 , p for interaction = 0.16), nor by the study-specific proportion of patients under mechanical ventilation (Supplemental figure 1, p for interaction = 0.37). Among the studies that reported echocardiographic data before SARS-CoV2 infection, we found a direct relationship between previous abnormal echocardiogram and proportions of LV dysfunction (Supplemental Figure 3, p for interaction < 0.001).

Proportion of left ventricular dysfunction in patients with Covid-19 across the studies according to the prevalence of cardiovascular diseases. CVD: cardiovascular diseases. LV: left ventricular. * Studies were divided according to the percentage of patients with CVD: Lowest tercile (less than 15%), Middle tercile (15 to 21%) and the highest tercile (>21%).

RV systolic dysfunction was present in 17% (95%CI 13, 21; I290%; Figure 3 ) of patients with Covid-19. However, despite the high heterogeneity, previous CVD (p=0.53), pulmonary hypertension (p=0.96), or mechanical ventilation (p=0.65) do not explain the variation in proportion of RV dysfunction across the studies ( Figure 3 , Supplemental Figures 2 and 4).

Proportion of right ventricular dysfunction in patients with Covid-19 across the studies according to the prevalence of cardiovascular diseases. CVD: cardiovascular diseases; RV: right ventricular. * Studies were divided according to the percentage of patients with CVD: Lowest tercile (less than 15), Middle tercile (15 to 21%) and Highest tercile (>21%).

Pulmonary hypertension was found in 23% (95%CI: 15, 33, I2 96%; Figure 4 ) and pericardial effusion was found in 17% (95%CI: 9, 26; I297%; Figure 5 ) of patients with Covid-19. Abnormal regional LV wall motion were reported in 23% (95% CI 12, 38; I296%; Figure 6 ) in Covid-19 patients. GLS was abnormal in 34% (95% CI 23, 45; I290%) of patients with Covid-19 (Figure 7 ).

Proportion of pulmonary hypertension in patients with Covid-19.

Proportion of pericardial effusion in patients with Covid-19.

Proportion of regional LV motion abnormality in patients with Covid-19. LV: left ventricular.

Proportion of Abnormal LV global longitudinal strain in patients with Covid-19. LV: left ventricular; GLS: global longitudinal strain.

Publication bias

We evaluated potential publication bias of studies reporting LV systolic dysfunction, RV systolic dysfunction, pericardial effusion, and pulmonary hypertension. Visual analysis of the funnel plot suggests publication bias of studies reporting RV systolic dysfunction, with a higher likelihood of small studies reporting a higher proportion of the outcome ( Supplemental Figure 5 ).

 Discussion

In this systematic review of echocardiographic findings in patients with Covid-19, we found that the estimated proportions of LV systolic dysfunction was 25%, RV systolic dysfunction was 17%, pulmonary hypertension was 23% and pericardial effusion was 17%. GLS, which is more sensitive to detect subclinical LV dysfunction, was abnormal in 34% of patients with Covid-19. Despite the method, the findings of LV systolic dysfunction varied considerably, with lower proportions in studies reporting proportionally fewer individuals with previous abnormal echocardiogram.

The echocardiographic findings in patients with Covid-19 have been very heterogeneous. The prevalence of LV systolic dysfunction, RV dysfunction and RV dilation have ranged from 5.48 to 37.4%,9 3.68 to 33%,16 and 017 to 46.9%,18 respectively. While most studies have pointed out RV dysfunction and/or dilation as the most frequent echocardiographic changes,19 - 22 others have found LV systolic dysfunction to be more prevalent.8 , 9 The contradictory results about the prevalence and consequences of echocardiographic changes among patients with Covid-19 may be explained by several factors. Relatively small samples, referral bias, different TTE protocols, inaccurate definitions of echocardiographic abnormalities, and differences of population characteristics, such as the proportion of patients on mechanical ventilation and/or with previous CVD, might have led to the wide-ranging conclusions about cardiac manifestations of Covid-19. In the search for sources of heterogeneity, some interesting points should be mentioned in our study. When we separated the studies by the proportion of patients under mechanical ventilation (as an indicator of disease severity), the proportions of LV and RV dysfunction did not change. When we analyzed a population composed of healthier individuals (the lowest tertile of prior CVD prevalence), the proportion of patients with LV dysfunction tended to be lower, but this difference was not statistically significant. On the other hand, it is conceivable that high proportions of abnormal echocardiographic findings at the beginning of the pandemic reflect previous LV dysfunction, as we found higher proportion of LV dysfunction in studies reporting proportionally more individuals with previous abnormal echocardiogram. An analysis from the Brazilian Echocardiographic Registry showed that patients with Covid-19 without previous CVD were less likely to have LV systolic dysfunction than those with previous CVD (13 vs 34%, p <0.001).23

The study by Dweck et al.9 was the first (and the largest) to show that echocardiographic abnormalities were very common in hospitalized Covid-19 patients. Using an online survey which collected data from 1,216 patients (26% with pre-existing CVD) of 69 countries, they found that more than half of the patients (55%) had an abnormal TTE. Subjects with abnormal echocardiographic findings were older, and had a higher prevalence of pre-existing CVD, HF or valvular heart disease. Any degree of LV systolic dysfunction was diagnosed in 37.4% of subjects and biventricular impairment in 14.3%. On the other hand, only 3% had evidence of a new myocardial infarction, 3% of myocarditis and 2% of findings suggestive of Takotsubo syndrome. The study was limited by selection bias, which might have led to the overestimation of cardiac findings.

In order to mitigate referral bias, Szekely et al.19 systematically performed TTE in 100 consecutive patients hospitalized for Covid-19, 43% of which had prior CVD. They found that the most frequent abnormality was RV dysfunction/dilation (39%) while only a minority of patients (10%) presented LV systolic dysfunction.19 In addition, Covid-19 patients with myocardial injury or worse clinical condition did not have any significant difference in LV systolic function but had worse RV function when compared to patients without myocardial injury or better clinical condition. The higher prevalence of RV dysfunction and small proportion of LV dysfunction have been similarly found in other smaller studies.20 , 21 , 24 Although most studies of this meta-analysis have not clearly identified the presence of pre-existing echocardiographic changes, it is possible that in a small proportion of patients, LV systolic dysfunction reflects a Covid-19-related “de novo” LV impairment, particularly in those without previous CVD. Moreover, echocardiographic abnormalities might denote the presence of pre-existing stable cardiac disease that has worsened because of the SARS-CoV-2 infection. Therefore, it appears that the prevalence of cardiac dysfunction is lower than that suggested at the beginning of the pandemic. Data regarding the use of echocardiography on hospitalized Covid-19 patients, retrieved from studies with variable designs, sample sizes, and severity scores, have shown that normal echocardiographic findings were reported in about 50% of subjects, with LVEF usually less affected.25 Indeed, it has been recently shown that persistent LV dysfunction is uncommon after Covid-19: in patients who had elevated troponin blood levels, cardiovascular magnetic resonance two months after infection revealed LV systolic dysfunction in only 11% of patients, although one-third had findings suggestive of myocarditis.6

Since the major efforts of the scientific community aim to prevent the severe health consequences of the Covid-19 pandemic, it has been challenging to balance the use of echocardiography to provide high-quality medical care without an increase in the risk of cross-infection between healthcare professionals and patients. On the other hand, it is important to emphasize that the presence of cardiac dysfunction is independently associated with worse prognosis in patients with severe Covid-19.26 , 27 Echocardiographic parameters that identify myocardial damage earlier and more accurately than the traditional ones, such as two-dimensional LV or RV GLS, have been less used in the context of Covid-19 due to the recommendations for using focused protocols, which reduces the exposure of health care professionals to infection. Our meta-analysis showed that studies that assessed LV systolic function with GLS detected a higher proportion of patients with LV dysfunction compared to those that used LVEF. A recently published meta-analysis showed that lower LV and RV GLS were independently associated with poor outcome in Covid-19.28

Our study has limitations that deserve attention. Most studies are subject to referral bias because echocardiograms were performed at the discretion of the attending physician, which may have overestimated the occurrence of abnormal echocardiographic findings. Most studies had a retrospective design, except for one prospective study in which TTE was performed in consecutive patients hospitalized for Covid-19, regardless of clinical indication.19 Moreover, population characteristics and presentation of Covid-19 varied across studies, resulting in considerable heterogeneity. Although we explored a few sources of heterogeneity, heterogeneity remained high within subgroups. Echocardiogram-related technical aspects, leading to potential misclassification bias, and different definitions of cardiac abnormalities may be additional sources of heterogeneity. For instance, bedside evaluation of RV function and pulmonary hypertension may be limited in critical ill patients. Also, most studies did not report the presence of prior cardiac abnormalities nor whether the echocardiographic findings were new. Finally, because of language restriction in our search, possible exclusion of relevant papers that were not published in Portuguese, English or Spanish may not be excluded.

 Conclusion

In hospitalized patients with Covid-19, abnormal echocardiographic findings indicating LV dysfunction have been reported in one of four patients. Lower prevalence of RV dysfunction and pericardial effusion was detected, although LV systolic dysfunction may be related to prior heart disease. Indeed, we found a direct association between previous abnormal echocardiogram and the proportions of LV dysfunction in the subgroup of studies that reported previous echocardiogram, which provide insights that help plan echocardiographic studies in Covid-19.

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.

Sources of Funding : There were no external funding sources for this study.

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