SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes

Abstract

Aims Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of mortality. It is unclear whether cardiac injury is caused by direct infection of cardiomyocytes or is mainly secondary to lung injury and inflammation. Here, we investigate whether cardiomyocytes are permissive for SARS-CoV-2 infection. Methods and results Two strains of SARS-CoV-2 infected human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) as demonstrated by detection of intracellular double-stranded viral RNA and viral spike glycoprotein expression. Increasing concentrations of viral RNA are detected in supernatants of infected cardiomyocytes, which induced infections in Caco-2 cell lines, documenting productive infections. SARS-COV-2 infection and induced cytotoxic and proapoptotic effects associated with it abolished cardiomyocyte beating. RNA sequencing confirmed a transcriptional response to viral infection as demonstrated by the up-regulation of genes associated with pathways related to viral response and interferon signalling, apoptosis, and reactive oxygen stress. SARS-CoV-2 infection and cardiotoxicity was confirmed in a 3D cardiosphere tissue model. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection with SARS-CoV-2. Coronavirus particles were further observed in cardiomyocytes of a patient with COVID-19. Infection of iPS-CMs was dependent on cathepsins and angiotensin-converting enzyme 2 (ACE2), and was blocked by remdesivir. Conclusions This study demonstrates that SARS-CoV-2 infects cardiomyocytes in vitro in an ACE2- and cathepsin-dependent manner. SARS-CoV-2 infection of cardiomyocytes is inhibited by the antiviral drug remdesivir. Translational Perspective Although this study cannot address whether cardiac injury and dysfunction in COVID-19 patients is caused by direct infection of cardiomyocytes, the demonstration of direct cardiotoxicity in cardiomyocytes, organ mimics, human heart slices and human hearts warrants the further monitoring of cardiotoxic effects in COVID-19 patients.

SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis

“…Viral entry was ACE2-dependent and relied on endosomal cysteine protease activity. Our findings are consistent with a recent report suggesting that SARS-CoV-2 infects human cardiac slices and hPSC-derived CMs in an ACE2 and cathespin dependent manner 34 . We extend these observations to show that cardiomyocytes supported viral replication, rapidly produced infectious virions, activated type I IFN signaling, and Numerous studies have reported that extrapulmonary cell types are susceptible to SARS-CoV-2 infection [38][39][40] .…”

ACE2 Interaction Networks in COVID-19: A Physiological Framework for Prediction of Outcome in Patients with Cardiovascular Risk Factors

“…The analysis focusing on the ACE2 tissue-specific expression showed that lungs and respiratory systems have similar ACE2 and TMPRSS2 expressions as the heart and cardiovascular systems and the nervous system. Recent publications regarding the impact of SARS-CoV-2 on the heart tissue showed that cardiomyocytes can indeed be infected with the virus [13,14].…”

“…The virus can enter into human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CMs) via ACE2, and the viral replication and cytopathic effects induce hiPSC-CM apoptosis and cessation of beating after 72 h of infection while inhibiting metabolic pathways and suppressing ACE2 expression during this initial infection stage [13]. Moreover, SARS-CoV-2 undergoes a full replication circle and induces a cytotoxic response in cardiomyocytes, by inducing pathways related to viral response and interferon signaling, apoptosis and reactive oxygen stress [14]. Consistently, ACE2 mRNA and protein are expressed in hiPSC-CM, whereas TMPRSS2 was detected only at very low levels by RNA sequencing [14].…”

“…Moreover, SARS-CoV-2 undergoes a full replication circle and induces a cytotoxic response in cardiomyocytes, by inducing pathways related to viral response and interferon signaling, apoptosis and reactive oxygen stress [14]. Consistently, ACE2 mRNA and protein are expressed in hiPSC-CM, whereas TMPRSS2 was detected only at very low levels by RNA sequencing [14]. Finally, SARS-CoV-2 was invariably detected in cardiomyocytes of COVID-19 patients without clinical signs of cardiac involvement, with degrees of injury ranging from the absence of cell death and subcellular alteration hallmarks to intracellular oedema and sarcomere ruptures [15].…”

Physiology of cardiomyocyte injury in COVID-19

“…Interleukins are known to affect cardiomyocyte function (19). Multiple reports have indicated that human cardiomyocytes can be infected by SARS-CoV-2 (20)(21)(22). In this study, we integrated findings from analyses of fully anonymized clinical data on COVID-19 patients from the Mount Sinai Health System, with those from studies on hiPSC-derived ventricular cardiomyocytes in culture, infected with SARS-CoV-2 in the absence and presence of interleukins.…”