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

Abstract

Epidemiological studies of the COVID-19 pandemic have revealed evidence of cardiac involvement and documented that myocardial injury and myocarditis are predictors of poor outcomes. Nonetheless, little is understood regarding SARS-CoV-2 tropism within the heart and whether cardiac complications result directly from myocardial infection. Here, we develop a human engineered heart tissue model and demonstrate that SARS-CoV-2 selectively infects cardiomyocytes. Viral infection is dependent on expression of angiotensin-I converting enzyme 2 (ACE2) and endosomal cysteine proteases, suggesting an endosomal mechanism of cell entry. After infection with SARS-CoV-2, engineered tissues display typical features of myocarditis, including cardiomyocyte cell death, impaired cardiac contractility, and innate immune cell activation. Consistent with these findings, autopsy tissue obtained from individuals with COVID-19 myocarditis demonstrated cardiomyocyte infection, cell death, and macrophage-predominate immune cell infiltrate. These findings establish human cardiomyocyte tropism for SARS-CoV-2 and provide an experimental platform for interrogating and mitigating cardiac complications of COVID-19.

COVID-19 and Cardiovascular Disease

“…Despite reports of SARS-CoV-2 in some hearts with histologically proven myocarditis, 31 viral RNA has been undetectable in other COVID-19 myocarditis cases or did not correlate with sites of myocarditis. 102 , 105 , 112 , 113 Furthermore, acute myocarditis as defined by Dallas criteria has rarely been detected in COVID-19 nonsurvivors.…”

“…Cellular cathepsins can also process the S2’ position. In some cell types, such as human ventricular myocardium 30 and inducible pluripotent stem cell–derived cardiomyocytes, 31 , 32 where TMPRSS2 is expressed at very low levels, cathepsin inhibitors, rather than TMPRSS2 inhibitors, prevent SARS-CoV-2 cell entry. Thus, mechanisms involved in membrane fusion and cell entry may be cell-specific.…”

“… 110 Autopsies in patients with acute myocarditis have recently demonstrated evidence of viral infection, processing, and replication within cardiomyocytes. 31 The preponderance of evidence suggests that SARS-CoV-2 can readily infect human cardiac myocytes 31 , 110 and can be detected in myocytes on autopsy or by endomyocardial biopsy in patients with 31 , 110 and without 111 clinical evidence of cardiac involvement.…”

“… 60 , 115 The presence of severe microvascular injury in postmortem analyses supports a role for pericytes, which show high ACE2 expression in single nuclei RNA sequencing studies, but whether the microvascular injury involves direct infection or indirect inflammatory mechanisms is unclear. Several groups have utilized human inducible pluripotent stem cell–derived cardiomyocytes, living tissue slices, and engineered heart tissue to model SARS-CoV2 infection, 31 , 116 – 118 demonstrating ACE2 expression and direct cardiomyocyte susceptibility to SARS-CoV-2 infection. Infection produced cytotoxic effects 110 , 118 and activated innate immune responses, including IFN signaling, apoptosis, reactive oxygen stress, and antiviral clearance pathways, as well as inhibition of metabolic pathways and suppression of ACE2 expression.…”

A novel coronavirus meets the cardiovascular system: Society for Cardiovascular Pathology Symposium 2021

“…A recent study has shown that the degree of both myocardial macrophage and lymphocyte infiltration correlates with the presence of SARS-CoV-2 infected cells in the interstitium and the duration of disease, but not with underlying medical conditions ( 22 ). Another study has found evidence of viral replication in cardiomyocytes in human engineered heart tissues ( 23 ). Further work is needed to resolve key issues relating to viral involvement of the myocardium, including the identification of the most commonly infected cell type ( 22 , 23 ).…”