Human Cardiac Pericytes are Susceptible to SARS-CoV-2 Infection.

Coronavirus disease 2019 (COVID-19) is associated with serious cardiovascular complications, with incompletely understood mechanism(s). Pericytes have key functions in supporting endothelial cells and maintaining vascular integrity. We demonstrate that human cardiac pericytes are permissive to SARS-CoV-2 infection in organotypic slice and primary cell cultures. Viral entry into pericytes is mediated by endosomal proteases, and infection leads to upregulation of inflammatory markers, vasoactive mediators, and NF-κB-dependent cell death. Furthermore, we present evidence of cardiac pericyte infection in COVID-19 myocarditis patients. These data demonstrate that human cardiac pericytes are susceptible to SARS-CoV-2 infection and suggest a role for pericyte infection in COVID-19.

Cardiovascular Tropism and Sequelae of SARS-CoV-2 Infection.

The extrapulmonary manifestation of coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), became apparent early in the ongoing pandemic. It is now recognized that cells of the cardiovascular system are targets of SARS-CoV-2 infection and associated disease pathogenesis. While some details are emerging, much remains to be understood pertaining to the mechanistic basis by which SARS-CoV-2 contributes to acute and chronic manifestations of COVID-19. This knowledge has the potential to improve clinical management for the growing populations of patients impacted by COVID-19. Here, we review the epidemiology and pathophysiology of cardiovascular sequelae of COVID-19 and outline proposed disease mechanisms, including direct SARS-CoV-2 infection of major cardiovascular cell types and pathogenic effects of non-infectious viral particles and elicited inflammatory mediators. Finally, we identify the major outstanding questions in cardiovascular COVID-19 research.

Cardiovascular Tropism and Sequelae of SARS-CoV-2 Infection

The extrapulmonary manifestation of coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), became apparent early in the ongoing pandemic. It is now recognized that cells of the cardiovascular system are targets of SARS-CoV-2 infection and associated disease pathogenesis. While some details are emerging, much remains to be understood pertaining to the mechanistic basis by which SARS-CoV-2 contributes to acute and chronic manifestations of COVID-19. This knowledge has the potential to improve clinical management for the growing populations of patients impacted by COVID-19. Here, we review the epidemiology and pathophysiology of cardiovascular sequelae of COVID-19 and outline proposed disease mechanisms, including direct SARS-CoV-2 infection of major cardiovascular cell types and pathogenic effects of non-infectious viral particles and elicited inflammatory mediators. Finally, we identify the major outstanding questions in cardiovascular COVID-19 research.

Boosting with variant-matched or historical mRNA vaccines protects against Omicron infection in mice.

The large number of spike substitutions in Omicron lineage variants (BA.1, BA.1.1., and BA.2) could jeopardize the efficacy of SARS-CoV-2 vaccines. We evaluated in mice the protective efficacy of the Moderna mRNA-1273 vaccine against BA.1 before or after boosting. Whereas two doses of mRNA-1273 vaccine induced high levels of neutralizing antibodies against historical WA1/2020 strains, lower levels against BA.1 were associated with breakthrough infection and inflammation in the lungs. A primary vaccination series with mRNA-1273.529, an Omicron-matched vaccine, potently neutralized BA.1 but inhibited historical or other SARS-CoV-2 variants less effectively. However, boosting with either mRNA-1273 or mRNA-1273.529 vaccines increased neutralizing titers and protection against BA.1 and BA.2 infection. Nonetheless, the neutralizing antibody titers were higher, and lung viral burden and cytokines were slightly lower in mice boosted with mRNA-1273.529 and challenged with BA.1. Thus, boosting with mRNA-1273 or mRNA-1273.529 enhances protection against Omicron infection with limited differences in efficacy measured.

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

There is ongoing debate as to whether cardiac complications of coronavirus disease-2019 (COVID-19) result from myocardial viral infection or are secondary to systemic inflammation and/or thrombosis. We provide evidence that cardiomyocytes are infected in patients with COVID-19 myocarditis and are susceptible to severe acute respiratory syndrome coronavirus 2. We establish an engineered heart tissue model of COVID-19 myocardial pathology, define mechanisms of viral pathogenesis, and demonstrate that cardiomyocyte severe acute respiratory syndrome coronavirus 2 infection results in contractile deficits, cytokine production, sarcomere disassembly, and cell death. These findings implicate direct infection of cardiomyocytes in the pathogenesis of COVID-19 myocardial pathology and provides a model system to study this emerging disease.