Cardiovascular pathophysiology upon SARS-CoV-2 infection and COVID-19 vaccination

Abstract

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, which lead to the coronavirus disease 2019 (COVID-19) has posed a major threat to the global public health-care system. Cardiac involvement has been frequently observed in severe cases of COVID-19. Meanwhile, although vaccination had played an important role in the fight against the pandemic, there have been major concerns about COVID-19 vaccine-associated severe adverse events, in particular cardiovascular complications. This project aims to model cardiovascular pathophysiology upon SARS-CoV-2 infection and COVID-19 vaccination in vitro, and thereby develop a deeper understanding on the underlying mechanisms. Three in vitro cardiovascular models including human embryonic stem cell (hESC)-derived cardiomyocytes, engineered human ventricular cardiac tissue strip (hvCTS), and engineered human blood vessel construct were employed. The cardiovascular tropism and pathogenesis of wild-type SARS-CoV-2 were compared with that of two variants of concern (VOCs): Delta, and Omicron BA. All three variants were found to have productive replication in hESC-derived cardiomyocytes, with the wild-type SARS-CoV-2 and Delta showing a significantly higher replication competency over Omicron BA.1. While cytokines and chemokines production were minimal, VEGF signalling pathway was shown to be altered upon infection, and cardiac contractile skeleton was found to be disrupted especially in wild-type SARS-CoV-2 infected cardiomyocytes. These results have implications for the understanding of the pathogenesis of cardiac dysfunction in COVID-19. The change in cardiac contractile function upon two types of COVID-19 vaccines, namely mRNA vaccine BNT162b2 and inactivated vaccine CoronaVac, was modelled with hvCTS. It was shown that hvCTS contractile functions were impeded upon treatment with either vaccine, accompanied with a depressed force-frequency relationship. Both contraction time and relaxation time of hvCTS were prolonged upon vaccine treatments, implicating a negative impact of the vaccines on the systolic and diastolic functions of the human heart. The negative effects of the vaccines on cardiac functionality were observed to resolve over a longer period of time. Finally, the effects of BNT162b2 mRNA vaccine and CoronaVac inactivated vaccine on vascular function were studied using an in vitro blood vessel construct. Both vaccines were found to impair vascular integrity and compromise endothelial cell survival. Distinct pathways of cell survival, inflammation, and coagulation were found to be involved BNT162b2 and CoronaVac-mediated vascular pathology. BNT162b2 was shown to trigger profound proinflammatory responses with upregulation endothelial activation markers in the blood vessel construct. On the other hand, cytokine or chemokine productions were not significant in CoronaVac-treated blood vessel construct, but expressions of biomolecules involved in platelet activation and thrombus formation were found dysregulated and may have implications on ischemic events. Overall, this study modelled cardiovascular events associated with SARS-CoV-2 infections and COVID-19 vaccinations. The study provided insight on the pathogenesis of these cardiovascular events that is crucial for the development of corresponding therapeutic and disease prevention strategies.