Abstract P3121: Serological Mechanisms Driving Cardiotoxicity In Covid-19

Abstract

Cardiac involvement is common in patients severely ill with COVID-19 and is associated with increased morbidity and mortality. The mechanism for myocardial injury in COVID-19 has been proposed to be at least in part due to a direct viral cytotoxic effect on cardiomyocytes. Preclinical data corroborate the notion that SARSCoV-2 can enter and replicate within hiPSC-derived cardiomyocytes. However, clinical evidence demonstrating direct viral effects on the heart remains limited. Alternatively, cardiac injury may result from excessive inflammatory cytokine production which is the main driver for the pathogenesis in COVID-19. Despite this, cardiotoxicity secondary to hyperinflammation constitutes a potentially amenable mechanism that remains largely unexplored. To investigate serological drivers of cardiotoxicity in COVID-19 we have established a bioassay that assessed the effects of serum from COVID-19 confirmed patients on human embryonic stem cell-derived cardiomyocytes (hESC-CMs). We demonstrate that serum from COVID-19 positive patients significantly reduced cardiomyocyte viability and contractility independent of viral transduction. Serum from patients with greater disease severity led to worse cardiomyocyte viability and this significantly correlated with levels of key inflammatory cytokines, including IL-6, TNF-α, IL1-β, IL-10, CRP and neutrophil to lymphocyte ratio with a specific reduction of CD4+ and CD8+ cells. Combinatorial blockade of IL-6 and TNF-α partially reversed the phenotype and preserved cardiomyocyte viability and function. Interestingly, treatment with serum from Systemic Inflammatory Response Syndrome (SIRS) patients recapitulates the effect observed with COVID-19 patients’ serum indicating that the phenotype observed is most likely not unique to COVID-19 disease. In conclusion, our results provide direct evidence that inflammatory cytokines are at least in part responsible for the cardiovascular damage seen in COVID-19 and indicate possible targets for therapeutic intervention.