Proinflammatory cytokines driving cardiotoxicity in Covid-19.

Publication date: Dec 02, 2023

Cardiac involvement is common in patients hospitalised with COVID-19 and correlates with an adverse disease trajectory. While cardiac injury has been largely attributed to direct viral cytotoxicity, serum-induced cardiotoxicity secondary to serological hyperinflammation constitutes a potentially amenable mechanism that remains largely unexplored. To investigate serological drivers of cardiotoxicity in COVID-19 we have established a robust bioassay that assessed the effects of serum from COVID-19 confirmed patients on human embryonic stem cell (hESC)-derived cardiomyocytes. We demonstrate that serum from COVID-19 positive patients significantly reduced cardiomyocyte viability independent of viral transduction, an effect that was also seen in acute respiratory distress syndrome (ARDS). 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 partly rescued the phenotype and preserved cardiomyocyte viability and function. Bulk RNA sequencing of serum-treated cardiomyocytes elucidated specific pathways involved in the COVID-19 response impacting cardiomyocyte viability, structure and function. The observed effects of serum-induced cytotoxicity were cell-type selective as serum exposure did not adversely affect microvascular endothelial cell viability but resulted in endothelial activation and a procoagulant state. These results provide direct evidence that inflammatory cytokines are at least in part responsible for the cardiovascular damage seen in COVID-19 and characterise the downstream activated pathways in human cardiomyocytes. The serum signature of patients with severe disease indicates possible targets for therapeutic intervention.

Concepts Keywords
Bioassay Cardiac
Cardiotoxicity Cardiomyocyte
Cd4 Cardiomyocytes
Unexplored Cardiotoxicity
Viral Covid
Cytokines
Cytotoxicity
Direct
Il
Induced
Inflammatory
Serological
Serum
Viability
Viral

Semantics

Type Source Name
disease MESH Covid-19
disease IDO cell
disease VO viability
disease MESH acute respiratory distress syndrome
drug DRUGBANK Interleukin-10
disease IDO intervention

Original Article

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