Abstract Fri044: CXCL10 and IFN-γ Drive Myocardial Injury Following COVID-19 mRNA Vaccination

Introduction: mRNA vaccines have demonstrated remarkable efficacy in preventing COVID-19, significantly impacting the pandemic. While generally safe, rare cases of myocarditis, primarily in young males after the second dose, have been reported. Symptoms appear around 2.6 days post-vaccination, with elevated cardiac Troponin I and cardiac MRI abnormalities. Most cases recover well, but understanding the unique mechanism behind vaccine-associated myocarditis is essential. As mRNA technology expands into new applications, ensuring its safety remains a critical priority for future advancements. Methodology and Results: Our study identified elevated levels of CXCL10 and IFN-γ following mRNA vaccination through human plasma analysis and in vitro experiments with human macrophages and T cells. Neutralizing these cytokines significantly reduced vaccine-induced cardiac injury in mice and iPSC-derived cardiac spheroids. In vitro, iPSC-derived cardiomyocytes exposed to these cytokines exhibited impaired contractility, arrhythmogenicity, and pro-inflammatory gene expression. Genistein, an anti-inflammatory phytoestrogen, effectively mitigated these effects by blocking cytokine-induced immunoproteasome activation. In vivo, genistein treatment reduced cardiac injury markers and suppressed immune cell infiltration in the hearts of mice exposed to these cytokines or receiving mRNA vaccination. These findings highlight CXCL10 and IFN-γ as key mediators of myocardial injury post-mRNA vaccination and suggest genistein as a potential therapeutic strategy to minimize adverse cardiac effects, providing valuable insights for the development of safer mRNA vaccines. Conclusion: These findings highlight CXCL10 and IFN-γ as key drivers of myocardial injury post-mRNA vaccination. Genistein effectively mitigates these effects, suggesting its potential as a therapeutic strategy. This insight could guide future advancements in mRNA vaccine technology, improving safety and reducing adverse cardiovascular outcomes.