Abstract We126: Myocarditis Following mRNA Vaccination for COVID-19 is Mediated by CXCL10 and IFN-γ

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Introduction: mRNA vaccines have shown remarkable efficacy against symptomatic COVID-19, reshaping the pandemic's trajectory. Despite a robust safety profile, ongoing monitoring is crucial due to the rare but concerning myocarditis cases, predominantly affecting males under 30. Symptoms appear around 2.6 days post-vaccination, with chest pain, shortness of breath, and palpitations. Elevated cTnI and ST-segment changes are common, along with late gadolinium enhancement in cardiac MRI. Understanding these rare adverse effects is essential for the expanding scope of mRNA technology, spanning infectious disease vaccines and anti-cancer immunotherapies. Hypothesis: Myocarditis linked to COVID-19 mRNA vaccines involves cytokine production from myeloid cells, leading to impaired cardiac function. Methodology: a, Reanalysis of proteomics data of healthy and myocarditis individuals following COVID-19 vaccination; b, Macrophages (N = 7 lines) were exposed to BNT162b2 or mRNA-1273, and analyzed by cytokine array and RNA-seq; c, Cardiomyocytes (N = 4 lines) were treated with CXCL10 (1 and 10 ng/mL) and IFN-γ (0.5 and 5 ng/mL), with or without genistein (10 μM), followed by functional assessment, transcriptomic and proteomic profiling; d, Mice (6 per group) were administered with CXCL10 and IFN-γ, with or without genistein pretreatment (7 days). Myeloid cell infiltration in the heart, serum cTnI levels, RNA-seq, and immunoproteasome activity were analyzed. Results: Examination of post-vaccination plasma revealed a notable rise in CXCL10 and IFN-γ levels in patients. Similarly, macrophages exposed to mRNA vaccines displayed heightened production of these cytokines. When cardiomyocytes were exposed to these cytokines, they exhibited compromised contractility, increased arrhythmogenicity, and gene expression patterns reminiscent of myocarditis. Genistein, an anti-inflammatory phytoestrogen, demonstrated significant alleviation of these effects, preventing cytokine-induced proteasomal activation and preserving contractile function. Mouse model of cytokine-induced myocarditis showed that genistein substantially reduced cardiac injury markers and immune cell infiltration. Conclusion: These findings highlight CXCL10 and IFN-γ as pivotal contributors to myocarditis following mRNA vaccination and suggest genistein as a potential therapeutic intervention to mitigate associated cardiovascular risks.

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