Abstract 12645: Role of Viral Rna-Triggered Innate Immune Activation on Cardiac Arrhythmias Associated With Covid-19

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Background: The COVID-19 pandemic has highlighted how little is known about how double stranded RNA (dsRNA) viruses like the SARS-CoV-2 impact cardiac physiology acutely and long-term. While it is unclear if the cardiac effects are direct or indirect, adverse effects in patients are common, including cardiac inflammation, electrophysiological changes in QT interval, atrial fibrillation, bradyarrhythmia, and ventricular tachycardia. Mechanisms underlying these COVID-19-associated arrhythmias are unknown. Methods: We assess the effects of SARS-CoV-2 infection on cardiac electrophysiology and inflammatory pathway activation in a hamster model over a 4-week timespan. We further test if activation of antiviral innate immune responses with a dsRNA mimetic, Poly I:C (PI:C) induces similar effects in uninfected hearts and in human iPSC-derived cardiomyocytes (hiPSC-CMs), examining the determinants of RNAseL activation, interferon (IFN) signaling, and cytokine release in vivo and in vitro. Results: Intranasal SARS-CoV-2 USA-WA1 infection of hamsters caused ECG abnormalities including bradycardia and cardiac conduction defects including sinus pauses, 2 nd and 3 rd degree Atrio-Ventricular block. Bradycardia peaked at 4-5 days after infection. Mean RR interval increased from 182±4ms pre- to 233±6ms post-infection, without significant increases in mock-infected hamsters. In the absence of viral infection, ventricular injection of PI:C induced similar arrhythmias and induction of IFN-stimulated genes. PI:C treatment of hiPSC-CMs induced robust increases in type-I IFN pathway proteins STAT1/pSTAT1, OAS2 (48% increase) and OAS3 (32% increase) and a robust cytokine response. Negative effects on excitation-contraction coupling after 72hr of PI:C treatment, manifested as a 25% reduction in hiPSC-CM Ca 2+ transient peaks. In vitro studies showed increased RNA degradation after PI:C, consistent with activation of the OAS/RNAseL dsRNA sensor pathway. Conclusions: COVID-19 in the hamster model recapitulates a subset of arrhythmias observed in COVID-19 patients. Activation of the viral dsRNA innate immune sensor pathway, even in the absence of active cardiac viral replication, may contribute to SARS-CoV-2-associated cardiac dysfunction.