Innate immune activation and mitochondrial ROS induce acute and persistent cardiac conduction system dysfunction after COVID-19
Deepthi Ashok, Ting Liu, Misato Nakanishi-Koakutsu, Joseph Criscione, Meghana Prakash, Alexis Tensfeldt, Byunggik Kim, Bryan Ho, Julian Chow, Morgan Craney, Mark J. Ranek, Brian L. Lin, Kyriakos Papanicolaou, Agnieszka Sidor, D. Brian Foster, Hee Cheol Cho, Andrew Pekosz, Jason Villano, Deok-Ho Kim, Brian O’Rourke
Deepthi Ashok, Ting Liu, Misato Nakanishi-Koakutsu, Joseph Criscione, Meghana Prakash, Alexis Tensfeldt, Byunggik Kim, Bryan Ho, Julian Chow, Morgan Craney, Mark J. Ranek, Brian L. Lin, Kyriakos Papanicolaou, Agnieszka Sidor, D. Brian Foster, Hee Cheol Cho, Andrew Pekosz, Jason Villano, Deok-Ho Kim, Brian O’Rourke
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Research Article Cardiology Immunology Infectious disease

Innate immune activation and mitochondrial ROS induce acute and persistent cardiac conduction system dysfunction after COVID-19

Abstract

Cardiac arrhythmias increase during acute SARS-CoV-2 infection and in long COVID syndrome, by unknown mechanisms. This study explored the acute and long-term effects of COVID-19 on cardiac electrophysiology and the cardiac conduction system (CCS) in a hamster model. Electrocardiograms and subpleural pressures were recorded by telemetry for 4 weeks after SARS-CoV-2 infection, and interferon-stimulated gene expression and macrophage infiltration of the CCS were assessed at 4 days and 4 weeks postinfection. COVID-19 induced pronounced tachypnea and cardiac arrhythmias, including bradycardia and persistent atrioventricular block, though no viral protein expression was detected in the heart. Arrhythmias developed rapidly, partially reversed, and then redeveloped, indicating persistent CCS injury. COVID-19 induced cardiac cytokine expression, connexin mislocalization, and CCS macrophage remodeling. Interestingly, sterile innate immune activation by direct cardiac injection of polyinosinic:polycytidylic acid (PIC) induced arrhythmias similar to those of COVID-19. PIC strongly induced cytokine secretion and interferon signaling in hearts, human induced pluripotent stem cell–derived cardiomyocytes, and engineered heart tissues, accompanied by alterations in excitation-contraction coupling. Importantly, the pulmonary and cardiac effects of COVID-19 were blunted by JAK/STAT inhibition or a mitochondrially targeted antioxidant, indicating that SARS-CoV-2 infection indirectly leads to arrhythmias by innate immune activation and redox stress, which could have implications for long COVID syndrome.

Authors

Deepthi Ashok, Ting Liu, Misato Nakanishi-Koakutsu, Joseph Criscione, Meghana Prakash, Alexis Tensfeldt, Byunggik Kim, Bryan Ho, Julian Chow, Morgan Craney, Mark J. Ranek, Brian L. Lin, Kyriakos Papanicolaou, Agnieszka Sidor, D. Brian Foster, Hee Cheol Cho, Andrew Pekosz, Jason Villano, Deok-Ho Kim, Brian O’Rourke

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Figure 4

The dsRNA mimetic PIC induces cardiac arrhythmias and innate immune responses in the absence of viral infection in guinea pigs.

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The dsRNA mimetic PIC induces cardiac arrhythmias and innate immune resp...
(A–D) Representative ECG traces showing regular cardiac rhythm in a vehicle-injected control (A) and bradycardia (B), sinus pauses (C; marked by arrows), and AV block (D) after cardiac injection of polyinosinic:polycytidylic acid (PIC) in guinea pigs (arrowheads in D indicate abnormal P waves; horizontal bar equals 2 seconds). (E–I) Summary data showing increase in RR interval (E), sinus pauses longer than mean RR+2SD (F), corrected QT (H), and QT interval (I) but no increase in PR interval (G) 4 days after myocardial PIC injection in guinea pigs. Welch’s 2-tailed t test was done for B–F. (J) Increased expression of innate immune response genes induced by PIC, expressed as fold-change from vehicle-injected controls, was observed. Mann-Whitney test was done for IL-1β, CCL2, and TNF-α. Welch’s 2-tailed t test was performed for TGF-β, Casp3, and OAS1. (K) Ca2+ transient analysis of adult cardiomyocytes isolated from guinea pig hearts injected with either PIC+AdV-GFP or AdV-GFP alone (AdV-GFP was used to identify myocytes near the injection site; unpaired 2-tailed t test).