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

## TL;DR

This study shows that heart rhythm problems after COVID-19 are caused by immune system activation and oxidative stress, not direct virus infection of the heart.

## Contribution

The study reveals that innate immune activation and mitochondrial ROS, not direct viral infection, cause persistent cardiac conduction dysfunction in a hamster model of COVID-19.

## Key findings

- Cardiac arrhythmias and conduction system dysfunction persist after SARS-CoV-2 infection in hamsters.
- Innate immune activation and mitochondrial ROS drive arrhythmias, even without viral presence in the heart.
- JAK/STAT inhibition or mitochondrial antioxidants reduce arrhythmias and inflammation in the model.

## 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.

Long-lasting cardiac arrhythmias linked to innate immune activation and oxidative stress in the absence of direct cardiac viral infection in an animal model of COVID-19.