Dynamic changes in cardiac autonomic function persist in the postacute phase after SARS-CoV-2 infection in a hamster model of COVID-19.

BACKGROUND: Autonomic nervous system (ANS) dysfunction is a central feature of long coronavirus disease syndrome, yet little is known about how it develops during and after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. OBJECTIVE: This study aimed to characterize the time course of dynamic changes in linear and nonlinear heart rate variability measurements as indices of ANS function for up to 2 months after infection. METHODS: Hamsters implanted with radiotelemetry devices were inoculated with SARS-CoV-2. Electrocardiograms and subpleural pressures were recorded before infection, and for 56 days postinfection (DPI). Heart rate variability and respiratory sinus arrhythmia were analyzed and compared with the preinfection baseline or mock-infected controls. Ruxolitinib or mitochondrially targeted 2,2,6,6-tetramethylpiperidine-1-oxyl was administered from 4 days before infection to 10 DPI to assess the effects of Jak/Stat inhibition or antioxidant treatment, respectively. RESULTS: ANS activity follows 3 phases after infection: (1) a pronounced increase in parasympathetic activity relative to sympathetic activity during the acute phase of infection (1-4 DPI), (2) a decrease in overall ANS activity in the subacute phase (7-14 DPI), and (3) re-emergence of elevated sympathetic and parasympathetic inputs that continue to increase during the postacute phase (28-56 DPI). The conclusions are corroborated by changes in respiratory sinus arrhythmia analysis and acute pharmacologic inhibition of cholinergic and β-adrenergic signaling. Postacute ANS remodeling was suppressed by early inhibition of innate immune signaling or mitochondrial oxidative stress. CONCLUSION: Cardiac dysautonomia after SARS-CoV-2 infection is phase dependent. Inhibiting early immune activation or mitochondrial oxidative stress during the acute phase offers a strategy to suppress postacute ANS remodeling that could contribute to long coronavirus disease syndrome.