Role Of Innate Immune Response And Mitochondrial Ros In The Cardiac And Pulmonary Sequelae Of Covid-19

Intro: Cardiac risk rises during acute SARS-CoV-2 infection and in long COVID syndrome, but the mechanisms behind COVID-19-linked arrhythmias are unknown. Here, we test the hypothesis that innate immune activation and mitochondrial ROS contribute to cardiac conduction abnormalities and pulmonary dysfunction in a COVID-19 hamster model. Results: ECGs and subpleural pressures were recorded by radiotelemetry over a 4-week timespan after SARS-CoV-2 infection. Multiple cardiac arrhythmias were observed, including bradycardia, sinus pauses, and atrioventricular block (AVB). RR intervals and sinus arrhythmia (RR> mean+100ms, RR100) increased transiently 3-5 days after SARS-CoV-2 infection (baseline/peak: RR, 167±3ms/241±7ms; RR100, 5.5±0.4min -1 /22.7±3.0min -1 ) and returned to levels ≤ baseline by 7 dpi. After the acute phase, these measures increased above baseline over 3 weeks (at 28dpi: RR, 190±2ms, p<0.05; RR100, 13.4±1.0 min -1 , p<0.01). AVB count peaked at 3.1±0.1 min -1 at 1 dpi and gradually decreased to 0.4±0.2 min -1 by 28 dpi (vs. 0.004±0.002 at 0 dpi, p<0.05). These parameters did not change in Mock-infected controls. RT-PCR showed that RIG-I, CXCL-10, OAS1, IL-1b and CCL-2 expression increased 18, 7, 2, 3, and 2-fold, respectively, over Mock controls at 4 dpi. IF analysis of the His-bundle region showed increased abundance of inflammatory IBA-1 + macrophages and decreased anti-inflammatory CD163 + macrophages. Ruxolitinib (Jak/Stat inhibitor) or mitochondrial antioxidant (mitoTEMPO) treatments were administered via implanted osmotic pumps. Subpleural pressure recordings indicated that infection induced tachypnea peaking at 7 dpi (272±11 versus 81±17 breaths/min at 0 dpi, p<0.0001), which was attenuated by either treatment (peak: mitoTEMPO, 170±10; Ruxo,184±14). MitoTEMPO, but not Ruxolitinib, suppressed the increases in RR, RR100, and AVB during the acute phase and prevented the secondary changes in these measures in the post-acute phase (up to 28 dpi). Conclusions: The hamster model recapitulates a subset of arrhythmias observed in COVID-19 patients. Jak/Stat inhibition or mitoTEMPO treatment both mitigated acute respiratory distress, but only the latter suppressed arrhythmias during the acute and late phases of COVID-19.