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 8

Effects of mitochondrial ROS scavenging or JAK/STAT inhibition on pulmonary and cardiac sequelae of COVID-19.

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Effects of mitochondrial ROS scavenging or JAK/STAT inhibition on pulmon...
(A and B) COVID-19–induced changes in body weight (A) or temperature (B) were not significantly altered by mitoTEMPO (mTEMPO) or ruxolitinib (Ruxo) treatments. (C) SARS-CoV-2–induced tachypnea was significantly attenuated by both mTEMPO and Ruxo treatments. †P < 0.005, ‡P < 0.0001. (D) mTEMPO, but not Ruxo, attenuated the increase in RR interval at 1 and 3 dpi. After returning to baseline level at 7 dpi, both treatments showed no impact on the redeveloped bradycardia. *P < 0.05, ‡P < 0.0001. (E and F) The early spike in sinus pauses (E) and RMSSD (F) at 1 dpi were not significantly decreased by either treatment. Both Ruxo and mTEMPO attenuated the late effects of SARS-CoV-2 infection on sinus pauses at 21 or 28 dpi, respectively (*P < 0.05). Only mTEMPO significantly suppressed RMSSD at 28 dpi (*P < 0.05). (G) Both treatments significantly attenuated the incidence of AV block 1–7 dpi and abrogated the sustained increase in AV block at 14–28 dpi. (*P < 0.05, †P < 0.01; compared with SARS-CoV-2 alone, blue symbols are Ruxo treatment, green symbols are mTEMPO treatment; see Supplemental Table 4 for additional within group comparisons with 0 dpi.) (H) Iba1+ macrophage density increased in the CCS region in all SARS-CoV-2–infected groups, regardless of treatment at 4 dpi, and returned to baseline level at 28 dpi, except in the mTEMPO-treated group). (I) Treatment with either mTEMPO or Ruxo prevented the decrease in CD163+ macrophage density in the conduction region at 4 dpi. Two-way mixed-effect ANOVA was performed for H and I. We analyzed 3–11 hamsters per group per parameter. n = 3 for groups of 4 dpi and n = 4 for groups of 28 dpi. Each heart has 3 repeats. Ruxo and mitoTEMPO treatment data are superimposed on that of mock- and untreated SARS-CoV-2–infected groups reproduced from Figures 1 and 2.