SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells

Abstract

Background: Increasing evidence suggests that cardiac arrhythmias are frequent clinical features of coronavirus disease 2019 (COVID-19). Sinus node damage may lead to bradycardia. However, it is challenging to explore human sinoatrial node (SAN) pathophysiology due to difficulty in isolating and culturing human SAN cells. Embryonic stem cells (ESCs) can be a source to derive human SAN-like pacemaker cells for disease modeling. Methods: We used both a hamster model and human ESC (hESC)–derived SAN-like pacemaker cells to explore the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pacemaker cells of the heart. In the hamster model, quantitative real-time polymerase chain reaction and immunostaining were used to detect viral RNA and protein, respectively. We then created a dual knock-in SHOX2:GFP;MYH6:mCherry hESC reporter line to establish a highly efficient strategy to derive functional human SAN-like pacemaker cells, which was further characterized by single-cell RNA sequencing. Following exposure to SARS-CoV-2, quantitative real-time polymerase chain reaction, immunostaining, and RNA sequencing were used to confirm infection and determine the host response of hESC-SAN–like pacemaker cells. Finally, a high content chemical screen was performed to identify drugs that can inhibit SARS-CoV-2 infection, and block SARS-CoV-2–induced ferroptosis. Results: Viral RNA and spike protein were detected in SAN cells in the hearts of infected hamsters. We established an efficient strategy to derive from hESCs functional human SAN-like pacemaker cells, which express pacemaker markers and display SAN-like action potentials. Furthermore, SARS-CoV-2 infection causes dysfunction of human SAN-like pacemaker cells and induces ferroptosis. Two drug candidates, deferoxamine and imatinib, were identified from the high content screen, able to block SARS-CoV-2 infection and infection-associated ferroptosis. Conclusions: Using a hamster model, we showed that primary pacemaker cells in the heart can be infected by SARS-CoV-2. Infection of hESC-derived functional SAN-like pacemaker cells demonstrates ferroptosis as a potential mechanism for causing cardiac arrhythmias in patients with COVID-19. Finally, we identified candidate drugs that can protect the SAN cells from SARS-CoV-2 infection.

Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID

“…Han et al elegantly demonstrated that SARS-CoV-2 can infect the sinoatrial node in hamsters and human embryonic stem cell-derived sinoatrial-like pacemaker cells resulting in sinoatrial node-dysfunction including changes in calcium handling, activated inflammatory pathways, and induced ferroptosis. 68 Although we did not find evidence of localized or diffuse fibrosis on cardiac MRI or evidence of sinus node dysfunction on ambulatory rhythm monitoring or ECG monitoring during CPET (ie sinus pauses, Wenckebach, blocked PACs), sinus node dysfunction could explain chronotropic incompetence.…”

The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease

“…Primary pacemaker cells in the heart have been shown to develop ferroptosis-associated cardiac dysfunction after infection with SARS-CoV-2 (ref. 221 ). Moreover, a high-throughput chemical screen showed that the tyrosine kinase inhibitor imatinib and the iron-chelating agent deferoxamine can block SARS-CoV-2 infection and associated ferroptosis 221 .…”

“… 221 ). Moreover, a high-throughput chemical screen showed that the tyrosine kinase inhibitor imatinib and the iron-chelating agent deferoxamine can block SARS-CoV-2 infection and associated ferroptosis 221 .…”

Genesis of arrhythmia in the course of COVID-19

“…Researchers using a type of pluripotent stem cell (hPSC) called human embryonic stem cells (hESC), have found that SARS-CoV-2 can readily infect pacemaker cells and induce a process known as ferroptosis [ 7 ]. Apoptosis, necrosis, autophagy, and other kinds of cell death are all distinct from ferroptosis, which is an iron-dependent cell death.…”

“…The researchers examined the impact of chelating agents on the elimination of iron from the circulation and thus prevent the ferroptosis process. The chelating agents deferoxamine and imatinib were shown to prevent SARS-CoV-2-induced ferroptosis in the heart’s pacemaker cells [ 7 ].…”