Pacemaker Cells Vulnerable to SARS-CoV-2

The SARS-CoV-2 virus can infect specialized pacemaker cells that maintain the heart’s rhythmic beat, setting off a self-destruction process within the cells, according to a preclinical study co-led by researchers at Weill Cornell Medicine, NewYork-Presbyterian and NYU Grossman School of Medicine. The findings offer a possible explanation for the heart arrhythmias that are commonly observed in patients with SARS-CoV-2 infection.

Using both an animal model and human stem cell-derived pacemaker cells, the team was able to show that SARS-CoV-2 can readily infect pacemaker cells and trigger ferroptosis, the process by which cells self-destruct but also produce reactive oxygen molecules that can impact nearby cells.

“This is a surprising and apparently unique vulnerability of these cells—we looked at a variety of other human cell types that can be infected by SARS-CoV-2, including even heart muscle cells, but found signs of ferroptosis only in the pacemaker cells,” says co-author Dr. Shuibing Chen, the Kilts Family Professor of Surgery and a professor of chemical biology in surgery and of chemical biology in biochemistry at Weill Cornell Medicine.

Arrhythmias including tachycardia and bradycardia heart rhythms have been noted among many COVID-19 patients, and multiple studies have linked these abnormal rhythms to worse COVID-19 outcomes. How SARS-CoV-2 infection caused such arrhythmias has been unclear, however.

Using golden hamsters—one of the only lab animals that reliably develops COVID-19-like signs from SARS-CoV-2 infection—the team found evidence that the virus can infect the cells of the natural cardiac pacemaker unit, known as the sinoatrial node. The team was also able to show that human embryonic stem cells coaxed into becoming cells closely resembling sinoatrial node cells express receptor ACE2 and other factors SARS-CoV-2 uses to get into cells. These cells were also readily infected by SARS-CoV-2, and large increases in inflammatory immune gene activity in the infected cells were observed.

The team’s most surprising finding, however, was that the pacemaker cells, in response to the stress of infection, showed clear signs of a cellular self-destruct process called ferroptosis. They were able to reverse these signs in the cells using compounds that are known to bind iron and inhibit ferroptosis.

“This finding suggests that some of the cardiac arrhythmias detected in COVID-19 patients could be caused by ferroptosis damage to the sinoatrial node,” says co-senior author Dr. Robert Schwartz, an associate professor of medicine in the Division of Gastroenterology and Hepatology at Weill Cornell Medicine and a hepatologist at NewYork-Presbyterian/Weill Cornell Medical Center.

Although in principle COVID-19 patients could be treated with ferroptosis inhibitors specifically to protect sinoatrial node cells, antiviral drugs that block the effects of SARS-CoV-2 infection in all cell types would be preferable, the researchers said.

The researchers plan to continue to use their cell and animal models to investigate sinoatrial node damage in COVID-19 and other diseases. “There are other human sinoatrial arrhythmia syndromes we could model with our platform,” says Dr. Todd Evans, the Peter I. Pressman M.D. Professor of Surgery and associate dean for research at Weill Cornell Medicine. “And, although physicians currently can use an artificial electronic pacemaker to replace the function of a damaged sinoatrial node, there’s the potential here to use sinoatrial cells such as we’ve developed as an alternative, cell-based pacemaker therapy.”

The findings were published recently in Circulation Research.