A new pre-clinical study co-led by researchers at Weill Cornell Medicine has found that the SARS-CoV-2 virus infecting cardiac pacemaker cells can set off a self-destruction process within the cells, offering a possible explanation for the heart arrhythmias that are commonly observed in patients with SARS-CoV-2 infection. In the study, reported in the March 8, 2022, issue of Circulation Research, the researchers used an animal model as well as human stem cell-derived pacemaker cells to show that infected pacemaker cells trigger ferroptosis. This process causes the cells to self-destruct and also produces reactive oxygen molecules that can impact nearby cells.
A new pre-clinical study co-led by researchers at Weill Cornell Medicine has found that the SARS-CoV-2 virus infecting cardiac pacemaker cells can set off a self-destruction process within the cells, offering a possible explanation for the heart arrhythmias that are commonly observed in patients with SARS-CoV-2 infection. In the study, reported in the March 8, 2022, issue of Circulation Research, the researchers used an animal model as well as human stem cell-derived pacemaker cells to show that infected pacemaker cells trigger ferroptosis. This process causes the cells to self-destruct and also produces reactive oxygen molecules that can impact nearby cells.
Dr. Shuibing Chen
“This is a surprising and apparently unique vulnerability of these cells,” says study co-senior author Shuibing Chen, PhD, the Kilts Family Professor of Surgery and a Professor of Chemical Biology in Surgery and of Chemical Biology in Biochemistry at Weill Cornell Medicine. “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.”
SARS-CoV-2 Spike protein (green) staining in the pacemaker cells (red) of SARS-CoV-2 infected hamsters. The nuclei of the cells are stained blue. (Image courtesy of Dr. Shuibing Chen)
Arrhythmias, including tachycardia and bradycardia, have been noted among many COVID-19 patients, and multiple studies have linked these abnormal rhythms to worse COVID-19 outcomes. However, how SARS-CoV-2 infection could cause such arrhythmias has been unclear. In the new study, the researchers examined golden hamsters, one of the only lab animals that reliably develops COVID-19-like signs from SARS-CoV-2 infection, and found evidence that following nasal exposure the virus can infect the sinoatrial node pacemaker cells.
To study SARS-CoV-2’s effects on pacemaker cells in more detail and with human cells, the Weill Cornell Medicine researchers used advanced stem cell techniques to induce human embryonic stem cells to mature into cells closely resembling sinoatrial node cells. They showed that these induced human pacemaker cells express the receptor ACE2 and other factors that SARS-CoV-2 uses to get into cells and are readily infected by the virus. The research team also observed large increases in inflammatory immune gene activity in the infected cells.
The pacemaker cells, in response to the stress of infection, showed clear signs of ferroptosis, a cellular self-destruct process that involves accumulation of iron and the runaway production of cell-destroying reactive oxygen molecules. The scientists were able to reverse these signs in the cells using compounds that are known to bind iron and inhibit ferroptosis.
Their most unexpected finding, however, was that the pacemaker cells, in response to the stress of infection, showed clear signs of ferroptosis, a cellular self-destruct process that involves accumulation of iron and the runaway production of cell-destroying reactive oxygen molecules. The scientists 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 Robert E. Schwartz, MD, PhD, a hepatologist at NewYork-Presbyterian/
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 noted. They plan to continue to use their cell and animal models to investigate sinoatrial node damage in COVID-19 and beyond.
“There are other human sinoatrial arrhythmia syndromes we could model with our platform,” says co-senior author Todd Evans, PhD, 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.”
