Researchers at Massachusetts General Hospital have identified an immune protein that damages heart cells after a myocardial infarction, leading to dangerous arrhythmias. By targeting this protein in mice, the team reduced arrhythmia incidents twelvefold. The findings suggest new ways to prevent sudden cardiac death.
A study published in Science reveals that resistin-like molecule gamma (RELMy), produced by neutrophils, attacks cardiomyocyte membranes following a heart attack, punching holes in the cells and promoting ventricular tachycardia (VT) and ventricular fibrillation (VF). These arrhythmias, which can cause sudden cardiac arrest within minutes, most often occur within 48 hours after myocardial infarction (MI), coinciding with immune cell infiltration into the heart tissue.
Lead author Nina Kumowski, MD, from the Department of Radiology and Center for Systems Biology at Massachusetts General Hospital, explained: "We found that the defense protein 'Resistin like molecule gamma' (Relmy), produced by neutrophils, punches holes into heart cells after a heart attack. This promotes dangerous, fast, and irregular heart rhythm and cell death in the heart."
Senior author Matthias Nahrendorf, MD, PhD, noted that the research investigated how neutrophils contribute to ventricular arrhythmia post-MI. Using single-cell and spatial RNA-sequencing on mouse models, along with confocal microscopy and in vitro assays, the team found that neutrophils upregulate the Retnlg gene, coding for RELMy, in the infarct area. Deleting this gene from neutrophils reduced arrhythmia burden twelvefold in mice. A human homolog, the RETN gene coding for resistin, showed higher expression in infarcted human heart tissue compared to non-infarcted areas.
The implications highlight the role of immune cells in sudden cardiac death. "We should think about treating both the myocardial infarction by quick recanalization of the vessel to restore oxygenated blood supply and also by targeting immune cells to mitigate the arrhythmic effects of the injury," Kumowski said. Future steps include neutralizing the protein in mouse models and testing in humans to reduce VT burden and infarct size, potentially leading to targeted therapies beyond broad immune suppression.
The study was supported by grants from the Leducq Foundation, National Institutes of Health, and others. Several authors disclosed ties to pharmaceutical companies.