In a groundbreaking study published in the journal Science, researchers from Massachusetts General Hospital have uncovered a previously unknown mechanism by which immune cells contribute to the deadly arrhythmias that frequently follow heart attacks. The study, led by Nina Kumowski, MD, and senior author Matthias Nahrendorf, MD, PhD, reveals that a protein secreted by neutrophils—key players in the immune response—directly damages heart muscle cells and promotes dangerous ventricular arrhythmias that can lead to sudden cardiac death.
Coronary artery disease remains the leading cause of death worldwide, with myocardial infarction (MI), or heart attack, representing its most catastrophic manifestation. Following an MI, the interruption of blood flow abruptly deprives cardiac muscle cells, or cardiomyocytes, of oxygen, leading to widespread cell death and tissue damage. Beyond the immediate loss of heart muscle, patients face a looming risk of arrhythmia—irregular heart rhythms characterized by either rapid coordinated beats known as ventricular tachycardia (VT) or chaotic uncoordinated contractions called ventricular fibrillation (VF). These arrhythmias often precipitate sudden cardiac arrest if not rapidly managed.
While cardiomyocytes themselves have long been the central focus in arrhythmia research, this study pivots attention toward the immune system’s role, specifically neutrophils, which flood the infarct area shortly after MI. Using advanced gene expression techniques, the researchers identified a striking upregulation of a gene called Retnlg in mouse neutrophils infiltrating the damaged heart tissue. Retnlg encodes the protein resistin-like molecule gamma (RELMy), a member of the resistin family known primarily for its involvement in inflammatory processes. Crucially, a homologous gene, RETN, was also found to be highly expressed in human heart tissue following infarction, underscoring the translational relevance of these findings.
Delving deeper into the molecular interactions, the team employed cutting-edge microscopy techniques, including confocal and super-resolution imaging, that allowed them to visualize how RELMy interacts directly with cardiomyocyte membranes. The protein essentially punches holes in the membranes of heart muscle cells, compromising their electrical stability and predisposing them to the dangerous, fast heart rhythms characteristic of VT and VF. This membrane disruption leads not only to arrhythmias but also to the death of cardiomyocytes, further exacerbating cardiac injury.
To establish causality, the researchers conducted genetic deletions of Retnlg in mouse models of myocardial infarction. Remarkably, mice lacking this gene in their bone marrow-derived cells, notably neutrophils, exhibited a dramatic 12-fold decrease in arrhythmia episodes after MI, starkly demonstrating the protein’s pivotal role in driving ventricular arrhythmias. These findings position RELMy—not cardiomyocytes alone—as a central factor in post-infarct arrhythmogenesis, reshaping our understanding of how immune cell activities can directly influence electrical stability in the heart.
The implications of this work extend far beyond academic insight. Current clinical management of myocardial infarction focuses primarily on restoring blood flow via recanalization and managing arrhythmias with broadly acting antiarrhythmic drugs or implantable devices, approaches that do not specifically target immune-mediated pathways. This study suggests that adjunct therapies aimed at modulating neutrophil activity or neutralizing RELMy could offer a novel and more targeted strategy to prevent life-threatening arrhythmias post-MI.
Furthermore, the research challenges the paradigm of nonspecific immune suppression by highlighting the potential to selectively block detrimental immune pathways while preserving necessary inflammatory responses. Fine-tuned immunomodulation could reduce off-target effects common to broad-spectrum immunosuppressants, such as increased susceptibility to infection, and unleash the full therapeutic potential in cardiovascular disease management.
The research team’s multi-faceted approach—spanning single-cell and spatial transcriptomics, comparative human tissue analysis, and innovative in vitro and in vivo experiments—represents a methodological tour de force. Utilizing spatial RNA sequencing allowed the precise mapping of Retnlg expression within the infarct zone, while liposome assays and cell culture experiments confirmed the membrane-perforating properties of RELMy in both mouse and human protein variants.
Looking ahead, the next critical step involves developing methods to neutralize RELMy or inhibit its interaction with cardiomyocyte membranes. Preclinical trials in mouse models will evaluate whether such interventions can reduce the arrhythmia burden and limit infarct size, improvements that could translate into significantly better outcomes for heart attack patients. Extending these findings to human clinical trials remains a hopeful yet challenging goal.
Moreover, given that neutrophil recruitment and activation are hallmarks of numerous inflammatory conditions, the discovery that RELMy drives arrhythmia may have broader implications. Other diseases with significant neutrophil involvement could also entail similar deleterious effects on tissue electrical stability or cell viability, opening new avenues of investigation into immune-mediated tissue injury across different organ systems.
This landmark study pushes the frontier of cardiovascular research by integrating immunology and electrophysiology, revealing a critical and actionable link between immune cell–derived proteins and the mechanisms of sudden cardiac death. It highlights the importance of looking beyond traditional cellular targets to understand complex disease processes and offers a promising new therapeutic angle for one of medicine’s most intractable post-infarct complications.
As the medical community grapples with improving survival and quality of life for millions of myocardial infarction survivors, this novel insight that neutrophil-derived RELMy undermines heart cell integrity and electrical stability signals a paradigm shift. By illuminating the molecular players bridging inflammation and arrhythmia, this research opens a path forward toward precision therapies that could save countless lives.
The study’s support from major institutions including the National Institutes of Health, the British Heart Foundation, and the Deutsche Forschungsgemeinschaft underscores its significance and the broad interest in targeting immune mechanisms within cardiovascular disease. Ongoing collaborations among scientists, clinicians, and pharmaceutical partners will be essential to translate these groundbreaking findings into new clinical tools for managing post-MI arrhythmias.
In conclusion, the identification of resistin-like molecule gamma as a key immune effector attacking cardiomyocyte membranes marks a major advance in our understanding of sudden cardiac death mechanisms. Through sophisticated genetic, molecular, and imaging techniques, Nina Kumowski, Matthias Nahrendorf, and their colleagues have revealed a critical immune-mediated driver of ventricular tachycardia, setting the stage for innovative therapies that target the intersection of immunity and cardiac electrophysiology.
Subject of Research: The role of neutrophil-derived resistin-like molecule gamma (RELMy) in promoting ventricular tachycardia post-myocardial infarction by disrupting cardiomyocyte membranes.
Article Title: Resistin-like molecule γ attacks cardiomyocyte membranes and promotes ventricular tachycardia
News Publication Date: 4-Sep-2025
Web References: https://doi.org/10.1126/science.adp7361
References: Kumowski N, et al. “Resistin-like molecule γ attacks cardiomyocyte membranes and promotes ventricular tachycardia.” Science. DOI: 10.1126/science.adp7361
Keywords: myocardial infarction, ventricular tachycardia, neutrophils, immune-mediated arrhythmia, resistin-like molecule gamma, cardiac electrophysiology, inflammation, cardiac cell membrane disruption, sudden cardiac death, immunomodulation, spatial RNA sequencing, cardiovascular disease
