In the aftermath of a myocardial infarction, the cascade of cellular events that reshapes the injured heart often culminates in one of the deadliest complications: life-threatening arrhythmias. These abnormal heart rhythms disrupt the electrical stability essential for coordinated cardiac contractions and pose a direct threat to patient survival. Despite the advances in cardiovascular care, the precise mechanisms that bridge ischemic injury to electrical instability have remained elusive. A groundbreaking study now illuminates the pivotal role played by an unexpected culprit: a neutrophil-derived peptide known as resistin-like molecule γ (RELMγ), which directly assaults the membranes of stressed cardiomyocytes, precipitating ventricular tachycardia.
Ischemic heart disease, clinically characterized by the narrowing and subsequent blockage of coronary arteries, remains among the leading causes of global mortality. The acute oxygen deprivation that ensues during a heart attack exerts profound metabolic and electrophysiological stress on cardiomyocytes. These electrically excitable cells rely on a meticulously balanced ion flux—primarily sodium, potassium, and calcium—to maintain the cardiac action potential and synchronous contraction. Disruption of this ion homeostasis fosters a vulnerable electrophysiological substrate prone to arrhythmogenesis. The inflammatory milieu following ischemia notably shapes this substrate, with immune cells infiltrating damaged tissue and modulating cardiac function in complex, often detrimental ways.
Among the earliest responders to ischemic injury are neutrophils, frontline immune cells traditionally recognized for their antimicrobial functions. Although their role in post-infarct inflammation and tissue remodeling is well-documented, the direct electrophysiological consequences of neutrophil activity on cardiomyocytes have only recently garnered focused investigation. Prior research acknowledged that neutrophil-mediated release of reactive oxygen species and proteases could exacerbate tissue injury, but the precise molecular mediators involved in electrical destabilization remained to be identified.
Through meticulous investigations employing murine models of ischemic injury integrated with analyses of human cardiac tissue, the research led by Nina Kumowski and colleagues uncovers RELMγ as a key molecular protagonist in promoting arrhythmic risk. RELMγ, classically classified as an antimicrobial peptide with pore-forming capabilities, is abundantly secreted by neutrophils infiltrating injured myocardium. Unlike other immune mediators that indirectly alter electrophysiological properties, RELMγ exerts a direct cytotoxic effect on stressed cardiomyocytes by creating pores in their cellular membranes.
At the cellular level, RELMγ’s binding to the cardiomyocyte membrane provokes the formation of transmembrane channels, disrupting the integrity of ion gradients critical for normal electrical conduction. This pore formation produces pathological ion fluxes that provoke delayed afterdepolarizations—a known arrhythmogenic trigger—ultimately catalyzing cell death and promoting structural remodeling. The resultant myocardial tissue abnormalities form arrhythmogenic substrates conducive to ventricular tachycardia and fibrillation, two arrhythmia types most closely associated with sudden cardiac death post-infarction.
The strength of Kumowski et al.’s findings emerges from functional in vivo validations wherein genetic ablation of RELMγ expression in neutrophils yielded a dramatic, approximately twelve-fold reduction in ventricular arrhythmia incidence in murine ischemia models. This compelling evidence not only solidifies the causal role of RELMγ but also presents it as an actionable therapeutic target. Interventions aimed at neutralizing this peptide or modulating neutrophil activity could revolutionize post-infarct arrhythmia management, shifting the paradigm from reactive defibrillation to proactive molecular inhibition.
Further amplifying the translational relevance of these discoveries is the human homolog of RELMγ: resistin (RETN). Detected in infarcted myocardial tissue samples from patients, elevated serum resistin correlated with poorer clinical outcomes, signifying its utility as both a biomarker and a contributor to arrhythmic risk. Resistin, long implicated in metabolic and inflammatory disorders, now assumes a novel pathogenic role within the cardiological landscape, intertwining immune activation and electrical instability in a manner previously unappreciated.
The implications of these insights extend beyond immediate arrhythmia prevention. By delineating a direct molecular effector linking innate immune responses to cardiomyocyte electrical dysfunction, this work opens avenues for hybrid therapeutic strategies that synergize immune modulation with electrophysiological stabilization. Such strategies could substantially reduce the burden of sudden cardiac death and improve long-term cardiac function following ischemic episodes.
Notably, the timing of arrhythmia onset post-myocardial infarction aligns closely with neutrophil recruitment dynamics, predominantly within the first 48 hours after ischemic insult. This temporal association underscores the clinical window during which therapeutic targeting of RELMγ or its human counterpart resistin may be most effective. Tailoring interventions to this critical juncture could suppress arrhythmogenic triggers before permanent tissue abnormalities establish irreversible susceptibility.
The study also invites a reevaluation of neutrophil function within the infarcted heart, highlighting a dichotomy whereby these immune cells, while essential for clearing necrotic debris and orchestrating reparative processes, simultaneously harbor mechanisms that exacerbate electrical instability. This nuanced understanding challenges prevailing approaches that seek blanket neutrophil suppression and instead supports targeted modulation of deleterious effector molecules like RELMγ.
Further mechanistic exploration is warranted to elucidate the precise binding affinities, structural characteristics, and pore-forming dynamics of RELMγ on cardiomyocyte membranes. Decoding these parameters may inform the design of novel inhibitors capable of selectively antagonizing pore formation without compromising essential immunological functions of neutrophils. Moreover, investigating downstream signaling pathways activated by membrane puncture could reveal additional therapeutic targets within the arrhythmia cascade.
Given the complexity of myocardial infarction pathophysiology—where ischemia, inflammation, and electrical remodeling intersect—these revelations concerning RELMγ provide a crucial missing link. They underscore the intricate cross-talk between the immune system and cardiac electrophysiology, advancing our understanding of why some patients succumb to sudden arrhythmic death despite optimal standard care. Ultimately, translating these findings from bench to bedside could markedly improve survival and quality of life for millions worldwide affected by ischemic heart disease.
As the cardiovascular research community digests these pivotal insights, the prospect of integrating immunomodulatory strategies with traditional anti-arrhythmic therapies gains newfound momentum. The paradigm shift catalyzed by this discovery heralds an era where targeting immune-derived peptides like RELMγ could mitigate lethal ventricular arrhythmias, transforming acute cardiac care and expanding therapeutic horizons.
Subject of Research: Post-myocardial infarction arrhythmogenesis mediated by neutrophil-derived resistin-like molecule γ (RELMγ) and its human homolog resistin (RETN).
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
Keywords: ischemic heart disease, myocardial infarction, ventricular tachycardia, arrhythmia, neutrophils, resistin-like molecule γ, RELMγ, resistin, RETN, cardiomyocyte membrane, pore-forming peptide, electrical instability
