Neutrophils Promote Arrhythmia After Heart Attacks

Neutrophils have recently been shown to puncture stressed heart cells after heart injury or heart attack, leading to deadly arrhythmias. 

Cardiovascular diseases are the leading cause of death globally, with four out of five cardiovascular deaths linked to heart attacks and stroke. 

Following a heart attack, some patients experience life-threatening arrhythmias, which occur when cardiomyocytes experience oxygen deprivation after a coronary artery is blocked. Oxygen deprivation disrupts ion management, leading to electrical instability and arrhythmia.

Neutrophils respond to heart injury

Neutrophils are recruited in high numbers during the cellular inflammatory response to cardiac injury, which usually occurs within the first two days of a heart attack, coinciding with when most arrhythmias occur. 

Dr. Matthias Nahrendorf, professor at Mass General Brigham and senior author on the new research, told Technology Networks that the “clinical association of high neutrophil levels and arrhythmia in patients” led his team to investigate the role of neutrophils in heart attack response more closely. 

Neutrophils are also implicated in unintended tissue damage and are known to interfere with cellular electrical conduction, making them a promising avenue for understanding arrhythmia.

By comparing neutrophils and macrophages in mouse models of heart attacks, the researchers identified that resistin-like molecule γ (RELMγ) was highly expressed by neutrophils – but not macrophages – in the ischemic myocardium. 

Resistin and RELMγ 

Resistin is the human homolog of RELMγ, which is expressed in human mononuclear leukocytes, macrophages, adipocytes and bone marrow cells. It was initially identified as a link between obesity and diabetes in mice through modulating insulin resistance. In humans, it plays a pro-inflammatory role in regulating chronic inflammatory diseases, metabolic diseases and infectious diseases. It also functions as a host defense peptide of innate immunity, with wide-spectrum antimicrobial activity. 

“Resistin is an ancient defence protein. It is released by neutrophils and drills holes into bacteria in the setting of infection. We found that this defence tool misfires in myocardial infarction, where it drills holes into heart muscle cells,” Nahrendorf explained. 

When the RELMγ peptide punches a hole through the heart muscle cells, it forms pores that alter cellular ion flux, causing cell death and the formation of tissue abnormalities that promote arrhythmia.

“As a consequence, electrical charges can now cross the membrane and confuse the otherwise well-organized action potentials in the heart,” Nahrendorf continued. 

A promising avenue for arrhythmia treatment

These findings offer a novel explanation and potential therapeutic avenue for arrhythmias, which have few treatment options beyond defibrillation.  

“Some patients may recruit more neutrophils into their hearts than others. Blood neutrophil levels can fluctuate quite a lot, influenced by many factors including infection, nutrition, psychosocial stress or exercise,” said Nahrendorf, potentially explaining why some patients develop arrhythmias while others do not.

Resistin was also detected in human heart samples from people who had heart attacks, with higher levels of circulating resistin linked to poorer outcomes. Human resistin was shown to attack liposome membranes and mammalian cells, indicating that the murine studies are likely to translate into people.

When RELMγ was removed from mice, the team saw a 12-fold reduction in ventricular arrhythmia in response, illustrating that targeting RELMγ could help to prevent arrhythmias.

Nahrendorf and his team are using this study to shape approaches to prevent or treat post-heart attack arrhythmias. “We are working on this, testing strategies to inhibit resistin,” he said. “We are developing strategies to block resistin’s membrane perforating function.” 

Reference: Kumowski N, Pabel S, Grune J, et al. Resistin-like molecule γ attacks cardiomyocyte membranes and promotes ventricular tachycardia. Science. 2025;389(6764):1043-1048. doi: 10.1126/science.adp7361 

About the interviewee: Matthias Nahrendorf, MD PhD, is the Richard Moerschner Endowed Chair at the MGH Research Institute, a Professor for Radiology at Harvard Medical School, a Principal Investigator at the MGH Center for Systems Biology and adjunct Professor of Medicine at the Julius-Maximilians-Universität Würzburg. He directs the GB Center for Inflammation Imaging. His laboratory focuses on the role of immunity in cardiovascular disease, specifically in atherosclerosis and heart failure. Dr. Nahrendorf is an editorial board member of JACC, Circ Res, European Heart Journal, ATVB, Circulation, Science Translational Medicine, and The Journal of Nuclear Medicine. He was the Chair of the 2017 Atherosclerosis Gordon Conference and currently serves on the NHLBI board of external experts.