Immune Cell Discovery Offers New Hope for Preventing Sudden Cardiac death
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A newly identified protein, released by immune cells after a heart attack, appears to directly damage heart tissue and trigger risky arrhythmias, offering a potential new target for preventing sudden cardiac death.
A team of researchers at Massachusetts General Hospital has uncovered a critical link between the body’s immune response to heart attacks and the development of life-threatening irregular heartbeats. The study, published in Science, reveals that a protein called resistin-like molecule gamma (Relmy) – produced by neutrophils, a type of white blood cell – attacks heart cells, increasing the risk of ventricular tachycardia (VT), a rapid and potentially fatal heart rhythm.
The Deadly Cascade After a Heart Attack
myocardial infarction (MI), commonly known as a heart attack, occurs when a block in a coronary artery deprives the heart muscle of oxygen. While restoring blood flow is crucial, the subsequent immune response can exacerbate the damage. The research team discovered that neutrophils, which rush to the site of a heart attack, substantially increase production of Relmy. They also found a comparable protein, Resistin, present in human heart tissue affected by infarction. Crucially, when researchers blocked the production of Relmy in mice, the incidence of VT following a heart attack decreased a remarkable 12-fold.
“We found that Relmy essentially punches holes into heart cells,” stated a lead investigator. “This damage promotes dangerous, fast, and irregular heart rhythms and ultimately contributes to cell death in the heart.”
Unraveling the Mechanism with Advanced Techniques
The team employed a variety of sophisticated techniques to understand Relmy’s impact. They analyzed gene expression data from both mouse and human heart tissue using single-cell and spatial RNA sequencing. High-resolution microscopy allowed them to visualize the protein’s interaction with heart muscle cells, while in vitro assays – including liposome models and cell culture – helped confirm the protein’s damaging effects.
The findings demonstrate that neutrophils play a far more active and detrimental role in post-heart attack complications than previously understood.
Implications for Future Treatments
These findings have significant implications for how heart attacks are treated. Currently, treatment focuses on restoring blood flow to the blocked artery. However, this research suggests that together targeting the immune response, specifically Relmy, could dramatically improve outcomes.
“We need to think about treating both the myocardial infarction – by quickly restoring blood supply – and also by targeting immune cells to mitigate the arrhythmic effects of the injury,” a researcher noted.”By understanding the underlying mechanisms, we can develop therapeutic targets that go beyond broad immune suppression, reducing unwanted side effects and unlocking the full potential of immune modulation in cardiovascular disease.”
Next Steps: Neutralizing the Threat
The next phase of research will focus on developing a way to neutralize Relmy and testing its effectiveness in reducing VT and limiting heart damage. Initial studies will be conducted in mouse models, with the ultimate goal of translating these findings into human clinical trials.
Researchers also plan to investigate the role of relmy in other diseases characterized by neutrophil recruitment and activation. The team believes this discovery could open new avenues for treating a range of inflammatory conditions.
The study was authored by Nina Kumowski and Matthias Nahrendorf, along with a large collaborative team from Mass General Brigham, including Steffen Pabel, Jana Grune, Noor Momin, kyle I. Mentkowski, Yoshiko Iwamoto, Yi Zheng, I-Hsiu Lee, Fadi E. Pulous, Hana Seung, Alexandre Paccalet, Charlotte G. Muse, Kenneth K. Y.Ting, Paul Delgado, Andrew J. M. Lewis, Vaishali Kaushal, Antonia Kreso, Dennis Brown, Kamila Naxerova, Michael A. Moskowitz, and Maarten Hulsmans. Funding for the research was provided by the Leducq Foundation, the National Institutes of Health, the Deutsche Forschungsgemeinschaft, the British Heart Foundation, and the NIHR Oxford Biomedical Research Centre.
