One protein could stop sudden death after heart attacks

Q: How would you summarize your study for a lay audience?

In summary: We found that the defense protein resistin-like gamma molecule (RELMI), produced by neutrophils, creates holes in heart cells after a heart attack. This promotes dangerous, rapid, irregular heartbeats and cell death in the heart.

The longer version: The most fatal complications of coronary artery disease are myocardial infarction (MI) and sudden cardiac death.

In myocardial infarction, a blockage of a heart artery results in insufficient oxygen supply to the heart muscle cells (cardiomyocytes). This compromises their ability to maintain a stable rhythm and can lead to dangerous, unstable heart rhythms (arrhythmias) called ventricular tachycardia (VT) and ventricular fibrillation (VF).

Both VT and VF are serious arrhythmias that can lead to sudden cardiac arrest and death within minutes. In VT, the heart beats very quickly, but with a coordinated rhythm. In VF, rhythm is chaotic and uncoordinated.

Most arrhythmias occur within 48 hours after myocardial infarction and coincide with massive immune cell infiltration into cardiac tissue. We were interested in how these immune cells promote arrhythmia.

We found neutrophils that are recruited into the infarct (the area of ​​dead tissue resulting from interruption of oxygen supply) in large numbers upregulate the gene.”feathers “ Protein encoding resistin like molecule gamma (RELMy). We also found a similar gene,”“Riten” In human heart-containing tissue. When we removed this protein from neutrophils in mice, the burden of arrhythmia after myocardial infarction was reduced by 12-fold.

Q: What question were you investigating?

We were investigating the question of how neutrophils, a specific type of immune cell, promote ventricular arrhythmias (dangerous fast, irregular heartbeats) after heart attacks. Cardiomyocytes as key players in arrhythmia have been very well studied, but whether and how immune cells can promote arrhythmia is less clear. This work is important because ventricular arrhythmia is the most lethal complication after myocardial infarction. We need to better understand what triggers arrhythmia to help us develop new antiarrhythmic drugs.

Q: What techniques or methods did you use?

We used a large number of methods to find out. To initially understand which proteins in neutrophils might be important, we used data on gene expression generated by single-cell sequencing and spatial RNA from mice that underwent myocardial infarction. But we also used data from human studies to find similarities in human tissue.

We also relied on confocal and super-resolution microscopy in isolated mouse cardiomyocytes treated with the labeled protein. Moreover, we published In the laboratory Assays such as model liposomes and cell culture techniques examine the mouse and human version of the protein to see if they function similarly.

Q: What did you find?

We found that after MI in murine models, neutrophils upregulate the expression of “feathers ” Gene coding for RELMy. We also found that human biological homology“Riten” Gene coding for resistin, It was expressed higher in human infarcted myocardial tissues than in non-infarcted tissues, similar to mice.

We have seen that deleting the gene from bone marrow-derived cells (such as neutrophils) and deleting the gene from neutrophils specifically resulted in a significant reduction in the incidence of ventricular arrhythmias in mouse models.

Q: What are the effects?

The implication is that immune cells play a crucial role in sudden death and arrhythmia.

We should consider treating myocardial infarction by rapid recanalization of the vessel to restore oxygenated blood supply and also by targeting immune cells to mitigate the arrhythmic effects of injury.

When we better understand the underlying mechanisms, we can pursue therapeutic targets that go beyond the broad immune suppression used today.

If we can treat targets more specifically, we can reduce unwanted side effects and reveal the full potential of immune modulation in cardiovascular disease.

Q: What are the next steps?

The next steps are to find a way to neutralize the harmful protein and test whether this can reduce the burden of VT and infarct size. First in mouse models, but, hopefully, eventually also in humans.

We must collect more evidence about the importance of this protein in human diseases. It is also interesting to see that these findings have implications for other diseases through neutrophil recruitment and activation.

Written by: In addition to Nina Komowski and Matthias Nehrendorf, General Brigham authors include Stephen Babel, Janna Grune, Nour Momen, Kyle Mintkowski, Yoshiko Iwamoto, Yi Cheng, Ai-Hsiu Lee, Fadi E. Poulos, Hanna Seung, Alexandre Bacalet, Charlotte Gee. Muse, Kenneth K. Y. Ting, Paul. Delgado, Andrew J.M. Lewis, Vaishali Kaushal, Antonia Creso, Dennis Brown, Kamila Naxerova, and Michael A. Moskowitz, and Martin Holsmans.

Financing: This work was supported by grants from the Leduc Foundation, National Institutes of Health (NIH grants HL155097, HL149647, HL142494, HL176359, NS136068, DP2AR075321); Walter Benjamin German Research Program (DFG) (491497342 and 530157297); British Heart Foundation (FS/ICRF/24/26111 and RE/18/3/342140), and NIHR Oxford Biomedical Research Centre.

Disclosures: Nehrendorff has received funding or material research support from Alnylam, Biotronik, CSL Behring, GlycoMimetics, GSK, Medtronic, Novartis, and Pfizer, and has received consulting fees from Biogen, Gimv, IFM Therapeutics, Molecular Imaging, Sigilon, Verseau Therapeutics, and Bitterroot. Matthias and Wirth are employees of Abberior Instruments America, which markets the MINFLUX technology. Lewis is a member of the advisory boards of Abbott, AstraZeneca and Novartis. Babel works at the Novartis Institute for Biomedical Research. Hayat is a co-founder and shareholder of Sequantrix GmbH and has received research funding from Novo Nordisk and AskBio. The remaining authors declare no competing interests.