RELMy from immune cells disrupts heart rhythm after heart attacks. Blocking it may improve survival
In a new study published in Science, researchers at Massachusetts General Hospital (MGH) uncover a surprising link between the immune system and life-threatening heart rhythm disorders.
The paper, titled “Resistin-like molecule γ attacks cardiomyocyte membranes and promotes ventricular tachycardia,” identifies a protein produced by immune cells that directly damages heart muscle cells following a heart attack.
The research was led by Nina Kumowski, MD, of the Department of Radiology and Centre for Systems Biology at MGH, with Matthias Nahrendorf, MD, PhD, serving as senior author.
Their work sheds light on how neutrophils, white blood cells best known for fighting infections, can instead contribute to arrhythmias such as ventricular tachycardia (VT) and ventricular fibrillation (VF), two of the most dangerous complications after myocardial infarction.
In the following Q&A, Dr Kumowski and Dr Nahrendorf explain their findings, methods, and the future implications of this research for preventing sudden cardiac death.
How Would you Summarise your Study for a Lay Audience?
In short, we found that the defence protein “Resistin-like molecule gamma” (Relmy), produced by neutrophils, punches holes into heart cells after a heart attack.
This promotes dangerous, fast, and irregular heart rhythm and cell death in the heart.
The more extended version: The most lethal complications of coronary artery disease are myocardial infarction (MI) and sudden cardiac death.
In MI, the blockage of a heart artery leads to insufficient oxygen supply to heart muscle cells (cardiomyocytes). This compromises their ability to maintain a stable rhythm and can give rise to dangerous, unstable heart rhythms (arrhythmia) called ventricular tachycardia (VT) and ventricular fibrillation (VF).
VT and VF are both serious arrhythmias that can lead to sudden cardiac arrest and death within minutes. In VT, the heart beats very rapidly, but in a coordinated rhythm. In VF, the rhythm is chaotic and uncoordinated.
Most arrhythmias occur within 48 hours after MI and coincide with massive immune cell infiltration into the heart tissue.
We were interested in how these immune cells may promote arrhythmia.
We found that neutrophils recruited into the infarct (the area of dead tissue resulting from the cutoff of oxygen supply) in large numbers upregulate the gene “Retnlg,” which codes for the protein resistin-like molecule gamma (RELMy).
We also found a comparable gene, “RETN,” in human infarcted heart tissue. When we removed this protein from neutrophils in mice, the arrhythmia burden after MI was reduced 12-fold.
What question were you Investigating?
We were investigating the question of how neutrophils, a specific kind of immune cell, promote ventricular arrhythmia (a dangerous fast irregular heartbeat) after heart attacks.
Cardiomyocytes, as the leading actors in arrhythmia, are very well studied, but the role of immune cells in promoting arrhythmia is less clear. This work is essential because ventricular arrhythmia is the most lethal complication after myocardial infarction. We need to understand better what promotes arrhythmia to help us develop new antiarrhythmic drugs.
What Methods or Approaches did you use?
We employed a wide range of methods to determine this. For an initial understanding of which proteins in neutrophils might be important, we used deposited data on gene expression generated by single-cell and spatial RNA-sequencing from mice that underwent myocardial infarction. We also utilised data from human studies to identify similarities in human tissue.
We also relied on confocal and super-high resolution microscopy in isolated mouse heart muscle cells that were treated with the labelled protein. Further, we employed in vitro assays, including a liposome model and cell culture techniques, to compare the mouse and human versions of the protein and determine if they exhibit similar functionality.
What Did You Find?
We found that after MI in mouse models, neutrophils upregulate the expression of “Retnlg,” the gene coding for RELMy.
We also found that the human biological homolog “RETN,” the gene coding for Resistin, was more highly expressed in human infarcted myocardial tissue compared to non-infarcted tissue, similar to mice.
We saw that deleting the gene from bone marrow-derived cells (such as neutrophils) and deleting the gene from neutrophils specifically significantly reduced incidents of ventricular arrhythmia in the mouse models.
Q: What Are the Implications?
The implications are that immune cells play a crucial role in sudden death and arrhythmia.
Treating myocardial infarction through a dual approach: quick recanalisation of the vessel to restore oxygenated blood supply, and targeting immune cells to mitigate the arrhythmic effects of the injury.
When we understand the underlying mechanisms better, we can pursue therapeutic targets that go beyond the broad immune suppression that is used today.
If we can treat targets more specifically, we can reduce unwanted side effects and unravel the full potential of immune modulation in cardiovascular disease.
Q: What are the Next Steps?
The following steps aim to neutralise the harmful protein and assess whether this reduces VT burden and infarct size. First in mouse models, but we hope eventually also in humans.
We should gather more evidence about the significance of this protein in human disease. It is also interesting to see that these findings have implications for other diseases with neutrophil recruitment and activation.
