Researchers have discovered a surprising trigger for heart damage after a heart attack: surviving heart cells near the damaged area become inflamed due to mechanical stress, not immune cells as previously believed.
These heart cells rupture and leak DNA, which sparks a damaging immune response. This breakthrough challenges long-held assumptions and offers fresh strategies for preventing heart failure by calming these stressed heart cells and blocking specific inflammatory signals.
Unexpected Trigger for Heart Damage Discovered
Ischemic heart disease is the leading cause of death worldwide. It often starts with a “heart attack,” medically known as a myocardial infarction (MI), which occurs when blood flow to part of the heart is blocked. This lack of circulation causes heart tissue to die, triggering intense inflammation, structural changes in the heart wall, and, ultimately, heart failure.
Despite inflammation playing a key role in this process, anti-inflammatory drugs have not been effective at preventing heart failure. As a result, they are not routinely used after a heart attack. Researchers suspect this may be because the most critical inflammatory pathways and cellular targets have not yet been identified.
In a study published in Nature, a team at the University of California, San Diego — led by Dr. Kevin King, associate professor of bioengineering and medicine, and cardiologist at the Sulpizio Cardiovascular Center — uncovered a previously unknown mechanism of inflammation in the heart. Their findings could open up new possibilities for therapies aimed at stopping a heart attack from progressing to heart failure.
Inflammation in a Surprising Place
Typically, post-MI inflammation is thought to come from immune cells like neutrophils and macrophages, which flood the damaged heart tissue and react to the debris from dying cells. But the UC San Diego team found something unexpected: a strong inflammatory response — specifically, the activation of type I interferon (IFN) signaling — was not located in the damaged area itself. Instead, it occurred in the “borderzone,” the area surrounding the infarct, where heart cells are still alive.
The borderzone has been a fascinating yet understudied area of the infarcted heart. It is where surviving heart muscle cells attempt to stabilize and even proliferate after being disconnected from their dying neighbor cells. Unfortunately, the borderzone has proven a challenging region to study because it is not easily isolated from the rest of the heart. Researchers overcame this obstacle using methods they recently reported based on single cell RNAseq and spatial transcriptomics where cells of the borderzone are recognized based on their patterns of gene expression.
Decoding Cell Behavior With Gene Tech
To determine which cell type initiates borderzone inflammation, the team created a library of conditional knockout mice, each unable to initiate IFN signaling in a different cell type. To their surprise, heart muscle cells called cardiomyocytes emerged as the dominant initiators of borderzone IFN signaling. They found that mechanically stressed cardiomyocytes in the borderzone frequently suffered nuclear envelope rupture, which allowed escape of nuclear DNA and sensing by cytosolic DNA sensors, leading to activation of IFN signaling. This in turn caused mechanical weakening of the heart wall and made it vulnerable to dilation, thinning, and rupture, providing a mechanistic explanation for the team’s previous reported observation that mice lacking IFN responses exhibited improved survival after MI.
New Targets Could Prevent Heart Failure
“In the hospital, we care for patients with heart attacks and heart failure every day. New therapeutic targets for MI with the potential to prevent the development of heart failure are incredibly important, said Dr. King, senior author of the study and on the faculty in the Shu Chien Gene Lay Department of Bioengineering and the Division of Cardiology at UC San Diego.
Many questions still need to be answered, but the new findings suggest promising strategies for preventing heart failure after a heart attack. These include reducing mechanical stress in the borderzone, blocking DNA sensing pathways, and inhibiting type I interferon (IFN) signaling — key steps that may help protect the heart during recovery.
Reference: “Spatially clustered type I interferon responses at injury borderzones” by V. K. Ninh, D. M. Calcagno, J. D. Yu, B. Zhang, N. Taghdiri, R. Sehgal, J. M. Mesfin, C. J. Chen, K. Kalhor, A. Toomu, J. M. Duran, E. Adler, J. Hu, K. Zhang, K. L. Christman, Z. Fu, B. Bintu and K. R. King, 28 August 2024, Nature.
DOI: 10.1038/s41586-024-07806-1
Funding support for the study came, in part, from the NIH DP2 New Innovator Award.
A version of this article was originally published in September 2024.
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