Researchers have unveiled a new mechanism linked to heart inflammation, which could open up new ways to prevent heart attacks from leading to heart failure.
Ischemic heart disease stands as the leading global cause of mortality. It starts with a “heart attack,” also known as a myocardial infarction (MI), causing damage to part of the heart due to poor blood supply. This initiates strong inflammation, alters the heart’s structure, and ultimately leads to heart failure.
Anti-inflammatory medications have surprisingly not been successful in preventing heart failure, and as a result, they are not commonly included in post-MI treatment. Still, it’s possible that the most effective molecular and cellular inflammation targets are yet to be identified.
In an article published on August 28, 2024, in Nature, researchers from the University of California San Diego, led by Dr. Kevin King, who is an associate professor in bioengineering and medicine as well as a cardiologist at the Sulpizio Cardiovascular Center, reveal the discovery of a new mechanism of cardiac inflammation. This could pave the way for new treatments to stop heart attacks from progressing to heart failure.
Traditionally, inflammation following an MI is attributed to immune cells like neutrophils and macrophages that invade the damaged area of the heart and react to debris from dead cells. However, the research team was surprised to find that the inflammatory “type I interferon (IFN) response” was triggered not in the damaged heart tissue, where immune cells congregated, but rather in the borderzone surrounding the injured area.
The borderzone is an intriguing but poorly understood region of the injured heart, where surviving heart muscle cells strive to stabilize and even replicate after disconnecting from their dying neighbors. Unfortunately, studying the borderzone is complex since it cannot be easily separated from the rest of the heart. However, the researchers managed to overcome this challenge using recent techniques involving single-cell RNA sequencing and spatial transcriptomics, which allowed them to identify borderzone cells based on their gene expression patterns.
To discover which cell type triggers inflammation in the borderzone, the team developed a library of conditional knockout mice, each incapable of initiating IFN signaling in specific cell types. Surprisingly, they found that heart muscle cells, known as cardiomyocytes, were the primary instigators of borderzone IFN signaling. They discovered that cardiomyocytes under mechanical stress in the borderzone often experienced ruptures in their nuclear envelope, allowing nuclear DNA to escape and be detected by cytosolic DNA sensors, thus initiating IFN signaling. This mechanism resulted in weakening of the heart wall, making it susceptible to dilation, thinning, and rupture. This finding explained the previously noted observation that mice lacking IFN responses showed better survival rates following MI.
“In the hospital, we see patients suffering from heart attacks and heart failure daily. Identifying new therapeutic targets for MIs that could help prevent heart failure is crucial,” stated Dr. King, senior author of the study and faculty member in the Shu Chien Gene Lay Department of Bioengineering and the Division of Cardiology at UC San Diego.
Many questions still exist, but the new findings indicate that strategies to reduce mechanical stress in the borderzone, inhibit DNA sensing, and block type I IFN signaling could offer valuable new approaches to help patients avoid heart failure after a heart attack.
This study received partial funding from the NIH DP2 New Innovator Award.