Ischemic heart disease is the single leading cause of death globally. A myocardial infarction, or “heart attack,” occurs due to inadequate coronary blood flow causing death of part of the heart muscle. The event consequently results in heart failure, a change in the structure of the wall of the heart, and severe inflammation.
While there is some progress made within treatment modalities, anti-inflammatory medications have failed to prevent heart failure following an MI. They have also not become a part of the standard management post-MI. This in turn would mean that the key cellular and molecular targets for inflammation may be as yet unknown.
A study, dated August 28, 2024, which was recently published in Nature, unveiled that answer. Researchers at the University of California San Diego uncovered a brand-new cardiac inflammation mechanism. The lead author of this study is Dr. Kevin Associate professor of bioengineering and medicine, and cardiologist at the Sulpizio Cardiovascular Center. These results could open new ways to prevent heart attacks from progressing to heart failure.
Traditionally, researchers have attributed post-MI inflammation to professional immune cells such as neutrophils and macrophages. These immune cells invade the infarcted heart in response to debris from dying cells. However, surprisingly, the UC San Diego team found this was not the case. The study found that the pro-inflammatory “type I interferon (IFN) response” activated not within the infarct itself but in the border zone surrounding it.
Researchers had previously conducted limited research on the border zone, focusing more on the infarcted tissue. This is a region where surviving heart muscle cells try to stabilize. And start proliferating after the loss of their immediate neighbors. This has been very difficult to study because it is not as well separated from the rest of the heart. With the use of single-cell RNA sequencing and spatial transcriptomics, researchers could follow the gene expression patterns that characterize borderline cells.
The group generated a library of conditional knockout mice to identify the type of cell that initiates the inflammation. Each one of the mice in the library had an added gene that blocked signaling through the IFN in one different type of cell. The most unexpected finding was that cardiomyocytes, the muscle cells in the borderzone, primarily initiated these IFN signals. Mechanical stress caused nuclear envelope rupture in these cardiomyocytes, leading to leakage of nuclear DNA into the cytosol. The cytosolic DNA sensors then recognized this DNA, which triggered the IFN signal.
The further activation of IFN signaling mechanically weakens the heart wall and predisposes the heart to dilation, thinning, and rupture. This new mechanistic understanding helps explain previous observations that mice lacking IFN responses have improved survival after MI.
Dr. King, the paper’s senior author, spotlighted some of the key implications of these results: “In the hospital, we care for patients with heart attacks and heart failure every day. New therapeutic targets for MI that could prevent the development of heart failure are incredibly important,” said Dr. King, a faculty member in the Shu Chien Gene Lay Department of Bioengineering and the Division of Cardiology at UC San Diego.
Although many questions remain, the study suggests several possible new approaches. Reducing mechanical stress in the border zone, inhibiting DNA sensing. And blocking type I IFN signaling emerge as strategies to prevent patients with an MI from developing heart failure. This insight will go a long way to help patients ameliorate heart diseases.
ANI
