Researchers at UC San Diego have made a breakthrough discovery that could lead to new therapies to prevent heart failure following a heart attack. The team, led by Dr. Kevin King, identified a novel inflammatory mechanism in the heart’s borderzone that is driven by stressed cardiomyocytes (heart muscle cells).
Ischemic heart disease, which typically begins with a heart attack, is the leading cause of death worldwide. During a heart attack, part of the heart muscle dies due to lack of blood flow from the coronary arteries.
This triggers intense inflammation, structural changes to the heart wall, and often progresses to heart failure.
Anti-inflammatory drugs have not been effective at preventing heart failure after a heart attack. The researchers believe the most potent inflammation targets have not been discovered until now.
In their study published in Nature, the UC San Diego team found that the pro-inflammatory “type I interferon (IFN) response” was activated in the borderzone surrounding the infarct, rather than in the infarct itself where immune cells were concentrated.
The borderzone is where surviving heart muscle cells try to stabilize and proliferate after being disconnected from their dying neighbor cells. Using advanced single-cell sequencing techniques, the researchers were able to isolate and study this challenging region.
Surprisingly, the team discovered that cardiomyocytes were the key initiators of borderzone inflammation. Mechanically stressed cardiomyocytes in the borderzone frequently suffered nuclear envelope rupture, allowing nuclear DNA to escape and activate cytosolic DNA sensors, leading to IFN signaling. This weakened the heart wall and made it vulnerable to dilation, thinning, and rupture.
“New therapeutic targets for myocardial infarction with the potential to prevent heart failure are incredibly important,” said Dr. King, a cardiologist at the Sulpizio Cardiovascular Center. “Limiting mechanical stress at the borderzone, inhibiting DNA sensing, and preventing type I IFN signaling may represent new opportunities to avoid heart failure after a heart attack.”