A small-scale study published in Circulation March 3 has revealed a potential new culprit behind sudden cardiac death in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC): integrin β1D.
Integrin β1D, which appears to regulate calcium levels in heart muscle cells, wasn’t top of mind for Long-Sheng Song, MD, and colleagues when they launched their study. The team was studying the explanted hearts of four ARVC patients in an attempt to better understand how the condition breaks down cardiac function.
ARVC is a rare genetic disease that triggers arrhythmias and, though it boosts a person’s risk for sudden cardiac death if they’re emotionally excited or physically stressed, as a whole, we still don’t know much about it. The condition seems to affect around 1 in 1,000 to 1 in 1,250 people, many of whom are young, healthy athletes who die suddenly after experiencing no signs or symptoms of CVD. Right now, treatment for ARVC involves medication or an implantable cardioverter-defibrillator.
Song, a professor of internal medicine at the University of Iowa Carver College of Medicine, and co-authors compared the cellular proteins in the hearts of the four transplant patients to proteins in healthy hearts, finding in the process that the transplant cardiomyocytes saw a significant reduction in integrin β1D. The researchers said the difference was one they hadn’t observed in other types of heart disease, including hypertrophic cardiomyopathy and ischemic heart disease.
Song et al. genetically modified mice to lack integrin β1D in their heart muscle cells and found that, though those mice seemed to have normal heart function at rest, under stress or exertion they were more likely to develop arrhythmias.
“Our findings suggest that preventing the loss of integrin β1D using existing or new drugs to inhibit this signaling pathway might provide a way to treat ARVC,” Song said in a release, noting that a paucity of research on ARVC means patients don’t have access to an effective treatment yet.
The team said the loss of integrin β1D seemed to prevent mouse heart cells from properly controlling the calcium levels necessary for maintaining a healthy heartbeat. Increased stress or heart rate just made the calcium control worse, suggesting that, by stabilizing another heart protein known as RyR2, integrin β1D helps regulate normal calcium signaling in the heart.
Song and colleagues said their next steps will include using the mouse model to identify compounds that target the signaling pathway and alter integrin β1D levels and calcium control.
“We have identified a new pathway in heart cells that explains how arrhythmias occur in patients with ARVC,” Song said. “We hope that new drugs targeting this pathway can now be developed, which might help us treat this devastating, progressive disease more effectively.”