Researchers may have discovered how immune cells disrupt the neuro-cardiac junction (NCJ) in Duchenne muscular dystrophy, with macrophages playing a key role as contributors to heart dysfunction. The study offered potential new targets for therapy.

An inherited disorder caused by mutations in the dystrophin gene, leading to the progressive breakdown of muscle tissue, including the heart, Duchenne muscular dystrophy (DMD) often leads to dilated cardiomyopathy—a condition characterized by weakened heart muscles.

In the study, published in The Journal of Pathology, the researchers identified the release of a specific proteoglycan—chondroitin sulfate proteoglycan-4 (CSPG4)—as a main driver of the mechanisms underlying cardiac complications in DMD, which are a leading cause of mortality in affected patients.

In mouse models of DMD, the study found that macrophages—immune cells that infiltrate damaged tissues—produce high levels of CSPG4, a molecule known to inhibit nerve growth and function. The researchers observed that this overproduction of CSPG4 disrupted the communication between the nervous system and the heart, exacerbating the loss of heart function.

The researchers tested the effects of givinostat, a histone deacetylase inhibitor currently in late-stage clinical trials for DMD. Givinostat was shown to reduce CSPG4 levels, curb inflammation, and restore normal neuro-cardiac signaling in the mouse model. Treated mice exhibited less fibrosis and improved heart function, measured by enhanced ejection fraction and other parameters.

The findings could also have broader implications for other conditions involving cardiac fibrosis and inflammation. While givinostat’s effects in mouse models were promising, questions remained regarding translating the findings to human patients. Future research will need to determine the precise timing of intervention to maximize therapeutic benefit and explore additional factors contributing to CSPG4 production.