An international team, led by the National Center for Cardiovascular Research Carlos III (CNIC), has identified a new molecular mechanism involved in hypertrophic cardiomyopathy, the most common genetic cardiovascular disease. The research, published in Nature Cardiovascular Research, also confirms the efficacy of mavacamten, the first targeted treatment for this condition, against various genetic mutations.
Hypertrophic cardiomyopathy, affecting approximately 1 in 250 to 500 people, is characterized by abnormal thickening of the heart muscle and excessive contractility, which can lead to fatal arrhythmias. It originates from mutations in genes encoding sarcomere proteins, particularly the MYBPC3 gene.
The study focuses on a subgroup of mutations in MYBPC3 that alter the interaction of the cMyBP-C protein with myosin, the heart's molecular motor. This finding, derived from a mouse model with the R502W variant, defines a new pathogenicity mechanism.
The efficacy of mavacamten, which modulates myosin activity, was evaluated in R502W mice. The treatment halted pathological remodeling of the heart muscle and improved exercise tolerance in this model, as well as in a model of complete cMyBP-C protein loss. Results from human heart tissue generated in vitro reinforce its clinical relevance.
Dr. Jorge Alegre-Cebollada, principal investigator, notes that mavacamten is transforming treatment, but patient responses vary. This work suggests that the cause of this unequal effectiveness may be related to the different mutations.
The research confirms the efficacy of mavacamten regardless of the underlying molecular mechanism, broadening the spectrum of patients who could benefit. The developed murine model will be essential for studying new targeted therapies for this specific subgroup.
