Scientists from the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), along with an international consortium, have described a novel molecular mechanism involved in hypertrophic cardiomyopathy, the most common genetic heart pathology and the most frequent cause of sudden death in young people and athletes.
This disorder is defined by abnormal thickening of the heart muscle and excessively intense contractility, meaning an excessively high capacity of cardiomyocytes to shorten and generate force with each beat, which can hinder blood ejection and, in the most severe cases, trigger lethal arrhythmias.
The origin of the disease lies in mutations of the genes that encode sarcomere proteins, the molecular machinery responsible for the heartbeat, among which the MYBPC3 gene stands out, which produces cardiac myosin-binding protein C (cMyBP-C), one of the most commonly associated with this pathology.
The work, published in "Nature Cardiovascular Research," has focused on a subgroup of mutations in MYBPC3 that, unlike the more common variants, do not decrease the amount of protein but rather modify its ability to interact with other cardiac proteins, as explained by researcher Laura Sen-Martín.
"Until now, the exact mechanism by which these mutations cause the disease was not well defined," indicated Sen-Martín, lead author of the study, in which the team generated a murine model that reproduces the key characteristics of hypertrophic cardiomyopathy and specifically carries the R502W variant.
Examination of this mouse model showed that the mutation reduces the ability of cMyBP-C to bind to myosin, the molecular motor that drives cardiac contraction. This alteration in the interaction between both proteins represents, according to the authors, a distinct pathogenicity mechanism for this group of patients.
Efficacy of mavacamten in different models
Given that the R502W mutation triggers different molecular cascades than those observed in other types of variants, the CNIC group analyzed the effect of mavacamten, the only targeted treatment approved for hypertrophic cardiomyopathy, in mice carrying R502W.
The data obtained indicate that the drug, which acts on myosin by regulating its activity and attenuating exaggerated heart contraction, stopped pathological myocardial remodeling in both the R502W model and a model with complete absence of cMyBP-C, only improving physical exertion tolerance in R502W mice.
The medication also showed benefits in cardiac tissue generated in vitro from human cardiomyocytes derived from induced stem cells, as it decreased the elevated contraction force of diseased tissue, reinforcing the potential clinical applicability of the results.
The study concludes that mavacamten is effective regardless of the specific molecular mechanism causing hypertrophic cardiomyopathy, thus broadening the range of patients who could benefit from the treatment.
The mouse model developed in this research also stands out as a useful tool for evaluating new therapies targeting this subgroup of affected individuals. "For example, our new experimental model can be used to understand if early administration of mavacamten can improve therapeutic outcomes, an issue that is not yet resolved in the clinical setting," emphasized Laura Sen-Martín.
Although not all patients respond in the same way to mavacamten and similar compounds, this work "suggests that the cause of this unequal effectiveness is not due to the different mutations carried by patients," stated lead researcher Jorge Alegre-Cebollada, head of the Cardiovascular System Molecular Mechanics Group at CNIC and researcher at the Cardiovascular Diseases area of the Biomedical Research Networking Center (CIBERCV).