Researchers have discovered a mechanism involving the enzyme calpain that contributes to a form of CPVT, suggesting a potential new target for treatment.
Key facts
- •The study identified that calpain activity is increased in subjects with the calsequestrin mutation.
- •Calpain targets triadin, a protein that stabilizes the calcium-release machinery in cardiomyocytes.
- •Pharmacological inhibition of calpain reduced the proportion of mice that developed sustained ventricular tachycardia.
- •The research was led by Dr. Enrique Lara-Pezzi of the CNIC and Dr. Silvia G. Priori of the University of Pavia.
- •The findings were published in the journal Circulation Research in 2026.
An international research team has identified a protein-degradation mechanism linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited heart condition that primarily affects children and young adults. The study, published in Circulation Research, suggests that inhibiting the enzyme calpain may offer a new therapeutic strategy for managing the disease, which often causes life-threatening arrhythmias during exercise or emotional stress.
Mechanism of Disease Progression
The research, led by the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) in collaboration with the University of Pavia and IRCCS Istituti Clinici Scientifici Maugeri, focused on a form of CPVT caused by a mutation in the gene encoding calsequestrin. This protein is vital for regulating calcium levels within heart cells, which is necessary for coordinated heart contractions. The team found that the initial calcium-handling disruption triggers cellular degradation mechanisms. Specifically, the calcium-dependent enzyme calpain becomes overactive in subjects with the mutation, targeting triadin, a protein responsible for stabilizing the heart's calcium-release machinery. This degradation of triadin precedes the loss of mutant calsequestrin, further destabilizing the system.
Preclinical Findings and Future Outlook
In experiments involving mice with the CPVT mutation, researchers demonstrated that pharmacological blockade of calpain restored key proteins in the calcium-release machinery. This intervention improved calcium handling in heart cells and reduced the occurrence of ventricular arrhythmias. While these results indicate that calpain could be a viable therapeutic target, the authors emphasize that the findings are currently preclinical. Further research is required to determine if this degradation mechanism is present in other forms of CPVT or different cardiac diseases before the approach can be considered for clinical practice.
Advertisement
This article was independently rewritten by ManyPress editorial AI from reporting originally published by Medical Xpress.
