Calpain inhibition may offer treatment path for inherited heart rhythm disorder
An international team linked a protein-degradation process to an inherited form of CPVT caused by a calsequestrin mutation. The mutation disrupts calcium handling in heart cells and activates degradation mechanisms. Inhibiting calpain reduced ventricular arrhythmias in mice, suggesting a possible therapeutic strategy.
An inherited CPVT subtype arises from the R33Q change in the calsequestrin 2 gene. This protein normally helps manage calcium inside heart muscle cells, and the mutation upsets that balance. Scientists used proteomics, animal models, and cellular and biochemical experiments.
They found the original calcium defect sets off protein-breakdown pathways. Calpain, an enzyme dependent on calcium, becomes overactive and attacks triadin, which stabilizes the calcium-release apparatus. Triadin loss happens before mutant calsequestrin disappears and helps make it unstable. In mice, blocking calpain restored apparatus proteins, improved calcium regulation, and reduced ventricular arrhythmias.
If these mouse findings translate to humans, calpain inhibition could eventually become a new treatment avenue for people with this inherited CPVT subtype, particularly children and young adults whose arrhythmias may be triggered by exercise or emotional stress. It may also shape how families and clinicians think about risk, though real patient benefit remains uncertain until clinical trials are done.