RyR2-Mediated Ca2+ Leak Drives Progressive Arrhythmogenic Cardiomyopathy

Background: Abnormal action of ryanodine receptor 2 (RyR2) in sarcoplasmic reticulum (SR) Ca2+ release is known to cause ventricular arrhythmias. It is unclear if persistent RyR2 dysfunction can also cause the structural changes seen in arrhythmogenic cardiomyopathy (ACM). This study aimed to determine if chronic RyR2-mediated Ca2+ leak can cause progressive cardiomyopathy alongside electrical instability.

Researchers created a rabbit with a severe RyR2-V2475F mutation and monitored its heart over time using cardiac imaging, electrophysiology tests, Ca2+ measurements, tissue analysis, and single-cell RNA sequencing. They also tested if a RyR2 inhibitor could slow down the disease progression.

Results showed that the mutant rabbit had spontaneous ventricular tachyarrhythmias, sudden cardiac death, and progressive right ventricular (RV) fibrofatty cardiomyopathy, similar to human ACM. The arrhythmias occurred before any visible changes in heart structure and were linked to early and frequent Ca2+ releases directly from the SR. In the early stages, the heart could still contract properly despite the RyR2 malfunction.

However, as the disease advanced, the SR Ca2+ levels dropped, the RV became weaker, and the left ventricle had to work harder to fill.

Single-cell RNA sequencing revealed early expansion of fibroblasts and predicted signaling from cardiomyocytes to fibroblasts before the fibrofatty infiltration became prominent. Cardiomyocytes also showed changes in lipid metabolism and increased lipid accumulation, along with enhanced uptake of intracellular Ca2+ from mitochondria.

When the researchers used the RyR2 inhibitor continuously for two months, it significantly decreased the number of ventricular tachycardias and maintained RV contraction and left ventricular filling during the disease progression.

Conclusion: The study found that a severe gain-of-function in RyR2 can cause both sudden and progressive arrhythmogenic cardiomyopathy in rabbits. This suggests that persistent intracellular Ca2+ dysregulation serves as a link between electrical and structural heart problems. The ability of selective RyR2 inhibition to reduce arrhythmias and preserve cardiac function indicates that RyR2 could be a promising target for treating arrhythmogenic cardiomyopathy.