A single intravenous AAV9-CASQ2 injection (3.5 × 1013 vg/kg) restored CASQ2 protein expression to ~60% of WT levels, reversed RyR2 mislocalization, and normalized jSR ultrastructure. Treated mice showed >85% reduction in arrhythmia incidence during exercise + epinephrine challenge (from 92% to 8%; p < 0.001), and >90% reduction in premature ventricular contractions. Intracellular Ca2+ cycling was restored with normalization of Ca2+ transients and reduced spontaneous waves. Effects were sustained for at least 3 months with no observed toxicity, confirming long-term efficacy and safety. Here, RYR2 is linked to Arrhythmia.