Ryanodine receptor 2 mutations in catecholaminergic polymorphic ventricular tachycardia: From molecular mechanisms to precision medicine.

Catecholaminergic polymorphic ventricular tachycardia is a classic example of the successful transfer of genetic cardiology from gene discovery to implementation of precision medicine. This inherited arrhythmia syndrome induces potentially lethal ventricular arrhythmias by catecholaminergic stress in normally structured hearts and is most commonly due to ryanodine receptor 2 (RyR2) mutations in 60%-70% families. Pathophysiology involves gain-of-function mutations forming "leaky" calcium channels with increased sensitivity to catecholaminergic stimulation. Store overload-induced calcium release is a key mechanism whereby mutations reduce thresholds for spontaneous calcium release events. Complex mitochondrial-sarcoplasmic reticulum crosstalk amplifies dysfunction by calcium-induced mitochondrial overload and generation of reactive oxygen species. Modern diagnosis combines next-generation sequencing with functional confirmation using patient-specific induced pluripotent stem cells, allowing for personalized stratification of risk. Male gender, early age of onset, frequent attacks, and central domain mutations are high-risk factors. Exercise testing continues to play a central role in diagnosis and follow-up. Treatment has progressed from empiric β-blocker therapy to mutation-targeted therapy for the condition. β-blockers decrease arrhythmia by 60%-70%, and flecainide adjunct therapy improves success to 80%-90%