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% via direct RyR2 modulation. Carvedilol is more beneficial because of the added alpha-blocking and antioxidant effect. Patients who are refractory are aided by left cardiac sympathetic denervation or implantable cardioverter defibrillators. Upcoming precision medicine includes clustered regularly interspaced short palindromic repeat-associated protein Cas9 gene editing, targeted molecular therapy, and artificial intelligence-based management. RyR2 stabilizers, calmodulin modulators, and mitochondrial protective therapies are promising targeted therapies. Implementation occurs through multidisciplinary care involving genetics, cardiology, and counseling services. Critical challenges are the management of asymptomatic carriers, the definition of exercise limitation, and the validation of biomarkers. Catecholaminergic polymorphic ventricular tachycardia illustrates successful translation of molecular cardiology with a paradigm for inherited arrhythmia syndromes and prevention of sudden cardiac death with mechanistically informed, personalized therapeutic strategies.