Catecholaminergic polymorphic ventricular tachycardia: a model for genotype-specific therapy

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening syndrome defined by exercise-induced or emotion-induced ventricular arrhythmias, typically caused by gain-of-function mutations in RYR2-encoded ryanodine receptor-2 (RyR2). This review will discuss recent advances and ongoing challenges in devising genotype-specific CPVT therapies.

CPVT patients were once universally thought to be at high risk of sudden death; however, as more cases emerge, CPVT is being re-defined as a complex syndrome of variable expressivity. Treatment was traditionally limited to β-blockers and implantable cardioverter defibrillators, and although β-blockers remain a mainstay of treatment, implantable cardioverter defibrillator use is associated with adverse events and should be limited. New applications for older therapies, like flecainide and cardiac denervation, appear to better target the mechanistic basis of CPVT arrhythmias. Recent advances in our understanding of RyR2 structure and function can help in identifying novel therapeutic targets.

CPVT is usually related to RyR2 or associated proteins. Emerging studies reveal several genotype-phenotype correlations, which may eventually influence therapeutic decision-making. Flecainide has improved CPVT outcomes and will likely have broader clinical indications in the near future. Gene therapy has shown promise in animal models but has yet to be studied in humans. Sudden death can occur as a sentinel symptom, making preventive therapy that targets molecular mechanism(s) of arrhythmia a key area of ongoing investigation. VIDEO ABSTRACT.