Precision medicine in catecholaminergic polymorphic ventricular tachycardia: Recent advances toward personalized care

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited cardiac ion channelopathy where the initial disease presentation is during childhood or adolescent stages, leading to increased risks of sudden cardiac death. Despite advances in medical science and technology, several gaps remain in the understanding of the molecular mechanisms, risk prediction, and therapeutic management of patients with CPVT. Recent studies have identified and validated seven sets of genes responsible for various CPVT phenotypes, including RyR2, CASQ-2, TRDN, CALM1, 2, and 3, and TECRL, providing novel insights into the molecular mechanisms. However, more data on atypical CPVT genotypes are required to investigate the underlying mechanisms further. The complexities of the underlying genetics contribute to challenges in risk stratification as well as the uncertainty surrounding nongenetic modifiers. Therapeutically, although medical management involving beta-blockers and flecainide, or insertion of an implantable cardioverter defibrillator remains the mainstay of treatment, animal and stem cell studies on gene therapy for CPVT have shown promising results. However, its clinical applicability remains unclear. Current gene therapy studies have primarily focused on the RyR2 and CASQ-2 variants, which constitute 75% of all CPVT cases. Alternative approaches that target a broader population, such as CaMKII inhibition, could be more feasible for clinical implementation. Together, this review provides an update on recent research on CPVT, highlighting the need for further investigation of the molecular mechanisms, risk stratification, and therapeutic management of this potentially lethal condition.

Keywords: Catecholaminergic polymorphic ventricular tachycardia; gene therapy; risk stratification; stress-induced arrhythmias.

Figure 1

General Mechanisms of Arrhythmia induction in catecholaminergic polymorphic ventricular tachycardia. Ca2+: Calcium ion, CaM: Calmodulin, CaMKII: Calcium-calmodulin (CaM)-dependent protein kinase II, CASQ2: Calsequestrin 2, FKBP: FK506 binding proteins, LTCC: L-Type Calcium Channel, PKA: Protein kinase A, RyR2: Ryanodine receptor 2 Reproduced from[6] with permission

Figure 2

Overview of traditional versus gene therapy for the treatment of catecholaminergic polymorphic ventricular tachycardia. CPVT: Catecholaminergic polymorphic ventricular tachycardia CRISPR: Clustered regularly interspaced short palindromic repeats, mRNA: Messenger ribonucleic acid, rAAV: Recombinant adeno-associated virus, siRNA: Small interfering ribonucleic acid, LCSD: Left cardiac sympathetic denervation, ICD: Implantable cardioverter-defibrillator

Figure 3

The number of publications on genetic therapy of catecholaminergic polymorphic ventricular tachycardia by year

Figure 4

The development of gene therapy strategies each year from 2012 to 2020. AAV9: Adeno-associated virus 9, GFP: Green fluorescent protein, AIP: Autocamtide-2-related inhibitory peptide

Figure 5

Distribution of gene therapy strategies. The number on each slice represents the number of studies using each strategy