Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: A Translational Perspective for the Clinician-Scientist

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and potentially lethal inherited arrhythmia disease characterized by exercise or emotion-induced bidirectional or polymorphic ventricular tachyarrhythmias. The median age of disease onset is reported to be approximately 10 years of age. The majority of CPVT patients have pathogenic variants in the gene encoding the cardiac ryanodine receptor, or calsequestrin 2. These lead to mishandling of calcium in cardiomyocytes resulting in after-depolarizations, and ventricular arrhythmias. Disease severity is particularly pronounced in younger individuals who usually present with cardiac arrest and arrhythmic syncope. Risk stratification is imprecise and long-term prognosis on therapy is unknown despite decades of research focused on pediatric CPVT populations. The purpose of this review is to summarize contemporary data on pediatric CPVT, highlight knowledge gaps and present future research directions for the clinician-scientist to address.

Keywords: catecholaminergic polymorphic ventricular tachycardia; inherited arrhythmia; pediatric electrophysiology; primary electrical disease; ryanodine receptor; sudden cardiac death; ventricular tachycardia.

Figure 1

Historic electrocardiogram recording showing frequent ventricular extrasystole in 1944. Image obtained with permission from: Berg, K. J. (1960). Multifocal ventricular extrasytoles with Adams–Stokes syndrome in siblings. American Heart Journal, 60(6), 965–970.

Figure 2

Ca²⁺ induced Ca²⁺ release mechanism: The cardiac action potential leads to membrane depolarization, thereby opening L-type Ca²⁺ channels (Ca_V1.2). Ca²⁺ in the cytosol then binds to the ryanodine receptor 2 (RyR2) leading to CICR from the sarcoplasmic reticulum (SR) lumen into the cytosol. During systole, the cytosolic Ca²⁺ then binds to troponin C which leads to myocardial contraction. Ca²⁺ in the cytoplasm is returned to the SR via the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA2a) and its regulatory protein phospholamban (PLB). CM = cardiomyocyte; ECM = extracellular matrix. Image adapted from Priori, S. G., and Chen, S. W. (2011), Circulation Research, 108(7), 871–883 [49].

Figure 3

Proposed mechanisms of RYR2-associated CPVT arrhythmogenesis: (A) Store overload-induced Ca²⁺ release: RyR2 mutant channels may exhibit an increased sensitivity to the luminal Ca²⁺ in the SR by decreasing the threshold needed to activate it, leading to increased Ca²⁺ release from the SR during diastole. This leads to delayed afterdepolarizations (DADs) and thus, uncoordinated activation of cardiac tissue and triggered ventricular arrhythmias. (B) FKBP12.6 dissociation from the RyR2-complex: FKBP12.6 is phosphorylated by protein kinase A, leading to its dissociation from mutant RyR2, increasing diastolic Ca²⁺ release and consequent contractility. (C) Unzipping of the N-terminal and central terminal of the RyR2 protein: N-terminal and the central domain of wildtype RyR2 interact to form a tight intramolecular structure or a “zip” to stabilize the channel. However, RyR2 mutant channels cause weak intramolecular domain interaction resulting in Ca²⁺ spill. P= phosphate group; Other abbreviations as indicated in Figure 2. Image adapted from Wleklinski, M. J., Kannankeril, P. J., and Knollmann, B. C. (2020). The Journal of Physiology, 598(14), 2817–2834 [60].