Intracellular calcium handling dysfunction and arrhythmogenesis: a new challenge for the electrophysiologist.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by the development of adrenergically mediated bidirectional and polymorphic ventricular tachycardia in individuals with a normal heart.1 Although this disease was initially described by Coumel2 in the seventies, it was only after the identification of its genetic substrate that interest about this uncommon clinical condition has extended beyond pediatric cardiology to involve a broader spectrum of clinicians and basic scientists. CPVT is caused by mutations in 2 genes encoding calsequestrin3 and the cardiac ryanodine receptor4,5; ie, 2 proteins strongly implicated in the regulation of intracellular calcium. The currently incomplete understanding of calcium homeostasis in the heart under normal settings as well as in disease states has led to consideration of CPVT as a simplified human and experimental model that may help to clarify intracellular calcium regulation. Since the clinical description of CPVT,2 it was noted that the bidirectional VT that is the distinguishing manifestation of the disease resembles the VT observed in patients with digitalis intoxication. For that reason it has been speculated that DAD-mediated triggered activity would be the most likely electrophysiologic mechanism for arrhythmia initiation in CPVT. As of today, a conclusive demonstration of this hypothesis is lacking, and this is why studies like the one presented by Jiang et al6 in this issue of Circulation Research are of major relevance. Jiang et6 al have investigated in vitro the functional characteristics of different point mutations identified in patients with CPVT: their study is not the first of this kind,7–10 yet it brings novel insight and provides new arguments that help addressing controversial aspects in the field. In this editorial we will examine the areas of debate in the understanding of CPVT and will discuss the data reported by Jiang et al6 in the context of the leading speculations that have been elaborated to account for arrhythmogenesis in CPVT. What Is the Role of FKBP12 in the Pathogenesis of CPVT? The results presented by Jiang et al6 address an important unresolved dispute that is present in the literature about the molecular mechanism that links a mutation in RYR2 protein and the development of tachyarrhythmias. In the last few years Wehrens et al11–14 have elaborated a converging theory to explain arrhythmogenesis in heart failure and in CPVT. Based on the evidence that arrhythmias in the failing heart are likely to be initiated by triggering rhythms,15 these authors have proposed that a common final pathway for arrhythmogenesis in CPVT and HF is provided by the reduced affinity of RyR2 for the FKBP12.6 protein. Functional characterization of RyR2 performed by investigators of this group has provided experimental evidence suggesting that RyR2 mutations reduce the affinity of the ryanodine receptor for FKP12.613 and that the same effect is produced by the disease process occurring in the failing heart. Additional compelling evidence to link FKBP12.6 binding to RyR2 and arrhythmias has come from studies based on a FKBP12.6 knock-out model in which reduced FKBP12.6 binding, assessed by FKBP12.6-RYR2 coimmunoprecipitation, has been linked to the development of adrenergically-mediated polymorphic VTs that resemble those occurring in CPVT patients.14 In the present study, however, Jiang et al6 further extend their previous observations7 and contest the data by Wehrens showing that CPVT mutations of RyR2 do not alter the binding of FKBP12.6 (see also George et al8). This debate is not limited to a theoretical interest, as it has remarkable practical implications: the hypothesis advanced by Wehrens et al6 had been accompanied by a remarkable effort of these authors to develop a novel pharmacological approach to restore FKBP12.6 binding. These authors tested a novel compound called JTV51916 that increases affinity of FKBP12.6 for RyR2, and they demonstrated that in vivo administration of JTV519 is able to restore binding of FKBP12.6 to RyR2 to levels observed in controls14 and to prevent the development of adrenergically-mediated arrhythmias. These results raised hope of having identified a new pharmacological strategy for the treatment of CPVT: this achievement would represent a major clinical finding. CPVT patients are incompletely protected by therapy with beta blockers, and the implant of an ICD, although life-saving, is certainly associated with reduction of the quality of life in this pediatric population that is more susceptible to device-related complications. The data presented here by Jiang et al6 raise the concern that, in carriers of mutations of RyR2, the pharmacological approach proposed by Wehrens et al may The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From Molecular Cardiology (S.G.P., C.N.), IRCCS Fondazione S. Maugeri, and the Department of Cardiology (S.G.P.), University of Pavia, Pavia, Italy. Correspondence to Silvia G. Priori MD, PhD, Molecular Cardiology, Maugeri Foundation, University of Pavia, Via Ferrata 8, 27100 Pavia, Italy. E-mail [email protected] (Circ Res. 2005;97:1077-1079.) © 2005 American Heart Association, Inc.