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Bridging the Dimensions of Research on Cardiac Ryanodine Receptor Mutations

In this issue of the Journal, Zhang et al.1 report a possible role for slowed electrical conduction in the pathogenesis of the RyR2-dependent, autosomal dominant, catecholaminergic polymorphic ventricular tachycardia (CPVT). Using epicardial multielectrode mapping in RyR2-P2328S mouse hearts, the authors found that conduction velocity is reduced during isoproterenol stimulation. Only homozygous mutant mice had this abnormal behavior, thus the clinical relevance of this finding deserves confirmation. Nonetheless, the observation is particularly interesting and surprising. The presence of a reduced conduction velocity may indeed be in agreement with previous data addressing the role of intracellular Ca2+ in gap junction conductance (see later). Therefore, the report from Zhang et al. may open a new unexplored area in the studies of CPVT pathophysiology. When looking backwards at the last 10 years of research on CPVT, it becomes clear that a whole category of studies has been almost neglected. Indeed, the electrocardiographic features of CPVT arrhythmias have been extensively studied in human patients and in transgenic mouse models. On the other hand, several investigators have pursued studies aimed at the identification of cellular and subcellular mechanisms. However, there is still scanty information on how the cellular abnormalities translate at the whole organ level to define the clinical phenotype of the disease. The study of Zhang et al. is one of the very few available that attempt to reach this goal. In the following paragraphs, the known pathophysiological mechanisms of CPVT, as detected in vivo and in vitro, are briefly summarized to highlight how the results of Zhang et al. may fit into the broad picture of these inherited calcium handling abnormalities.