Clinical utility gene card for: Catecholaminergic polymorphic ventricular tachycardia (CPVT).

Rationale: The recessive form of catecholaminergic polymorphic ventricular tachycardia is caused by mutations in the cardiac calsequestrin-2 gene; this variant of catecholaminergic polymorphic ventricular tachycardia is less well characterized than the autosomal-dominant form caused by mutations in the ryanodine receptor-2 gene. Objective: We characterized the intracellular Ca(2+) homeostasis, electrophysiological properties, and ultrastructural features of the Ca(2+) release units in the homozygous calsequestrin 2-R33Q knock-in mouse model (R33Q) R33Q knock-in mouse model. Methods and Results: We studied isolated R33Q and wild-type ventricular myocytes and observed properties not previously identified in a catecholaminergic polymorphic ventricular tachycardia model. As compared with wild-type cells, R33Q myocytes (1) show spontaneous Ca(2+) waves unable to propagate as cell-wide waves; (2) show smaller Ca(2+)sparks with shortened coupling intervals, suggesting a reduced refractoriness of Ca(2+) release events; (3) have a reduction of the area of membrane contact, of the junctions between junctional sarcoplasmic reticulum and T tubules (couplons), and of junctional sarcoplasmic reticulum volume; (4) have a propensity to develop phase 2 to 4 afterdepolarizations that can elicit triggered beats; and (5) involve viral gene transfer with wild-type cardiac calsequestrin-2 that is able to normalize structural abnormalities and to restore cell-wide calcium wave propagation. Conclusions: Our data show that homozygous cardiac calsequestrin-2-R33Q myocytes develop spontaneous Ca(2+) release events with a broad range of intervals coupled to preceding beats, leading to the formation of early and delayed afterdepolarizations. They also display a major disruption of the Ca(2+) release unit architecture that leads to fragmentation of spontaneous Ca(2+) waves. We propose that these 2 substrates in R33Q myocytes synergize to provide a new arrhythmogenic mechanism for catecholaminergic polymorphic ventricular tachycardia.