Rationale: The recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac calsequestrin gene (CASQ2): this variant of CPVT is less well characterized than the autosomal dominant form caused by mutations in the RyR2 gene. Objective: We characterized intracellular Ca2+ homeostasis, electrophysiological properties and the ultrastructural features of the Ca2+ release units (CRUs) in the homozygous R33Q knock-in mouse model. Methods and Results: We studied isolated R33Q and wild-type (WT) ventricular myocytes and observed properties not previously identified in a CPVT model. As compared to WT cells, R33Q myocytes: 1) show spontaneous Ca2+ waves unable to propagate as cell-wide waves; 2) show smaller Ca2+ sparks with shortened coupling intervals suggesting a reduced refractoriness of Ca2+ release events; 3) have a reduction of the area of membrane contact and the of junctions between jSR and T-tubules (couplons) and of jSR volume; 4) have a propensity to develop phase 2-4 afterdepolarizations that can elicit triggered beats 5) Viral gene transfer with WT CASQ2 is able to normalize structural abnormalities and restore cell-wide calcium wave propagation. Conclusions: Our data show that homozygous CASQ2-R33Q myocytes develop spontaneous Ca2+ 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 CRU architecture that leads to fragmentation of spontaneous Ca2+ waves. We propose that these two substrates in R33Q myocytes synergize to provide a new arrhythmogenic mechanism for CPVT.

Abnormal Propagation of Calcium Waves and Ultrastructural Remodeling in Recessive Catecholaminergic Polymorphic Ventricular Tachycardia.

Napolitano C;PRIORI, SILVIA GIULIANA
2013-01-01

Abstract

Rationale: The recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac calsequestrin gene (CASQ2): this variant of CPVT is less well characterized than the autosomal dominant form caused by mutations in the RyR2 gene. Objective: We characterized intracellular Ca2+ homeostasis, electrophysiological properties and the ultrastructural features of the Ca2+ release units (CRUs) in the homozygous R33Q knock-in mouse model. Methods and Results: We studied isolated R33Q and wild-type (WT) ventricular myocytes and observed properties not previously identified in a CPVT model. As compared to WT cells, R33Q myocytes: 1) show spontaneous Ca2+ waves unable to propagate as cell-wide waves; 2) show smaller Ca2+ sparks with shortened coupling intervals suggesting a reduced refractoriness of Ca2+ release events; 3) have a reduction of the area of membrane contact and the of junctions between jSR and T-tubules (couplons) and of jSR volume; 4) have a propensity to develop phase 2-4 afterdepolarizations that can elicit triggered beats 5) Viral gene transfer with WT CASQ2 is able to normalize structural abnormalities and restore cell-wide calcium wave propagation. Conclusions: Our data show that homozygous CASQ2-R33Q myocytes develop spontaneous Ca2+ 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 CRU architecture that leads to fragmentation of spontaneous Ca2+ waves. We propose that these two substrates in R33Q myocytes synergize to provide a new arrhythmogenic mechanism for CPVT.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11571/688630
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