| First Author | Liu N | Year | 2013 |
| Journal | Circ Res | Volume | 113 |
| Issue | 2 | Pages | 142-52 |
| PubMed ID | 23674379 | Mgi Jnum | J:213408 |
| Mgi Id | MGI:5584279 | Doi | 10.1161/CIRCRESAHA.113.301783 |
| Citation | Liu N, et al. (2013) Abnormal propagation of calcium waves and ultrastructural remodeling in recessive catecholaminergic polymorphic ventricular tachycardia. Circ Res 113(2):142-52 |
| abstractText | 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. |
