title: Abnormal propagation of calcium waves and ultrastructural remodeling in recessive catecholaminergic polymorphic ventricular tachycardia.
abstract: BACKGROUND
  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 Ca²⁺ homeostasis, electrophysiological properties, and ultrastructural features of the Ca²⁺ release units in the homozygous calsequestrin 2-R33Q knock-in mouse model (R33Q) R33Q knock-in mouse model.
  
  
  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 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, 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 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 Ca²⁺ release unit architecture that leads to fragmentation of spontaneous Ca²⁺ waves. We propose that these 2 substrates in R33Q myocytes synergize to provide a new arrhythmogenic mechanism for catecholaminergic polymorphic ventricular tachycardia.
authors.affiliation: Leon H. Charney Division of Cardiology, Cardiovascular Genetics Program, New York University School of Medicine, New York, NY, USA.
authors.forename: Nian
authors.initials: N
authors.lastname: Liu
authors.forename: Marco
authors.initials: M
authors.lastname: Denegri
authors.forename: Wen
authors.initials: W
authors.lastname: Dun
authors.forename: Simona
authors.initials: S
authors.lastname: Boncompagni
authors.forename: Francesco
authors.initials: F
authors.lastname: Lodola
authors.forename: Feliciano
authors.initials: F
authors.lastname: Protasi
authors.forename: Carlo
authors.initials: C
authors.lastname: Napolitano
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Boyden
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Priori
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000473:pathology / Q000648:ultrastructure*; D017180:Tachycardia, Ventricular / Q000473:pathology* / Q000503:physiopathology*; D020257:Ventricular Remodeling / Q000502:physiology*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
keywords: arrhythmias; calcium; calsequestrin; cardiomyopathies; chronic disease; electrophysiology; genetic diseases