Abnormal propagation of calcium waves and ultrastructural remodeling in recessive catecholaminergic polymorphic ventricular tachycardia

Nian Liu, Marco Denegri, Wen Dun, Simona Boncompagni, Francesco Lodola, Feliciano Protasi, Carlo Napolitano, Penelope A. Boyden, Silvia G. Priori

Research output: Contribution to journalArticle

Abstract

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 homeostasis, electrophysiological properties, and ultrastructural features of the Ca 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 waves unable to propagate as cell-wide waves; (2) show smaller Casparks with shortened coupling intervals, suggesting a reduced refractoriness of Ca 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 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 release unit architecture that leads to fragmentation of spontaneous Ca waves. We propose that these 2 substrates in R33Q myocytes synergize to provide a new arrhythmogenic mechanism for catecholaminergic polymorphic ventricular tachycardia.

Original languageEnglish
Pages (from-to)142-152
Number of pages11
JournalCirculation Research
Volume113
Issue number2
DOIs
Publication statusPublished - Jul 5 2013

Fingerprint

Calsequestrin
Calcium Signaling
Muscle Cells
Sarcoplasmic Reticulum
Ryanodine Receptor Calcium Release Channel
Mutation
Viral Genes
Genes
Homeostasis
Membranes
Polymorphic catecholergic ventricular tachycardia

Keywords

  • arrhythmias
  • calcium
  • calsequestrin
  • cardiomyopathies
  • chronic disease
  • electrophysiology
  • genetic diseases

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Abnormal propagation of calcium waves and ultrastructural remodeling in recessive catecholaminergic polymorphic ventricular tachycardia. / Liu, Nian; Denegri, Marco; Dun, Wen; Boncompagni, Simona; Lodola, Francesco; Protasi, Feliciano; Napolitano, Carlo; Boyden, Penelope A.; Priori, Silvia G.

In: Circulation Research, Vol. 113, No. 2, 05.07.2013, p. 142-152.

Research output: Contribution to journalArticle

Liu, Nian ; Denegri, Marco ; Dun, Wen ; Boncompagni, Simona ; Lodola, Francesco ; Protasi, Feliciano ; Napolitano, Carlo ; Boyden, Penelope A. ; Priori, Silvia G. / Abnormal propagation of calcium waves and ultrastructural remodeling in recessive catecholaminergic polymorphic ventricular tachycardia. In: Circulation Research. 2013 ; Vol. 113, No. 2. pp. 142-152.
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AU - Denegri, Marco

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AU - Lodola, Francesco

AU - Protasi, Feliciano

AU - Napolitano, Carlo

AU - Boyden, Penelope A.

AU - Priori, Silvia G.

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AB - 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 homeostasis, electrophysiological properties, and ultrastructural features of the Ca 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 waves unable to propagate as cell-wide waves; (2) show smaller Casparks with shortened coupling intervals, suggesting a reduced refractoriness of Ca 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 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 release unit architecture that leads to fragmentation of spontaneous Ca waves. We propose that these 2 substrates in R33Q myocytes synergize to provide a new arrhythmogenic mechanism for catecholaminergic polymorphic ventricular tachycardia.

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