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Updated: May 11, 2026
Dual-Dye Optical Mapping of Hearts from RyR2R2474S Knock-In Mice of Catecholaminergic Polymorphic Ventricular Tachycardia
Published on: December 22, 2023
Abnormal propagation of calcium waves and ultrastructural remodeling in recessive catecholaminergic polymorphic
Nian Liu1, Marco Denegri, Wen Dun
1Leon H. Charney Division of Cardiology, Cardiovascular Genetics Program, New York University School of Medicine, New York, NY, USA.
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 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.
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 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.
Insights
Mutations in cardiac calsequestrin-2 cause a rare form of catecholaminergic polymorphic ventricular tachycardia. This study reveals disrupted calcium handling and afterdepolarizations in a mouse model, suggesting a novel arrhythmogenic mechanism.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Genetics
Background:
- Recessive catecholaminergic polymorphic ventricular tachycardia (CPVT) is linked to cardiac calsequestrin-2 gene mutations.
- This form is less understood than the dominant CPVT caused by ryanodine receptor-2 mutations.
Purpose of the Study:
- Characterize intracellular Ca²⁺ homeostasis, electrophysiology, and ultrastructure of Ca²⁺ release units.
- Investigate the homozygous calsequestrin 2-R33Q knock-in mouse model (R33Q).
Main Methods:
- Studied isolated R33Q and wild-type ventricular myocytes.
- Assessed Ca²⁺ waves, Ca²⁺ sparks, coupling intervals, and sarcoplasmic reticulum structure.
- Utilized viral gene transfer to deliver wild-type cardiac calsequestrin-2.
Main Results:
- R33Q myocytes exhibited spontaneous Ca²⁺ waves that did not propagate cell-wide.
- Observed smaller Ca²⁺ sparks, shortened coupling intervals, and reduced junctional sarcoplasmic reticulum volume.
- R33Q myocytes showed afterdepolarizations and viral gene transfer normalized abnormalities.
Conclusions:
- Homozygous R33Q myocytes develop spontaneous Ca²⁺ release and afterdepolarizations.
- Disrupted Ca²⁺ release unit architecture fragments spontaneous Ca²⁺ waves.
- These factors synergize, proposing a novel arrhythmogenic mechanism for CPVT.
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