Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmia syndrome caused by gene mutations that render RYR2 Ca release channels hyperactive, provoking spontaneous Ca release and delayed afterdepolarizations (DADs). What remains unknown is the cellular source of ventricular arrhythmia triggered by DADs: Purkinje cells in the conduction system or ventricular cardiomyocytes in the working myocardium. To answer this question, we used a genetic approach in mice to knock out cardiac calsequestrin either in Purkinje cells or in ventricular cardiomyocytes. Total loss of calsequestrin in the heart causes a severe CPVT phenotype in mice and humans. We found that loss of calsequestrin only in ventricular myocytes produced a full-blown CPVT phenotype, whereas mice with loss of calsequestrin only in Purkinje cells were comparable to WT mice. Subendocardial chemical ablation or restoration of calsequestrin expression in subendocardial cardiomyocytes neighboring Purkinje cells was sufficient to protect against catecholamine-induced arrhythmias. In silico modeling demonstrated that DADs in ventricular myocardium can trigger full action potentials in the Purkinje fiber, but not vice versa. Hence, ectopic beats in CPVT are likely generated at the Purkinje–myocardial junction via a heretofore unrecognized tissue mechanism, whereby DADs in the ventricular myocardium trigger full action potentials in adjacent Purkinje cells.
Highlights
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disorder characterized by emotional or physical stress-induced arrhythmias in structurally normal hearts [1]
We found that loss of calsequestrin only in ventricular myocytes produced a full-blown CPVT phenotype, whereas mice with loss of calsequestrin only in Purkinje cells were comparable to wild-type mice
The results of our experiments indicate that polymorphic ventricular tachycardia due to loss of Casq2 is triggered by cardiomyocytes located in subendocardial working myocardium and not by Purkinje cells in the specialized conduction system, as previously suggested
Summary
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disorder characterized by emotional or physical stress-induced arrhythmias in structurally normal hearts [1]. A less common, but more severe autosomal-recessive form is caused by loss of function mutations in the gene encoding cardiac calsequestrin (CASQ2), the major Ca-binding protein in the sarcoplasmic reticulum (SR) [4, 5]. Both RYR2 and CASQ2 mutations cause spontaneous premature SR Ca releases in ventricular myocytes [6, 7] that facilitate the generation of delayed afterdepolarizations (DAD) and focal ventricular arrhythmias [5, 8]. Since increased RYR2 activity and spontaneous diastolic Ca release is an accepted cellular mechanism for the generation of ectopic ventricular beats, CPVT can be considered as a model to study Ca-triggered ventricular arrhythmia [12]
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