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The Purkinje-myocardial junction is the anatomic origin of ventricular
arrhythmia in CPVT.
Blackwell DJ, Faggioni M, Wleklinski MJ, Gomez-Hurtado N, Venkataraman R, Gibbs
CE, Baudenbacher FJ, Gong S, Fishman GI, Boyle PM, Pfeifer K, Knollmann BC
Submitted Externally on 3/9/2022
Volume : Pages
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.
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
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