Purkinje Cells From RyR2 Mutant Mice Are Highly Arrhythmogenic But Responsive to Targeted Therapy

Abstract

Rationale: The Purkinje fiber network has been proposed as the source of arrhythmogenic Ca 2؉ release events in catecholaminergic polymorphic ventricular tachycardia (CPVT), yet evidence supporting this mechanism at the cellular level is lacking.

PCP4 regulates Purkinje cell excitability and cardiac rhythmicity

“…Cardiac Purkinje cells (PCs) have been implicated in the genesis of ventricular arrhythmias in a variety of inherited conditions, such as long QT syndrome (1) and catecholaminergic polymorphic ventricular tachycardia (2), as well as acquired conditions, such as post-myocardial infarction (3) and dilated cardiomyopathy (4)(5)(6). The mechanisms responsible for this proarrhythmic propensity are incompletely understood, but compared with working ventricular myocytes (VMs), differences in T-tubular density (7), relative abundance of L and T type calcium channels (8), presence of IP 3 -sensitive Ca 2+ channels (9), greater intracellular sodium load (10), and the differential density of various repolarizing currents (11), are all considered contributory factors underlying the unique action potential (AP) and calcium-handling characteristics of PCs (12,13).…”

Mechanisms of Ca2+-Triggered Arrhythmias

“…Of the different cell types in the heart, Purkinje cells are particularly prone to initiating afterdepolarizations, suggesting that Ca 2+ -dependent arrhythmic triggers may arise from the Purkinje fiber network (Boyden et al, 2000;Cerrone et al, 2007). This pro-arrhythmic behaviour is enhanced by disease-causing mutations in the RyR2 and greatly exacerbated by cathecholaminergic stimulation (Kang et al, 2010).…”

“…In analogy with the local anaesthetic-tetracaine, flecainide is effective in suppressing spontaneous SR Ca 2+ release by directly inhibiting RyR2 activity in mice and in humans with calsequestrin-associated CPVT (Watanabe et al, 2009) and murine Purkinje cells harbouring RyR2 R4496C+/-mutation (Kang et al, 2010). This effect has been attributed to the reduced duration of channel openings without affecting closed channel duration and net spark-mediated Ca 2+ leak (Hilliard et al, 2010).…”

Targeting ryanodine receptors for anti-arrhythmic therapy

“…Knock-in mice heterozygous for mutation R4496/+ in RyR2 were crossed with Cntn2-EGFP transgenic mice expressing a fl uorescent marker for the cardiac conduction system [65] . Whereas tetracaine reduced spontaneous SR Ca 2+ release events in ventricular myocytes and Purkinje cells equally, fl ecainide more specifi cally targeted mutant RyR2 in Purkinje cells, implicating the Purkinje conduction system as a potent mediator of ventricular arrhythmias in CPVT.…”