Supervisor: Chris Huang
Arrhythmic tendency becomes an increasing problem in the ageing population. Adrenergically-driven ventricular arrhythmias produce significant clinical morbidity and mortality through sudden cardiac death (SCD). They are associated with the inherited arrhythmic condition, catecholaminergic polymorphic ventricular tachycardia (CPVT), and heart failure. In the classical scheme, beta-adrenoreceptor stimulation results in activation of the Gs G-protein, then adenylate cyclase activation elevates cytosolic Ca2+ in turn activating protein kinase A and phosphorylation of its targets including sarcolemmal ion channels, the ryanodine receptor (RyR2), sarcoplasmic reticular ATPase and calcium/calmodulin-dependent protein kinase II. These changes lead to potentially arrhythmogenic, altered Ca2+ handling.This research project will test the hypothesis that the exchange protein directly activated by cAMP (Epac) mediates adrenergic effects upon Ca2+ release and membrane excitability to influence ventricular arrhythmic tendency, thereby offering a novel antiarrhythmic target for adrenergically-driven ventricular arrhythmias. RyR2 P2328S-/- mice will provide a system modelling CPVT and a paradigm for Ca2+-mediated arrhythmias. WT hearts provide a system with normal baseline RyR2 function. The acute role of Epac signalling as an antiarrhythmic target in adrenergically mediated arrhythmogenesis, and the actions of dantrolene sodium as a pharmacological manoeuvre directed at RyR2-mediated Ca2+ release will be investigated. We will study (1) The mechanisms by which Epac activation alters spontaneous Ca2+ release in (a) isolated cells and (b) the whole heart. (2) The mechanisms by which Epac activation mediates changes in membrane excitability in (a) cells and (b) the whole heart, and the effects of pharmacological manipulation upon this through investigation of: (i) spontaneous depolarization events (ii) action potential activation: conduction velocity and sodium current and (iii)action potential recovery: action potential duration (APD) and refractoriness. Finally we will explore the effects of Epac activation upon ventricular arrhythmogenic tendency, re-entrant excitation and the effects of pharmacological manipulation upon these.
De Rooij J, Zwartkruis FJT, Verheijen MHG, et al. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 1998;396(6710):474–7.
Hothi SS, Gurung IS, Heathcote JC, Zhang Y, Booth SW, Skepper JN, Grace AA, Huang CL. Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart. Pflugers Arch. 2008 Nov;457(2):253-70.
Zhang Y, Wu J, Jeevaratnam K, King JH, Guzadhur L, Ren X, Grace AA, Lei M, Huang CL, Fraser JA. Conduction slowing contributes to spontaneous ventricular arrhythmias in intrinsically active murine RyR2-P2328S hearts. J Cardiovasc Electrophysiol. 2013 Feb;24(2):210-8.