Impact of RyR2 Mutation Responsible for Cathecolaminergic Polymorphic Ventricular Tachycardia (CPTV) on the Short Term Interval-Force Relationship of Atrial and Ventricular Myocardium

Abstract

Mutant RyR2 responsible for CPVT can trigger on stress and exercise cathecolaminergic induced-ventricular arrhythmias and sudden death. Defective RyR2, ubiquitously expressed in the heart, is responsible for sarcoplasmic reticulum dysfunction that may lead to atrial and ventricular contractile changes also detectable under basal conditions. Left atrial and right ventricular trabeculae were dissected from control (WT) and heterozygous mice (HE) carrying one of the most common CPVT-related RyR2 mutations (R4496C). Preparations underwent various stimulation protocols, including pause-delayed and premature stimuli while isometric tension was recorded. For intracellular Ca2+ and action potential recordings ventricular and atrial cardiomyocytes were isolated. In HE myocytes maximum post-rest increase in the amplitude of intracellular Ca2+transients was reduced compared to WT. Maximum post-rest potentiation of isometric tension was lower in HE than in WT trabeculae (e.g.228±37% vs.386±71%, p<0.05, in atrial trabeculae) and was reached at shorter rest-intervals in HE preparations. Steady-state frequency and isoproterenol-induced positive inotropic responses were less pronounced in HE vs. WT trabeculae. These results seem consistent with the “leaky phenotype” of the mutant RyR2. Electrical refractoriness was the same in HE and WT myocytes but in HE trabeculae mechanical refractoriness was shorter and restitution of isometric tension was significantly faster than in WT. The rate constant of mechanical restitution at 1 Hz basal frequency was 10.07±1.40 s−1 in HE atrial trabeculae vs. 5.28±1.25 s−1 in WT and 3.68±0.37 s−1 in HE ventricular trabeculae vs. 1.49±0.99 s−1 in WT (p<0.05). Isoproterenol accelerated mechanical restitution of all types of trabeculae but did not abolish the difference between HE and WT preparations. A faster recovery from refractoriness of the mutant RyR2 may be responsible for these findings. Supported by Telethon-Italy GGP06007.