Abstract 370: Malignant Hyperthermia Mutation of RyR1 (Y522S) Increases Catecholamine-Induced Cardiac Arrhythmia Through Mitochondrial Injury

Abstract

Introduction: Mutations in skeletal muscle type ryanodine receptor (RyR1) exhibit life-treating human disorders including malignant hyperthermia (MH) and central core disease, which features skeletal muscle rigidity triggered by anesthesia and body temperature elevation. However, cardiac arrhythmias and/or sudden cardiac death in these patients are also frequently reported during anesthesia or even under the conscious condition. Hypothesis: Chronic mitochondrial Ca 2+ overload through leaky mutant RyR1 expressed at cardiac mitochondria leads to mitochondria injury and cardiac arrhythmia. Methods: We determined the cardiac phenotype of knock-in mice carrying a leaky RyR1 MH mutation Y522S (YS). Results: WT- and YS - RyR1 were expressed at mitochondria but not at SR in heart. Ultra-structure of heterozygous YS hearts exhibited severe abnormal/disrupted mitochondrial morphology as well as myofibril contractures (Fig. A-E). YS cardiac mitochondria showed high susceptibility to Ca 2+ -induced opening of mitochondrial permeability transition pores and depolarized mitochondrial membrane potential compared to WT, suggesting compromised mitochondrial functions. Langendorff perfusion developed similar LV pressure in response to high dose bolus of Isoproterenol in WT and YS, but only YS heart frequently developed multiple ventricular extrasystoles after Isoproterenol (Fig. F). Conclusion: Chronic mitochondrial damage by Ca 2+ overload through leaky mutant RyR1 induces mitochondrial structural and functional disruption, which facilitates arrhythmogenic outbursts under acute catecholaminergic stress.