RyR1 mutation associated with malignant hyperthermia facilitates catecholaminergic stress‐included arrhythmia via mitochondrial injury and oxidative stress (893.8)

Abstract

Mutations of the type 1 isoform of the ryanodine receptor (RyR1) form leaky channels and exhibit inherited skeletal muscle disorders including malignant hyperthermia (MH). Cardiac arrhythmias and sudden cardiac death in MH patients are also frequently observed during anesthesia or even under the conscious condition, but the mechanism is still unknown. We hypothesize that chronic mitochondrial Ca2+ overload through leaky mutant RyR1 expressed at cardiac mitochondria incudes mitochondrial injury and oxidative stress, which leads to cardiac arrhythmia. We used the knock‐in mice carrying a RyR1 MH mutation Y522S (YS) and found that YS‐RyR1 was expressed at mitochondria but not at SR in heart. Heterozygous YS hearts showed disrupted mitochondrial morphology as well as compromised mitochondrial functions with high cellular oxidative state. In vivo measurements of cardiac functions showed that basal function of YS heart is maintained at the similar level of WT, but YS heart are insensitive to Isoproterenol (Iso)‐induced positive inotropy and chronotropy in vivo due to its higher basal levels of catecholamine signaling. Moreover, only YS heart frequently developed multiple ventricular extrasystoles in response to Iso bolus under ex vivo Langendorff perfusion. In summary, chronic mitochondrial damage by Ca2+ overload via leaky mutant RyR1 induces cellular oxidation, which facilitates catecholaminergic stress‐triggered arrhythmia.