Abstract P3045: The Role Of Mitochondrial Dysfunction In Arrhythmogenesis

Cardiac arrhythmia is triggered by deregulated ion channels and abnormal electrical activity, and it increases susceptibility of patients to sudden death. The regulations of ion movement in and out of the myocytes or subcellular compartments are highly energy-dependent. Although impaired energetics has been implicated in arrhythmia, the causal roles and intricate details of how mitochondrial dysfunction contributes to arrhythmogenesis are far from established. We employed a mouse model with cardiac-specific mitochondrial dysfunction by deleting Ndufs4, a protein of mitochondrial complex I (Ndufs4-cKO). Complex I deficiency in Ndufs4-cKO mice lowered cardiac NAD/NADH ratio but did not affect cardiac function and geometry at baseline. Control and Ndufs4-cKO mice showed normal sinus rhythm at baseline. Ndufs4-cKO mice had 3-fold increases non-sinus arrhythmic events upon an arrhythmogenic stress test. 50% of Ndufs4-cKO mice succumbed to sudden cardiac death with displays of pre-ventricular contractions and ventricular fibrillation. We collected cardiac tissues at baseline and post stress. We observed increased ryanodine receptor, RyR2-S2814 phosphorylation, reduced phospholamban PLN S16 phosphorylation and decreased calsequestrin 2 expression in Ndufs4-cKO hearts post stress, but not at baseline. Isolated Ndfus4-cKO cardiomyocytes after stress test show a trend towards prolonged time to peak shortening and time to peak Ca 2+ transient. In addition, elevating cardiac NAD levels lowered arrhythmic events of Ndufs4-cKO mice after stress test. These results revealed direct evidence that mitochondrial dysfunction increases susceptibility of hearts to arrhythmia by regulating NAD redox balance and SR calcium homeostasis.Ndufs4-cKO mice with chronic high fat diet (HFD) had accelerated declines in systolic and diastolic function and increased hypertrophy, compared to control mice. WT mice with HFD showed diastolic dysfunction and increased arrhythmic events after stress test, while diastolic dysfunction was reversed by elevating cardiac NAD levels. Our data suggest an arrhythmogenic mechanism linking mitochondrial dysfunction and NAD redox imbalance with SR calcium homeostasis, which may explain HFD-induced arrhythmogenesis.