Suppression Of Arrhythmia By Enhancing Mitochondrial Calcium Uptake In Experimental Models Of Catecholaminergic Ventricular Tachycardia

We have recently identified a critical role of mitochondria to shape intracellular Ca2+ signals and to regulate cardiac rhythmicity. Activation of mitochondrial Ca2+ uptake by efsevin, an agonist of the voltage-dependent anion channel 2 in the outer mitochondrial membrane, restored rhythmic cardiac contractions in a zebrafish cardiac arrhythmia model. Here we investigated the potential of pharmacological activation of mitochondrial Ca2+ uptake as a novel pharmacological strategy for human cardiac arrhythmia in a translational approach. To this aim we first used a murine model of ryanodine receptor 2 (RyR2)-mediated catecholaminergic polymorphic ventricular tachycardia (CPVT). In freshly isolated cardiomyocytes of RyR2R4496C/WT mice, harboring the human RyR2R4496C mutation associated with CPVT, efsevin restricted diastolic Ca2+ sparks and prevented the formation of propagating Ca2+ waves and spontaneous, diastolic action potentials. This anti-arrhythmic effect was abolished in the presence of mitochondrial Ca2+ uniporter (MCU) blocker Ru360 , but could be reproduced with the MCU activator kaempferol, demonstrating an immediate role of mitochondrial Ca2+ uptake for the anti-arrhythmic effect of efsevin. In RyR2R4496C/WT mice both mitochondrial Ca2+ uptake enhancers (MiCUps), efsevin and kaempferol, significantly reduced episodes of ventricular tachycardia after catecholaminergic stimulation by a bolus injection of epinephrine and caffeine in vivo while baseline ECG was unaffected. Finally, we used stem cell-derived cardiomyocytes from a CPVT patient to show efficacy of MiCUps in a human model. Both MiCUps abolished arrhythmogenic events in human CPVT cardiomyocytes. Our results demonstrate that enhancement of mitochondrial Ca2+ uptake by MiCUps is a promising pharmacological strategy for treatment and prevention of Ca2+-triggered arrhythmias, such as CPVT.