Suppression of Arrhythmia by Enhancing Mitochondrial Ca 2+ Uptake in Catecholaminergic Ventricular Tachycardia Models

Cardiovascular disease-related deaths frequently arise from arrhythmias, but treatment options are limited due to perilous side effects of commonly used antiarrhythmic drugs. Cardiac rhythmicity strongly depends on cardiomyocyte Ca handling and prevalent cardiac diseases are causally associated with perturbations in intracellular Ca handling. Therefore, intracellular Ca transporters are lead candidate structures for novel and safer antiarrhythmic therapies. Mitochondria and mitochondrial Ca transport proteins are important regulators of cardiac Ca handling. Here we evaluated the potential of pharmacological activation of mitochondrial Ca uptake for the treatment of cardiac arrhythmia. To this aim,we tested substances that enhance mitochondrial Ca uptake for their ability to suppress arrhythmia in a murine model for ryanodine receptor 2 (RyR2)-mediated catecholaminergic polymorphic ventricular tachycardia (CPVT) in vitro and in vivo and in induced pluripotent stem cell-derived cardiomyocytes from a CPVT patient. In freshly isolated cardiomyocytes of RyR2 mice efsevin, a synthetic agonist of the voltage-dependent anion channel 2 (VDAC2) in the outer mitochondrial membrane, prevented the formation of diastolic Ca waves and spontaneous action potentials. The antiarrhythmic effect of efsevin was abolished by blockade of the mitochondrial Ca uniporter (MCU), but could be reproduced using the natural MCU activator kaempferol. Both mitochondrial Ca uptake enhancers (MiCUps), efsevin and kaempferol, significantly reduced episodes of stress-induced ventricular tachycardia in RyR2 mice in vivo and abolished diastolic, arrhythmogenic Ca events in human iPSC-derived cardiomyocytes.