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 Ca²⁺ handling and prevalent cardiac diseases are causally associated with perturbations in intracellular Ca²⁺ handling. Therefore, intracellular Ca²⁺ transporters are lead candidate structures for novel and safer antiarrhythmic therapies. Mitochondria and mitochondrial Ca²⁺ transport proteins are important regulators of cardiac Ca²⁺ handling. Here we evaluated the potential of pharmacological activation of mitochondrial Ca²⁺ uptake for the treatment of cardiac arrhythmia. To this aim,we tested substances that enhance mitochondrial Ca²⁺ 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^R4496C/WT mice efsevin, a synthetic agonist of the voltage-dependent anion channel 2 (VDAC2) in the outer mitochondrial membrane, prevented the formation of diastolic Ca²⁺ waves and spontaneous action potentials. The antiarrhythmic effect of efsevin was abolished by blockade of the mitochondrial Ca²⁺ uniporter (MCU), but could be reproduced using the natural MCU activator kaempferol. Both mitochondrial Ca²⁺ uptake enhancers (MiCUps), efsevin and kaempferol, significantly reduced episodes of stress-induced ventricular tachycardia in RyR2^R4496C/WT mice in vivo and abolished diastolic, arrhythmogenic Ca²⁺ events in human iPSC-derived cardiomyocytes.

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