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Suppression of Arrhythmia by Enhancing Mitochondrial Ca2+ Uptake in Catecholaminergic Ventricular Tachycardia Models

Schweitzer MK, Wilting F, Sedej S, Dreizehnter L, Dupper NJ, Tian Q, Moretti A, My I, Kwon O, Priori SG, Laugwitz KL, Storch U, Lipp P, Breit A, Mederos y Schnitzler M, Gudermann T, Schredelseker J (2017)

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Publication Type: Journal article

Publication year: 2017

Journal

Book Volume: 2

Pages Range: 737-747

Journal Issue: 6

DOI: 10.1016/j.jacbts.2017.06.008

Abstract

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, the authors evaluated the potential of pharmacological activation of mitochondrial Ca²⁺ uptake for the treatment of cardiac arrhythmia. To this aim, the authors 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. These results highlight an immediate potential of enhanced mitochondrial Ca²⁺ uptake to suppress arrhythmogenic events in experimental models of CPVT and establish MiCUps as promising pharmacological tools for the treatment and prevention of Ca²⁺-triggered arrhythmias such as CPVT.

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How to cite

APA:

Schweitzer, M.K., Wilting, F., Sedej, S., Dreizehnter, L., Dupper, N.J., Tian, Q.,... Schredelseker, J. (2017). Suppression of Arrhythmia by Enhancing Mitochondrial Ca2+ Uptake in Catecholaminergic Ventricular Tachycardia Models. JACC: Basic To Translational Science, 2(6), 737-747. https://doi.org/10.1016/j.jacbts.2017.06.008

MLA:

Schweitzer, Maria K., et al. "Suppression of Arrhythmia by Enhancing Mitochondrial Ca2+ Uptake in Catecholaminergic Ventricular Tachycardia Models." JACC: Basic To Translational Science 2.6 (2017): 737-747.

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