JACC: Basic to Translational Science (Dec 2017)

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

  • Maria K. Schweitzer, MSc,
  • Fabiola Wilting, MSc,
  • Simon Sedej, PhD,
  • Lisa Dreizehnter, PhD,
  • Nathan J. Dupper, BSc,
  • Qinghai Tian, PhD,
  • Alessandra Moretti, PhD,
  • Ilaria My, MD,
  • Ohyun Kwon, PhD,
  • Silvia G. Priori, MD, PhD,
  • Karl-Ludwig Laugwitz, MD,
  • Ursula Storch, PhD,
  • Peter Lipp, PhD,
  • Andreas Breit, PhD,
  • Michael Mederos y Schnitzler, PhD,
  • Thomas Gudermann, MD,
  • Johann Schredelseker, PhD

DOI
https://doi.org/10.1016/j.jacbts.2017.06.008
Journal volume & issue
Vol. 2, no. 6
pp. 737 – 747

Abstract

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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 RyR2R4496C/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 RyR2R4496C/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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