Author + information
- Received April 10, 2017
- Revision received June 26, 2017
- Accepted June 27, 2017
- Published online December 25, 2017.
- Maria K. Schweitzer, MSca,
- Fabiola Wilting, MSca,
- Simon Sedej, PhDb,
- Lisa Dreizehnter, PhDc,
- Nathan J. Dupper, BScd,
- Qinghai Tian, PhDe,
- Alessandra Moretti, PhDc,f,
- Ilaria My, MDc,
- Ohyun Kwon, PhDd,
- Silvia G. Priori, MD, PhDg,h,
- Karl-Ludwig Laugwitz, MDc,f,
- Ursula Storch, PhDa,
- Peter Lipp, PhDe,
- Andreas Breit, PhDa,
- Michael Mederos y Schnitzler, PhDa,f,
- Thomas Gudermann, MDa,f and
- Johann Schredelseker, PhDa,∗ ()
- aWalther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, Munich, Germany
- bDepartment of Cardiology, Medical University of Graz, Graz, Austria
- cDepartment of Medicine (Cardiology), Klinikum rechts der Isar, Technische Universität München, Munich, Germany
- dDepartment of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California
- eInstitute for Molecular Cell Biology, University Medical Center, Saarland University, Homburg/Saar, Germany
- fDeutsches Zentrum für Herz-Kreislauf-Forschung, Partner Site Munich Heart Alliance, Munich, Germany
- gMolecular Cardiology, Istituto di ricovero e cura a carattere scientifico (IRCCS) Salvatore Maugeri Foundation, Pavia, Italy
- hDepartment of Molecular Medicine, University of Pavia, Pavia, Italy
- ↵∗Address for correspondence:
Dr. Johann Schredelseker, Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München Nußbaumstrasse 26, D-80336 München, Germany.
• Fast transfer of Ca2+ from the sarcoplasmic reticulum into mitochondria in cardiomyocytes can be enhanced by the MiCUps efsevin, targeting the VDAC2, and kaempferol, targeting the MCU.
• Enhancing sarcoplasmic reticulum-to-mitochondria Ca2+ transfer with MiCUps suppresses arrhythmogenic Ca2+ events and spontaneous action potentials in cardiomyocytes from a mouse model of CPVT.
• In vivo treatment of CPVT mice with MiCUps reduces episodes of ventricular tachycardia after adrenergic stimulation.
• In induced pluripotent stem cell-derived cardiomyocytes from a CPVT patient, both MiCUps reduce arrhythmogenic Ca2+ events.
• Our data establish fast mitochondrial Ca2+ uptake as a promising candidate structure for pharmacological treatment of human cardiac arrhythmia.
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.
Supported by Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany (SCHR 1471/1-1 to Dr. Schredelseker; TRR152 to Drs. Gudermann, Lipp, Moretti, and Laugwitz), the Friedrich-Baur-Stiftung, Munich, Germany (to Dr. Schredelseker), and U.S. National Institutes of Health (R01GM071779 to Dr. Kwon). Dr. Sedej is supported by the Austrian Science Fund FWF, Vienna, Austria (P27637-B28). Dr. Priori has received research support from Boston Scientific; and is a member of the advisory boards for General Electric and Audentes. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received April 10, 2017.
- Revision received June 26, 2017.
- Accepted June 27, 2017.
- 2017 The Authors