Nico Hartmann1, Steffen Pabel1, Jonas Herting1, Felix Schatter1, André Renner2, Jan Gummert2, Hanna Schotola3, Bernhard C Danner4, Lars S Maier5, Norbert Frey6, Gerd Hasenfuss7, Thomas H Fischer1, Samuel Sossalla8. 1. Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany. 2. Department of Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany. 3. Department of Anesthesiology, Emergency and Intensive Care Medicine, Georg-August-University Göttingen, Göttingen, Germany. 4. Department of Thoracic and Cardiovascular Surgery, Georg-August-University Göttingen, Göttingen, Germany. 5. Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany. 6. Department of Internal Medicine III: Cardiology and Angiology, University of Kiel, Kiel, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Göttingen, Germany. 7. Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Göttingen, Germany. 8. Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany; Department of Internal Medicine III: Cardiology and Angiology, University of Kiel, Kiel, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Göttingen, Germany. Electronic address: ssossalla@med.uni-goettingen.de.
Abstract
BACKGROUND: Cardiac type 2 ryanodine receptors (RyR2s) play a pivotal role in cellular electrophysiology and contractility. Increased RyR2-mediated diastolic sarcoplasmic reticulum (SR) Ca2+ release is linked to heart failure (HF) and arrhythmias. Dantrolene, a drug used for the treatment of malignant hyperthermia, is known to stabilize RyRs in skeletal muscle. OBJECTIVE: The purpose of this study was to investigate the effects of dantrolene on arrhythmogenic triggers and contractile function in human atrial fibrillation (AF) and HF cardiomyocytes (CM). METHODS: Human CM were isolated from either patients with HF (ventricular) or patients with AF (atrial), and Ca2+ imaging, patch-clamp, or muscle strip experiments were performed. RESULTS: After exposure to dantrolene, human atrial AF and left ventricular HF CM showed significant reductions in proarrhythmic SR Ca2+ spark frequency and diastolic SR Ca2+ leak. Moreover, dantrolene decreased the frequency of Ca2+ waves and spontaneous Ca2+ transients in HF CM. Patch-clamp experiments revealed that dantrolene significantly suppressed delayed afterdepolarizations in HF and AF CM. Importantly, dantrolene had no effect on action potential duration in AF or in HF CM. In addition, dantrolene had neutral effects on contractile force of human isometrically twitching ventricular HF trabeculae. CONCLUSION: Our study showed that dantrolene beneficially influenced disrupted SR Ca2+ homeostasis in human HF and AF CM. Cellular arrhythmogenic triggers were potently suppressed by dantrolene, whereas action potential duration and contractility were not affected. As a clinically approved drug for the treatment of malignant hyperthermia, dantrolene may be a potential antiarrhythmic drug for patients with rhythm disorders and merits further clinical investigation. Copyright Â
BACKGROUND: Cardiac type 2 ryanodine receptors (RyR2s) play a pivotal role in cellular electrophysiology and contractility. Increased RyR2-mediated diastolic sarcoplasmic reticulum (SR) Ca2+ release is linked to heart failure (HF) and arrhythmias. Dantrolene, a drug used for the treatment of malignant hyperthermia, is known to stabilize RyRs in skeletal muscle. OBJECTIVE: The purpose of this study was to investigate the effects of dantrolene on arrhythmogenic triggers and contractile function in humanatrial fibrillation (AF) and HF cardiomyocytes (CM). METHODS:Human CM were isolated from either patients with HF (ventricular) or patients with AF (atrial), and Ca2+ imaging, patch-clamp, or muscle strip experiments were performed. RESULTS: After exposure to dantrolene, humanatrial AF and left ventricular HF CM showed significant reductions in proarrhythmic SR Ca2+ spark frequency and diastolic SR Ca2+ leak. Moreover, dantrolene decreased the frequency of Ca2+ waves and spontaneous Ca2+ transients in HF CM. Patch-clamp experiments revealed that dantrolene significantly suppressed delayed afterdepolarizations in HF and AF CM. Importantly, dantrolene had no effect on action potential duration in AF or in HF CM. In addition, dantrolene had neutral effects on contractile force of human isometrically twitching ventricular HF trabeculae. CONCLUSION: Our study showed that dantrolene beneficially influenced disrupted SR Ca2+ homeostasis in human HF and AF CM. Cellular arrhythmogenic triggers were potently suppressed by dantrolene, whereas action potential duration and contractility were not affected. As a clinically approved drug for the treatment of malignant hyperthermia, dantrolene may be a potential antiarrhythmic drug for patients with rhythm disorders and merits further clinical investigation. Copyright Â
Authors: Wenqian Chen; Andrea Koop; Yingjie Liu; Wenting Guo; Jinhong Wei; Ruiwu Wang; David H MacLennan; Robert T Dirksen; Sui Rong Wayne Chen Journal: Biochem J Date: 2017-08-07 Impact factor: 3.857
Authors: Andrea Orosz; István Baczkó; Szabolcs Nyiraty; Anna E Körei; Zsuzsanna Putz; Róbert Takács; Attila Nemes; Tamás T Várkonyi; László Balogh; György Ábrahám; Péter Kempler; Julius Gy Papp; András Varró; Csaba Lengyel Journal: Front Endocrinol (Lausanne) Date: 2017-06-13 Impact factor: 5.555