Hartmann, Nico and Pabel, Steffen and Herting, Jonas and Schatter, Felix and Renner, Andre and Gummert, Jan and Schotola, Hanna and Danner, Bernhard C. and Maier, Lars S. and Frey, Norbert and Hasenfuss, Gerd and Fischer, Thomas H. and Sossalla, Samuel (2017) Antiarrhythmic effects of dantrolene in human diseased cardiomyocytes. HEART RHYTHM, 14 (3). pp. 412-419. ISSN 1547-5271, 1556-3871
Full text not available from this repository. (Request a copy)Abstract
BACKGROUND Cardiac type 2 ryanodine receptors (RyR(2)s) Play a pivotal role in cellular electrophysiology and contractility. Increased RyR(2)-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 damp, 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 Ca" spark frequency and diastolic SR Ca2+ leak. Moreover, dantrolene decreased the frequency of Ca2+ waves and spontaneous Ca" transients in HF CM. Patch-damp 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | POLYMORPHIC VENTRICULAR-TACHYCARDIA; RETICULUM CA2+ LEAK; PROTEIN-KINASE-II; RYANODINE RECEPTOR; MALIGNANT HYPERTHERMIA; SARCOPLASMIC-RETICULUM; ATRIAL-FIBRILLATION; HEART-FAILURE; DELAYED AFTERDEPOLARIZATIONS; INTERDOMAIN INTERACTIONS; Dantrolene; Sarcoplasmic reticulum Ca2+ leak; Arrhythmia; Atrial fibrillation; Heart failure; Ryanodine receptor; Electrophysiology; Antiarrhythmic agent |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:01 |
| Last Modified: | 19 Feb 2019 09:32 |
| URI: | https://pred.uni-regensburg.de/id/eprint/302 |
Actions (login required)
 |
View Item |
