Hartmann Nico, Pabel Steffen, Herting Jonas, Schatter Felix, Renner André, Gummert Jan, Schotola Hanna, Danner Bernhard C, Maier Lars S, Frey Norbert, Hasenfuss Gerd, Fischer Thomas H, Sossalla Samuel
Department of Cardiology and Pneumology, Georg-August-University Göttingen, Göttingen, Germany.
Department of Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany.
Heart Rhythm. 2017 Mar;14(3):412-419. doi: 10.1016/j.hrthm.2016.09.014. Epub 2016 Sep 17.
Cardiac type 2 ryanodine receptors (RyRs) play a pivotal role in cellular electrophysiology and contractility. Increased RyR-mediated diastolic sarcoplasmic reticulum (SR) Ca 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.
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).
Human CM were isolated from either patients with HF (ventricular) or patients with AF (atrial), and Ca imaging, patch-clamp, or muscle strip experiments were performed.
After exposure to dantrolene, human atrial AF and left ventricular HF CM showed significant reductions in proarrhythmic SR Ca spark frequency and diastolic SR Ca leak. Moreover, dantrolene decreased the frequency of Ca waves and spontaneous Ca 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.
Our study showed that dantrolene beneficially influenced disrupted SR Ca 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.
心脏2型兰尼碱受体（RyRs）在细胞电生理和收缩性中起关键作用。RyR介导的舒张期肌浆网（SR）钙释放增加与心力衰竭（HF）和心律失常有关。丹曲林是一种用于治疗恶性高热的药物，已知可稳定骨骼肌中的RyRs。
本研究旨在探讨丹曲林对人类心房颤动（AF）和HF心肌细胞（CM）中致心律失常触发因素和收缩功能的影响。
从HF患者（心室）或AF患者（心房）中分离出人CM，并进行钙成像、膜片钳或肌条实验。
暴露于丹曲林后，人类心房AF和左心室HF CM的促心律失常SR钙火花频率和舒张期SR钙泄漏显著降低。此外，丹曲林降低了HF CM中钙波和自发性钙瞬变的频率。膜片钳实验表明，丹曲林显著抑制了HF和AF CM中的延迟后去极化。重要的是，丹曲林对AF或HF CM中的动作电位持续时间没有影响。此外，丹曲林对人类等长收缩心室HF小梁的收缩力具有中性作用。
我们的研究表明，丹曲林对人类HF和AF CM中破坏的SR钙稳态有有益影响。丹曲林可有效抑制细胞致心律失常触发因素，而动作电位持续时间和收缩性不受影响。作为一种临床上批准用于治疗恶性高热的药物，丹曲林可能是一种治疗心律失常患者的潜在抗心律失常药物，值得进一步临床研究。
