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.
Keywords
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References
- Epidemiology and stratification of risk for sudden cardiac death.Clin Cardiol. 2005; 28: I3-I11
- What causes sudden death in heart failure?.Circ Res. 2004; 95: 754-763
- European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery.Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).Europace. 2010; 12: 1360-1420
- Cardiac sarcoplasmic reticulum calcium leak: basis and roles in cardiac dysfunction.Annu Rev Physiol. 2014; 76: 107-127
- Diastolic release of calcium from the sarcoplasmic reticulum: a potential target for treating triggered arrhythmias and heart failure.J Am Coll Cardiol. 2009; 53: 2006-2008
- Ca(2+)/calmodulin-dependent protein kinase II equally induces sarcoplasmic reticulum Ca(2+) leak in human ischaemic and dilated cardiomyopathy.Eur J Heart Fail. 2014; 16: 1292-1300
- Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+-Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation.Circulation. 2012; 125: 2059-2070
- CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation.Circ Res. 2010; 106: 1134-1144
- Catecholaminergic polymorphic ventricular tachycardia is caused by mutation-linked defective conformational regulation of the ryanodine receptor.Circ Res. 2010; 106: 1413-1424
- Defective regulation of interdomain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure.Circulation. 2005; 111: 3400-3410
- Dantrolene, a therapeutic agent for malignant hyperthermia, markedly improves the function of failing cardiomyocytes by stabilizing interdomain interactions within the ryanodine receptor.J Am Coll Cardiol. 2009; 53: 1993-2005
- Dantrolene, a therapeutic agent for malignant hyperthermia, inhibits catecholaminergic polymorphic ventricular tachycardia in a RyR2(R2474S/+) knock-in mouse model.Circ J. 2010; 74: 2579-2584
- Essential role of calmodulin in RyR inhibition by dantrolene.Mol Pharmacol. 2015; 88: 57-63
- Oxidation of ryanodine receptor (RyR) and calmodulin enhance Ca release and pathologically alter, RyR structure and calmodulin affinity.J Mol Cell Cardiol. 2015; 85: 240-248
- Dantrolene prevents arrhythmogenic Ca2+ release in heart failure.Am J Physiol Heart Circ Physiol. 2012; 302: H953-H963
- Malignant hyperthermia and central core disease: disorders of Ca2+ release channels.Am J Med. 1998; 104: 470-486
- Dantrolene dose response in awake man: implications for management of malignant hyperthermia.Anesthesiology. 1983; 59: 275-280
- Dantrolene in human malignant hyperthermia.Anesthesiology. 1982; 56: 254-262
- CaMKII-dependent phosphorylation of RyR2 promotes targetable pathological RyR2 conformational shift.J Mol Cell Cardiol. 2016; 98: 62-72
- Ca2+/calmodulin-dependent protein kinase II and protein kinase A differentially regulate sarcoplasmic reticulum Ca2+ leak in human cardiac pathology.Circulation. 2013; 128: 970-981
- INaCa and ICl(Ca) contribute to isoproterenol-induced delayed after depolarizations in midmyocardial cells.Am J Physiol. 1998; 275 (Dec): H1979-H1992
- Calcium sparks.Physiol Rev. 2008; 88: 1491-1545
- Dantrolene suppresses spontaneous Ca2+ release without altering excitation-contraction coupling in cardiomyocytes of aged mice.Am J Physiol Heart Circ Physiol. 2014; 307: H818-H829
- Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia.EMBO Mol Med. 2012; 4: 180-191
- Dantrolene improves survival after ventricular fibrillation by mitigating impaired calcium handling in animal models.Circulation. 2014; 129: 875-885
- Effects of dantrolene treatment on ventricular electrophysiology and arrhythmogenesis in rats with chronic beta-adrenergic receptor activation.J Cardiovasc Pharmacol Ther. 2015; 20: 414-427
- Late INa increases diastolic SR-Ca2+-leak in atrial myocardium by activating PKA and CaMKII.Cardiovasc Res. 2015; 107: 184-196
- Inhibition of elevated Ca2+/calmodulin-dependent protein kinase II improves contractility in human failing myocardium.Circ Res. 2010; 107: 1150-1161
- Calcium leak through ryanodine receptors leads to atrial fibrillation in 3 mouse models of catecholaminergic polymorphic ventricular tachycardia.Circ Res. 2012; 111: 708-717
- Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca2+ leak in failing hearts.Cardiovasc Res. 2009; 81: 536-545
- Dantrolene stabilizes domain interactions within the ryanodine receptor.J Biol Chem. 2005; 280: 6580-6587
- Probing a putative dantrolene-binding site on the cardiac ryanodine receptor.Biochem J. 2005; 387: 905-909
- Effects of dantrolene sodium on the electrophysiological properties of canine cardiac Purkinje fibers.J Pharmacol Exp Ther. 1982; 220: 157-166
- Dantrolene sodium: effects on isolated cardiac tissues.J Mol Cell Cardiol. 1983; 15: 233-243
- Effect of the skeletal muscle relaxant dantrolene sodium on the isolated, perfused heart.Proc Soc Exp Biol Med. 1979; 160: 42-45
- Myocardial depression associated with effective refractory period prolongation after pentobarbital and procainamide but not after dantrolene.Res Commun Chem Pathol Pharmacol. 1980; 28: 13-26
- Action of dantrolene sodium on electrical and mechanical activity of guinea-pig ventricular muscles.Jpn J Physiol. 1985; 35: 123-138
- Antiarrhythmic effects of dantrolene in patients with catecholaminergic polymorphic ventricular tachycardia and replication of the responses using iPSC models.PLoS One. 2015; 10: e0125366
Article info
Publication history
Published online: September 17, 2016
Footnotes
Drs. Sossalla and Hasenfuss contributed equally to this article and are funded by the Deutsche Forschungsgemeinschaft (DFG) through the SFB 1002. Dr. Sossalla is funded by the Marga und Walter Boll-Stiftung. Mr. Pabel is supported by a research grant from the German Cardiac Society. Both first authors Dr. Hartmann and Mr. Pabel contributed equally to this work. Both senior authors Drs. Fischer and Sossalla contributed equally to this work.
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© 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
