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• W2098648894 abstract "HomeCirculationVol. 129, No. 8Dantrolene Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBDantroleneFrom Better Bacon to a Treatment for Ventricular Fibrillation Dan M. Roden, MD and Björn C. Knollmann, MD, PhD Dan M. RodenDan M. Roden From the Vanderbilt University School of Medicine, Nashville, TN. Search for more papers by this author and Björn C. KnollmannBjörn C. Knollmann From the Vanderbilt University School of Medicine, Nashville, TN. Search for more papers by this author Originally published8 Jan 2014https://doi.org/10.1161/CIRCULATIONAHA.113.007657Circulation. 2014;129:834–836Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 4, 2014: Previous Version 1 The porcine stress syndrome is a major cause of poor meat quality and death in the pork industry. It is known to be more prevalent in some pig strains than others,1 and susceptible animals can be identified by a challenge with halothane, which results in striking elevation in body temperature. This scenario parallels the clinical entity of familial malignant hyperthermia on exposure to general anesthetics, which was one of the earliest recognized human pharmacogenetic syndromes. We now know that affected pigs and people share the same molecular mechanism, mutations in the sarcoplasmic reticulum (SR) calcium release channel of skeletal muscle encoded by RYR1.2,3 In the pig world, selective breeding programs have been used to develop strains resistant to malignant hyperthermia. In humans, malignant hyperthermia is an anesthetic emergency and is treated by immediate intravenous administration of dantrolene, which is effective and thought to be safe. Chronic oral dantrolene is also approved to treat severe muscle spasticity, and, in this setting, the limiting toxicity is hepatitis, which can be fulminant and fatal in up to 1% of exposed subjects.Article see p 875Leaky Ryanodine Receptor Channels in Skeletal Muscle and HeartAbrupt membrane depolarization (excitation) in skeletal or in cardiac muscle results in calcium release from SR stores via ryanodine receptor (RyR) calcium release channels, and the ensuing rise in intracellular calcium then activates the contractile apparatus. The details of the way in which excitation couples to contraction differs somewhat in the 2 types of muscle (in the heart, but not in skeletal muscle, calcium influx via voltage-gated Cav1.2 channels is required to activate RyR channels; Figure), and there are different genes encoding the channels, RYR1 in skeletal muscle and RYR2 in cardiac muscle. Early studies of the mechanism of action of dantrolene highlighted its ability to decouple excitation from contraction in skeletal muscle,4 and we now know that, in malignant hyperthermia, mutant RyR1 channels become leaky on exposure to drugs like halothane, and dantrolene is thought to act by preventing this leak. A body of evidence over the past decade has shown that, in heart failure models, RyR2 channels display a baseline leak that is thought to contribute to arrhythmia susceptibility and may also exacerbate contractile dysfunction.5 Further, phosphorylation of the cardiac channel by protein kinase A or calmodulin kinase II increases calcium release, and RyR2 hyperphosphorylation has been implicated as an exacerbating mechanism in these clinical settings.6,7 Although the extent to which RyR2 phosphorylation maintains or exacerbates contractile dysfunction and arrhythmias in human heart failure is controversial,8 molecular genetic studies have left no doubt that leaky RyR2 channels cause arrhythmias, because mutations in RYR29 or CASQ210 (encoding the major SR calcium-buffering protein) are the predominant cause of the syndrome of catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare disease first described by Coumel and colleagues in the 1970s.11,12Download figureDownload PowerPointFigure. During physiological excitation-contraction coupling (left and top), ryanodine receptor (RyR2) calcium release channels are activated by calcium influx via voltage-gated Cav1.2 channels during the cardiac action potential. In pathological conditions, such as heart failure, RyR2 mutations, or ventricular fibrillation (as in the present study), RyR2 channels become hyperactive and can open independent of an action potential (right and bottom); this pathological calcium release can depolarize the cell membrane and trigger ventricular arrhythmias. Dantrolene interrupts this arrhythmogenic chain of events by inhibiting RyR2 channels, likely by stabilizing calmodulin (CaM) binding to abnormal RyR2 channels. HF indicates heart failure; and VF, ventricular fibrillation.Dantrolene as an AntiarrhythmicThe striking mechanistic parallels between RYR1 mutations causing malignant hyperthermia and RYR2 mutations causing CPVT, both attributable to leaky ryanodine release channels, raises the question of whether dantrolene could be effective in CPVT or other settings in which defective RyR2 function leads to arrhythmias. In fact, dantrolene’s effects on cardiac rhythm were first investigated in the 1980s, with somewhat mixed results. Dantrolene significantly reduced the frequency and duration of episodes of ventricular fibrillation after coronary artery ligation in rats,13 but another early study suggested that pretreatment with dantrolene actually increased the frequency of ventricular fibrillation induced by coronary artery occlusion in dogs.14 More recent studies demonstrated that dantrolene prevents abnormal calcium leak in both malignant hyperthermia RyR115 and CPVT RyR216 channels. In vitro, a CPVT mutant channel (R2474S) was shown to decrease the threshold at which luminal calcium elicited RyR2 channel opening, and thereby induced calcium sparks and delayed afterdepolarizations17; in mice with this mutation, dantrolene stabilized the channels and was antiarrhythmic.16 Studies using myocytes derived from induced pluripotent stem cells of a subject with a different CPVT mutation,18 and myocytes from rabbits with heart failure19 similarly demonstrated that dantrolene decreased calcium leak through abnormal RyR2 channels and increased the threshold for spontaneous calcium release, both effects predicted to normalize pathophysiologic RyR2 function and thus be antiarrhythmic without altering, or perhaps even improving, contractile dysfunction.Interestingly, although effective in failing rabbit myocytes, dantrolene had no effect on SR calcium release in healthy rabbit myocytes,19 and, in healthy pigs, dantrolene only inhibited SR calcium release in skeletal but not in cardiac muscle.20 These findings beget the question of how dantrolene acts on RyR channels. Recent work has demonstrated that dantrolene binds to the Leu590-Cys609 region of RyR1 and stabilizes interdomain interactions within the RyR1 channel, which are thought to be disrupted by mutations that cause malignant hyperthermia. The dantrolene binding site has not yet been identified in cardiac RyR2, but dantrolene action in the heart may require altered calmodulin binding to RyR2: calmodulin physiologically bound to RyR2 reduces channel activity.21 Calmodulin binding is reduced either in heart failure22 or by CPVT mutations,23 rendering RyR2 channels hyperactive (Figure). Defective calmodulin binding can be restored by dantrolene (Figure),22 providing a possible explanation as to why dantrolene apparently affects SR calcium release in diseased but not in healthy hearts.Use of Dantrolene in Ventricular Fibrillation – The Present StudyZamiri and colleagues24 report in this issue of Circulation that dantrolene, administered after initiation of ventricular fibrillation (VF) in pigs (ironically enough) exerted dramatic beneficial effects on a range of indices of recovery of normal function after cardiopulmonary resuscitation and defibrillation; these included a dramatic decrease in the time to return to spontaneous circulation, decreases in the number of shock-resistant VF episodes, and a decrease in refibrillation. Dantrolene pretreatment in isolated perfused rabbit hearts reduced the ability to induce VF and reduced calcium leak. Interestingly, modeling dantrolene effects in ventricular muscle and in the Purkinje network suggested that, whereas VF or very rapid stimulation promotes calcium-dependent delayed afterdepolarizations in both cell types, only delayed afterdepolarizations arising in the Purkinje network propagate to other sites to cause the VF; the extent to which abnormal calcium control and delayed afterdepolarizations in ventricular muscle serve to create a VF-prone substrate is not addressed. The finding is in keeping with studies suggesting that ablation of the Purkinje network renders VF much more difficult to elicit and maintain in isolated perfused dog hearts.25 The demonstration of dantrolene efficacy when administered only minutes after the initiation of VF provides evidence that disordered RyR2 function plays a critical role in determining the lethality of VF within minutes of its onset. This, of course, makes the assumption that dantrolene lacks effects on other important electrogenic pathways such as ion channels, exchangers, or other signaling pathways affecting cardiac electrogenesis. Although studies to date have not been comprehensive, there is no evidence that dantrolene exerts such effects.Where to Next?In the present study, an old drug with an increasingly well-understood mechanism of action was used as a probe to define the contribution of perturbed RyR2 function early in VF. We have demonstrated that the sodium channel blocker flecainide also inhibits RyR2 channels; it is antiarrhythmic in both mouse models of CPVT, and in humans with the disease, as well26,27; and a randomized clinical trial comparing flecainide with placebo in patients with CPVT and implanted defibrillators is underway. In addition, new compounds have been reported that target RyR2 channels28,29 and may therefore find a clinical niche. Whether chronic therapy would be feasible would require a lot more work: in the Zamiri experiment, pretreatment was beneficial in isolated rabbit hearts, but pretreatment also exacerbated arrhythmias in earlier dog studies.14Anesthesiologists have little compunction in reaching for intravenous dantrolene in the occasional patient with malignant hyperthermia. It is therefore possible to envision a similar use of intravenous dantrolene in the setting of VF. Developing the drug for this indication would be challenging, because it is long off a patent for arrhythmias and finding a sponsor would be problematic. Nevertheless, dantrolene could serve as a lead to other compounds with similar actions. The long road from the search for more tender pork to reversal of VF once again illustrates the importance that understanding underlying mechanisms can contribute to the development or deployment of rational drug therapies.Sources of FundingThis work was supported in part by grants from the US Public Health Service (R01 HL049989, R01 HL118952, R01 HL071670, R01 HL108173, and R01 HL088635).DisclosuresNone.FootnotesThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Correspondence to Dan M. Roden, MD, Professor of Medicine and Pharmacology, Director, Oates Institute for Experimental Therapeutics, Assistant Vice-Chancellor for Personalized Medicine, Vanderbilt University School of Medicine, 1285 MRB IV, Nashville, TN 37232-0575. E-mail [email protected]References1. Kukoyi EA, Addis PB, McGrath CJ, Rempel WE, Martin FB. 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Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release.Nat Med. 2011; 17:1003–1009.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Szentandrássy N, Magyar Z, Hevesi J, Bányász T, Nánási P and Almássy J (2022) Therapeutic Approaches of Ryanodine Receptor-Associated Heart Diseases, International Journal of Molecular Sciences, 10.3390/ijms23084435, 23:8, (4435) Saljic A, Heijman J and Dobrev D (2022) Emerging Antiarrhythmic Drugs for Atrial Fibrillation, International Journal of Molecular Sciences, 10.3390/ijms23084096, 23:8, (4096) Román M, Ramírez J, Morales M and Crespo M (2019) Significant reduction of vascular reactivity with dantrolene and nimodipine in diabetic rats: a potential approach to cerebral vasospasm management in diabetes, Pharmacological Reports, 10.1007/s43440-019-00038-5, 72:1, (126-134), Online publication date: 1-Feb-2020. Avula U, Hernandez J, Yamazaki M, Valdivia C, Chu A, Rojas-Pena A, Kaur K, Ramos-Mondragón R, Anumonwo J, Nattel S, Valdivia H and Kalifa J (2018) Atrial Infarction-Induced Spontaneous Focal Discharges and Atrial Fibrillation in Sheep, Circulation: Arrhythmia and Electrophysiology, 11:3, Online publication date: 1-Mar-2018. Frommeyer G, Krawczyk J, Ellermann C, Bögeholz N, Kochhäuser S, Dechering D, Fehr M and Eckardt L (2018) Ryanodine-receptor inhibition by dantrolene effectively suppresses ventricular arrhythmias in an ex vivo model of long-QT syndrome , Journal of Cardiovascular Electrophysiology, 10.1111/jce.13412, 29:3, (471-476), Online publication date: 1-Mar-2018. Wiesmann T, Freitag D, Dersch W, Eschbach D, Irqsusi M, Steinfeldt T, Wulf H and Feldmann C (2017) Dantrolene versus amiodarone for cardiopulmonary resuscitation: a randomized, double-blinded experimental study, Scientific Reports, 10.1038/srep40875, 7:1, Online publication date: 1-Feb-2017. Rosenberg H, Hall D and Rosenbaum H (2017) Malignant Hyperthermia Critical Care Toxicology, 10.1007/978-3-319-17900-1_64, (619-642), . Rosenberg H, Hall D and Rosenbaum H (2016) Malignant Hyperthermia Critical Care Toxicology, 10.1007/978-3-319-20790-2_64-2, (1-25), . Rosenberg H, Hall D and Rosenbaum H (2016) Malignant Hyperthermia Critical Care Toxicology, 10.1007/978-3-319-20790-2_64-1, (1-25), . February 25, 2014Vol 129, Issue 8 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.113.007657PMID: 24403562 Originally publishedJanuary 8, 2014 Keywordsdantroleneventricular fibrillationEditorialsryanodine receptor calcium release channelexcitation contraction couplingPDF download Advertisement SubjectsAnimal Models of Human DiseaseArrhythmiasPharmacology" @default.
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