Dantrolene, a Therapeutic Agent for Malignant Hyperthermia, Inhibits Catecholaminergic Polymorphic Ventricular Tachycardia in a RyR2R2474S/+ Knock-In Mouse Model

Abstract

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp he N-terminal (1-619 amino acid) and central (2,000-2,500 amino acid) domains of the ryanodine receptors (skeletal: RyR1, cardiac: RyR2) harbor many mutations associated with malignant hyperthermia (MH), catecholaminergic polymorphic ventricular tachycardia (CPVT), and arrhythmogenic right ventricular cardiomyopathy type 2. 1 There is strong evidence to suggest that the interdomain interaction between these regions plays an important role in the mechanism of channel regulation. 2- 16 We reported that dantrolene, a specific agent for the treatment of MH, prevented abnormal Ca 2+ leak by correction of the defective inter-domain interaction between the N-terminal and central domains within MH RyR1 (i.e., aberrant formation of a channel-activating unzipped configuration of the N-terminal/central domain pair in an otherwise resting state). 9 We further showed that, in failing hearts, dantrolene corrected the defective inter-domain interaction within the RyR2, thereby inhibiting Ca 2+ leak through RyR2. 11 More recently, by using the knock-in (KI) mouse model with a human CPVT-associated RyR2 mutation (R2474S), we clarified that a single amino acid mutation within the RyR2 sensitizes the RyR2 channel to activation by luminal [Ca 2+ ] (i.e., a decreased threshold of luminal [Ca 2+ ] for channel activation), and in turn induces spontaneous Ca 2+ sparks and DAD, leading to CPVT, and that danrrolene stabilized the leaky RyR2 by correcting the defective inter-domain interaction. 13 Here, we investigated the in vivo anti-arrhythmic effect of dantrolene in the KI mice model. Background: Dantrolene, a specific agent for the treatment of malignant hyperthermia, was found to inhibit Ca 2+ leak through not only the skeletal ryanodine receptor (RyR1), but also the cardiac ryanodine receptor (RyR2) by correcting the defective inter-domain interaction between N-terminal (1-619 amino acid) and central (2,000-2,500 amino acid) domains of RyRs. Here, the in vivo anti-arrhythmic effect of dantrolene in a human catecholaminergic polymorphic ventricular tachycardia (CPVT)-associated RyR2 R2474S/+ knock-in (KI) mouse model was investigated.

Possible Targets of Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia - Insight From a Theoretical Model -

“…Otherwise, several studies reveal that the class IC antiarrhythmic drug, flecainide, is effective in CPVT management. 21,24, 25 The efficacy of flecanide is not only due to its blockade of INa (suppress TA) but also its ability to block Irel (suppress DADs), which is compatible with our simulation showing the synergistic effect of dual blockade of INa and Irel. This is important for flecainide dual channel blockade capability since other class I drugs with sole blockade of INa may be pro-arrhythmic and even harmful for ventricular arrhythmia management.…”

Long-Term Prognosis of Catecholaminergic Polymorphic Ventricular Tachycardia Patients With Ryanodine Receptor (RYR2) Mutations

“…11 In addition, dantrolene, a RYR2 channel inhibitor and effective in malignant hyperthermia, has been shown to prevent exercise-and epinephrineinduced ventricular arrhythmias in CPVT mouse models. 12 More recently, in CPVT-patient induced pluripotent stem cells-derived cardiomyocytes, dantrolene restored normal calcium spark properties and rescued the arrhythmogenic phenotype. 13, 14 Further clinical trials are needed to confirm the safety and effectiveness in CPVT patients with RyR2 mutations.…”

Targeting ryanodine receptors for anti-arrhythmic therapy

“…Dantrolene has previously been described as an inhibitor of arrhythmias in animal models of ischemia-reperfusion [33][34][35] . More recently, dantrolene was demonstrated to inhibit catecholaminergic polymorphic ventricular tachycardia in a knock-in mouse model heterozygous for mutation R2474S in RyR2 [36] (Figure 1). Dantrolene was shown to suppress isoproterenol-induced spontaneous SR Ca 2+ releases (ie, sparks) in intact myocytes isolated from RyR2-R2474A/+ mice.…”

“…Flecainide initially showed promise as an antiarrhythmic agent against both ventricular [59] and atrial arrhythmias [60] . Because a predomi- [36] . Adapted from Wehrens et al [47] .…”