Stabilizing Tetrameric Structure of Ryanodine Receptor Cures Lethal Arrhythmia in Heart Failure
Stabilizing Tetrameric Structure of Ryanodine Receptor Cures Lethal Arrhythmia in Heart Failure
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稳定瑞尼定受体的四聚体结构可治愈心力衰竭的致命性心律失常
DOI：
10.1161/circep.122.011220
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Yano Masafumi
中科院分区：
文献类型：
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作者：
Kobayashi Shigeki;Yamamoto Takeshi;Yoshiga Yasuhiro;Okamura Takayuki;Kawano Reo;Yano Masafumi
通过心脏Ryanodine受体(RyR2)的舒张期钙离子异常泄漏是心力衰竭(HF)致死性心律失常的重要原因，是触发活动的机制之一。1-4这种泄漏归因于RyR2内N-末端和中央结构域之间的缺陷相互作用，这导致钙调素(CaM)的解离和心律失常。1-4Dantrolene通过与突变的骨架兰尼定受体(RyR1)结合用于治疗恶性高热，可通过N端的Leu601-Cys620直接与RyR2结合。这种结合增强了CaM与RyR2的亲和力，从而抑制钙离子泄漏和抑制心律失常(图[A])。丹曲烯的结合部位在三维上靠近拉链界面(N-末端：1-220；中心：2300-2500)和CaM结合结构域(3583-3603)，5表明丹曲烯在结构上抑制了应激过程中CaM的解离，防止了亚单位间有缺陷的相互作用，从而稳定了四聚体，这与我们的临床前研究(图[A])一致。1-4丹曲林的抗心律失常作用迄今已在犬心动过速诱导的心动过速、小鼠横断主动脉收缩和小鼠儿茶酚胺能多形性室性心动过速模型中得到报道。1、3、4在这项单中心、介入、开放、无对照的研究中，我们旨在评估静脉注射丹曲林(丹曲林IV)在室性心动过速(VT)或持续性VT(SVT)的情况下对心力衰竭(HF)患者的急性疗效，这些患者对β阻滞剂和III类抗心律失常药物的指导药物治疗无效。在其他抗心律失常药物的基础上给予起始剂量20 mg，然后丹曲林1 mg/kg(以2 mg/min的速度)，直到终止VT或最大剂量为7 mg/kg。终止VT后，考虑到丹曲林的半衰期为4~8小时，根据日本恶性热疗指南，丹曲林维持剂量调整为0.5~1.0 mg/kg，每4~8小时一次，持续至少2天。支持这项研究结果的数据可以从相应的作者那里获得，只要提出合理的要求。我们连续招募了10名患有难治性室上性心动过速或室速风暴的患者(9名男性，1名女性)。所有患者都有纽约心脏协会III或IV级，高BNP水平和左心功能不全(LVEF；30±9%)。≤剂量为3 mg/kg时终止VT者8例(80.0%)。注药后终止室速的时间为≤120min。静脉注射丹曲林后24小时内室上性心动过速/室性心动过速的发生率(95%CI，−32.7000[−73.8799~8.4799])和持续时间(95%CI，−6.4264[−12.1816~−0.6712])均明显低于注射丹曲林前(图B)。根据Kaplan-Meier方法，VT/VT首次停止后48h内无再发SVT/VT的比例为90.0%(9/10)。丹曲林治疗后校正QT间期(QT间期)和LVEF无明显变化。具有代表性的案例如图[C]和图[D]所示。对胺碘酮和其他抗心律失常药物无效的室速风暴对丹曲林IV完全有效。据我们所知，这是第一次评价丹曲林IV对心力衰竭患者难治性室速风暴的急性抗心律失常作用。丹曲林最重要的抗心律失常作用是
Aberrant diastolic Ca2+ leakage through cardiac ryanodine receptor (RyR2) is an important cause of lethal arrhythmia in heart failure (HF), as a mechanism of triggered activity. 1-4 This leakage is attributed to a defective interaction between the N-terminal and central domains within RyR2, which leads to the dissociation of CaM (calmodulin) and arrhythmia. 1–4 Dantrolene, used to treat malignant hyperthermia via binding to a mutant skeletal ryanodine receptor (RyR1), can directly bind to RyR2 via the Leu601-Cys620 in the N-terminus. This binding enhances the affinity of CaM to RyR2, thereby inhibiting Ca2+ leakage and suppressing arrhythmia (Figure [A]). The binding site of dantrolene is 3-dimensionally close to both the zipping interface (N-terminal: 1-220; Central: 2300-2500) and the CaM-binding domain (3583-3603), 5 suggesting that dantrolene structurally suppresses CaM dissociation during stress, prevents defective inter-subunit interactions, thereby stabilizing tetramer, in consistent with our preclinical studies (Figure [A]). 1–4 The antiarrhythmic effect of dantrolene has been reported to date in canine tachycardia-induced HF, mouse transverse aortic constriction, and mouse catecholaminergic polymorphic ventricular tachycardia models. 1, 3, 4 In this single-center, interventional, open-label, uncontrolled study, we aimed to evaluate the acute effect of intravenous dantrolene (dantrolene IV) in the context of ventricular tachycardia (VT) storm or sustained VT (sVT) in patients with HF, resistant to the guideline-directed medical therapy with β-blockers and class III antiarrhythmic drugs. An initial dose of 20 mg was administered on top of other antiarrhythmic agents, followed by 1 mg/kg of dantrolene (at a rate of 2 mg/min) until the termination of VT or up to a maximum of 7 mg/kg. After the termination of VT, the maintenance dose of dantrolene was adjusted to 0.5 to 1.0 mg/kg every 4 to 8 hours for at least 2 days according to the Japanese guideline of malignant hyperthermia, considering that the half-life of dantrolene is 4 to 8 hours. The data that support the findings of this study are available from the corresponding author upon reasonable request. We enrolled 10 consecutive patients (9 males, 1 female) with refractory sVT or VT storm. All patients had New York Heart Association III or IV, high BNP level, and left ventricular dysfunction (LVEF; 30±9%). VT was terminated at a dosage of≤ 3 mg/kg in 8/10 (80.0%) patients. The time to the termination of VT after injection was≤ 120 minutes. The incidence (95% CI,− 32.7000 [− 73.8799 to 8.4799]) and duration (95% CI,− 6.4264 [− 12.1816 to− 0.6712]) of sVT/VT storm within 24 hours of dantrolene IV were markedly lower than those of pre-injection (Figure [B]). The proportion of patients free from recurrent sVT/VT storm within 48 hours after the first cessation of VT/VT storm was 90.0%(9/10) according to the Kaplan-Meier method. Corrected QT intervals (QTc) and LVEF had been unchanged after dantrolene therapy. Representative cases are shown in Figure [C] and Figure [D]. The VT storms refractory to amiodarone and other anti-arrhythmic drugs showed complete response to dantrolene IV. To our knowledge, this is the first study to evaluate the acute antiarrhythmic effect of dantrolene IV against the refractory VT storm in patients with HF. The most important anti-arrhythmic action of dantrolene is that