儿茶酚胺敏感多形性室性心动过速的临床与基因学研究进展

儿茶酚胺敏感多形性室性心动过速(catecholaminergic polymorphic ventricular tachycardia,CPVT)又称儿茶酚胺依赖型多形性或家族性多形性室性心动过速(VT),多发生于心脏结构及QT间期正常的儿童和年轻人,以运动或情绪激动时出现双向或多形性VT、导致晕厥和猝死为特征.CPVT为一种遗传性疾病,依据致病基因不同分为两种类型:(1)CPVT1:常染色体显性遗传,编码利罗丁受体2(ryanodine receptor 2,RyB2)基因突变所致;(2)CPVT2:常染色体隐性遗传,编码肌集钙蛋白2(calsequestrin2,CASQ2)基因突变所致.     

儿茶酚胺敏感性室性心动过速的遗传学和治疗学研究

儿茶酚胺敏感性室性心动过速(CPVT)是以双向或多形性室性心动过速为特征的遗传性心律失常,多发生于无结构性心脏病的青少年,呈明显的家族聚集性,有常染色体显性和隐性两种遗传形式。目前较成熟的治疗方法有β受体阻滞剂、植入埋藏式心脏转复除颤器、Ⅰ类抗心律失常药及交感神经消融术。随着对CPVT认识的深入,基因和干细胞研究及部分学者提出的迷走神经松弛和心房超速起搏等有望为CPVT治疗提供新的策略。     

儿茶酚胺敏感性室性心动过速2例报告

儿茶酚胺敏感性室性心动过速(室速)又称儿茶酚胺敏感性多形性室速(CPVT),是一种家族遗传性离子通道病,也是导致年轻人心脏性晕厥及猝死的常见疾病之一。由于CPVT发病多为青少年,     

儿茶酚胺敏感性多形性室速与心肌复极异常

儿茶酚胺敏感性多形性室速(catecholaminergic polymorphic ventricular tachycardia,CPVT)是一种恶性化程度较高的家族遗传性心律失常性疾病,临床上主要表现为由运动或情绪激动诱发(肾上腺素介导)的双向性和/或多形性室速、晕厥和猝死。CPVT的致病基因主要为RyR2和CASQ2。RyR2通道功能障碍造成的钙释放异常是引发CPVT的主要病理基础。本文对CPVT患者发生心肌复极异常的机制进行了综述。研究表明,肾上腺素刺激可加剧CPVT患者心肌细胞钙瞬变的不规则性与交替性变化,引起心肌复极不规则、QT间期变异程度加深,从而导致恶性心律失常。     

儿茶酚胺敏感性室性心动过速的植入式心律转复除颤器治疗

正儿茶酚胺敏感性多形性室性心动过速(catecholaminergic polymorphic ventricular tachy-cardia,CPVT)是一种高度恶性的遗传性心律失常疾病,以运动或情绪激动诱发的双向型和(或)多形性室性心动过速为特征,多发生于无器质性心脏病、QT间期正常的青少年。目前研究认为CPVT可分为常染色体显性遗传和隐性遗传两种形式,分别与编码心肌细胞肌浆网钙通道的RyR2基因和肌浆网内     

儿茶酚胺诱发的多形性室性心动过速：心电图特征及预防猝死的最佳方案

儿茶酚胺诱发的多形性室性心动过速 (CPVT)是运动或静滴儿茶酚胺时发生的两种以上形态的室性心动过速。CPVT不存在电解质紊乱、药物治疗及原发性心脏疾病等诱因 ,且无长QT及Brugada综合征等原发性电生理紊乱。目前对CPVT的预后 ,临床及心电图特征尚未完全明确 ,本文对有关问题进行了探讨。方法 :对 2 9例符合CPVT诊断标准的患者分别在控制期及发作期进行了完整体表心电图记录。患者均经心血管专科医师体检 ,并完成X胸片及UCG检查。CPVT来源位置由束支阻滞类型及QRS电轴判定。结果 :2 9例患者 (男 13 ,女 16)平均年龄 10 .3± 6.…     

儿茶酚胺敏感性多形性室性心动过速的研究进展

儿茶酚胺敏感性多形性室性心动过速(CPVT)是一种原发性心脏电紊乱,可能是非器质性心脏病患者发生猝死的重要原因。少年及成人均可患病。异常的RyR2通道或CASQ2蛋白在交感兴奋的条件下诱发的延迟后除极可能是CPVT发生的机制。任何患者无论年龄大小,只要是交感神经系统兴奋诱发的双向或多形性室性心动过速,无器质性心脏病且QT间期正常,都应考虑CPVT的诊断。β受体阻滞剂可以控制大部分患者的心动过速发作。CPVT患者发生过心脏骤停为埋藏式心脏转复除颤器(ICD)治疗的Ⅰ类适应证。服用β受体阻滞剂时出现晕厥者为ICD治疗的Ⅱa类适应证。对于致病基因的携带者,特别是儿童,都应服用β受体阻滞剂进行一级预防。     

儿茶酚胺依赖性多形室速的心率变异性及其β-受体阻滞剂干预后的变化

目的:探讨心率变异在儿茶酚胺依赖性多形室速(catecholaminergic polymorphic ventricular tachycardia,CPVT)危险分层中的应用价值,及其β-受体阻滞剂干预后的变化。方法:根据不同预后对22例(未发猝死组18例,猝死组4例)CPVT患者进行HRV时域指标分析,与正常对照组比较;并比较β-受体阻滞剂干预前、后HRV时域指标的变化。结果:22例CPVT患者HRV各项时域指标均显著低于正常对照组(P<0.001),猝死组显著低于未发猝死组(P<0.001);β-受体阻滞剂可以使其HRV时域指标显著升高(P<0.05)。结论:HRV可以作为CPVT患者发生心脏性猝死的独立预测指标。     

儿茶酚胺敏感性多形性室性心动过速基因特异性管理

儿茶酚胺敏感性多形性室性心动过速(catecholaminergic polymorphic ventricular tachycardia，CPVT)是一种罕见的遗传性疾病，与基因突变导致的心肌细胞内钙稳态的失衡有关，运动或情绪激动可诱发致命性的室性心律失常。CPVT的诊断基于肾上腺素引起的双向性或多形性室性心动过速，部分患者通过基因检测确诊。在治疗上可通过内、外科方法，抑制或阻断肾上腺素对心肌钙稳态的影响。未正规治疗的患者死亡率高，且猝死常为首发症状。文章阐述CPVT的遗传学新发现及其对临床管理的影响，同时阐述基因检测的局限性和级联筛查的最佳应用。     

平板运动试验对儿童儿茶酚胺敏感性多形性室性心动过速的诊治价值分析

目的 分析儿茶酚胺敏感性多形性室性心动过速(CPVT)患儿的平板运动试验特点,探讨其在CPVT患儿诊治中的意义.方法 回顾性分析2015年1月至2019年9月就诊于清华大学第一附属医院心脏中心小儿科的18例CPVT患儿,依据指南推荐进行规律治疗,服用普萘洛尔或美托洛尔,部分联合普罗帕酮.治疗前后进行平板运动试验,对比相...     

Catecholaminergic Polymorphic Ventricular Tachycardia from Bedside to Bench and Beyond

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a primary electrical myocardial disease characterized by exercise- and stress-related ventricular tachycardia manifested as syncope and sudden death. The disease has a heterogeneous genetic basis, with mutations in the cardiac Ryanodine Receptor channel (RyR2) gene accounting for an autosomal-dominant form (CPVT1) in approximately 50% and mutations in the cardiac calsequestrin gene (CASQ2) accounting for an autosomal-recessive form (CPVT2) in up to 2% of CPVT cases. Both RyR2 and calsequestrin are important participants in the cardiac cellular calcium homeostasis.We review the physiology of the cardiac calcium homeostasis, including the cardiac excitation contraction coupling and myocyte calcium cycling. The pathophysiology of cardiac arrhythmias related to myocyte calcium handling and the effects of different modulators are discussed.The putative derangements in myocyte calcium homeostasis responsible for CPVT, as well as the clinical manifestations and therapeutic options available, are described.     

Calcium channel blockers and beta-blockers versus beta-blockers alone for preventing exercise-induced arrhythmias in catecholaminergic polymorphic ventricular tachycardia

BACKGROUND: The mainstay of therapy for catecholaminergic polymorphic ventricular tachycardia (CPVT) is maximal doses of beta-blockers. However, although beta-blockers prevent exercise-induced ventricular tachycardia (VT), most patients continue to have ventricular ectopy during exercise, and some studies report high mortality rates despite beta-blockade. OBJECTIVE: The purpose of this study was to investigate whether combining a calcium channel blocker with beta-blockers would prevent ventricular arrhythmias during exercise better than beta-blockers alone since the mutations causing CPVT lead to intracellular calcium overload. METHODS: Five patients with CPVT and one with polymorphic VT (PVT) and hypertrophic cardiomyopathy who had exercise-induced ventricular ectopy despite beta-blocker therapy were studied. Symptom-limited exercise was first performed during maximal beta-blocker therapy and repeated after addition of oral verapamil. RESULTS: When comparing exercise during beta-blockers with exercise during beta-blockers + verapamil, exercise-induced arrhythmias were reduced: (1) Three patients had nonsustained VT on beta-blockers, and none of them had VT on combination therapy. (2) The number of ventricular ectopics during the whole exercise test went down from 78 +/- 59 beats to 6 +/- 8 beats; the ratio of ventricular ectopic to sinus beats during the 10-second period recorded at the time of the worst ventricular arrhythmia went down from 0.9 +/- 0.4 to 0.2 +/- 0.2. One patient with recurrent spontaneous VT leading to multiple shocks from her implanted cardioverter-defibrillator (ICD) despite maximal beta-blocker therapy (14 ICD shocks over 6 months while on beta-blockers) has remained free of arrhythmias (for 7 months) since the addition of verapamil therapy. CONCLUSIONS: This preliminary evidence suggests that beta-blockers and calcium blockers could be better than beta-blockers alone for preventing exercise-induced arrhythmias in CPVT.     

Molecular and electrophysiological bases of catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by adrenergically mediated polymorphic ventricular tachyarrhythmias. Genetic investigations have identified two variants of the disease: an autosomal dominant form associated with mutations in the gene encoding the cardiac ryanodine receptor (RyR2) and a recessive form associated with homozygous mutations in the gene encoding the cardiac isoform of calsequestrin (CASQ2). Functional characterization of mutations identified in the RyR2 and CASQ2 genes has demonstrated that CPVT are caused by derangements of the control of intracellular calcium. Investigations in a knock-in mouse model have shown that CPVT arrhythmias are initiated by delayed afterdepolarizations and triggered activity. In the present article, we review clinical and molecular understanding of CPVT and discuss the most recent approaches to develop novel therapeutic strategies for the disease.     

Disruption of calcium homeostasis and arrhythmogenesis induced by mutations in the cardiac ryanodine receptor and calsequestrin

Development of cardiac arrhythmias in several degenerative cardiac disorders such as heart failure is precipitated by abnormalities in intracellular calcium regulation. Recently, the identification of mutations in proteins responsible for the control of intracellular calcium has been associated with an inherited arrhythmogenic syndrome called catecholaminergic polymorphic ventricular tachycardia (CPVT). Here, we review the current knowledge about the molecular pathophysiology of CPVT and we discuss some potentially innovative strategies for controlling calcium-handling abnormalities in CPVT that may provide novel therapeutic options for affected patients.     

Prevention of Ventricular Arrhythmia and Calcium Dysregulation in a Catecholaminergic Polymorphic Ventricular Tachycardia Mouse Model Carrying Calsequestrin‐2 Mutation

Arrhythmia Prevention in CPVT . Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmic syndrome caused by mutations in genes encoding the calcium‐regulation proteins cardiac ryanodine receptor (RyR2) or calsequestrin‐2 (CASQ2). Mechanistic studies indicate that CPVT is mediated by diastolic Ca²⁺ overload and increased Ca²⁺ leak through the RyR2 channel, implying that treatment targeting these defects might be efficacious in CPVT. Method and results: CPVT mouse models that lack CASQ2 were treated with Ca²⁺‐channel inhibitors, β‐adrenergic inhibitors, or Mg²⁺. Treatment effects on ventricular arrhythmia, sarcoplasmic reticulum (SR) protein expression and Ca²⁺ transients of isolated myocytes were assessed. Each study agent reduced the frequency of stress‐induced ventricular arrhythmia in mutant mice. The Ca²⁺ channel blocker verapamil was most efficacious and completely prevented arrhythmia in 85% of mice. Verapamil significantly increased the SR Ca²⁺ content in mutant myocytes, diminished diastolic Ca²⁺ overload, increased systolic Ca²⁺ amplitude, and prevented Ca²⁺ oscillations in stressed mutant myocytes. Conclusions: Ca²⁺ channel inhibition by verapamil rectified abnormal calcium handling in CPVT myocytes and prevented ventricular arrhythmias. Verapamil‐induced partial normalization of SR Ca²⁺ content in mutant myocytes implicates CASQ2 as modulator of RyR2 activity, rather than or in addition to, Ca²⁺ buffer protein. Agents such as verapamil that attenuate cardiomyocyte calcium overload are appropriate for assessing clinical efficacy in human CPVT . (J Cardiovasc Electrophysiol, Vol. 22, pp. 316‐324, March 2011)     

Catecholaminergic polymorphic ventricular tachycardia: recent mechanistic insights

Cardiac excitation-contraction coupling occurs by a calcium ion-mediated mechanism in which the signal of action potential is converted into Ca2+ influx into the cardiomyocytes through the sarcolemmal L-type calcium channels. This is followed by Ca2+-induced release of additional Ca2+ ions from the lumen of the sarcoplasmic reticulum into the cytosol via type 2 ryanodine receptors (RyR2). RyR2 channels form large complexes with additional regulatory proteins, including FKBP12.6 and calsequestrin 2 (CASQ2). Catecholamines, released into the body fluids during emotional or physical stress, activate Ca2+-induced Ca2+ release by protein kinase A-mediated phosphorylation of RyR2. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an insidious, early-onset and highly malignant, inherited disorder characterized by effort-induced ventricular arrhythmias in the absence of structural alterations of the heart. At least some cases of sudden, unexplained death in young individuals may be ascribed to CPVT. Mutations of the RyR2 gene cause autosomal dominant CPVT, while mutations of the CASQ2 gene may cause an autosomal recessive or dominant form of CPVT. The steps of the molecular pathogenesis of CPVT are not entirely clear, but inappropriate "leakiness" of RyR2 channels is thought to play a role; the underlying mechanisms may involve an increase in the basal activity of the RyR2 channel, alterations in its phosphorylation status, a defective interaction of RyR2 with other molecules or ions, such as FKBP12.6, CASQ2, or Mg2+, or its abnormal activation by extra- or intraluminal Ca2+ ions. Beta-adrenergic antagonists have proven to be of value in prevention of arrhythmias in CPVT patients, but occasional treatment failures call for alternative measures. There is great interest at present for the development of novel antiarrhythmic drugs for CPVT, as the same approaches may be applied for treatment of more common forms of life-threatening arrhythmias, such as those arising during ischemia and heart failure.     

Bidirectional ventricular tachycardia and fibrillation elicited in a knock-in mouse model carrier of a mutation in the cardiac ryanodine receptor

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by adrenergically mediated polymorphic ventricular tachycardia leading to syncope and sudden cardiac death. The autosomal dominant form of CPVT is caused by mutations in the RyR2 gene encoding the cardiac isoform of the ryanodine receptor. In vitro functional characterization of mutant RyR2 channels showed altered behavior on adrenergic stimulation and caffeine administration with enhanced calcium release from the sarcoplasmic reticulum. As of today no experimental evidence is available to demonstrate that RyR2 mutations can reproduce the arrhythmias observed in CPVT patients. We developed a conditional knock-in mouse model carrier of the R4496C mutation, the mouse equivalent to the R4497C mutations identified in CPVT families, to evaluate if the animals would develop a CPVT phenotype and if beta blockers would prevent arrhythmias. Twenty-six mice (12 wild-type (WT) and 14RyR(R4496C)) underwent exercise stress testing followed by epinephrine administration: none of the WT developed ventricular tachycardia (VT) versus 5/14 RyR(R4496C) mice (P=0.02). Twenty-one mice (8 WT, 8 RyR(R4496C), and 5 RyR(R4496C) pretreated with beta-blockers) received epinephrine and caffeine: 4/8 (50%) RyR(R4496C) mice but none of the WT developed VT (P=0.02); 4/5 RyR(R4496C) mice pretreated with propranolol developed VT (P=0.56 nonsignificant versus RyR(R4496C) mice). These data provide the first experimental demonstration that the R4496C RyR2 mutation predisposes the murine heart to VT and VF in response caffeine and/or adrenergic stimulation. Furthermore, the results show that analogous to what is observed in patients, beta adrenergic stimulation seems ineffective in preventing life-threatening arrhythmias.     

Calmodulin kinase II inhibition prevents arrhythmias in RyR2(R4496C+/-) mice with catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by life-threatening arrhythmias elicited by adrenergic activation. CPVT is caused by mutations in the cardiac ryanodine receptor gene (RyR2). In vitro studies demonstrated that RyR2 mutations respond to sympathetic activation with an abnormal diastolic Ca(2+) leak from the sarcoplasmic reticulum; however the pathways that mediate the response to adrenergic stimulation have not been defined. In our RyR2(R4496C+/-) knock-in mouse model of CPVT we tested the hypothesis that inhibition of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) counteracts the effects of adrenergic stimulation resulting in an antiarrhythmic activity. CaMKII inhibition with KN-93 completely prevented catecholamine-induced sustained ventricular tachyarrhythmia in RyR2(R4496C+/-) mice, while the inactive congener KN-92 had no effect. In ventricular myocytes isolated from the hearts of RyR2(R4496C+/-) mice, CaMKII inhibition with an autocamtide-2 related inhibitory peptide or with KN-93 blunted triggered activity and transient inward currents induced by isoproterenol. Isoproterenol also enhanced the activity of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), increased spontaneous Ca(2+) release and spark frequency. CaMKII inhibition blunted each of these parameters without having an effect on the SR Ca(2+) content. Our data therefore indicate that CaMKII inhibition is an effective intervention to prevent arrhythmogenesis (both in vivo and in vitro) in the RyR2(R4496C+/-) knock-in mouse model of CPVT. Mechanistically, CAMKII inhibition acts on several elements of the EC coupling cascade, including an attenuation of SR Ca(2+) leak and blunting catecholamine-mediated SERCA activation. CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT.     

Human cardiac ryanodine receptor mutations in ion channel disorders in Japan

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by adrenergic induced bidirectional or polymorphic ventricular tachycardias. Some of CPVT families were reported to be associated with cardiac ryanodine receptor gene (RyR2) mutations. However, association between RyR2 and other arrhythmogenic disorders is not clarified. In this study, we analyzed 83 Japanese patients including patients with long-QT syndrome, Brugada syndrome, idiopathic ventricular fibrillation, arrhythmogenic right ventricular cardiomyopathy and CPVT. Genetic screening of RyR2 revealed 3 distinct mutations among 4 families with CPVT (75% of incidence). However, no mutation was found in other groups. This is the first report to demonstrate prevalence of RyR2 mutations in various arrhythmogenic disorders in Japan. RyR2 mutations were detected frequently in CPVT but not in other diseases.