Catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly malignant form of arrhythmogenic disorder characterized by exercise- or emotional-induced polymorphic ventricular tachycardia in the absence of detectable structural heart disease. Because of the typical pattern of arrhythmias (bidirectional ventricular tachycardia and the occurrence and severity of arrhythmia correlated well with exercise workload) during exercise stress test, CPVT can be identified promptly. Molecular genetic screening of the genes encoding the cardiac ryanodine receptor and calsequestrin is critical to confirm uncertain diagnosis of CPVT. With the exception of beta-blockers, no pharmacologic therapy of proven effectiveness is available: although beta-blockers reduce the occurrence of ventricular tachycardia, 30% of patients treated with beta-blockers still experience cardiac arrhythmias and eventually require implantable cardioverter defibrillator implantation to prevent cardiac arrest.     

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。     

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.     

Leaky ryanodine receptors cause delayed afterdepolarizations and ventricular arrhythmias.

Catecholaminergic polymorphic ventricular tachycardia (CPVT)is an inherited arrhythmogenic disease characterized by theabsence of structural heart disease, syncope, and sudden cardiacdeath.¹ Typically, acceleration of the heart rate during physicalexercise or emotional distress provokes an increasing numberof ventricular premature complexes followed by runs of bidirectionalor polymorphic ventricular tachycardia (VT). During clinicaltesting, about 30–50% of the patients will reproduciblydevelop VT following exercise testing or catecholamine injection.^1,2 The ECG morphology of ventricular tachyarrhythmias observedin patients with CPVT resembles that of VTs commonly describedin digitalis toxicity (which is associated with cellular calciumoverload), and in metabolic disturbances as seen in severe HF(which is associated with high adrenergic tone).³ In conditionsof cytoplasmic Ca²⁺ overload or enhanced ß-adrenergicsignalling, cardiac myocytes exhibit greater ectopic activity.It has therefore been suggested that arrhythmias in CPVT aremediated by triggered activity and delayed afterdepolarizations(DADs),     

Cardiac Calsequestrin: The New Kid on the Block in Arrhythmias

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited disease characterized by physical or emotional stress-induced ventricular arrhythmias in the absence of any structural heart disease or QT prolongation. Thus far, mutations in genes encoding the sarcoplasmic reticulum Ca²⁺ release channel (RYR2) and the sarcoplasmic reticulum Ca²⁺ binding protein cardiac calsequestrin (CASQ2) have been identified in CPVT patients. Here, we review the role of cardiac calsequestrin in health and disease, with a particular focus on how calsequestrin deficiency can cause arrhythmia susceptibility. Clinical implications and a promising new drug therapy for CPVT are discussed.     

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.     

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.     

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.     

Unusual clinical presentation in a family with catecholaminergic polymorphic ventricular tachycardia due to a G14876A ryanodine receptor gene mutation

A family was identified, of whom which 11 members were carriers of the G14876A ryanodine 2 receptor mutation. All but 1 were symptomatic at the time of the study. Exercise testing showed bidirectional or polymorphic arrhythmias in 4 patients, whereas in 5 patients, it showed monomorphic or rare minor polymorphic ventricular arrhythmias. Two young patients died suddenly at rest while asleep. This study demonstrates that arrhythmias occurring during exercise stress testing in patients affected by catecholaminergic polymorphic ventricular tachycardia (CPVT) could be minor even in very symptomatic patients. The diagnosis of CPVT must be considered in these patients with a familial history of typical CPVT.     

A novel mutation in FKBP12.6 binding region of the human cardiac ryanodine receptor gene (R2401H) in a Japanese patient with catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an autosomal dominant inherited disorder characterized by adrenergic induced polymorphic ventricular tachycardias and associated with sudden cardiac death. The human cardiac ryanodine receptor gene (RyR2) was linked to CPVT. A 20-year-old male was referred to our hospital because of recurrent syncope after physical and emotional stress. Routine cardiac examinations including catheterization revealed no structural abnormality. Exercise on treadmill induced premature ventricular contraction in bigeminy and bidirectional ventricular tachycardia was induced during isoproterenol infusion. Beta-blocking drug was effective in suppressing the arrhythmias. We performed genetic screening by PCR-SSCP method followed by DNA sequencing, and a novel missense mutation R2401H in RyR2 located in FKBP12.6 binding region was identified. This mutation was not detected in 190 healthy controls. Since FKBP12.6 plays a critical role in Ca channel gating, the R2401H mutation can be expected to alter Ca-induced Ca release and E-C coupling resulting in CPVT. This is the first report of RyR2 mutation in CPVT patient from Asia including Japan.     

Therapeutic approach for patients with catecholaminergic polymorphic ventricular tachycardia: state of the art and future developments

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by bidirectional or polymorphic ventricular arrhythmias under conditions of increased sympathetic activity in young patients with structurally normal hearts. Patients with CPVT are at high risk of developing life-threatening ventricular arrhythmias when untreated. A wide variety of arrhythmic event rates on conventional therapy, with β-blockers as the cornerstone, has been reported. Here, we systematically review all available studies describing the efficacy of β-blocker therapy for prevention of arrhythmic events in CPVT. Because of heterogeneity between the studies, a random-effects meta-analysis model was used to assess the efficacy of β-blocker therapy in preventing any arrhythmic event [syncope, aborted cardiac arrest (ACA), and sudden cardiac death (SCD)], near-fatal arrhythmic events (ACA and SCD), and fatal arrhythmic events. Eleven studies including 403 patients, of whom 354 (88%) had a β-blocker prescribed, were identified. Mean follow-up ranged from 20 months to 8 years. Estimated 8-year arrhythmic, near-fatal, and fatal event rates were 37.2% [95% confidence interval (CI): 16.6-57.7], 15.3% (95% CI: 7.4-23.3), and 6.4% (95% CI: 3.2-9.6), respectively. In addition, we review the recent developments in alternate chronic treatment options for CPVT patients, including calcium channel blockers, flecainide, left cardiac sympathetic denervation, and implantable cardioverter defibrillators. A new treatment strategy is proposed, including a stepwise addition of the alternate treatment options to β-blockers in patients who do not respond sufficiently to this first-line therapy. Finally, future developments in chronic treatment options and acute treatment options of ventricular arrhythmias are discussed.     

Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease occurring in patients with a structurally normal heart: the disease is characterized by life-threatening arrhythmias elicited by stress and emotion. In 2001, the ryanodine receptor was identified as the gene that is linked to CPVT; shortly thereafter, cardiac calsequestrin was implicated in the recessive form of the same disease. It became clear that abnormalities in intracellular Ca(2+) regulation could profoundly disrupt the electrophysiological properties of the heart. In this article, we discuss the molecular basis of the disease and the pathophysiological mechanisms that are impacting clinical diagnosis and management of affected individuals. As of today, the interaction between basic scientists and clinicians to understand CPVT and identify new therapeutic strategies is one of the most compelling examples of the importance of translational research in cardiology.     

Electrocardiogram in Andersen-Tawil Syndrome. New Electrocardiographic Criteria for Diagnosis of Type-1 Andersen-Tawil Syndrome

Andersen - Tawil syndrome (ATS) is an autosomal - dominant or sporadic disorder characterized by ventricular arrhythmias, periodic paralysis, and distinctive facial and skeletal dysmorphism. Mutations in KCNJ2, which encodes the α-subunit of the potassium channel Kir2.1, were identified in patients with ATS. This genotype has been designated as type-1 ATS (ATS1). KCNJ2 mutations are detectable in up to 60 % of patients with ATS. Cardiac manifestations of ATS include frequent premature ventricular contractions (PVC), Q-U interval prolongation, prominent U-waves, and a special type of polymorphic ventricular tachycardia (PMVT) called bidirectional ventricular tachycardia (BiVT). The presence of frequent PVCs at rest are helpful in distinguishing ATS from typical catecholaminergic polymorphic ventricular tachycardia (CPVT). In typical CPVT, rapid PMVT and BiVT usually manifest during or after exercising. Additionally, CPVT or torsade de pointes in LQTS are faster, very symptomatic causing syncope or often deteriorate into VF resulting in sudden cardiac death. PVCs at rest are quite frequent in ATS1 patients, however, in LQTS patients, PVCs and asymptomatic VT are uncommon which also contributes to differentiating them. The article describes the new electrocardiographic criteria proposed for diagnosis of type-1 Andersen-Tawil syndrome. A differential diagnosis between Andersen-Tawil syndrome, the catecholamine polymorphic ventiruclar tachycardia and long QT syndrome is depicted. Special attention is paid on the repolarization abnormalities, QT interval and the pathologic U wave. In this article, we aim to provide five new electrocardiographic clues for the diagnosis of ATS1.     

Guidelines for the diagnosis and management of Catecholaminergic Polymorphic Ventricular Tachycardia

BACKGROUND: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is an inherited arrhythmia syndrome, characterised by polymorphic ventricular tachycardia induced by adrenergic stress. CPVT can be caused by mutations the cardiac ryanodine receptor gene (RYR2) or mutations in the cardiac calsequestrin gene CASQ2. Structural heart disease is usually absent and the baseline ECG is usually normal. Patients with CPVT often present with exercise- or emotion induced syncope, the first presentation can also be sudden cardiac death. MANAGEMENT: Besides removal of triggers treatment with beta blockers is currently a class I indication in clinically diagnosed patients. Beta blockage should be titrated up to an effective level. The addition of flecainide seems to be a promising approach in patients where arrhythmias are not completely suppressed by beta blockers. A cardioverter-defibrillator (ICD) or left cervical sympathetic denervation might be considered under special circumstances. Genetic counselling is recommended and all first degree relatives should be properly evaluated.     

儿茶酚胺敏感性多形性室性心动过速

摘要：儿茶酚胺敏感性多形性室速(CPVT)是一种是好发于青少年的遗传性心律失常综合征,其核心是由肾上腺素所诱发的心律紊乱。其典型的临床特征是运动或情绪激动时诱发室性心动过速,常伴发晕厥,甚至发生猝死。对于既往有晕厥或室速发作的患者,应当坚持使用β-受体阻滞剂(Ⅰa类证据),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Ⅱa类适应证。     

Molecular mechanisms of inherited ventricular arrhythmias

BACKGROUND: Inherited ventricular arrhythmias such as the long QT syndrome (LQTS), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), idiopathic ventricular fibrillation (VF), and arrhythmogenic right ventricular cardiomyopathy (ARVC) account for a relevant proportion of sudden cardiac death cases in young patients cohorts. The detailed pathogenetic mechanisms of inherited ventricular arrhythmias are still poorly understood because systematic investigations are difficult to perform due to low patient numbers and the lack of appropriate experimental models. However, recent advances in research and science have identified a genetic background for many of these diseases. PRESENT KNOWLEDGE: In LQTS, various mutations in different genes encoding for cardiac potassium and sodium channel proteins have been identified ("channelopathy"), and initial progress in genotype-phenotype correlation is made. Mutations in the cardiac sodium channel gene have also been identified in a subset of patients with Brugada syndrome, whereas a genetic background has not yet been demonstrated in idiopathic VF and right ventricular outflow-tract tachycardia (RVO-VT). Very recently, mutations in the cardiac ryanodine receptor gene have been identified in CPVT and in a subgroup of patients with ARVC. Although several chromosomal loci were suggested, no other responsible genes or mutations have been found in autosomal dominant forms of ARVC. However, in Naxos disease, a recessive form of ARVC with coexpression of palmoplantar keratoderma and woolly hair, a mutation in the plakoglobin gene has recently been discovered, thus underscoring the potential role of genetic alterations in cytoskeletal proteins in ARVC. FUTURE PERSPECTIVES: In the next years, significant progress in the genetic diagnosis pathophysiologic understanding of disease mechanisms, genotype-phenotype correlation, and the development of gene- or target-directed treatment strategies can be expected in the field of inherited ventricular arrhythmias. CONCLUSION: This review summarizes the current knowledge of the molecular mechanisms, including aspects of pathoanatomy, autonomic innervation, genetics, and genotype-phenotype correlations with their potential implications for diagnosis and treatment of inherited ventricular arrhythmias.     

儿茶酚胺敏感性多形性室速的基因诊治进展

儿茶酚胺敏感性多形性室速(CPVT)是具有较高猝死风险的罕见单基因遗传病.已知多种CPVT基因突变可通过影响肌浆网钙通道蛋白RyR2的功能,破坏细胞内钙稳态,触发室性心律失常,而依靠腺相关病毒载体(AAVs)及CRISPR/Cas9技术进行基因层面的干预有望为CPVT的治疗提供新思路.本文就其遗传特征及基因干预等领域的研究现状作一总结.     

儿茶酚胺敏感性多形性室性心动过速患者的平板运动试验特点分析

目的研究儿茶酚胺敏感性多形性室性心动过速(CPVT)患者的平板运动试验特点。方法回顾性分析2006年9月至2014年3月在北京大学人民医院心内科临床诊断为CPVT的15例患者(其中男性9例,60.0%)的平板运动心电图资料。结果 (1)服用药物前,15例患者行平板运动试验均诱发出室性心律失常,阈值心率为(122.3±26.1)次/min,其中9例(60.0%)记录到特征性双向性室性心动过速,6例(40.0%)记录到双向性室性心动过速和多形性室性心动过速;(2)同时,8例患者(53.3%)记录到运动后的房性心律失常,且房性期前收缩阈值心率明显低于室性期前收缩[(91.5±26.3)次/min比(115.2±18.5)次/min,P=0.003];(3)15例患者在良好的监测下,平板运动试验安全性可靠。结论平板运动试验可安全有效诱发室性心律失常,对于CPVT的诊断有重要价值。     

A novel mutation in the RYR2 gene leading to catecholaminergic polymorphic ventricular tachycardia and paroxysmal atrial fibrillation: dose-dependent arrhythmia-event suppression by β-blocker therapy

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic condition that presents with exercise-induced polymorphic arrhythmias. We describe a case report of a 25-year-old woman who had a cardiac arrest due to ventricular fibrillation. Genetic analysis revealed a novel missense mutation in exon 90 of the ryanodine receptor (RyR2) gene resulting in substitution of arginine for serine at residue 4153 (S4153R). The patient received an implantable cardioverter-defibrillator and low-dose β-blocker therapy. She had recurrent polymorphic ventricular arrhythmias treated with appropriate cardioverter-defibrillator shocks and paroxysmal atrial fibrillation. Titration of β-blocker to a much higher dose suppressed further episodes of ventricular arrhythmia and paroxysmal atrial fibrillation, resulting in reduction in device therapies.     

Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare arrhythmogenic disorder characterized by syncopal events and sudden cardiac death at a young age during physical stress or emotion, in the absence of structural heart disease. We report the first nonsense mutations in the cardiac calsequestrin gene, CASQ2, in three CPVT families. The three mutations, a nonsense R33X, a splicing 532+1 G>A, and a 1-bp deletion, 62delA, are thought to induce premature stop codons. Two patients who experienced syncopes before the age of 7 years were homozygous carriers, suggesting a complete absence of calsequestrin 2. One patient was heterozygous for the stop codon and experienced syncopes from the age of 11 years. Despite the different mutations, there is little phenotypic variation of CPVT for the CASQ2 mutations. Of the 16 heterozygous carriers of these various mutations, 14 were devoid of clinical symptoms or ECG anomalies, whereas 2 of them had ventricular arrhythmias at ECG on exercise tests. In line with this, the diagnosis of the probands was difficult because of the absence of a positive family history. In conclusion, these additional three CASQ2 CPVT families suggest that CASQ2 mutations are more common than previously thought and produce a severe form of CPVT. The full text of this article is available at http://www.circresaha.org.