Catecholaminergic polymorphic ventricular tachycardia,an update

Catecholaminergic polymorphic ventricular tachycardia is a rare devastating lethal inherited disorder or sporadic cardiac ion channelopathy characterized by unexplained syncopal episodes, and/or sudden cardiac death (SCD), aborted SCD (ASCD), or sudden cardiac arrest (SCA) observed in children, adolescents, and young adults without structural heart disease, consequence of adrenergically mediated arrhythmias: exercise‐induced, by acute emotional stress, atrial pacing, or β‐stimulant infusion, even when the electrocardiogram is normal. The entity is difficult to diagnose in the emergency department, given the range of presentations; thus, a familiarity with and high index of suspicion for this pathology are crucial. Furthermore, recognition of the characteristic findings and knowledge of the management of symptomatic patients are necessary, given the risk of arrhythmia recurrence and SCA. In this review, we will discuss the concept, epidemiology, genetic background, genetic subtypes, clinical presentation, electrocardiographic features, diagnosis criteria, differential diagnosis, and management.     

Prognosis of patients with frequent premature ventricular complexes and nonsustained ventricular tachycardia after coronary artery bypass graft surgery

Background: Previous studies in small groups of predominantly nongeriatic patients showed that complè ventricular arrhythmias occurring after coronary artery graft (CABG) surgery are of no prognostic significance. The purpose of this study was to compare the prognosis of patients with and without advanced grade ventricular arrhythmias (AGVA) after CABG in a large group of patients. [In this paper, AGVA is used as an abridged definition of frequent premature ventricular complexes (PVCs) and nonsustained ventricular tachycardia (NSVT) which represent advanced grade ventricular arrhythmias.] Methods: Twenty-four hour ambulatory electrocardiographic (ECG) monitoring was performed 3 days after CABG in 185 consecutive patients with and 185 closely matched control patients without AGVA. Of 185 patients with AGVA, 77 had frequent PVCs, 45 had NSVT, and 63 patients had both. The average age of both groups was 65 ± 9.7 years. Patients were followed for 34 ± 10 months, and in 30 patients ambulatory monitoring was repeated at the end of the follow-up. Results: Fifteen AGVA and nine control patients died. In each group seven deaths were noncardiac. Six nonsudden and two sudden cardiac deaths (SCD) occurred in the AGVA group at 2-36 months after CABG and two nonsudden cardiac deaths in the control group at 3 and 35 months after CABG (p = 0.053). Both SCDs occurred 33 months after CABG after new events known to predispose to SCD. In 18 of 30 patients AGVÀ was no longer present when ambulatory ECG monitoring was repeated 36 ± 11 months after CABG. Conclusions: AGVA after CABG was not a marker of an early sudden cardiac death. In 60% of patients not treated with antiarrhythmic drugs, AGVA was no longer present late after operation.     

Implantable cardioverter-defibrillator use in catecholaminergic polymorphic ventricular tachycardia: A systematic review

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A novel early onset lethal form of catecholaminergic polymorphic ventricular tachycardia maps to chromosome 7p14-p22

Introduction: Previously, autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT [1]) was mapped to chromosome 1q42–43 with identification of pathogenic mutations in RYR2. Autosomal recessive CPVT (2) was mapped to chromosome 1p13–21, leading to the identification of mutations in CASQ2. In this study, we aimed to elucidate clinical phenotypes of a new variant of CPVT (3) in an inbred Arab family and also delineate the chromosomal location of the gene causing CPVT (3).
Methods and Results: In a highly inbred family, clinical symptoms of CPVT appeared early in childhood (7–12 years) and in three of the four cases, the first appearance of symptoms turned into a fatal outcome. Parents of the affected children were first-degree cousins and without any symptoms. Segregation analysis suggested an autosomal recessive inheritance. A genome-wide search using polymorphic DNA markers mapped the disease locus to a 25-Mb interval on chromosome 7p14-p22. A maximal multipoint LOD score of 3.17 was obtained at marker D7S493. Sequencing of putative candidate genes, SP4 , NPY , FKBP9 , FKBP14 , PDE1C , and TBX20 , in and around this locus, did not reveal any mutation.
Conclusions: We have identified a novel highly malignant autosomal recessive form of CPVT and mapped this disorder to a 25-Mb interval on chromosome 7p14-p22.     

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.     

Intravenous epinephrine infusion test in diagnosis of catecholaminergic polymorphic ventricular tachycardia

Epinephrine Infusion in Diagnosis of CPVT. Introduction: A test involving intravenous infusion of epinephrine has been proposed as a method alternative to exercise stress test in diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT). We aimed at estimating the predictive value of intravenous epinephrine administration in CPVT patients with frequent exercise‐induced ventricular ectopy. Methods and Results: We recruited 81 subjects, including 25 CPVT‐linked ryanodine receptor 2 (RYR2) mutation carriers, 11 genetically undefined CPVT patients, and 45 unaffected family members. All subjects underwent a maximal exercise stress test and an intravenous epinephrine infusion test. Exercise stress test was positive in 25 (31%) patients including 14 of 25 (56%) established RYR2‐mutation carriers and all 11 (100%) genetically undefined CPVT patients. Epinephrine infusion induced arrhythmias in 3 (12%) RYR2‐mutation carriers, 4 (36%) genetically undefined CPVT patients, and 1 (2%) unaffected family member. A total of 18 exercise stress test positive patients did not respond to intravenous epinephrine administration, whereas only 1 epinephrine test responder had a normal exercise stress test. Thus, if exercise stress test is used as a standard, the sensitivity of the epinephrine infusion test is 28% and specificity is 98%. Conclusions: Intravenous epinephrine infusion has low sensitivity and may not be considered as an alternative method for a maximal exercise stress test in diagnosis of CPVT. (J Cardiovasc Electrophysiol, Vol. 23, pp. 194‐199, February 2012)     

Peripartum management of a patient with catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal cardiac channelopathy characterized by episodes of ventricular tachycardia (VT) during exercise or in stressful situations. As the peripartum period creates a stressful environment, we describe our approach of this rare condition in a very common situation, child birth.     

Beta1 and beta2-adrenergic receptor polymorphisms and idiopathic ventricular arrhythmias

Introduction: Idiopathic ventricular arrhythmias commonly refer to ventricular tachycardia (VT) and/or frequent/monomorphic premature ventricular contractions (PVC) in patients with structurally normal heart. Activation of sympathetic tone has been shown to play an important role in the provocation and maintenance of these arrhythmias. We investigated whether common single nucleotide polymorphisms in the β₁ and β₂‐adrenergic receptors are associated with idiopathic ventricular arrhythmias. Methods: A total of 143 unrelated patients presenting with idiopathic ventricular arrhythmias were prospectively included in a case‐control association study. Patient population was matched by age and gender to the unrelated, healthy control subjects (N = 307). All study subjects were of Turkish (Anatolian Caucasian) descent. Allele and genotype frequencies of the Gly389Arg and Ser49Gly polymorphisms of the β₁‐adrenergic receptor and Arg16Gly, Gln27Glu, and Thr164Ile polymorphisms of the β₂‐adrenergic receptor were compared between patient population and control subjects. The genotype frequencies were in Hardy‐Weinberg equilibrium. Results: Patients with idiopathic ventricular arrhythmias had higher frequency of Arg389Arg genotype (22.4% vs 1.6%, P < 0.001), Arg389Gly49 (5.24% vs 0.73%, P = 0.005), and Arg389Ser49 (36.7% vs 13.6%, P < 0.001) haplotypes of the β₁‐adrenergic receptor, and higher frequency of Gly16Gly (31.5% vs 13.4%, P < 0.001), Glu27Glu genotypes (18.2% vs 10.1%, P = 0.006) and Gly16Gln27Thr164 (15.3% vs 7.4%, P = 0.002), Gly16Glu27Thr164 (13.1% vs 7%, P = 0.004), and Gly16Glu27Ile164 (13.2% vs 6%, P = 0.002) haplotypes of the β₂‐adrenergic receptor compared to control subjects. Conclusion: Our data suggest that common single nucleotide polymorphisms in the β₁ and β₂‐adrenergic receptors are significantly associated with idiopathic ventricular arrhythmias in Turkish population.     

非持续性室速患者心率变异及临床观察

观察60例非持续性室性心动过速(NSVT)病人和50例正常人在临床表现、DCG、心功能以及心率变异方面的改变.结果表明:NSVT多见于冠心病(70%),且63.3?G表现为缺血型ST段压低≥1mm,其中23.7%压低>2mm,其心室异位节奏点73.3%来源于左心室.NSVT组与对照组SDNN分别为86.6±29.4ms及128.9±20.9ms,HRVI分别为8.45±2.3及12.7±2.0,均有非常显著性差异.NSVT组平均EF为0.54±0.18,其中41?<0.40.提示:NSVT多见于器质性心脏病人,它可能影响预后,尤其HRV降低可能是心性猝死的重要危险因素.     

Genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing

BACKGROUND: Mutations in the RyR2-encoded cardiac ryanodine receptor/calcium release channel and in CASQ2-encoded calsequestrin cause catecholaminergic polymorphic ventricular tachycardia (CPVT1 and CPVT2, respectively). OBJECTIVES: The purpose of this study was to evaluate the extent of genotypic and phenotypic heterogeneity among referrals for CPVT genetic testing. METHODS: Using denaturing high-performance liquid chromatography and DNA sequencing, mutational analysis of 23 RyR2 exons previously implicated in CPVT1, comprehensive analysis of all translated exons in CASQ2 (CPVT2), KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), KCNE2 (LQT6), and KCNJ2 (Andersen-Tawil syndrome [ATS1], also annotated LQT7), and analysis of 10 ANK2 exons implicated in LQT4 were performed on genomic DNA from 11 unrelated patients (8 females) referred to Mayo Clinic's Sudden Death Genomics Laboratory explicitly for CPVT genetic testing. RESULTS: Overall, putative disease causing mutations were identified in 8 patients (72%). Only 4 patients (3 males) hosted CPVT1-associated RyR2 mutations: P164S, V186M, S3938R, and T4196A. Interestingly, 4 females instead possessed either ATS1- or LQT5-associated mutations. Mutations were absent in >400 reference alleles. CONCLUSION: Putative CPVT1-causing mutations in RyR2 were seen in <40% of unrelated patients referred with a diagnosis of CPVT and preferentially in males. Phenotypic mimicry is evident with the identification of ATS1- and LQT5-associated mutations in females displaying a normal QT interval and exercise-induced bidirectional VT, suggesting that observed exercise-induced polymorphic VT in patients may reflect disorders other than CPVT. Clinical consideration for either Andersen-Tawil syndrome or long QT syndrome and appropriate genetic testing may be warranted for individuals with RyR2 mutation-negative CPVT, particularly females.     

Isolated noncompaction left ventricular myocardium and polymorphic ventricular tachycardia

A 57-year-old woman with syncope was admitted. She had a family history of sudden death: two brothers had died suddenly at the age of 47. Transesophageal echocardiography showed numerous prominent trabeculations and deep intertrabecular recesses in the anterior and lateroapical zones. Isotopic left ventricular ejection fraction was 46%. Cardiac catheterization showed coronary arteries with no angiographic lesions. A prominent trabecular zone and deep intertrabecular recesses were seen in the anterior wall on left ventriculography. Right ventriculography was normal. The diagnosis of isolated noncompaction left ventricular myocardium was established. Continuous 24-h electrocardiographic registry showed episodes of polymorphic ventricular tachycardia. Programmed ventricular stimulation performed at the right ventricular apex with up to three extrastimuli failed to induce ventricular arrhythmias. Treatment with beta blockers was initiated, but short runs of polymorphic ventricular tachycardia persisted. A dual-chamber automatic implantable defibrillator was implanted. We discuss the physiopathology of the arrhythmia. It appears that several factors could be responsible for the malignant arrhythmias in this entity.     

Effects of flecainide therapy on inappropriate shocks and arrythmias in catecholaminergic polymorphic ventricular tachycardia

We report the case of a child with catecholaminergic polymorphic ventricular tachycardia, who had inappropriate electric shocks by an implantable cardioverter defibrillator and from recurrence of arrhythmias despite an appropriate β-blocking treatment. An additional treatment by flecainide completely suppressed inappropriate shocks due to sinusal tachycardia and ventricular tachyarrhythmias. We briefly discuss the potentially interesting effect of flecainide in this specific arrhythmia.     

Apical hypertrophic cardiomyopathy and ventricular tachycardia

Apical hypertrophic cardiomyopathy was originally reported fromJapan as one of the subsets of hypertrophic cardiomyopathy withoutgradient, usually associated with deep T-wave inversion anda spade-like appearance of the left ventricle. Although manyreports from Japan have indicated that these patients with apicalhypertrophic cardiomyopathy are mostly asymptomatic and haverelatively good prognosis, data on serious ventricular arrhythmiasare not yet available. Present documentation of ventriculartachycardia in a patient with this disease suggests that atleast some of such patients are also at risk of sudden deathand that a systematic study for life-threatening arrhythmiaby ambulatory electrocardiographic monitoring may be necessaryin these cases.     

Focal initiation of sustained and nonsustained ventricular tachycardia in a canine model of ischemic cardiomyopathy

Focal Initiation of Ventricular Tachycardia in Ischemic HF. Introduction: To define the role of focal and reentrant mechanisms underlying nonsustained (NSVT) and sustained ventricular tachycardia (SuVT) induced by programmed stimulation, 3‐dimensional cardiac mapping was performed in 8 dogs with heart failure (HF) created by multiple intracoronary microsphere embolizations. Methods and Results: Continuous recording from 232 intramural sites throughout the left and right ventricles and the interventricular septum was performed during programmed stimulation in the absence and presence of isoproterenol (Iso, 0.1 μg/kg/min). Sinus beats and the last extrastimuli preceding induced VT conducted with total activation times (TA) of 51 ± 10 and 111 ± 8 milliseconds, respectively, that did not change during Iso infusion (47 ± 4 and 109 ± 5 milliseconds, P = NS). NSVT was induced in 75% of HF dogs; SuVT was induced in 38%. In all cases, initiation and maintenance of SuVT and NSVT arose by a focal mechanism. Compared to NSVT, SuVT had a shorter coupling interval (CI; 150 ± 7 vs 186 ± 16, P < 0.05) and a predilection for certain critical subendocardial initiation sites (that were initiation sites for only 29% of NSVT beats). After 21–30 beats, acceleration of SuVT by a focal mechanism to a CI less than 120 milliseconds led to functional conduction delay (TA increasing from 111 ± 3 to 137 ± 3 milliseconds, P < 0.0001), intramural reentry, and transition to ventricular fibrillation. Conclusions: Thus, initiation of SuVT in a model of ischemic HF is due to a focal mechanism. However, subsequent acceleration of this focal mechanism can ultimately lead to functional conduction delay and development of intramural reentry. (J Cardiovasc Electrophysiol, Vol. 23, pp. 543‐552, May 2012)