Diagnosis Of Catecholaminergic Polymorphic Ventricular Tachycardia Research Articles

Catecholaminergic polymorphic ventricular tachycardia (CPVT): an insidious disease that can often lead to sudden cardiac death in young people

The first symptoms of catecholaminergic polymorphic ventricular tachycardia (CPVT) usually occur in childhood and adolescence. 60% of patients experience syncope before the age of 40. Sudden cardiac death (SCD) is the first symptom of the disease in 30-50% of patients with CPVT. Early diagnosis is therefore crucial for the patient's prognosis. The diagnosis of CPVT is confirmed by a normal resting ECG, exclusion of structural heart disease, detection of bidirectional or polymorphic ventricular tachycardia (VT) in the stress ECG and/or detection of a pathogenic mutant in a gene associated with CPVT. Up to 60% of CPVT patients carry changes in the RYR2 gene. This gene encodes the cardiac ryanodine receptor, the most important Ca2+-releasing channel of the sarcoplasmic reticulum, which plays a central role in the contraction and relaxation of the heart muscle. If the function of the ryanodine receptor is impaired, too much calcium enters the cells, which triggers life-threatening arrhythmias. The overactive ryanodine receptor is therefore the main target for gene therapy methods. Even though the development of gene therapy is progressing, there is still no causal therapy available and it is all the more important to make a diagnosis as early as possible, which enables appropriate behavior and adequate symptomatic therapy. The decisive factor here is the evaluation of the genetic analysis in the context of the clinical findings. Based on this, recommendations can be made for preventive measures and the avoidance of specific triggers that could lead to life-threatening arrhythmias.

Prognosis and clinical management of asymptomatic family members with RYR2-mediated catecholaminergic polymorphic ventricular tachycardia: a review.

Despite its low prevalence, the potential diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) should be at the forefront of a paediatric cardiologists mind in children with syncope during exercise or emotions. Over the years, the number of children with a genetic diagnosis of CPVT due to a (likely) pathogenic RYR2 variant early in life and prior to the onset of symptoms has increased due to cascade screening programmes. Limited guidance for this group of patients is currently available. Therefore, we aimed to summarise currently available literature for asymptomatic patients with a (likely) pathogenic RYR2 variant, particularly the history of CPVT and its genetic architecture, the currently available diagnostic tests and their limitations, and the development of a CPVT phenotype - both electrocardiographically and symptomatic - of affected family members. Their risk of arrhythmic events is presumably low and a phenotype seems to develop in the first two decades of life. Future research should focus on this group in particular, to better understand the development of a phenotype over time, and therefore, to be able to better guide clinical management - including the frequency of diagnostic tests, the timing of the initiation of drug therapy, and lifestyle recommendations.

Importance of exercise stress testing in evaluation of unexplained cardiac arrest survivor.

In sudden cardiac arrest survivors without an immediately identifiable cause, additional extensive yet individualised testing is required. We describe 3survivors of sudden cardiac arrest in whom exercise stress testing was not performed during the initial hospital admission. All 3patients were incorrectly diagnosed with long QT syndrome based on temporary sudden cardiac arrest-related heart rate-corrected QT interval prolongation, and exercise stress testing was not performed during the initial work-up. When they were subjected to exercise stress testing during follow-up, adelayed diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) was made. As aresult, these patients were initially managed inappropriately, and their family members were initially not screened for CPVT. In sudden cardiac arrest survivors without an immediately identifiable cause, omission of exercise stress testing or erroneous interpretation of the results can lead to adelayed or missed diagnosis of CPVT, which may have considerable implications for survivors and their family.

Flecainide is associated with a reduction in arrhythmic events in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by the ZonMW Priority Medicines for Rare Diseases and Orphan Drugs (grant 113304045 to Dr Van der Werf) and the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences (PREDICT2 to Dr. Wilde). Background In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), β-blocker may be insufficiently protective. A randomized clinical trial showed that flecainide reduces ventricular arrhythmias (VAs) in CPVT and small retrospective cohort studies suggest that this translates into a reduction of arrhythmic events. Objective To evaluate the efficacy of flecainide when added to β-blockers for the prevention of arrhythmic events (AE) in a large cohort of patients with CPVT using paired analysis. Methods From two international registries, this multicentre retrospective cohort study included patients with a clinical and/or genetic diagnosis of CPVT using flecainide as an adjunct to β-blockers. The study period, which comprised a pre- and on-flecianide period, was defined as the period in which background therapy, i.e. β-blocker type (β1-selective or nonselective), left cardiac sympathetic denervation (LCSD), and implantable cardioverter-defibrillator (ICD) treatment status, remained unchanged within individual patients. The primary endpoint was AEs, defined as SCD, sudden cardiac arrest (SCA), appropriate ICD shock, and arrhythmic syncope. The effect of flecainide on AE rates was assessed using a generalized linear mixed model assuming Poisson distribution and random effects for patients. Results Two-hundred forty-seven patients (median age at start of flecainide 18 years [IQR 14-29], 123 [50%] female, median flecainide dose 2.2 mg/kg/day [IQR 1.7-3.1]) were included. At baseline, 70 (28%) patients had an ICD and 21 (9%) had a LCSD performed. Nonselective β-blockers were used by 133 (54%) patients. During a median pre-flecainide follow-up of 2.1 years (IQR 0.4-7.2), 41 patients experienced 58 AEs. During a median on-flecainide follow-up of 2.9 years (IQR 1.0-6.0), 23 patients experienced 38 AEs. There was a significant reduction in AEs after initiation of flecainide (OR 0.55 [0.38-0.83]; p=0.007). Among patients who were symptomatic before diagnosis or before the initiation of flecainide (n=167), flecainide was associated with a significant reduction in AEs (OR 0.49 [0.31-0.77]; p=0.002). Among patients with ≥1 AE on β-blocker therapy (n=41), adding flecainide was associated with a significant reduction in AEs (OR 0.25 [0.14-0.45]; p<0.001). Conclusion Flecainide was associated with a reduction in AEs when added to β-blockers in patients with CPVT in the overall cohort, symptomatic patients, and particularly in patients with breakthrough AEs on β-blocker therapy.

Catecholaminergic polymorphic ventricular tachycardia: risk modulators in patients treated with beta-blockers

Abstract Background Due to the catecholaminergic nature of arrhythmias that define the Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), beta-blockers (BBs) represent the first line therapy for this severe arrhythmogenic syndrome. Despite optimal BB therapy, a proportion of patients continue to suffer breakthrough life-threatening arrhythmias (LAE). Purpose To evaluate the role different classes of BBs (β1-selective vs. non-selective) in LAE reduction and to identify risk factors for breakthrough LAE while on BB monotherapy. Methods We studied 238 consecutive patients with CPVT and treated with BB monotherapy followed-up prospectively. CPVT was diagnosed according to the 2015 European Society of Cardiology Guidelines. The endpoint was the occurrence of the first LAE (sudden cardiac death, aborted cardiac arrest, or hemodynamically non-tolerated ventricular tachycardia) in BB monotherapy. The follow-up for each patient was calculated from BB therapy start to the occurrence of the endpoint, death from non-arrhythmic cause, the date of last visit, or the initiation of other treatments (i.e.: other antiarrhythmics or left cardiac sympathetic denervation [LCSD]), whichever occurred first. Multivariable Cox proportional hazards model was used to evaluate the effects of history of LAE before diagnosis of CPVT, occurrence of unexplained syncope before diagnosis of CPVT, genotype, and type of BB therapy, as a time-dependent variable, on the risk of experiencing an LAE during BB monotherapy. Results We enrolled 238 CPVT patients (135 probands, 135 females): 226 with typical CPVT (n=216 RYR2; n=10 CASQ2) and 12 with atypical CPVT (n=5 RYR2-Loss-of-Function, n=4 TRDN and n=3 TECRL). Prior to BB monotherapy, 48/238 (20%) patients had survived an LAE, and 110/238 (46%) patients had experienced an unexplained syncope. During 1,629 person-years of follow-up during BB monotherapy, 35 patients experienced an LAE (annual LAE rate 2.1%, 95% CI: 1.5%–3.0%; Figure A). Five-year cumulative probability of experiencing an LAE during BB monotherapy was 11.9% (95% CI: 7.0%-16.6%). In this population, multivariable analysis showed that history of LAE before diagnosis (HR 3.6; 95% CI: 1.6–8.1; p=0.002) and syncope before diagnosis (HR 6.1; 95% CI: 2.5–14.9; p<0.001) were clinical risk factors for LAE occurrence. Patients with TRDN mutations were significantly more likely to suffer LAE (HR 20.9; 95% CI: 2.2–196.3; p=0.008). Using nadolol as the gold standard, the use of β1-selective BBs (HR 3.4; 95% CI: 1.4–8.6; p=0.009), but not propranolol (HR: 0.9; 95% CI: 0.2–3.8; p=0.887), was associated with poorer outcome during BB monotherapy (Figure B). Conclusions In patients with CPVT, selective BBs are associated with a higher risk of LAE as compared to nadolol. Patients who have survived an LAE and/or experienced an unexplained syncope prior to diagnosis, as well as carriers of TRDN mutations are at high risk of BB failure. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ricerca Corrente Funding scheme of the Italian Ministry of Health and Italian Ministry of Research and University Dipartimenti di Eccellenza 2018–2022 grant to the Molecular Medicine Department (University of Pavia).

Natural History of Patients with Typical and Atypical Catecholaminergic Polymorphic Ventricular Tachycardia

Abstract Background Recently, a novel genetic-based classification for Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) has been proposed to distinguish “typical” (RYR2 and CASQ2 genes) and “atypical” (TRDN, TECRL, CALM1–3, RYR2 loss-of-function [RYR2-LoF]) CPVT variants. Although some genetic forms were reported as malignant forms of CPVT, natural history data comparing typical and atypical CPVT variants are lacking. Purpose We compared the natural history of “typical” and “atypical” forms of CPVT in a large cohort of patients with genetically confirmed CPVT. Methods CPVT was diagnosed according to the criteria defined in the 2015 European Society of Cardiology Guidelines. Based on the genetic background, we classified the patients in two groups: 1) “Typical” CPVT (i.e., carriers of pathogenic or likely pathogenic mutations in RYR2 and CASQ2 genes); 2) “Atypical” CPVT (i.e., carriers of pathogenic or likely pathogenic mutations in TRDN, TECRL, CALM1–3 and RYR2-LoF). Patients with mutations in the CALM1, CALM2 or CALM3 were not identified in our cohort. The outcome was the occurrence of a life-threatening arrhythmic event (LAE), defined as: sudden cardiac death, aborted cardiac arrest or hemodynamically non-tolerated ventricular tachycardia. The Kaplan-Meier life-table method was used to determine the cumulative probability of experiencing a first LAE before the age of 40 years and in the absence of treatment. Outcomes in two groups were compared using the log-rank test. Results The study cohort included 238 patients (56% females, median age at diagnosis 14 years [IQR: 9–28 years]), of whom 226/238 (95%) patients with “typical” CPVT (216 RYR2, 10 CASQ2), and 12/238 (5%) patients with “atypical” CPVT (5 RYR2-LoF, 4 TRDN, 3 TECRL). In the entire population, the cumulative probability of experiencing a first LAE between birth and the diagnosis of CPVT was 2.3%, 21.2 and 40.8% at 5, 20, and 40 years, respectively. At any given age, the probability of a first LAE in the absence of therapy was significantly higher in patients with atypical CPVT (25%, 36%, and 100% at 5, 20, and 40 years, respectively), as compared to patients with typical CPVT (1%, 20%, and 39% at 5, 20, and 40 years, respectively; p=0.003, Figure 1). Patients with atypical CPVT suffered LAEs in early childhood (i.e., by the age of 5 years) significantly more often than patients with typical CPVT (3/5 patients [60%] in atypical CPVT vs. 2/43 patients [5%] in typical CPVT, p<0.001; Figure 2). Conclusions The natural history of CPVT is modulated by the genetic cause. Atypical CPVT variants are rare but are characterized by a worse outcome and a greater likelihood of experiencing an LAE since the early childhood, as compared to typical CPVT. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ricerca Corrente funding scheme of the Italian Ministry of Health

Clinical Characteristics, Genetic Findings and Arrhythmic Outcomes of Patients with Catecholaminergic Polymorphic Ventricular Tachycardia from China: A Systematic Review.

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited cardiac ion channelopathy. The present study aims to examine the clinical characteristics, genetic basis, and arrhythmic outcomes of CPVT patients from China to elucidate the difference between CPVT patients in Asia and Western countries. Methods: PubMed and Embase were systematically searched for case reports or series reporting on CPVT patients from China until 19 February 2022 using the keyword: “Catecholaminergic Polymorphic Ventricular Tachycardia” or “CPVT”, with the location limited to: “China” or “Hong Kong” or “Macau” in Embase, with no language or publication-type restriction. Articles that did not state a definite diagnosis of CPVT and articles with duplicate cases found in larger cohorts were excluded. All the included publications in this review were critically appraised based on the Joanna Briggs Institute Critical Appraisal Checklist. Clinical characteristics, genetic findings, and the primary outcome of spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF) were analyzed. Results: A total of 58 unique cases from 15 studies (median presentation age: 8 (5.0–11.8) years old) were included. All patients, except one, presented at or before 19 years of age. There were 56 patients (96.6%) who were initially symptomatic. Premature ventricular complexes (PVCs) were present in 44 out of 51 patients (86.3%) and VT in 52 out of 58 patients (89.7%). Genetic tests were performed on 54 patients (93.1%) with a yield of 87%. RyR2, CASQ2, TERCL, and SCN10A mutations were found in 35 (71.4%), 12 (24.5%), 1 (0.02%) patient, and 1 patient (0.02%), respectively. There were 54 patients who were treated with beta-blockers, 8 received flecainide, 5 received amiodarone, 2 received verapamil and 2 received propafenone. Sympathectomy (n = 10), implantable cardioverter-defibrillator implantation (n = 8) and ablation (n = 1) were performed. On follow-up, 13 patients developed VT/VF. Conclusion: This was the first systematic review of CPVT patients from China. Most patients had symptoms on initial presentation, with syncope as the presenting complaint. RyR2 mutation accounts for more than half of the CPVT cases, followed by CASQ2, TERCL and SCN10A mutations.

Clinical challenges in the management of catecholaminergic polymorphic ventricular tachycardia in children

Objective: Catecholaminergic polymorphic ventricular tachycardia (CPVT) accounts for up to 10%-15% sudden cardiac death (SCD) in the children and young population. This study aimed to assess the current situation and challenges in CPVT clinical diagnosis. Method: A retrospective review included 11 children (7 male patients) at the First Hospital of Tsinghua University clinically diagnosed with CPVT from June 2014 to July 2017. Each patient was evaluated with detailed history, physical examination, resting 12-lead electrocardiogram(ECG), 24-h Holter, exercise stress test, Doppler echocardiography and genetic test. Result: During physical activity and/or emotional stress, ten children presented with recurrent syncope and one child presented with palpitation and chest distress. The mean age of symptom onset was 8.4 (4.0-13.7) years with a delayed diagnosis of 2.4 (0.04-5.00) years. Two children had a familial history of syncope or sudden death. Nine children were initially misdiagnosed as complex arrhythmic conditions (n=4), syncope of unknown origin (n=3), and drug-resistant epilepsy (n=2) treated with antiepileptic medication for several years. Bidirectional VT and (or) polymorphic VT were detected using Holter recording or exercise test ECG in all patients. Genetic test revealed CPVT-associated pathologic or possible pathologic mutations in nine patients. All patients were treated with beta-blockers. Six patients were asymptomatic, four patients reported infrequent syncope, and one sudden death occurred during a mean follow-up of 0.97 years. Conclusion: CPVT mainly occurs in children and adolescents with recurrent syncope during physical activities and/or emotional stress. Early diagnosis of CPVT remains challenging due to delayed diagnosis or misdiagnosis. Detailed clinical history and exercise stress test improve the early diagnosis and intervention for CPVT patients.

Efficacy of Flecainide in the Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal genetic arrhythmia syndrome characterized by polymorphic ventricular tachycardia with physical or emotional stress, for which current therapy with β-blockers is incompletely effective. Flecainide acetate directly suppresses sarcoplasmic reticulum calcium release-the cellular mechanism responsible for triggering ventricular arrhythmias in CPVT-but has never been assessed prospectively. To determine whether flecainide dosed to therapeutic levels and added to β-blocker therapy is superior to β-blocker therapy alone for the prevention of exercise-induced arrhythmias in CPVT. This investigator-initiated, multicenter, single-blind, placebo-controlled crossover clinical trial was conducted from December 19, 2011, through December 29, 2015, with a midtrial protocol change at 10 US sites. Patients with a clinical diagnosis of CPVT and an implantable cardioverter-defibrillator underwent a baseline exercise test while receiving maximally tolerated β-blocker therapy that was continued throughout the trial. Patients were then randomized to treatment A (flecainide or placebo) for 3 months, followed by exercise testing. After a 1-week washout period, patients crossed over to treatment B (placebo or flecainide) for 3 months, followed by exercise testing. Patients received oral flecainide or placebo twice daily, with the dosage guided by trough serum levels. The primary end point of ventricular arrhythmias during exercise was compared between the flecainide and placebo arms. Exercise tests were scored on an ordinal scale of worst ventricular arrhythmia observed (0 indicates no ectopy; 1, isolated premature ventricular beats; 2, bigeminy; 3, couplets; and 4, nonsustained ventricular tachycardia). Of 14 patients (7 males and 7 females; median age, 16 years [interquartile range, 15.0-22.5 years]) randomized, 13 completed the study. The median baseline exercise test score was 3.0 (range, 0-4), with no difference noted between the baseline and placebo (median, 2.5; range, 0-4) exercise scores. The median ventricular arrhythmia score during exercise was significantly reduced by flecainide (0 [range, 0-2] vs 2.5 [range, 0-4] for placebo; P < .01), with complete suppression observed in 11 of 13 patients (85%). Overall and serious adverse events did not differ between the flecainide and placebo arms. In this randomized clinical trial of patients with CPVT, flecainide plus β-blocker significantly reduced ventricular ectopy during exercise compared with placebo plus β-blocker and β-blocker alone. clinicaltrials.gov Identifier: NCT01117454.

Discerning From the Good, the Bad, and the Ugly

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the most malignant inherited arrhythmias, with onset of symptoms in childhood and a 70% risk of experiencing a cardiac event before the age of 20 years if untreated.1 Presymptomatic diagnosis is challenging, because the resting ECG is normal, and a family history of adrenergic-related sudden cardiac death or syncope is only present in 30% of individuals.1 The hRyR2 gene, coding for the ryanodine receptor channel, has been linked to the autosomal dominant form of CPVT, and a mutation may be detected in ≈65% of probands.2 A rare autosomal recessive form, linked to CASQ2 homozygous mutations, has also been described.2 Additional genes have been linked to the phenotype, but their prevalence is to date limited to sporadic cases.2 See Article by Landstrom et al Initially, it was suggested that RyR2 mutations causing CPVT cluster in specific residues of the genes; however, reports of CPVT patients harboring mutations outside these clusters prompted the recommendation of screening the entire coding region of the gene.2 Overall, the gene has a negative residual variation intolerance score (a gene-based score that ranks genes from intolerant to tolerant based on whether they have more or less common functional genetic variation),3 hence suggesting that most variants are expected to be deleterious. The Heart Rhythm Society/European Heart Rhythm Association Expert Consensus2 advises the use of genetic testing in everyone with a suspect clinical diagnosis of CPVT, based on the high yield of the test and on the malignancy of the disease that could manifest with sudden cardiac …

Competitive Sports Participation inPatients With Catecholaminergic Polymorphic Ventricular Tachycardia: A Single Center's Early Experience.

The study sought to determine the outcomes of continued sports participation in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). Patients with CPVT are at increased risk of sudden death with exertion. Currently, CPVT patients are advised disqualification from nearly all sports in accordance with expert opinion guidelines. However, we have approached this complex issue with a shared decision making model respecting a patient's and their family's right to be a competitive athlete following institution of comprehensive CPVT-directed treatment program. A retrospective record review was performed on patients with CPVT who were >6 years of age at the time of initial evaluation to determine their athlete status and frequency/scope of subsequent CPVT-triggered events. Among 63 eligible patients with CPVT (34 females, mean age at diagnosis 16.6 ± 12.9 years), 31 (49%) were athletes at some point in their life. Compared to the nonathletes, these athletes were significantly younger at diagnosis (11.8 ± 6.6 years vs. 21.3 ± 15.6 years; p= 0.003) and more symptomatic (21 [68%] vs. 13 [41%]; p= 0.04). Following diagnosis, 21 of 24 athletes (88%) continued competition. For these 21 athletes, 16 (76%) had experienced 32 CPVT-triggered events prior to diagnosis versus 57 events in 18 nonathletes (43%; p= 0.02). During follow-up, 3 events occurred in 3 of 21 athletes (14%) compared to 7 events in 6 of 42 nonathletes (14%, p= 1.00). No event resulted in death, and all received an adjustment in their CPVT therapy. Although sports participation is a risk taking behavior in undiagnosed and untreated CPVT, the risk may be acceptable for a well-treated and well-informed athlete following the diagnosis of CPVT.

Effective cascade screening through identification of a mutation in RYR2 in a large family with a history of sudden death

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder which usually presents in the first or second decade of life with syncope, which is typically induced by emotional stress or exercise. We describe a large family with a history of three sudden unexpected deaths. Investigations in the sibling of a deceased individual affected by emotion-induced syncope revealed ventricular bigeminy. Molecular genetic testing was performed on one symptomatic individual and a missense mutation in RYR2 was identified consistent with a diagnosis of CPVT. Subsequent cascade testing of family members excluded 37 of 43 individuals from risk and facilitated preventative intervention. This case highlights the value of genotyping in sudden cardiac death by defining the precise diagnosis and through the identification and exclusion of at-risk individuals.<Learning objective: The diagnosis of CPVT should be considered in families with a history of sudden death in a previously asymptomatic young person. Cascade molecular genetic testing should be undertaken as, if a pathogenic mutation is found, this can distinguish it from other arrhythmogenic disorders and can identify at-risk individuals allowing treatment to be targeted at those in need, thus helping to reduce the mortality associated with the condition.>

Catecholaminergic Polymorphic Ventricular Tachycardia: A Rare Cause of Cardiac Arrest Following Blunt Chest Trauma.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an electrophysiological disorder of a physically normal heart that occurs in children when the body is subjected to intense emotional or physical stress that causes adrenergic discharge. This troubling disease can be sporadic (spontaneous) or familial (genetic/inherited). Unfortunately, its associated ventricular tachycardia may cause sudden death, so early diagnosis of CPVT is very important. Treatment modalities include medical treatment, implantation of a cardioverter defibrillator, or surgical sympatectomy; but the implantable cardioverter defibrillator (ICD) should be the first choice in patients with a history of cardiac arrest. We herein present the case of a patient diagnosed with CPVT after a successful cardiopulmonary resuscitation triggered by blunt chest trauma. We implanted an implantable cardioverter defibrillator and started oral B-blocker treatment. During the course of follow-up, flecainide was added to his treatment depending on the patient's status regarding recurrent ICD shock. The patient has now continued follow-up without recurrent ICD shock since flecainide treatment was initiated. In conclusion, in patients with syncope and sudden cardiac arrest secondary to physical stress or blunt chest trauma, CPVT should be considered and an implantable cardioverter defibrillator must be implanted. Additionally, flecainide theraphy should be considered to decrease recurrent ICD shock. Blunt chest trauma; Cardiac arrest; CPVT.

Genetic Background of Catecholaminergic Polymorphic Ventricular Tachycardia in Japan

The genetic background of catecholaminergic polymorphic ventricular tachycardia (CPVT) has been extensively investigated for the last decade in Western countries, but it remains unstudied in the Asian population. In 50 Japanese probands from unrelated families who satisfied clinical criteria for CPVT, genetic testing was conducted in all exons on 3 CPVT-related genes: cardiac ryanodine receptor 2 (RYR2), calsequestrin 2 (CASQ2) and inward rectifier potassium channel 2 (KCNJ2), and the clinical features between RYR2-genotyped and -non-genotyped patient groups were compared. Genetic and clinical evaluation was also done in 46 family members. In the genetic screening, 28 (18 novel) RYR2 (56.0%), 1 compound heterozygous CASQ2 (2.0%) and 1 KCNJ2 (2.0%) mutation carriers were identified. In the RYR2 mutation-positive group, the frequency of bidirectional ventricular tachycardia and the use of β-blockers were significantly higher than in the mutation-negative group. In contrast, there was no significant difference in supraventricular arrhythmias between the 2 groups. With regard to disease penetrance, the number of family members of RYR2-genotyped probands with a clinical diagnosis of CPVT was high. Thirty gene mutation carriers were found for 3 genes in 50 probands clinically diagnosed as having CPVT. The penetrance of CPVT phenotype was significantly higher in RYR2 mutation carriers, thus RYR2 gene screening in CPVT patients would be indispensable to prevent unexpected cardiac sudden death of young family members.

Left cardiac sympathetic denervation for the management of life-threatening ventricular tachyarrhythmias in young patients with catecholaminergic polymorphic ventricular tachycardia and long QT syndrome

BackgroundLeft cardiac sympathetic denervation (LCSD) may be a therapeutic adjunct for young patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) and long QT syndrome (LQTS) who are not fully protected by beta-blockade.ObjectiveThe objective of this analysis was to report our institutional experience with LSCD in young patients for the management of life-threatening ventricular arrhythmias in CPVT and LQTS.MethodsTen young patients with CPVT and LQTS underwent transaxillary LSCD at our institution. Mean age at surgery was 14.0 (range 3.9–42) years, mean body weight was 45.7 (range 15.5–90) kg. Five patients had the clinical diagnosis of CPVT, three were genotype positive for a mutation in the ryanodine-receptor-2-gene. Four of five LQTS patients were genotype positive. Indications for LCSD were recurrent syncope, symptomatic episodes of ventricular tachycardias and/or internal cardioverter–defibrillator (ICD) discharges, and aborted cardiac arrest despite high doses of beta-blockers.ResultsLCSD was performed via the transaxillary approach. No significant complications were observed. Two patients already had an ICD, 6 patients received an ICD at the same operation or shortly thereafter. Median length of follow-up after LCSD was 2.3 (range 0.6–3.9) years. After LCSD a marked reduction in arrhythmia burden and cardiac events was observed in all patients while medication was continued. None of the patients had any further ICD discharge for sustained VT.ConclusionsAfter LCSD, arrhythmia burden could significantly be reduced in all our young patients with CPVT and LQTS.

Clinical Characteristics and Mutational Analysis of the RyR2 Gene in Seven Czech Families with Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare hereditary arrhythmia. The onset of clinical symptoms usually occurs during childhood, and is typically related to exercise. The aim of our study was to describe the clinical characteristics of seven Czech families with CPVT and the results of mutational analysis of the RyR2 gene in these families. The subjects and their relatives were investigated at the participating departments. They underwent basic clinical investigation, and history was focused on possible CPVT symptoms, that is, syncopes during exercise. Bicycle ergometry was performed to obtain electrocardiogram recording during adrenergic stimulation. In all the investigated individuals, blood samples were taken for mutation analysis of the RyR2 gene. To date, seven families have been investigated, comprising 11 adults and 13 children. In seven CPVT patients, the indication for examination was syncope during exercise. Diagnosis was confirmed by bicycle ergometry-induced polymorphic ventricular tachycardia. In one relative, polymorphic ventricular tachycardia was also induced. All eight affected individuals were treated with β-blockers and in two, a cardioverter-defibrillator was implanted due to recurrent syncopi. Coding variants of the RyR2 gene were found in four probands. This is a systematic description of CPVT families in the Czech Republic. Our data support the importance of exercise testing for the diagnosis of CPVT. In addition, RyR2 gene coding variants were found in 50% of affected individuals.

Deadly Proposal

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare adrenergically mediated arrhythmogenic disorder classically induced by exercise or emotional stress and found in structurally normal hearts. It is an important cause of cardiac syncope and sudden death in childhood. Catecholaminergic polymorphic ventricular tachycardia is a genetic cardiac channelopathy with known mutations involving genes affecting intracellular calcium regulation. We present a case of a 14-year-old boy who had cardiopulmonary arrest after an emotionally induced episode of CPVT while attempting to invite a girl to the school dance. Review of his presenting cardiac rhythm, induction of concerning ventricular arrhythmias during an exercise stress test, and genetic testing confirmed the diagnosis of CPVT. He recovered fully and was treated with β-blocker therapy and placement of an implantable cardioverter-defibrillator. In this report, we discuss this rare but important entity, including its molecular foundation, clinical presentation, basics of diagnosis, therapeutic options, and implications of genetic testing for family members. We also compare CPVT to other notable cardiomyopathic and channelopathic causes of sudden death in youth including hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, long QT syndrome, short QT syndrome, and Brugada syndrome.

Intravenous Epinephrine Infusion Test in Diagnosis of Catecholaminergic Polymorphic Ventricular Tachycardia

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. 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%. 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.

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.

Abstract 2257: KCNJ2 Mutations in Patients Referred for Catecholaminergic Polymorphic Ventricular Tachycardia Gene Screening

Background : Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by adrenergically mediated polymorphic or bidirectional ventricular tachycardia (BVT). Andersen-Tawil syndrome (ATS1), which are mainly caused by KCNJ2 mutations, phenocopies CPVT and may manifest the typical adrenergically mediated BVT. The purpose of this study was assess whether patients (pts) lacking periodic paralysis typical of ATS1 and diagnosed as CPVT because of BVT carry KCNJ2 mutations. Methods and Results : Mutational analysis of KCNJ2 was performed in 23 RyR2 and CASQ2 genotype-negative CPVT pts with normal QT interval. Two novel missense mutations (S220I and T305I) were identified. Mutations were absent in &gt;400 reference alleles. Both of the pts present exercise or isoproterenol induced BVT, baseline ECG with prominent U wave and mild facial abnormalities. In vitro characterization showed that no current is detectable when S220I and T305I mutants clones are expressed; on the contrary co-expression of WT and mutant KCNJ2 to mimic heterozygosis present in patients, caused significant dominant negative effect (see figure ). Confocal laser microscopy revealed normal sarcolemmal localization of the mutant channels and of the heterozygous channels. Conclusions : KCNJ2 mutation with loss of function are present in a minority of pts with clinical diagnosis of CPVT. Given the limited number of CPVT pts with KCNJ2 mutations it is impossible to determine whether their prognosis is identical to that of RyR2 and CASQ2 related CPVT. Screening of KCNJ2 should be considered in CPVT pts without mutations in RyR2 and CASQ2 genes.