Clinical Presentation and Outcome of Brugada Syndrome Diagnosed With the New 2013 Criteria.

INTRODUCTION: The 2013 HRS/EHRA/APHRS consensus statement recommends the use of V1 and V2 leads recorded in the second and third intercostal spaces (High-ICS) for diagnosis of Brugada syndrome (BrS) creating a new category of patients discovered only with modified leads. The clinical presentation and the arrhythmic risk in these patients are ill defined. This study was aimed at assessing the role of High-ICS in the analysis of BrS and the clinical profile of the patients diagnosed only when ECG leads are moved to upper intercostal spaces. METHODS AND RESULTS: We searched our Brugada syndrome registry and identified 300 subjects (age 36 ± 13 years), without a diagnostic coved ST-segment elevation in conventional V1 -V3 leads, both at baseline and after provocative drug challenge. Sixty-four subjects (21.3%, mean age at last follow-up 42 ± 11 years) were diagnosed with High-ICS. Diagnosis was possible at baseline only in 4 subjects while in 60 it was made after drug challenge with sodium channel blockers. Three subjects (4.7%) with spontaneous abnormal ECG experienced cardiac events with an annual event rate (0.11%) superimposable to that of the low risk category of BrS diagnosed in standard leads. CONCLUSION: This study demonstrates that the use of new diagnostic criteria for BrS allows increasing the diagnostic yield by 20% and that the arrhythmic risk is low when BrS can be established only in High-ICS. We also show that the prognostic value of spontaneous ECG pattern is confirmed in this subgroup.

Role of CACNA1C in Brugada syndrome: Prevalence and phenotype of probands referred for genetic testing.

BACKGROUND: Evidence for the role of the CACNA1C gene, which encodes for the α-subunit of the cardiac L-type calcium channel CaV1.2, as a cause of the BrS3 variant of Brugada syndrome (BrS) is contradictory. OBJECTIVE: The purpose of this study was to define in a large BrS cohort the yield of molecular screening and to test whether appropriate patient selection could improve clinical utility. METHODS: A total of 709 patients were included in this study. BrS probands (n = 563, consecutively referred) underwent CACNA1C sequencing. Two matched cohorts where defined: discovery cohort (n = 200) and confirmation cohort (n = 363). In addition, the clinical phenotypes of a matched SCN5A-positive BrS cohort (n = 146) were included for comparative genotype-phenotype correlation. RESULTS: In the discovery cohort, we identified 11 different rare variants in 9 patients; 10 of the variants (5%) were considered potentially causative based on their frequency in the general population. However, American College of Medical Genetics criteria were unable to classify the majority (80%) of them, which eventually were labeled as variants of unknown significance (VUS). Functional studies revealed a loss of function for 9 variants, pointing to a prevalence of CACNA1C causative variants in 4% of the discovery cohort. Genotype-phenotype correlation showed that pathogenic variants are significantly more frequent in patients with shorter QTc (12.9% vs 2.2% in patients with QTc <390 ms). CONCLUSION: CACNA1C is an infrequent but definitive cause of BrS typically associated with short QT. Functional studies are highly relevant to improve variant interpretation.

Outcomes of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia Treated With ß-Blockers.

Importance: Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) may experience life-threatening arrhythmic events (LTAEs) despite ß-blocker treatment. Further complicating management, the role of implantable cardioverter defibrillator (ICD) in CPVT is debated. Objective: To investigate the long-term outcomes of patients with RYR2 CPVT treated with ß-blockers only and the cost to benefit ratio of ICD. Design, Settings, and Participants: This prospective cohort study conducted from January 1988 to October 2020 with a mean (SD) follow-up of 9.4 (7.5) years included patients who were referred to the Molecular Cardiology Clinics of ICS Maugeri Hospital, Pavia, Italy. Participants included consecutive patients with CPVT who were carriers of a pathogenic or likely pathogenic RYR2 variant with long-term clinical follow-up. Exposures: Treatment with selective and nonselective ß-blocker only and ICD implant when indicated. Main Outcome and Measures: The main outcome was the occurrence of the first LTAE while taking a ß-blocker. LTAE was defined as a composite of 3 hard end points: sudden cardiac death, aborted cardiac arrest, and hemodynamically nontolerated ventricular tachycardia. Results: The cohort included 216 patients with RYR2 CPVT (121 of 216 female [55%], median [IQR] age 14, [9-30] years). During a mean (SD) follow-up of 9.4 (7.5) years taking ß-blockers only, 28 of 216 patients (13%) experienced an LTAE (annual rate, 1.9%; 95% CI, 1.3-2.7). In multivariable analysis, experiencing either an LTAE (hazard ratio [HR], 3.3; 95% CI, 1.2-8.9; P = .02) or syncope before diagnosis (HR, 4.5; 95% CI, 1.8-11.1; P = .001) and carrying a C-terminal domain variant (HR, 18.1; 95% CI, 4.1-80.8; P < .001) were associated with an increased LTAE risk during ß-blocker therapy only. The risk of LTAE among those taking selective ß-blockers vs nadolol was increased 6-fold (HR, 5.8; 95% CI, 2.1-16.3; P = .001). Conversely, no significant difference was present between propranolol and nadolol (HR, 1.8; 95% CI, 0.4-7.3; P = .44). An ICD was implanted in 79 of 216 patients (37%) who were followed up for a mean (SD) of 8.6 (6.3) years. At the occurrence of LTAE, ICD carriers were more likely to survive (18 of 18 [100%]) than non-ICD carriers (6 of 10 [60%]; P = .01). Conclusions and Relevance: In this cohort study, selective ß-blockers were associated with a higher risk of LTAE as compared with nadolol. Independently from treatment, LTAE and syncope before diagnosis and C-terminal domain variants identified patients at higher risk of ß-blocker failure, and the ICD was associated with reduced mortality in high-risk patients with CPVT.

Identification of a SCN5A founder mutation causing sudden death, Brugada syndrome, and conduction blocks in Southern Italy.

BACKGROUND: The genetic architecture of Brugada syndrome (BrS) is emerging as an increasingly complex area of investigation. The identification of genetically homogeneous populations can provide mechanistic insights and improve genotype-phenotype correlation. OBJECTIVE: To characterize and define the clinical implications of a novel BrS founder mutation. Using a haplotype-based approach we investigated whether 2 SCN5A genetic variants could derive from founder events. METHODS: Single nucleotide polymorphisms were genotyped in 201 subjects, haplotypes reconstructed, and mutational age estimated. Clinical phenotypes and historical records were collected. RESULTS: A SCN5A variant (c.3352C>T; p.Gln1118Ter) was identified in 3 probands with BrS originating from south Italy. The same mutation was identified in a proband from central Italy and in 1 U.S. resident subject with Italian ancestry. The 5 individuals carried a common core haplotype, whose frequency was extremely low in local noncarrier probands and in population controls (0%-6.06%). The clinical presentation included multigenerational dominant transmission of Brugada electrocardiographic pattern, high incidence of sudden cardiac death (SCD), and cardiac conduction defects (CCD). We reconstructed 7-generation pedigrees with common geographic origin. Variant's age estimates suggested that origin of the p.Gln1118Ter dates back 76 generations (95% confidence interval: 28-200). A second SCN5A variant (c.5350G>A; p.Glu1784Lys) identified in the region did not show similar founder signal. CONCLUSION: p.Gln1118Ter is a novel BrS/CCD/SCD founder mutation. We illustrate how these findings provide insights on the inheritance patterns and phenotypes associated with SCN5A mutation.

Magnetic resonance investigations in Brugada syndrome reveal unexpectedly high rate of structural abnormalities.

AIMS: Recent data suggest that sub-clinical structural abnormalities may be part of the Brugada syndrome (BrS) phenotype, a disease traditionally thought to occur in the structurally normal heart. In this study, we carried out detailed assessment of cardiac morphology and function using cardiac magnetic resonance imaging (CMRI). METHODS AND RESULTS: Thirty consecutive patients with BrS were compared with 30 sex- (26/4 male/female), body surface area- (+/-0.2 m(2)), and age-matched (+/-5 years) normal volunteers. CMRI exam included long- and short-axis ECG-gated breath-hold morphological T1-TSE sequences for fatty infiltration and cine-SSFP sequences for kinetic assessment. Fatty infiltration was not found in any subject. Patients with BrS compared with normal subjects showed higher incidence of mild right ventricle (RV) wall-motion abnormalities [15 (50%) vs. 5 (17%) subjects (P = 0.006) with reduced radial fractional shortening in more than two segments], reduction of outflow tract ejection fraction (49 +/- 11% vs. 55 +/- 10%; P = 0.032), enlargement of the inflow tract diameter (46 +/- 4 vs. 41 +/- 5 mm, P < 0.001 in short-axis; 46 +/- 4 vs. 42 +/- 5 mm, P = 0.001 in four-chamber long-axis view) and area (22 +/- 2 vs. 20 +/- 3 cm(2); P = 0.050), and of global RV end-systolic volume (34 +/- 10 vs. 30 +/- 6 mL/m(2); P = 0.031) but comparable outflow tract dimensions, global RV end-diastolic volume, left ventricle parameters, and atria areas. CONCLUSION: CMRI detects a high prevalence of mild structural changes of the RV, and suggests further pathophysiological complexity in BrS. Prospective studies to assess the long-term evolution of such abnormalities are warranted.

Natural History and Risk Stratification in Andersen-Tawil Syndrome Type 1.

BACKGROUND: Andersen-Tawil Syndrome type 1 (ATS1) is a rare arrhythmogenic disorder, caused by loss-of-function mutations in the KCNJ2 gene. We present here the largest cohort of patients with ATS1 with outcome data reported. OBJECTIVES: This study sought to define the risk of life-threatening arrhythmic events (LAE), identify predictors of such events, and define the efficacy of antiarrhythmic therapy in patients with ATS1. METHODS: Clinical and genetic data from consecutive patients with ATS1 from 23 centers were entered in a database implemented at ICS Maugeri in Pavia, Italy, and pooled for analysis. RESULTS: We enrolled 118 patients with ATS1 from 57 families (age 23 ± 17 years at enrollment). Over a median follow-up of 6.2 years (interquartile range: 2.7 to 16.5 years), 17 patients experienced a first LAE, with a cumulative probability of 7.9% at 5 years. An increased risk of LAE was associated with a history of syncope (hazard ratio [HR]: 4.54; p = 0.02), with the documentation of sustained ventricular tachycardia (HR 9.34; p = 0.001) and with the administration of amiodarone (HR: 268; p < 0.001). The rate of LAE without therapy (1.24 per 100 person-years [py]) was not reduced by beta-blockers alone (1.37 per 100 py; p = 1.00), or in combination with Class Ic antiarrhythmic drugs (1.46 per 100 py, p = 1.00). CONCLUSIONS: Our data demonstrate that the clinical course of patients with ATS1 is characterized by a high rate of LAE. A history of unexplained syncope or of documented sustained ventricular tachycardia is associated with a higher risk of LAE. Amiodarone is proarrhythmic and should be avoided in patients with ATS1.

Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients.

BACKGROUND: Mexiletine (Mex) has been proposed as a gene-specific therapy for patients with long-QT syndrome type 3 (LQT3) caused by mutations in the cardiac sodium channel gene (SCN5A). The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations. We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations. METHODS AND RESULTS: We identified 4 SCN5A mutations in 5 symptomatic LQT3 patients with different responses to Mex (6 to 8 mg . kg(-1) . d(-1)). We classified the mutations as sensitive to Mex (P1332L, R1626P; >/=10% of QTc shortening and QTc <500 ms or no arrhythmias) or insensitive to Mex (S941N, M1652R; negligible or no QTc shortening and sudden death). We measured Na(+) current from HEK 293 cells transfected with wild-type (WT) or mutant Nav1.5. All mutations showed impaired inactivation of Na(+) current, but the mutations identified in patient responders to Mex (P1332L, R1626P) showed a hyperpolarizing shift of V(1/2) of steady-state inactivation. Furthermore, Mex produced use-dependent block with the order R1626P=P1332L>S941N=WT>M1652R, suggesting that Mex-sensitive mutants present prolonged recovery from Mex block. CONCLUSIONS: We propose that voltage dependence of channel availability and shifts of V(1/2) of steady-state inactivation correlate with the clinical response observed in LQT3 patients. This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3.

Interplay Between Genetic Substrate, QTc Duration, and Arrhythmia Risk in Patients With Long QT Syndrome.

BACKGROUND: Long QT syndrome (LQTS) is a common inheritable arrhythmogenic disorder, often secondary to mutations in the KCNQ1, KCNH2, and SCN5A genes. The disease is characterized by a prolonged ventricular repolarization (QTc interval) that confers susceptibility to life-threatening arrhythmic events (LAEs). OBJECTIVES: This study sought to create an evidence-based risk stratification scheme to personalize the quantification of the arrhythmic risk in patients with LQTS. METHODS: Data from 1,710 patients with LQTS followed up for a median of 7.1 years (interquartile range [IQR]: 2.7 to 13.4 years) were analyzed to estimate the 5-year risk of LAEs based on QTc duration and genotype and to assess the antiarrhythmic efficacy of beta-blockers. RESULTS: The relationship between QTc duration and risk of events was investigated by comparison of linear and cubic spline models, and the linear model provided the best fit. The 5-year risk of LAEs while patients were off therapy was then calculated in a multivariable Cox model with QTc and genotype considered as independent factors. The estimated risk of LAEs increased by 15% for every 10-ms increment of QTc duration for all genotypes. Intergenotype comparison showed that the risk for patients with LQT2 and LQT3 increased by 130% and 157% at any QTc duration versus patients with LQT1. Analysis of response to beta-blockers showed that only nadolol reduced the arrhythmic risk in all genotypes significantly compared with no therapy (hazard ratio: 0.38; 95% confidence interval: 0.15 to 0.93; p = 0.03). CONCLUSIONS: The study provides an estimator of risk of LAEs in LQTS that allows a granular estimate of 5-year arrhythmic risk and demonstrate the superiority of nadolol in reducing the risk of LAEs in LQTS.

Risk stratification in the long-QT syndrome.

BACKGROUND: Mutations in potassium-channel genes KCNQ1 (LQT1 locus) and KCNH2 (LQT2 locus) and the sodium-channel gene SCN5A (LQT3 locus) are the most common causes of the long-QT syndrome. We stratified risk according to the genotype, in conjunction with other clinical variables such as sex and the length of the QT interval. METHODS: We evaluated 647 patients (386 with a mutation at the LQT1 locus, 206 with a mutation at the LQT2 locus, and 55 with a mutation at the LQT3 locus) from 193 consecutively genotyped families with the long-QT syndrome. The cumulative probability of a first cardiac event, defined as the occurrence of syncope, cardiac arrest, or sudden death before the age of 40 years and before the initiation of therapy, was determined according to genotype, sex, and the QT interval corrected for heart rate (QTc). Within each genotype we also assessed risk in the four categories derived from the combination of sex and QTc (<500 msec or > or =500 msec). RESULTS: The incidence of a first cardiac event before the age of 40 years and before the initiation of therapy was lower among patients with a mutation at the LQT1 locus (30 percent) than among those with a mutation at the LQT2 locus (46 percent) or those with a mutation at the LQT3 locus (42 percent) (P<0.001 by Fisher's exact test). Multivariate analysis showed that the genetic locus and the QTc, but not sex, were independent predictors of risk. The QTc was an independent predictor of risk among patients with a mutation at the LQT1 locus and those with a mutation at the LQT2 locus but not among those with a mutation at the LQT3 locus, whereas sex was an independent predictor of events only among those with a mutation at the LQT3 locus. CONCLUSIONS: The locus of the causative mutation affects the clinical course of the long-QT syndrome and modulates the effects of the QTc and sex on clinical manifestations. We propose an approach to risk stratification based on these variables.

Gene-specific therapy for inherited arrhythmogenic diseases.

In the last few years, major advancement has been made in the understanding of the genetic basis of inherited arrhythmogenic diseases. Interestingly, the information obtained with the application of molecular genetics to these diseases is now influencing their clinical management, allowing gene-specific risk stratification and gene-specific management. The first attempt for a gene-specific therapy was made in 1995 with the use of mexiletine in long-QT syndrome (LQTS) patients with mutations in the SCN5A gene. Since then, several investigators have proposed novel therapeutic approaches based on the identification of the functional consequences of genetic mutations. In some instances, these novel therapies have already been introduced in clinical practice, and data are being collected to establish their long-term efficacy. In this review, we will summarize the current understanding of the molecular bases of inherited arrhythmias, with a specific focus toward discussing the most recent advancements toward the development of gene-specific therapies.

Hydroquinidine Prevents Life-Threatening Arrhythmic Events in Patients With Short QT Syndrome.

BACKGROUND: Short QT syndrome (SQTS) is a rare and life-threatening arrhythmogenic syndrome characterized by abbreviated repolarization. Hydroquinidine (HQ) prolongs the QT interval in SQTS patients, although whether it reduces cardiac events is currently unknown. OBJECTIVES: This study investigated whether long-term treatment with HQ reduces the occurrence of life-threatening arrhythmic events (LAE) (cardiac arrest or sudden cardiac death) in SQTS patients. METHODS: In this cohort study on consecutive SQTS patients, 2 analyses were performed: 1) a matched-period analysis for the occurrence of LAE in 17 SQTS patients who received long-term HQ; and 2) a comparison of the annual incidence of LAE off- and on-HQ in 16 SQTS patients who survived a cardiac arrest. RESULTS: A total of 17 patients (82% male, age 29 ± 3 years, QTc before treatment 331 ± 3 ms) received HQ therapy (584 ± 53 mg/day). Therapy was stopped in 2 cases (12%) due to gastrointestinal intolerance, and 15 patients continued treatment for 6 ± 1 year. QTc prolongation was observed in all patients (by 60 ± 6 ms; p < 0.001). We compared the occurrence of LAE during 6 ± 1 years before and after HQ, observing that patients on HQ experienced a reduction in both the rate of LAE from 40% to 0% (p = 0.03) and the number of LAE per patient from 0.73 ± 0.3 to 0 (p = 0.026). Furthermore, the annual rate of LAE in the 16 patients with a previous cardiac arrest dropped from 12% before HQ to 0 on therapy (p = 0.028). CONCLUSIONS: We demonstrated for the first time that treatment with HQ was associated with a lower incidence of LAE in SQTS patients. These data point to the importance that quinidine, that in several countries has been removed from the market, remains available worldwide for patients with SQTS. In the present study, therapy with HQ has been proven to be safe, with a relatively low rate of side effects.

Gene-Specific Therapy With Mexiletine Reduces Arrhythmic Events in Patients With Long QT Syndrome Type 3.

BACKGROUND: Long QT syndrome type 3 (LQT3) is a lethal disease caused by gain-of-function mutations in the SCN5A gene, coding for the alpha-subunit of the sodium channel NaV1.5. Mexiletine is used to block late sodium current and to shorten QT interval in LQT3 patients. OBJECTIVES: The aim of this study was to determine whether mexiletine prevents arrhythmic events (arrhythmic syncope, aborted cardiac arrest, or sudden cardiac death) in LQT3 patients. METHODS: The endpoint of this retrospective cohort study, which studied consecutive LQT3 patients who were referred to our center and treated with mexiletine, was to evaluate the antiarrhythmic efficacy of mexiletine by comparing the number of arrhythmic events per patient and the annual rate of arrhythmic events during observation periods of equal duration before and after the beginning of therapy with mexiletine. RESULTS: The study population comprised 34 LQT3 patients, 19 (56%) of whom were male. The median age at beginning of treatment with mexiletine was 22 years, and median QTc interval before therapy 509 ms. The median duration of oral mexiletine therapy was 36 months, at an average daily dose of 8 ± 0.5 mg/kg. Mexiletine significantly shortened QTc (by 63 ± 6 ms; p < 0.0001) and reduced the percentage of patients with arrhythmic events (from 22% to 3%; p = 0.031), the mean number of arrhythmic events per patient (from 0.43 ± 0.17 to 0.03 ± 0.03; p = 0.027), and the annual rate of arrhythmic events (from 10.3% to 0.7%; p = 0.0097). CONCLUSIONS: Besides shortening QTc interval, mexiletine caused a major reduction of life-threatening arrhythmic events in LQT3 patients, thus representing an efficacious therapeutic strategy.

Arrhythmogenic Right Ventricular Cardiomyopathy: Clinical Course and Predictors of Arrhythmic Risk.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading cause of sudden cardiac death, but its progression over time and predictors of arrhythmias are still being defined. OBJECTIVES: This study sought to describe the clinical course of ARVC and occurrence of life-threatening arrhythmic events (LAE) and cardiovascular mortality; identify risk factors associated with increased LAE risk; and define the response to therapy. METHODS: We determined the clinical course of 301 consecutive patients with ARVC using the Kaplan-Meier method adjusted to avoid the bias of delayed entry. Predictors of LAE over 5.8 years of follow-up were determined with Cox multivariable analysis. Treatment efficacy was assessed comparing LAE rates during matched time intervals. RESULTS: A first LAE occurred in 1.5 per 100 person-years between birth and age 20 years, in 4.0 per 100 person-years between ages 21 and 40 years, and in 2.4 per 100 person-years between ages 41 and 60 years. Cumulative probability of a first LAE at follow-up was 14% at 5 years, 23% at 10 years, and 30% at 15 years. Higher risk of LAE was predicted by atrial fibrillation (hazard ratio [HR]: 4.38; p = 0.002), syncope (HR: 3.36; p < 0.001), participation in strenuous exercise after the diagnosis (HR: 2.98; p = 0.028), hemodynamically tolerated sustained monomorphic ventricular tachycardia (HR: 2.19; p = 0.023), and male sex (HR: 2.49; p = 0.012). No difference was observed in the occurrence of LAE before and after treatment with amiodarone, beta-blockers, sotalol, or ablation. A total of 81 patients received an implantable cardioverter-defibrillator, 34 were successfully defibrillated. CONCLUSIONS: The high risk of life-threatening arrhythmias in patients with ARVC spans from adolescence to advanced age, reaching its peak between ages 21 and 40 years. Atrial fibrillation, syncope, participation in strenuous exercise after the diagnosis of ARVC, hemodynamically tolerated sustained monomorphic ventricular tachycardia, and male sex predicted lethal arrhythmias at follow-up. The lack of efficacy of antiarrhythmic therapy and the life-saving role of the implantable cardioverter-defibrillator highlight the importance of risk stratification for patient management.

Natural history of Brugada syndrome: insights for risk stratification and management.

BACKGROUND: Treatment of patients with Brugada syndrome is complicated by the incomplete information on the natural history of the disease related to the small number of cases reported. Furthermore, the value of programmed electrical stimulation (PES) for risk stratification is highly debated. The objective of this study was to search for novel parameters to identify patients at risk of sudden death. METHODS AND RESULTS: Clinical data were collected for 200 patients (152 men, 48 women; age, 41+/-18 years) and stored in a dedicated database. Genetic analysis was performed, and mutations on the SCN5A gene were identified in 28 of 130 probands and in 56 of 121 family members. The life-table method of Kaplan-Meier used to define the cardiac arrest-free interval in patients undergoing PES failed to demonstrate an association between PES inducibility and spontaneous occurrence of ventricular fibrillation. Multivariate Cox regression analysis showed that after adjusting for sex, family history of sudden death, and SCN5A mutations, the combined presence of a spontaneous ST-segment elevation in leads V1 through V3 and the history of syncope identifies subjects at risk of cardiac arrest (HR, 6.4; 95% CI, 1.9 to 21; P<0.002). CONCLUSIONS: The information on the natural history of patients obtained in this study allowed elaboration of a risk-stratification scheme to quantify the risk for sudden cardiac death and to target the use of the implantable cardioverter-defibrillator.

Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Mutations in the cardiac ryanodine receptor gene (RyR2) underlie catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmogenic disease occurring in the structurally intact heart. The proportion of patients with CPVT carrying RyR2 mutations is unknown, and the clinical features of RyR2-CPVT as compared with nongenotyped CPVT are undefined. METHODS AND RESULTS: Patients with documented polymorphic ventricular arrhythmias occurring during physical or emotional stress with a normal heart entered the study. The clinical phenotype of the 30 probands and of 118 family members was evaluated, and mutation screening on the RyR2 gene was performed. Arrhythmias documented in probands were: 14 of 30 bidirectional ventricular tachycardia, 12 of 30 polymorphic ventricular tachycardia, and 4 of 30 catecholaminergic idiopathic ventricular fibrillation; RyR2 mutations were identified in 14 of 30 probands (36% bidirectional ventricular tachycardia, 58% polymorphic ventricular tachycardia, 50% catecholaminergic idiopathic ventricular fibrillation) and in 9 family members (4 silent gene carriers). Genotype-phenotype analysis showed that patients with RyR2 CPVT have events at a younger age than do patients with nongenotyped CPVT and that male sex is a risk factor for syncope in RyR2-CPVT (relative risk=4.2). CONCLUSIONS: CPVT is a clinically and genetically heterogeneous disease manifesting beyond pediatric age with a spectrum of polymorphic arrhythmias. beta-Blockers reduce arrhythmias, but in 30% of patients an implantable defibrillator may be required. Genetic analysis identifies two groups of patients: Patients with nongenotyped CPVT are predominantly women and become symptomatic later in life; patients with RyR2 CPVT become symptomatic earlier, and men are at higher risk of cardiac events. These data provide a rationale for prompt evaluation and treatment of young men with RyR2 mutations.

Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome.

BACKGROUND: The management of long-QT syndrome (LQTS) patients who continue to have cardiac events (CEs) despite beta-blockers is complex. We assessed the long-term efficacy of left cardiac sympathetic denervation (LCSD) in a group of high-risk patients. METHODS AND RESULTS: We identified 147 LQTS patients who underwent LCSD. Their QT interval was very prolonged (QTc, 543+/-65 ms); 99% were symptomatic; 48% had a cardiac arrest; and 75% of those treated with beta-blockers remained symptomatic. The average follow-up periods between first CE and LCSD and post-LCSD were 4.6 and 7.8 years, respectively. After LCSD, 46% remained asymptomatic. Syncope occurred in 31%, aborted cardiac arrest in 16%, and sudden death in 7%. The mean yearly number of CEs per patient dropped by 91% (P<0.001). Among 74 patients with only syncope before LCSD, all types of CEs decreased significantly as in the entire group, and a post-LCSD QTc <500 ms predicted very low risk. The percentage of patients with >5 CEs declined from 55% to 8% (P<0.001). In 5 patients with preoperative implantable defibrillator and multiple discharges, the post-LCSD count of shocks decreased by 95% (P=0.02) from a median number of 25 to 0 per patient. Among 51 genotyped patients, LCSD appeared more effective in LQT1 and LQT3 patients. CONCLUSIONS: LCSD is associated with a significant reduction in the incidence of aborted cardiac arrest and syncope in high-risk LQTS patients when compared with pre-LCSD events. However, LCSD is not entirely effective in preventing cardiac events including sudden cardiac death during long-term follow-up. LCSD should be considered in patients with recurrent syncope despite beta-blockade and in patients who experience arrhythmia storms with an implanted defibrillator.

Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice.

CONTEXT: In long QT syndrome (LQTS), disease severity and response to therapy vary according to the genetic loci. There exists a critical need to devise strategies to expedite genetic analysis. OBJECTIVE: To perform genetic screening in patients with LQTS to determine the yield of genetic testing, as well as the type and the prevalence of mutations. DESIGN, PATIENTS, AND SETTING: We investigated whether the detection of a set of frequently mutated codons in the KCNQ1, KCNH2, and SCN5A genes may translate in a novel strategy for rapid efficient genetic testing of 430 consecutive patients referred to our center between June 1996 and June 2004. The entire coding regions of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 were screened by denaturing high-performance liquid chromatography and DNA sequencing. The frequency and the type of mutations were defined to identify a set of recurring mutations. A separate cohort of 75 consecutive probands was used as a validation group to quantify prospectively the prevalence of the recurring mutations identified in the primary LQTS population. MAIN OUTCOME MEASURES: Development of a novel approach to LQTS genotyping. RESULTS: We identified 235 different mutations, 138 of which were novel, in 310 (72%) of 430 probands (49% KCNQ1, 39% KCNH2, 10% SCN5A, 1.7% KCNE1, and 0.7% KCNE2). Fifty-eight percent of probands carried nonprivate mutations in 64 codons of KCNQ1, KCNH2, and SCN5A genes. A similar occurrence of mutations at these codons (52%) was confirmed in the prospective cohort of 75 probands and in previously published LQTS cohorts. CONCLUSIONS: We have developed an approach to improve the efficiency of genetic screening for LQTS. This novel method may facilitate wider access to genotyping resulting in better risk stratification and treatment of LQTS patients.