Genetic characterization of KCNQ1 variants improves risk stratification in type 1 long QT syndrome patients.

AIMS: KCNQ1 mutations cause QTc prolongation increasing life-threatening arrhythmias risks. Heterozygous mutations [type 1 long QT syndrome (LQT1)] are common. Homozygous KCNQ1 mutations cause type 1 Jervell and Lange-Nielsen syndrome (JLNS) with deafness and higher sudden cardiac death risk. KCNQ1 variants causing JLNS or LQT1 might have distinct phenotypic expressions in heterozygous patients. The aim of this study is to evaluate QTc duration and incidence of long QT syndrome-related cardiac events according to genetic presentation. METHODS AND RESULTS: We enrolled LQT1 or JLNS patients with class IV/V KCNQ1 variants from our inherited arrhythmia clinic (September 1993 to January 2023). Medical history, ECG, and follow-up were collected. Additionally, we conducted a thorough literature review for JLNS variants. Survival curves were compared between groups, and multivariate Cox regression models identified genetic and clinical risk factors. Among the 789 KCNQ1 variant carriers, 3 groups were identified: 30 JLNS, 161 heterozygous carriers of JLNS variants (HTZ-JLNS), and 550 LQT1 heterozygous carriers of non-JLNS variants (HTZ-Non-JLNS). At diagnosis, mean age was 3.4 ± 4.7 years for JLNS, 26.7 ± 21 years for HTZ-JLNS, and 26 ± 21 years for HTZ-non-JLNS; 55.3% were female; and the mean QTc was 551 ± 54 ms for JLNS, 441 ± 32 ms for HTZ-JLNS, and 467 ± 36 ms for HTZ-Non-JLNS. Patients with heterozygous JLNS mutations (HTZ-JLNS) represented 22% of heterozygous KCNQ1 variant carriers and had a lower risk of cardiac events than heterozygous non-JLNS variant carriers (HTZ-Non-JLNS) [hazard ratio (HR) = 0.34 (0.22-0.54); P < 0.01]. After multivariate analysis, four genetic parameters were independently associated with events: haploinsufficiency [HR = 0.60 (0.37-0.97); P = 0.04], pore localization [HR = 1.61 (1.14-1.2.26); P < 0.01], C-terminal localization [HR = 0.67 (0.46-0.98); P = 0.04], and group [HR = 0.43 (0.27-0.69); P < 0.01]. CONCLUSION: Heterozygous carriers of JLNS variants have a lower risk of cardiac arrhythmic events than other LQT1 patients.

An international multicenter cohort study on implantable cardioverter-defibrillators for the treatment of symptomatic children with catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable cardioverter-defibrillators (ICDs) are commonly advised. However, there is limited data on the outcomes of ICD use in children. OBJECTIVE: The purpose of this study was to compare the risk of arrhythmic events in pediatric patients with CPVT with and without an ICD. METHODS: We compared the risk of SCD in patients with RYR2 (ryanodine receptor 2) variants and phenotype-positive symptomatic CPVT patients with and without an ICD who were younger than 19 years and had no history of sudden cardiac arrest at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite end points of SCD, sudden cardiac arrest, or appropriate ICD shocks with or without arrhythmic syncope. RESULTS: The study included 235 patients, 73 with an ICD (31.1%) and 162 without an ICD (68.9%). Over a median follow-up of 8.0 years (interquartile range 4.3-13.4 years), SCD occurred in 7 patients (3.0%), of whom 4 (57.1%) were noncompliant with medications and none had an ICD. Patients with ICD had a higher risk of both secondary composite outcomes (without syncope: hazard ratio 5.85; 95% confidence interval 3.40-10.09; P < .0001; with syncope: hazard ratio 2.55; 95% confidence interval 1.50-4.34; P = .0005). Thirty-one patients with ICD (42.5%) experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications. CONCLUSION: SCD events occurred only in patients without an ICD and mostly in those not on optimal medical therapy. Patients with an ICD had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common, and risks vs benefits of ICDs need to be considered.

Type 3 long QT syndrome: Is the effectiveness of treatment with beta-blockers population-specific?

BACKGROUND: The efficacy of beta-blocker treatment in type 3 long QT syndrome (LQT3) remains debated. OBJECTIVES: The purpose of this study was to test the hypothesis that beta-blocker use is associated with cardiac events (CEs) in a French cohort of LQT3 patients. METHODS: All patients with a likely pathogenic/pathogenic variant in the SCN5A gene (linked to LQT3) were included and followed-up. Documented ventricular tachycardia/ventricular fibrillation, torsades de pointes, aborted cardiac arrest, sudden death, and appropriate shocks were considered as severe cardiac events (SCEs). CEs also included syncope. RESULTS: We included 147 patients from 54 families carrying 23 variants. Six of the patients developed symptoms before the age of 1 year and were analyzed separately. The 141 remaining patients (52.5% male; median age at diagnosis 24.0 years) were followed-up for a median of 11 years. The probabilities of a CE and an SCE from birth to the age of 40 were 20.5% and 9.9%, respectively. QTc prolongation (hazard ratio [HR] 1.12 [1.0-1.2]; P = .005]) and proband status (HR 4.07 [1.9-8.9]; P <.001) were independently associated with the occurrence of CEs. Proband status (HR 8.13 [1.7-38.8]; P = .009) was found to be independently associated with SCEs, whereas QTc prolongation (HR 1.11 [1.0-1.3]; P = .108) did not reach statistical significance. The cumulative probability of the age at first CE/SCE was not lower in patients treated with a beta-blocker. CONCLUSION: In agreement with the literature, proband status and lengthened QTc were associated with a higher risk of CEs. Our data do not show a protective effect of beta-blocker treatment.

Flecainide Is Associated With a Lower Incidence of Arrhythmic Events in a Large Cohort of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia. METHODS: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients. RESULTS: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; P=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; P=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; P<0.001). CONCLUSIONS: For patients with catecholaminergic polymorphic ventricular tachycardia, adding flecainide to beta-blocker therapy was associated with a lower incidence of AEs in the overall cohort, in symptomatic patients, and particularly in patients with breakthrough AEs while on beta-blocker therapy.

Idiopathic ventricular fibrillation associated with long-coupled Purkinje ectopy.

INTRODUCTION: Idiopathic ventricular fibrillation (IVF) is mainly associated with and triggered by short-coupled (R-on-T) ventricular ectopics. However, little is known about the risk of VF associated with long-coupled premature ventricular complexes (LCPVCs). OBJECTIVE: To examine the prevalence and characteristics of IVF patients presenting with LCPVCs. METHODS: Consecutive patients with IVF and PVCs from five arrhythmia referral centers were reviewed. We included patients presenting LCPVCs, defined as PVCs falling after the end of the T wave, with a normal QTc interval. We evaluated demographics, medical history, and clinical circumstances associated with PVCs and VF episodes. The origin of PVCs was determined by invasive mapping. RESULTS: Seventy-nine patients with IVF were reviewed. Among them, 12 (15.2%) met the inclusion criteria (8 women, age 36 ± 14 years). Eleven patients had documented LCPVCs initiating repetitive PVCs or sustained VF, whereas 1 had only documented isolated PVCs. In 10 of 12 patients, PVCs were recorded showing both long and short coupling intervals of 418 ± 46 and 304 ± 33 ms, respectively. Mapping showed that PVCs originated from the left Purkinje in 10 patients, from the right Purkinje in 1 patient, and both in 1 patient. Compared to other patients from the initial cohort, IVF with LCPVCs was associated with a left-sided origin of PVCs (92% in long-coupled IVF vs. 46% of left Purkinje PVCs in short-coupled IVF, p = .004). CONCLUSION: Long-coupled fascicular PVCs, traditionally recognized as benign, can be associated with IVF in a subset of patients. They can induce IVF by themselves or in association with short-coupled PVCs.

Continuous Bayesian variant interpretation accounts for incomplete penetrance among Mendelian cardiac channelopathies.

PURPOSE: The congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon. METHODS: We generated Bayesian penetrance models for KCNQ1-LQT1 and SCN5A-LQT3 using variant-specific features and clinical data from the literature, international arrhythmia genetic centers, and population controls. We analyzed the distribution of posterior penetrance estimates across 4 genotype-phenotype relationships and compared continuous estimates with ClinVar annotations. Posterior estimates were mapped onto protein structure. RESULTS: Bayesian penetrance estimates of KCNQ1-LQT1 and SCN5A-LQT3 are empirically equivalent to 10 and 5 clinically phenotype heterozygotes, respectively. Posterior penetrance estimates were bimodal for KCNQ1-LQT1 and KCNH2-LQT2, with a higher fraction of missense variants with high penetrance among KCNQ1 variants. There was a wide distribution of variant penetrance estimates among identical ClinVar categories. Structural mapping revealed heterogeneity among "hot spot" regions and featured high penetrance estimates for KCNQ1 variants in contact with calmodulin and the S6 domain. CONCLUSIONS: Bayesian penetrance estimates provide a continuous framework for variant interpretation.

Outcome of patients with early repolarization pattern and syncope.

BACKGROUND: Syncope in patients with an early repolarization (ER) pattern presents a challenge for clinicians as it has been identified as an indicator of a higher risk of life-threatening ventricular arrhythmias (VAs). OBJECTIVES: This study aimed to analyze the outcome of patients with an ER pattern and syncope and to evaluate the factors predictive of VAs. METHODS: Over a period of 5 years, we enrolled 143 patients with an ER pattern and syncope in a multicenter prospective registry. RESULTS: After the initial examinations, 97 patients (67.8%) were implanted with a device allowing electrocardiogram monitoring, including 84 (58.7%) with an implantable loop recorder. During a mean follow-up period of 68 ± 34 months, we documented 16 arrhythmias presumably responsible for syncope (5 VAs, 10 bradycardias, and 1 supraventricular tachycardia). Additionally, recurrent syncope not associated with electrocardiogram documentation occurred in 16 patients (11.2%). The cause of syncope was identified in 23 of 97 patients with a monitoring device (23.8%). The 5-year incidence of VAs and arrhythmic events presumably responsible for syncope was 4.9% and 11.0%, respectively. Patients who developed VAs showed no prodromes or specific triggers at the time of syncope. Neither the presence of a family history of sudden cardiac death nor the previously reported high-risk electrocardiographic parameters differed between patients with and without VAs. CONCLUSION: VAs occurred in 4.9% of patients with an ER pattern and syncope. Device implantation based on detailed history taking seems to be a reasonable strategy. Previously reported high-risk electrocardiographic patterns did not identify patients with VAs.

An International Multicenter Cohort Study on ß-Blockers for the Treatment of Symptomatic Children With Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. ß-Blockers decrease this risk, but studies comparing individual ß-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of ß-blocker in a large cohort of symptomatic children with CPVT. METHODS: From 2 international registries of patients with CPVT, RYR2 variant-carrying symptomatic children (defined as syncope or sudden cardiac arrest before ß-blocker initiation and age at start of ß-blocker therapy <18 years), treated with a ß-blocker were included. Cox regression analyses with time-dependent covariates for ß-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope. RESULTS: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7-15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8-12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective ß-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a ß1-selective ß-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial ß-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for ß1-selective compared with nonselective ß-blockers (HR, 2.04 [95% CI, 1.31-3.17]; and HR, 1.99 [95% CI, 1.20-3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44-4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47-7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08-4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30-5.55]). CONCLUSIONS: ß1-selective ß-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective ß-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred ß-blocker for treating symptomatic children with CPVT.

Deep learning analysis of electrocardiogram for risk prediction of drug-induced arrhythmias and diagnosis of long QT syndrome.

AIMS: Congenital long-QT syndromes (cLQTS) or drug-induced long-QT syndromes (diLQTS) can cause torsade de pointes (TdP), a life-threatening ventricular arrhythmia. The current strategy for the identification of drugs at the high risk of TdP relies on measuring the QT interval corrected for heart rate (QTc) on the electrocardiogram (ECG). However, QTc has a low positive predictive value. METHODS AND RESULTS: We used convolutional neural network (CNN) models to quantify ECG alterations induced by sotalol, an IKr blocker associated with TdP, aiming to provide new tools (CNN models) to enhance the prediction of drug-induced TdP (diTdP) and diagnosis of cLQTS. Tested CNN models used single or multiple 10-s recordings/patient using 8 leads or single leads in various cohorts: 1029 healthy subjects before and after sotalol intake (n = 14 135 ECGs); 487 cLQTS patients (n = 1083 ECGs: 560 type 1, 456 type 2, 67 type 3); and 48 patients with diTdP (n = 1105 ECGs, with 147 obtained within 48 h of a diTdP episode). CNN models outperformed models using QTc to identify exposure to sotalol [area under the receiver operating characteristic curve (ROC-AUC) = 0.98 vs. 0.72, P ≤ 0.001]. CNN models had higher ROC-AUC using multiple vs. single 10-s ECG (P ≤ 0.001). Performances were comparable for 8-lead vs. single-lead models. CNN models predicting sotalol exposure also accurately detected the presence and type of cLQTS vs. healthy controls, particularly for cLQT2 (AUC-ROC = 0.9) and were greatest shortly after a diTdP event and declining over time (P ≤ 0.001), after controlling for QTc and intake of culprit drugs. ECG segment analysis identified the J-Tpeak interval as the best discriminator of sotalol intake. CONCLUSION: CNN models applied to ECGs outperform QTc measurements to identify exposure to drugs altering the QT interval, congenital LQTS, and are greatest shortly after a diTdP episode.

Computerized automated algorithm-based analyses of digitized paper ECGs in Brugada syndrome.

BACKGROUND: Brugada syndrome is a rare inherited arrhythmic syndrome with a coved type 1 ST-segment elevation on ECG and an increased risk of sudden death. Many studies have evaluated risk stratification performance based on ECG-derived parameters. However, since historical Brugada patient cohorts included mostly paper ECGs, most studies have been based on manual ECG parameter measurements. We hypothesized that it would be possible to run automated algorithm-based analysis of paper ECGs. We aimed: 1) to validate the digitization process for paper ECGs in Brugada patients; and 2) to quantify the acute class I antiarrhythmic drug effect on relevant ECG parameters in Brugada syndrome. METHODS: A total of 176 patients (30% female, 43 ± 13 years old) with induced type 1 Brugada syndrome ECG were included in the study. All of the patients had paper ECGs before and during class I antiarrhythmic drug challenge. Twenty patients also had a digital ECG, in whom printouts were used to validate the digitization process. Paper ECGs were scanned and then digitized using ECGScan software, version 3.4.0 (AMPS, LLC, New York, NY, USA) to obtain FDA HL7 XML format ECGs. Measurements were automatically performed using the Bravo (AMPS, LLC, New York, NY, USA) and Glasgow algorithms. RESULTS: ECG parameters obtained from digital and digitized ECGs were closely correlated (r = 0.96 ± 0.07, R2 = 0.93 ± 0.12). Class I antiarrhythmic drugs significantly increased the global QRS duration (from 113 ± 20 to 138 ± 23, p < 0.0001). On lead V2, class I antiarrhythmic drugs increased ST-segment elevation (from 110 ± 84 to 338 ± 227 µV, p < 0.0001), decreased the ST slope (from 14.9 ± 23.3 to -27.4 ± 28.5, p < 0.0001) and increased the TpTe interval (from 88 ± 18 to 104 ± 33, p < 0.0001). CONCLUSIONS: Automated algorithm-based measurements of depolarization and repolarization parameters from digitized paper ECGs are reliable and could quantify the acute effects of class 1 antiarrhythmic drug challenge in Brugada patients. Our results support using computerized automated algorithm-based analyses from digitized paper ECGs to establish risk stratification decision trees in Brugada syndrome.

Genotype-Phenotype Correlation of SCN5A Genotype in Patients With Brugada Syndrome and Arrhythmic Events: Insights From the SABRUS in 392 Probands.

BACKGROUND: Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, SCN5A. However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to SCN5A genotype in a large cohort of BrS probands with first arrhythmic event. METHODS: Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, and SCN5A genotype adjudicated. Patients without appropriate genetic data were excluded. Associations of genotype with clinical features were analyzed. RESULTS: The study group comprised 392 probands: 92 (23.5%) SCN5A+(44 pathogenic/likely pathogenic [P/LP] and 48 variants of unknown significance) and 300 (76.5%) SCN5A-.SCN5A missense variants and the patients hosting them were similar regardless of adjudication. A higher proportion of patients with P/LP were pediatric (<16 years) compared with SCN5A- (11.4% versus 3%, P=0.023). The proportion of females was higher among patients with P/LP compared with SCN5A- (18.2% versus 6.3%, P=0.013). P/LP probands were more likely to have a family history of sudden cardiac death compared with SCN5A- (41.9% versus 16.8%, P<0.001). A higher proportion of patients with P/LP were White compared with SCN5A- (87.5% versus 47%, P<0.001). Ethnicity (odds ratio, 5.41 [2.8-11.19], P<0.001) and family history of sudden cardiac death (odds ratio, 2.73 [1.28-5.82], P=0.009) were independent variables associated with P/LP genotype following logistic regression. CONCLUSIONS: The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with SCN5A-. In addition, they were more likely to be White and to have family history of sudden cardiac death. Among females, a P/LP variant suggests an increased risk of being symptomatic. This association should be further studied on an ethnically specific basis in large prospectively collected international cohorts.

Sex differences in the origin of Purkinje ectopy-initiated idiopathic ventricular fibrillation.

BACKGROUND: Purkinje ectopics (PurkEs) are major triggers of idiopathic ventricular fibrillation (VF). Identifying clinical factors associated with specific PurkE characteristics could yield insights into the mechanisms of Purkinje-mediated arrhythmogenicity. OBJECTIVE: The purpose of this study was to examine the associations of clinical, environmental, and genetic factors with PurkE origin in patients with PurkE-initiated idiopathic VF. METHODS: Consecutive patients with PurkE-initiated idiopathic VF from 4 arrhythmia referral centers were included. We evaluated demographic characteristics, medical history, clinical circumstances associated with index VF events, and electrophysiological characteristics of PurkEs. An electrophysiology study was performed in most patients to confirm the Purkinje origin. RESULTS: Eighty-three patients were included (mean age 38 ± 14 years; 44 [53%] women), of whom 32 had a history of syncope. Forty-four patients had VF at rest. PurkEs originated from the right ventricle (RV) in 41 patients (49%), from the left ventricle (LV) in 36 (44%), and from both ventricles in 6 (7%). Seasonal and circadian distributions of VF episodes were similar according to PurkE origin. The clinical characteristics of patients with RV vs LV PurkE origins were similar, except for sex. RV PurkEs were more frequent in men than in women (76% vs 24%), whereas LV and biventricular PurkEs were more frequent in women (81% vs 19% and 83% vs 17%, respectively) (P < .0001). CONCLUSION: PurkEs triggering idiopathic VF originate dominantly from the RV in men and from the LV or both ventricles in women, adding to other sex-related arrhythmias such as Brugada syndrome or long QT syndrome. Sex-based factors influencing Purkinje arrhythmogenicity warrant investigation.

Estimating the Posttest Probability of Long QT Syndrome Diagnosis for Rare KCNH2 Variants.

BACKGROUND: The proliferation of genetic profiling has revealed many associations between genetic variations and disease. However, large-scale phenotyping efforts in largely healthy populations, coupled with DNA sequencing, suggest variants currently annotated as pathogenic are more common in healthy populations than previously thought. In addition, novel and rare variants are frequently observed in genes associated with disease both in healthy individuals and those under suspicion of disease. This raises the question of whether these variants can be useful predictors of disease. To answer this question, we assessed the degree to which the presence of a variant in the cardiac potassium channel gene KCNH2 was diagnostically predictive for the autosomal dominant long QT syndrome. METHODS: We estimated the probability of a long QT diagnosis given the presence of each KCNH2 variant using Bayesian methods that incorporated variant features such as changes in variant function, protein structure, and in silico predictions. We call this estimate the posttest probability of disease. Our method was applied to over 4000 individuals heterozygous for 871 missense or in-frame insertion/deletion variants in KCNH2 and validated against a separate international cohort of 933 individuals heterozygous for 266 missense or in-frame insertion/deletion variants. RESULTS: Our method was well-calibrated for the observed fraction of heterozygotes diagnosed with long QT syndrome. Heuristically, we found that the innate diagnostic information one learns about a variant from 3-dimensional variant location, in vitro functional data, and in silico predictors is equivalent to the diagnostic information one learns about that same variant by clinically phenotyping 10 heterozygotes. Most importantly, these data can be obtained in the absence of any clinical observations. CONCLUSIONS: We show how variant-specific features can inform a prior probability of disease for rare variants even in the absence of clinically phenotyped heterozygotes.

A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes.

Idiopathic ventricular fibrillation (IVF) causes sudden death in young adult patients without structural or ischemic heart disease. Most IVF cases are sporadic and some patients present with short-coupled torsade de pointes, the genetics of which are poorly understood. A man who had a first syncope at the age of 35 presented with frequent short-coupled premature ventricular beats with bursts of polymorphic ventricular tachycardia and then died suddenly. By exome sequencing, we identified three rare variants: p.I784F in the SPRY1 of the ryanodine receptor 2 (RyR2), p.A96S in connexin 40 (Cx40), reported to affect electrical coupling and cardiac conduction, and a nonsense p.R244X in the cardiac-specific troponin I-interacting kinase (TNNI3K). We assessed intracellular Ca2+ handling in WT and mutant human RYR2 transfected HEK293 cells by fluorescent microscopy and an enhanced store overload-induced Ca2+ release in response to cytosolic Ca2+ was observed in RyR2-I784F cells. In addition, crystal structures and thermal melting temperatures revealed a conformational change in the I784F-SPRY1 domain compared to the WT-domain. The novel RyR2-I784F variant in SPRY1 domain causes a leaky channel under non-stress conditions. The presence of several variants affecting Ca2+ handling and cardiac conduction suggests a possible oligogenic origin for the ectopies originating from Purkinje fibres.

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.

Predictive value of premature atrial complex characteristics in pulmonary vein isolation for patients with paroxysmal atrial fibrillation.

BACKGROUND: Premature atrial complexes from pulmonary veins are the main triggers for atrial fibrillation in the early stages. Thus, pulmonary vein isolation is the cornerstone of catheter ablation for paroxysmal atrial fibrillation. However, the success rate remains perfectible. AIM: To assess whether premature atrial complex characteristics before catheter ablation can predict pulmonary vein isolation success in paroxysmal atrial fibrillation. METHODS: We investigated consecutive patients who underwent catheter ablation for paroxysmal atrial fibrillation from January 2013 to April 2017 in two French centres. Patients were included if they were treated with pulmonary vein isolation alone, and had 24-hour Holter electrocardiogram data before catheter ablation available and a follow-up of≥6 months. Catheter ablation success was defined as freedom from any sustained atrial arrhythmia recurrence after a 3-month blanking period following catheter ablation. RESULTS: One hundred and three patients were included; all had an acute successful pulmonary vein isolation procedure, and 34 (33%) had atrial arrhythmia recurrences during a mean follow-up of 30±15 months (group 1). Patients in group 1 presented a longer history of atrial fibrillation (71.9±65.8 vs. 42.9±48.4 months; P=0.008) compared with those who were "free from arrhythmia" (group 2). Importantly, the daily number of premature atrial complexes before catheter ablation was significantly lower in group 1 (498±1413 vs. 1493±3366 in group 2; P=0.028). A daily premature atrial complex cut-off number of<670 predicted recurrences after pulmonary vein isolation (41.1% vs. 13.3%; sensitivity 88.2%; specificity 37.7%; area under the curve 0.635; P=0.017), and was the only independent predictive criterion in the multivariable analysis (4-fold increased risk). CONCLUSION: Preprocedural premature atrial complex analysis on 24-hour Holter electrocardiogram in paroxysmal atrial fibrillation may improve patient selection for pulmonary vein isolation.

Prognostic significance of a low T/R ratio in Brugada syndrome.

OBJECTIVES: To determine the prognostic value of a low T/R ratio, defined as the amplitude ratio between the T waves and the R waves, in patients (pts) with a spontaneous type-1 Brugada pattern (SBT1). BACKGROUND: Abnormalities of myocardial repolarization may play a key role in the initiation of ventricular fibrillation (VF) in Brugada syndrome (BrS). Recent studies have shown that the height of the T waves and the T/R ratio are inversely proportional to sudden cardiac arrest (SCA) risk in early repolarization syndrome and hypertrophic cardiomyopathy. METHODS: In an international retrospective study, we reviewed 115 pts. (105 males, 91.3%). 45 had VF and/or SCA (38.7 ±â€¯11.5 years old, all males), while 70 (49.3 ±â€¯12.0 years, 10 women) remained free of ventricular arrhythmia. 6 ECG markers plus the T/R ratio in leads V5 & II were studied. RESULTS: The T/R ratio among leads II & V5 was significantly lower in the VF/SCA group (0.24 [0.14; 0.38]vs. 0.34 [0.24; 0.45]; p = 0.006). 44.4% of pts. in the VF/SCA group had a lowest T/R ratio among leads II & V5 ≤ 0.17 compared to 11.4% in the non-VF/SCA group (p < 0.001). In multivariate analysis, a lowest T/R ratio among leads II & V5 ≤ 0.17 was independently associated with VF/SCA (OR 6.10, 95% CI 1.92-19.40; p = 0.002). Type 1 Brugada pattern in the peripheral leads (OR 10.78) and early repolarization (OR 3.60) were other independent markers of VF/SCA. CONCLUSION: A low T/R ratio among leads II & V5 is an independent marker for VF/SCA risk in patients with type-1 Brugada pattern.

Sex influences on ventricular repolarization duration in normal subjects and in type 1, 2 and 3 long QT syndrome patients: Different effect in acquired and congenital type 2 LQTS.

AIM: To evaluate the interaction between sex and rate corrected QT interval (QTc) duration in normal subjects after drug-induced QT prolongation and in LQTS patients. METHODS: Semi-automated measurements were performed on 875 digital ECGs (200 normal subjects off drugs (100 females), 200 normal subjects on Moxifloxacin (100 females), 259 LQT1 patients (161 females), 183 LQT2 patients (100 females) and 33 LQT3 patients (15 females)). A sex specific coefficient was calculated in each group and was used to calculate group specific corrected QT intervals (QTci). RESULTS: The mean sex difference (female minus male) in QTci interval duration was 17 ms 95%CI(12.7; 21.3) in normal subjects, 19 ms (14.5; 23.5) on Moxifloxacin, and 13 ms (4.8; 21.2) in LQT1 patients. The mean difference was 2 ms (-7.9; 11.9) in LQT2 and - 5 ms (-32.2; 22.2) in LQT3 patients (p = 0.0067 for the group and sex interaction). In the subgroup of patients above 15 years and without beta blocker treatment, the sex effect (female minus male) on QTci interval duration was 17 ms (4.1; 29.9) in LQT1 patients. QTc duration was not different between sex in LQT2 and in LQT3 patients (mean difference - 3 ms (-21.6; 15.6) and 12 ms (-28.4; 52.4), respectively) (p = 0.0191 for group and sex interaction). CONCLUSIONS: The interaction between sex and QTc interval is preserved in type 1 LQTS and drug-induced QTc prolongation but blurred in type 2 LQTS. Further experimental studies are warranted to better understand the interaction of sexual hormones with malfunctioning KCNH2 encoded repolarizing potassium channel.