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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., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare inherited arrhythmia syndrome, arrhythmic events can be prevented by medication and lifestyle recommendations. In patients who experience breakthrough arrhythmic events, non-adherence plays an essential role. We aimed to investigate the incidence and potential reasons for non-adherence to medication and lifestyle recommendations in a large, international cohort of patients with CPVT., Methods and Results: An online multilingual survey was shared with CPVT patients worldwide by their cardiologists, through peer-recruitment, and on social media from November 2022 until July 2023. Self-reported non-adherence was measured using the validated Medication Adherence Rating Scale (MARS) and a newly developed questionnaire about lifestyle. Additionally, validated questionnaires were used to assess potential reasons for medication non-adherence. Two-hundred-and-eighteen patients completed the survey, of whom 200 (92%) were prescribed medication [122 (61%) female; median age 33.5 years (interquartile range: 22-50)]. One-hundred-and-three (52%) were prescribed beta-blocker and flecainide, 85 (43%) beta-blocker, and 11 (6%) flecainide. Thirty-four (17%) patients experienced a syncope, aborted cardiac arrest or appropriate implantable cardioverter defibrillator shock after diagnosis. Nineteen (13.4%) patients were exercising more than recommended. Thirty (15%) patients were non-adherent to medication. Female sex [odds ratio (OR) 3.7, 95% confidence interval (CI) 1.3-12.0, P = 0.019], flecainide monotherapy compared to combination therapy (OR 6.8, 95% CI 1.6-31.0, P = 0.010), and a higher agreement with statements regarding concerns about CPVT medication (OR 1.2, 95% CI 1.1-1.3, P < 0.001) were independently associated with non-adherence., Conclusion: The significant rate of non-adherence associated with concerns regarding CPVT-related medication, emphasizes the potential for improving therapy adherence by targeted patient education., Competing Interests: Conflict of interest: A.A.W. is a member of the scientific advisor board of ARMGO (unpaid) and a member of the scientific advisor board of Thryvv therapeutics (unpaid). E.J.B. is a consultant for Boston Scientific. M.J.A. has royalty/equity relationship with AliveCor, ARMGO, anumana, Pfizer, Trhyvv therapeutics. M.J.A. is a consultant for Abbott, Boston scientific, Daiichi Sankyo, Invitae, Tenaya Therapeutics, BioMarin Pharmaceutical, Bristol Myers Squibb, Illumina, Medtronic, and UpToDate. E.F. is supported by the Max’s foundation. All other authors report no disclosures., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Data on predictors of time-to-first appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with Brugada Syndrome (BrS) and prophylactically implanted ICD's are scarce., Methods and Results: SABRUS (Survey on Arrhythmic Events in BRUgada Syndrome) is an international survey on 678 BrS patients who experienced arrhythmic event (AE) including 252 patients in whom AE occurred after prophylactic ICD implantation. Analysis was performed on time-to-first appropriate ICD discharge regarding patients' characteristics. Multivariate logistic regression models were utilized to identify which parameters predicted time to arrhythmia ≤5 years. The median time-to-first appropriate ICD therapy was 24.8 ± 2.8 months. A shorter time was observed in patients from Asian ethnicity (P < 0.05), those with syncope (P = 0.001), and those with Class IIa indication for ICD (P = 0.001). A longer time was associated with a positive family history of sudden cardiac death (P < 0.05). Multivariate Cox regression revealed shorter time-to-ICD therapy in patients with syncope [odds ratio (OR) 1.65, P = 0.001]. In 193 patients (76.6%), therapy was delivered during the first 5 years. Factors associated with this time were syncope (OR 0.36, P = 0.001), spontaneous Type 1 Brugada electrocardiogram (ECG) (OR 0.5, P < 0.05), and Class IIa indication (OR 0.38, P < 0.01) as opposed to Class IIb (OR 2.41, P < 0.01). A near-significant trend for female gender was also noted (OR 0.13, P = 0.052). Two score models for prediction of <5 years to shock were built., Conclusion: First appropriate therapy in BrS patients with prophylactic ICD's occurred during the first 5 years in 76.6% of patients. Syncope and spontaneous Type 1 Brugada ECG correlated with a shorter time to ICD therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Aims: To evaluate the long-term efficacy and safety of an electrophysiologically guided therapy, based on a strategy of treatment using hydroquinidine (HQ) among asymptomatic Brugada patients with inducible ventricular fibrillation (VF)., Methods and Results: In two French reference centres, consecutive asymptomatic type 1 Brugada patients with inducible VF were treated with HQ (600 mg/day, targeting a therapeutic range between 3 and 6 µmol/L) and enroled in a specific follow-up (mean 6.6 ± 3 years), including a second programmed ventricular stimulation (PVS) under HQ. An implantable cardioverter defibrillator (ICD) was eventually implanted in patients inducible under HQ, or during follow-up in case of HQ intolerance, as well as occurrence of arrhythmic events. From a total of 397 Brugada patients, 44 were enroled (47 ± 10 years, 95% male). Of these, 34 (77%) were no more inducible (Group PVS-), and were maintained under HQ alone during a mean follow-up of 6.2 ± 3 years. In this group, an ICD was eventually implanted in four patients (12%), with occurrence of appropriate ICD therapies in one. Among the 10 other patients (22%), who remained inducible and received ICD (Group PVS+), none of them received appropriate therapy during a mean follow-up of 7.7 ± 2 years. The overall annual rate of arrhythmic events was 1.04% (95% confidence interval 0.00-2.21), without any significant difference according to the result of PVS under HQ. One-third of patients experienced device-related complications., Conclusion: Our long-term follow-up results emphasize that the rate of arrhythmic events among asymptomatic Brugada patients with inducible VF remains low over time. Our results also suggest that residual inducibility under HQ is of limited value to predict events during follow-up.

Aims: Andersen-Tawil syndrome (ATS) is an uncommon form of channelopathy linked to mutations in the KCNJ2 gene. Currently, little is known about the long-term arrhythmic prognosis of this disease., Methods and Results: We conducted a retrospective multicentre study in nine French hospitals. Patients were recruited only if they were KCNJ2 mutation carriers. Thirty-six patients (female n = 22, 61%) from 20 unrelated kindred were included with a mean follow-up of 9.5 ± 8.2 years. We found 12 distinct KCNJ2 mutations in the 20 probands. Three of them were novel. Thirteen patients (36%) experienced syncope and one patient was resuscitated from cardiac arrest before diagnosis. The mean QTc interval was 439 ± 57 ms and QUc was 642 ± 64 ms. All patients had normal ejection fraction. Holter recordings in 33 patients found 11 272 premature ventricular complexes (PVCs) per day on average, 25 patients had episodes of bigeminy, and 25 patients had polymorphic PVCs. Twenty-three patients (70%) had non-sustained polymorphic ventricular tachycardia (VT), and six sustained polymorphic VT. Only one patient presented with torsades de pointes. Patients were treated with beta-blocker (n = 20), beta-blocker and amiodarone (n = 2), beta-blocker and flecainide (n = 6), or acetazolamide (n = 6). Radiofrequency ablation was attempted in five patients without clinical success. An implantable cardiac defibrillator was implanted in three patients. During follow-up, none of the patients died, four patients experienced syncope under treatment, and one patient had non-fatal cardiac arrest., Conclusion: Despite a severe clinical presentation with a very high rate of ventricular arrhythmias, the arrhythmic prognosis of the ATS patients is relatively good under treatment.

Aims: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmic disorder with a highly malignant clinical course. Exercise-stress test is the first-line approach to diagnose suspected individuals. We sought to elucidate the value of exercise-stress test for predicting mutations and future cardiac events in CPVT-family relatives., Methods and Results: The present study included 67 asymptomatic relatives (24 ± 15 years) of 17 genetically positive CPVT probands, who underwent exercise-stress test without any medication and genetic testing. Exercise-stress test, which was considered positive with the induction of ventricular tachycardia or premature ventricular contractions consisting of bigeminy or couplets, was positive in 17 relatives (25%). Genetic analysis disclosed mutations in 16 of these 17 relatives (94%) and in 16 of the 50 relatives (32%) with negative exercise-stress test; the sensitivity and specificity for a positive genotype were 50 and 97%, respectively (P< 0.001). Among 32 mutation carriers, cardiac events occurred in 7 of the 16 relatives with positive and 2 of the 16 relatives with negative exercise-stress test during the follow-up period of 9.6 ± 3.8 years, and four with positive and two with negative stress test were not on regular beta-blocker treatment at these events. In the 16 relatives with positive stress test, those on beta-blocker treatment demonstrated a trend of lower cardiac event rate (Log-rank P= 0.054)., Conclusion: In asymptomatic relatives of CPVT probands, exercise-stress test can be used as a simple diagnostic tool. Nevertheless, because of the low sensitivity for predicting mutations and future cardiac events in those with negative stress test, genetic analysis should be performed to improve patient management.

We identified a heterozygous p.Arg2401His mutation of RYR2 by sequencing the DNA of a 7-year-old girl who was referred for catecholaminergic polymorphic ventricular tachycardia (CPVT). Using high-resolution melting assay, we have demonstrated a mosaicism for this mutation in her asymptomatic mother which illustrates the benefit of extensive genetic analysis in CPVT, in particular regarding genetic counselling.

Aims: Long QT syndrome (LQTS) is a primary electrical disease characterized by QT prolongation and increased repolarization dispersion leading to T-wave amplitude beat-to-beat changes. We aimed to quantify beat-to-beat T-wave amplitude variability from ambulatory Holter recordings in genotyped LQTS patients., Methods and Results: Seventy genotyped LQTS patients (mean age 23 +/- 15 years, 42 males, 50% LQT1, 39% LQT2, and 11% LQT3) and 70 normal matched control subjects underwent a 24-h digital Holter recording. Using the Tvar software (Ela Medical, Sorin group), the beat-to-beat variance of the T-wave amplitude (TAV in microV) [corrected] was assessed on 50-ms consecutive clusters during three 1-h periods: one with around average diurnal heart rate (Day Fast), one nocturnal period (Night), and one diurnal period with around average nocturnal heart rate (Day Slow). TAV was increased in LQTS patients during the two diurnal periods but not at night (during the Day Fast period, mean TAV was 34 +/- 20 microV [corrected] in LQTS patients vs. 27 +/- 10 microV [corrected] in controls, P < 0.05). This effect depended on the genotype. In LQT1, TAV was larger when compared with controls for both Day Fast and Slow periods, but in LQT2 only Day Fast shows higher TAV. Oppositely, in LQT3 the TAV was higher than in the control group during the Day slow period (mean TAV = 34 +/- 20 vs. 25 +/- 8 microV [corrected] in controls, P < 0.05)., Conclusion: In genotyped LQTS patients beat-to-beat T-wave amplitude variability was increased when compared with control subjects. That pattern was modulated by circadian influences in a gene-dependent manner.

Aims: Patients with atrial fibrillation (AF) consider the related symptoms disruptive to their quality of life (QoL). This study aimed to evaluate the impact of the control of symptomatic paroxysmal AF (PAF) on QoL., Methods and Results: Patients with symptomatic PAF were treated for 48 weeks with open-label flecainide acetate controlled release (Flec CR). Quality of life was assessed by SF-36 and Atrial Fibrillation Severity Scale scores at baseline, Week 12 (W12), W24, and W48. Of the 229 treated patients, 217 were analysed for QoL (123 with controlled and 94 with uncontrolled symptomatic PAF at inclusion). The controlled group had a similar or better QoL (SF-36) at baseline compared with a reference population (significantly better for: physical functioning, bodily pain, and physical component). The uncontrolled group had an inferior QoL (significantly worse for: role physical, general health, vitality, role emotional, social functioning, mental health, and mental component). When treated with Flec CR, the controlled group baseline QoL scores were maintained and the uncontrolled group scores were improved to a level comparable to the controlled group scores. Safety findings reflect the known clinical safety profile of flecainide acetate., Conclusion: In this study, patients with uncontrolled symptomatic PAF at baseline had an inferior QoL to those with controlled symptomatic PAF. Following treatment with controlled-release flecainide acetate, their QoL improved to a level comparable to controlled patients.

Aims: The distinct cardiac arrhythmia diseases, Brugada syndrome (BS) and isolated cardiac conduction disease (ICCD) are caused by heterozygous mutations in the SCN5A gene. Previous studies have demonstrated an intriguing association between ICCD and BS with the same mutation in the SCN5A gene., Methods and Results: The proband of a multigenerational family presented BS and a familial history of sudden death. We performed clinical evaluations in family members including drug testing and screening for SCN5A mutations. Based on electrocardiogram features, we identified four individuals with BS, two with ICCD and one compatible with both. For five individuals, one with BS and ICCD, three with BS and one with ICCD, we characterized a heterozygous C- to T- mutation at position 4313 (P1438L) in the SCN5A gene. Expression studies of the P1438L mutation showed non-functional channels. The proband's father with the BS phenotype was not a carrier of the new SCN5A mutation., Conclusion: We report the case of a family with BS and/or ICCD and describe a novel mutation, the P1438L SCN5A mutation. In this family, the occurrence of BS and ICCD could be due to this single mutation but also to the accidental association of both diseases.

Aim: To identify ECG predictors of Brugada type response during Na channel blockade challenge., Methods: We studied prospectively 103 patients (M = 76, 45 +/- 13 years) in whom ECGs were collected during ajmaline challenge. ECG recordings included the high right precordial leads (-2V(1) and -2V(2)). A positive response was defined by a >0.2 mV J point or ST segment elevation and a down-sloping pattern of the ST segment in at least one right precordial lead., Results: Ajmaline challenge was positive in 48 (47%) of the 103 cases. Baseline J wave elevation was greater in -2V(1) (0.077 +/- 0.078 mV vs. 0.038 +/- 0.046 mV, P = 0.003) and -2V(2) (0.149 +/- 0.103 mV vs. 0.043 +/- 0.088 mV, P < 0.001) in cases with a subsequent positive response. In contrast, ST segment elevation and T wave amplitudes were reduced in V(1), V(2) and V(3). Logistic regression showed that J wave elevation in -2V(2) and decreased T wave amplitude in V(3) at baseline were independent predictors of a positive response. Baseline J wave elevation >0.16 mV in -2V(2) had a specificity of 100%, a sensitivity of 40%, a positive predictive value of 100% and a negative predictive value of 28%., Conclusion: J wave elevation >0.16 mV in -2V(2) was the strongest predictor of a Brugada type response to Na channel blockade challenge when Brugada syndrome was suspected on a baseline ECG.