Wilde, Arthur A.M.

ABSTRACT J‐wave syndromes (JWS)—comprising Brugada syndrome (BrS) and early repolarization syndrome (ERS)—are important causes of malignant ventricular arrhythmias and sudden cardiac death in patients whose hearts appear structurally normal. Since the 2016 consensus, advances in genetics, pathophysiology, and therapy have redefined both understanding and management. BrS, once viewed as a purely electrical disorder, is now recognized along a microstructural–electrical continuum, with sodium‐channel dysfunction and subtle epicardial fibrosis of the right ventricular outflow tract as key contributors. Likewise, ERS—historically considered benign—carries significant risk when inferolateral J‐waves coexist with arrhythmic events. Genetically, SCN5A remains the sole gene with definitive disease association, while polygenic susceptibility materially modulates risk, underscoring complex inheritance. Risk stratification remains challenging: patients with prior cardiac arrest or arrhythmic syncope are highest risk, whereas asymptomatic individuals warrant multiparametric assessment integrating clinical features, ECG markers, electrophysiologic studies, and genetics. For decades, treatment centered on implantable cardioverter‐defibrillators and quinidine, both limited by availability, tolerance, and device complications. More recently, epicardial substrate ablation has emerged as a transformative therapy, with large registries and randomized trials demonstrating durable suppression of ventricular fibrillation and acceptable safety. This APHRS‐organized international consensus updates and extends the 2016 Expert Consensus and the 2022 ESC Guidelines, providing contemporary diagnostic frameworks, pragmatic risk‐stratification tools, and treatment algorithms for BrS and ERS. It emphasizes JWS as a microstructural–electrical disease spectrum and elevates substrate ablation as a major therapeutic advance, while outlining priorities for genetics, risk‐stratification and treatment algorithms.

Abstract Background Increased QRS voltages in athletes’ ECGs are attributed to electrophysiological cellular adaptations, complicating the detection of left ventricular hypertrophy (LVH). Conversely, higher extracellular volume (ECV), indicative of diffuse fibrosis, reduces QRS voltages – so-called ‘relative voltage deficiency’– and can mask true LVH on ECG. Purpose To investigate sex-specific associations between QRS voltages and myocardial ECV and assess the impact of ECV on false-positive and negative ECG-LVH detection in elite athletes. Methods We conducted a cross-sectional, sex-specific, contrast-enhanced CMR study in healthy, elite athletes with normal ECGs and no complete right bundle branch blocks. Myocardial ECV (%) was measured from pre- and post-contrast T1 mapping. LVH on CMR was defined as an indexed LVM >75 g/m² (men) or >59 g/m² (women). Primary analyses evaluated correlations between ECV, LVM, and summed 12-lead ECG voltages (including voltage/LVM to assess independence), as well as Sokolow-Lyon and Cornell voltages. Secondary multivariable logistic regression examined the association of ECV on false-positive and false-negative ECG-LVH rates using Sokolow-Lyon (≥3.5 mV) and sex-specific Cornell (≥2.8 mV in men; ≥2.3 mV in women) criteria for CMR-LVH. Results In 162 elite athletes (median age 25 years, 44% female, 45% endurance, 96% Caucasian), 23% met Sokolow-Lyon criteria, 6% met Cornell criteria, and 17% had LVH on CMR. The median myocardial ECV was 23% (range 19–31%), which was lower in male compared to female athletes (22% [Q1-Q3: 21–23%] vs 25% [23–26%]; p<0.001). In both sexes, summed 12-lead voltages were inversely correlated with ECV (ρ=–0.36 to –0.37; p=0.001), independent of LVM (voltage/LVM: ρ=–0.33; p=0.004). Only in female athletes did 12-lead voltages correlate with LVM (ρ=0.37; p=0.001). Logistic regression confirmed that lower ECV was associated with an increased likelihood of false-positive Sokolow-Lyon (OR: 0.64 per 1% ECV increment; p=0.011), independent of body mass index (OR: 0.77 per kg/m²; p=0.039) male sex (OR: 2.7; p=0.123) and age (OR: 0.93 per year; p=0.075; AUROC 0.82). Higher ECV conferred greater odds of a false-negative (OR 3.98 per %; p=0.041), though this was limited by small LVH-positive sample size. In Cornell-based models, lower ECV was not statistically significantly associated with increased false-positive rate (OR 0.59; p=0.059). Conclusion In elite athletes, lower ECV ("denser" myocardium) is associated with increased QRS voltages and higher false-positive ECG-LVH rate, particularly for Sokolow-Lyon, while higher ECV may dampen voltages and can mask true LVH on the ECG. Although sex-specific criteria partly mitigate ECV-related effects, these findings demonstrate inherent limitations of voltage-based LVH criteria in athletes. Unexpectedly low QRS voltages in athletes with otherwise high LVM may imply increased ECV, though further research is warranted.Figure:Likelihood of False Pos SL rate Table:Population characteristics

Abstract Background and Aims Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy. Methods The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter–defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated. Results A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62–0.72] and 0.59 (95% CI 0.48–0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68–0.80) and 0.60 (95% CI 0.47–0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59–1.41) for AE and 1.00 (95% CI 0.69–1.32) for nf/fAE. Conclusions These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

Abstract The pharmacological provocation test is a pivotal tool in cardiac electrophysiology for the diagnosis of potential causes of sudden cardiac death, sudden cardiac arrest (SCA), arrhythmias, symptoms, or ECG abnormalities. The 2022 European Society of Cardiology Guidelines for the Treatment of Ventricular Arrhythmias and Prevention of Sudden Cardiac Death offered guidance on provocation testing but did not describe the indications and requirements in depth. This clinical consensus statement, led by the European Heart Rhythm Association and approved by major international stakeholders, aims to advise the general cardiologist and the arrhythmia expert who to test and when, where, and how to do it. The statement focuses on current practice for the diagnosis of subclinical arrhythmia syndromes and the causes of SCA, building upon the recommendations of the Guidelines. We address the sodium channel blocker provocation test for patients suspected of Brugada syndrome as well as the use of epinephrine, isoproterenol, adenosine, ergonovine, and acetylcholine.

Importance Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. Objective To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. Design, Setting, and Participants An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Intervention Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Main Outcomes and Measures Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Results Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS ( P < .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases ( P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. Conclusions and Relevance There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.

Abstract 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.

Abstract Background and Aims Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. Methods This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%–25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. Results One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. Conclusions North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

Although there is consensus on the management of patients with Brugada Syndrome with high risk for sudden cardiac arrest, asymptomatic or intermediate-risk patients present clinical management challenges. This document explores the management opinions of experts throughout the world for patients with Brugada Syndrome who do not fit guideline recommendations. Four real-world clinical scenarios were presented with commentary from small expert groups for each case. All authors voted on case-specific questions to evaluate the level of consensus among the entire group in nuanced diagnostic and management decisions relevant to each case. Points of agreement, points of controversy, and gaps in knowledge are highlighted.

Abstract Aims In long QT syndrome (LQTS), primary prevention improves outcome; thus, early identification is key. The most common LQTS phenotype is a foetal heart rate (FHR) < 3rd percentile for gestational age (GA) but the effects of cohort, genotype, variant, and maternal β-blocker therapy on FHR are unknown. We assessed the influence of these factors on FHR in pregnancies with familial LQTS and developed a FHR/GA threshold for LQTS. Methods and results In an international cohort of pregnancies in which one parent had LQTS, LQTS genotype, familial variant, and maternal β-blocker effects on FHR were assessed. We developed a testing algorithm for LQTS using FHR and GA as continuous predictors. Data included 1966 FHRs at 7–42 weeks’ GA from 267 pregnancies/164 LQTS families [220 LQTS type 1 (LQT1), 35 LQTS type 2 (LQT2), and 12 LQTS type 3 (LQT3)]. The FHRs were significantly lower in LQT1 and LQT2 but not LQT3 or LQTS negative. The LQT1 variants with non-nonsense and severe function loss (current density or β-adrenergic response) had lower FHR. Maternal β-blockers potentiated bradycardia in LQT1 and LQT2 but did not affect FHR in LQTS negative. A FHR/GA threshold predicted LQT1 and LQT2 with 74.9% accuracy, 71% sensitivity, and 81% specificity. Conclusion Genotype, LQT1 variant, and maternal β-blocker therapy affect FHR. A predictive threshold of FHR/GA significantly improves the accuracy, sensitivity, and specificity for LQT1 and LQT2, above the infant’s a priori 50% probability. We speculate this model may be useful in screening for LQTS in perinatal subjects without a known LQTS family history.