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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: The optimal strategy after a failed ablation for persistent atrial fibrillation (perAF) is unknown. This study evaluated the value of an anatomically guided strategy using a systematic set of linear lesions with adjunctive ethanol infusion into the vein of Marshall (Et‐VOM) in patients referred for second perAF ablation procedures. Methods and Results: Patients with perAF who underwent a second procedure were grouped according to the two strategies. The first strategy was an anatomically guided approach using systematic linear ablation with adjunctive Et‐VOM, with bidirectional blocks at the posterior mitral isthmus (MI), roof, and cavotricuspid isthmus (CTI) as the procedural endpoint (Group I). The second one was an electrophysiology‐guided strategy, with atrial tachyarrhythmia termination as the procedural endpoint (Group II). Arrhythmia behavior during the procedure guided the ablation strategy. Groups I and II consisted of 96 patients (65 ± 9 years; 71 men) and 102 patients (63 ± 10 years; 83 men), respectively. Baseline characteristics were comparable. In Group I, Et‐VOM was successfully performed in 91/96 (95%), and procedural endpoint (bidirectional block across all three anatomical lines) was achieved in 89/96 (93%). In Group II, procedural endpoint (atrial tachyarrhythmia termination) was achieved in 80/102 (78%). One‐year follow‐up demonstrated Group I (21/96 [22%]) experienced less recurrence compared to Group II (38/102 [37%], Log‐rank p =.01). This was driven by lower AT recurrence in Group I (Group I: 10/96 [10%] vs. Group II: 29/102 [28%]; p =.002). Conclusion: Anatomically guided strategy with adjunctive Et‐VOM is superior to an electrophysiology‐guided strategy for second procedures in patients with perAF at 1‐year follow‐up. [ABSTRACT FROM AUTHOR]

Aims Mapping data of human ventricular fibrillation (VF) are limited. We performed detailed mapping of the activities underlying the onset of VF and targeted ablation in patients with structural cardiac abnormalities. Methods and results We evaluated 54 patients (50 ± 16 years) with VF in the setting of ischaemic (n  = 15), hypertrophic (n  = 8) or dilated cardiomyopathy (n  = 12), or Brugada syndrome (n  = 19). Ventricular fibrillation was mapped using body-surface mapping to identify driver (reentrant and focal) areas and invasive Purkinje mapping. Purkinje drivers were defined as Purkinje activities faster than the local ventricular rate. Structural substrate was delineated by electrogram criteria and by imaging. Catheter ablation was performed in 41 patients with recurrent VF. Sixty-one episodes of spontaneous (n  = 10) or induced (n  = 51) VF were mapped. Ventricular fibrillation was organized for the initial 5.0 ± 3.4 s, exhibiting large wavefronts with similar cycle lengths (CLs) across both ventricles (197 ± 23 vs. 196 ± 22 ms, P  = 0.9). Most drivers (81%) originated from areas associated with the structural substrate. The Purkinje system was implicated as a trigger or driver in 43% of patients with cardiomyopathy. The transition to disorganized VF was associated with the acceleration of initial reentrant activities (CL shortening from 187 ± 17 to 175 ± 20 ms, P  < 0.001), then spatial dissemination of drivers. Purkinje and substrate ablation resulted in the reduction of VF recurrences from a pre-procedural median of seven episodes [interquartile range (IQR) 4–16] to 0 episode (IQR 0–2) (P  < 0.001) at 56 ± 30 months. Conclusions The onset of human VF is sustained by activities originating from Purkinje and structural substrate, before spreading throughout the ventricles to establish disorganized VF. Targeted ablation results in effective reduction of VF burden. Key question The initial phase of human ventricular fibrillation (VF) is critical as it involves the primary activities leading to sustained VF and arrhythmic sudden death. The origin of such activities is unknown. Key finding Body-surface mapping shows that most drivers (≈80%) during the initial VF phase originate from electrophysiologically defined structural substrates. Repetitive Purkinje activities can be elicited by programmed stimulation and are implicated as drivers in 37% of cardiomyopathy patients. Take-home message The onset of human VF is mostly associated with activities from the Purkinje network and structural substrate, before spreading throughout the ventricles to establish sustained VF. Targeted ablation reduces or eliminates VF recurrence. [ABSTRACT FROM AUTHOR]

Evidence on sex differences in the pathophysiology and interventional treatment of ventricular arrhythmia in ischemic (ICM) or non-ischemic cardiomyopathies (NICM) is limited. However, women have different etiologies and types of structural heart disease due to sex differences in genetics, proteomics and sex hormones. These differences may influence ventricular electrophysiological parameters and may require different treatment strategies. Considering that women were consistently under-represented in all randomized-controlled trials on VT ablation, the applicability of the study results to female patients is not known. In this article, we review the current knowledge and gaps in evidence about sex differences in the epidemiology, pathophysiology and catheter ablation in patients with ventricular arrhythmias. [ABSTRACT FROM AUTHOR]

Background: Conventional bipolar electrodes (CBE) may be suboptimal to detect local abnormal ventricular activities (LAVAs). Microelectrodes (ME) may improve the detection of LAVAs. This study sought to elucidate the detectability of LAVAs using ME compared with CBE in patients with scar‐related ventricular tachycardia (VT). Methods: We included consecutive patients with structural heart disease who underwent radiofrequency catheter ablation for scar‐related VT using either of the following catheters equipped with ME: QDOTTM or IntellaTip MIFITM. Detection field of LAVA potentials were classified as three types: Type 1 (both CBE and ME detected LAVA), Type 2 (CBE did not detect LAVA while ME did), and Type 3 (CBE detected LAVA while ME did not). Results: In 16 patients (68 ± 16 years; 14 males), 260 LAVAs electrograms (QDOT = 72; MIFI = 188) were analyzed. Type 1, type 2, and type 3 detections were 70.8% (QDOT, 69.4%; MIFI, 71.3%), 20.0% (QDOT, 23.6%; MIFI, 18.6%) and 9.2% (QDOT, 6.9%; MIFI, 10.1%), respectively. The LAVAs amplitudes detected by ME were higher than those detected by CBE in both catheters (QDOT: ME 0.79 ± 0.50 mV vs. CBE 0.41 ± 0.42 mV, p =.001; MIFI: ME 0.73 ± 0.64 mV vs. CBE 0.38 ± 0.36 mV, p <.001). Conclusions: ME allow to identify 20% of LAVAs missed by CBE. ME showed higher amplitude LAVAs than CBE. However, 9.2% of LAVAs can still be missed by ME. [ABSTRACT FROM AUTHOR]

Background: Data on the optimal location of the electrocardiogram (ECG) leads for the diagnosis of drug‐induced long QT syndrome (diLQTS) with torsades de pointes (TdP) are lacking. Methods: We systematically reviewed the literature for the ECGs of patients with diLQTS and subsequent TdP. We assessed T wave morphology in each lead and measured the longest QT interval in the limb and chest leads in a standardized fashion. Results: Of 84 patients, 61.9% were female and the mean age was 58.8 years. QTc was significantly longer in chest versus limb leads (mean (SD) 671 (102) vs. 655 (97) ms, p =.02). Using only limb leads for QT interpretation, 18 (21.4%) ECGs were noninterpretable: 10 (11.9%) due to too flat T waves, 7 (8.3%) due to frequent, early PVCs and 1 (1.2%) due to too low ECG recording quality. In the chest leads, ECGs were noninterpretable in nine (10.7%) patients: six (7.1%) due to frequent, early PVCs, one (1.2%) due to insufficient ECG quality, two (2.4%) due to missing chest leads but none due to too flat T waves. The most common T wave morphologies in the limb leads were flat (51.0%), broad (14.3%), and late peaking (12.6%) T waves. Corresponding chest lead morphologies were inverted (35.5%), flat (19.6%), and biphasic (15.2%) T waves. Conclusions: Our results indicate that QT evaluation by limb leads only underestimates the incidence of diLQTS experiencing TdP and favors the screening using both limb and chest lead ECG. [ABSTRACT FROM AUTHOR]

Background: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) is an inherited cardiomyopathy mainly caused by heterozygous desmosomal gene mutations, the major gene being PKP2. The genetic cause remains unknown in ~50% of probands with routine desmosomal gene screening. The aim of this study was to assess the diagnostic accuracy of whole exome sequencing (WES) in ARVC/D with negative genetic testing. Methods: WES was performed in 22 patients, all without a mutation identified in desmosomal genes. Putative pathogenic variants were screened in 96 candidate genes associated with other cardiomyopathies/channelopathies. The sequencing coverage depth of PKP2, DSP, DSG2, DSC2, JUP and TMEM43 exons was compared to the mean coverage distribution to detect large insertions/deletions. All suspected deletions were verified by real-time qPCR, Multiplex-Ligation-dependent-Probe-Amplification (MLPA) and cGH-Array. MLPA was performed in 50 additional gene-negative probands. Results: Coverage-depth analysis from the 22 WES data identified two large heterozygous PKP2 deletions: one from exon 1 to 14 and one restricted to exon 4, confirmed by qPCR and MLPA. MLPA identified 2 additional PKP2 deletions (exon 1–7 and exon 1–14) in 50 additional probands confirming a significant frequency of large PKP2 deletions (5.7%) in gene-negative ARVC/D. Putative pathogenic heterozygous variants in EYA4, RBM20, PSEN1, and COX15 were identified in 4 unrelated probands. Conclusion: A rather high frequency (5.7%) of large PKP2 deletions, undetectable by Sanger sequencing, was detected as the cause of ARVC/D. Coverage-depth analysis through next-generation sequencing appears accurate to detect large deletions at the same time than conventional putative mutations in desmosomal and cardiomyopathy-associated genes. [ABSTRACT FROM AUTHOR]