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Aims: During the diagnostic work-up of patients with idiopathic ventricular fibrillation (VF), next-generation sequencing panels can be considered to identify genotypes associated with arrhythmias. However, consensus for gene panel testing is still lacking, and variants of uncertain significance (VUS) are often identified. The aim of this study was to evaluate genetic testing and its results in idiopathic VF patients., Methods and Results: We investigated 419 patients with available medical records from the Dutch Idiopathic VF Registry. Genetic testing was performed in 379 (91%) patients [median age at event 39 years (27-51), 60% male]. Single-gene testing was performed in 87 patients (23%) and was initiated more often in patients with idiopathic VF before 2010. Panel testing was performed in 292 patients (77%). The majority of causal (likely) pathogenic variants (LP/P, n = 56, 15%) entailed the DPP6 risk haplotype (n = 39, 70%). Moreover, 10 LP/P variants were found in cardiomyopathy genes (FLNC, MYL2, MYH7, PLN (two), TTN (four), RBM20), and 7 LP/P variants were identified in genes associated with cardiac arrhythmias (KCNQ1, SCN5A (2), RYR2 (four)). For eight patients (2%), identification of an LP/P variant resulted in a change of diagnosis. In 113 patients (30%), a VUS was identified. Broad panel testing resulted in a higher incidence of VUS in comparison to single-gene testing (38% vs. 3%, P < 0.001)., Conclusion: Almost all patients from the registry underwent, albeit not broad, genetic testing. The genetic yield of causal LP/P variants in idiopathic VF patients is 5%, increasing to 15% when including DPP6. In specific cases, the LP/P variant is the underlying diagnosis. A gene panel specifically for idiopathic VF patients is proposed., Competing Interests: Conflict of interest: P.G.P. is an associate editor of Europace and was not involved in the peer review process or publication decision. S.-C.Y. is a consultant for Boston Scientific and has received lecture fees and research grants from Medtronic, Biotronik, and Boston Scientific. All remaining authors have declared no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To perform a comparative analysis of right ventricle (RV) myocardial mechanics, assessed by 2D speckle-tracking echocardiography (2D-STE), between patients with Fabry disease and patients with sarcomeric disease., Methods and Results: Patients with Fabry cardiomyopathy (FC) (n = 28) were compared with patients with sarcomeric hypertrophic cardiomyopathy (HCM), matched for degree of left ventricle hypertrophy (LVH) and demographic characteristics (n = 112). In addition, patients with Fabry disease and no LVH [phenotype-negative carriers of pathogenic α-galactosidase gene mutations (GLA LVH-)] (n = 28) were compared with age and sex-matched carriers of sarcomeric gene mutations without LVH [Phenotype-negative carriers of pathogenic sarcomeric gene mutations (Sarc LVH-)] (n = 56). Standard echocardiography and 2D-STE were performed in all participants. Despite a subtle impairment of RV global longitudinal strain (RV-GLS) was common in both groups, patients with FC showed a more prominent reduction of RV free wall longitudinal strain (RV-FWS) and lower values of difference between RV-FWS and RV-GLS (ΔRV strain), in comparison to individuals with HCM (P < 0.001 and P = 0.002, respectively). RV-FWS and ΔRV strain demonstrated an independent and additive value in discriminating FC from HCM, over the presence of symmetric LVH, systolic anterior motion of the mitral valve and RV hypertrophy. Similar results were found in GLA LVH- patients: they had worse RV-FWS and lower values of ΔRV strain as compared to Sarc LVH- patients (both P < 0.001)., Conclusion: Patients with FC show a specific pattern of RV myocardial mechanics, characterized by a larger impairment of RV-FWS and lower ΔRV strain in comparison to patients with HCM, which may be helpful in the differential diagnosis between these two diseases., Competing Interests: Conflict of interest: The Department of Cardiology, Heart Lung Center, Leiden University Medical Center, received research grants from Abbott Vascular, Bayer, Bioventrix, Medtronic, Biotronik, Boston Scientific, GE Healthcare and Edwards Lifesciences. J.B. received speaker fees from Abbott Vascular and Edwards Lifesciences. N.A.M. received speaker fees from Abbott Vascular and GE Healthcare and has been in the Medical Advisory Board of Philips Ultrasound. F.G. and R.L. received board meetings and speaker honoraria from Sanofi-Genzyme and Takeda. The remaining authors have nothing to disclose., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: We describe five patients with syncope caused by a complete atrioventricular block (AVB) while they were bending forward, not rising after bending, and aim to describe the occurrence and the association between bending forward and AVB., Methods and Results: In two patients, bending forward was the exclusive trigger for syncope, while in the remaining three, other postural changes (sitting down, standing up, and exertion) could also provoke syncope. Complete AVB as the cause of syncope was documented using ECG monitoring in two cases and an implantable loop recorder in the other three. Ectopic beats without preceding sinus slowing occurred before syncope in four cases. Two cases had a left bundle branch block. All patients responded favourably to cardiac pacing., Conclusion: This is the first case series on complete AVB provoked by bending forward. Syncope during bending forward should suggest a search for an AVB. Arguments in favour of a vagal mechanism were syncope triggered by bending forward, and that other triggers could also evoke syncope. However, the absence of sinus slowing before syncope in some cases and the fact that bending forward did not seem to provoke reflex syncope without AVB, cast doubts on a reflex mechanism. There were also arguments favouring conduction disorder: i.e. ectopic beats before syncope and pre-existing conduction disturbances in two cases. The cases are reminiscent of paroxysmal AVB. Discrimination between paroxysmal AVB and vagal AVB is important because a pacemaker is warranted in arrhythmic complete AVB, while the benefit is limited or absent in reflex AVB., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: Atrial fibrillation (AF) is frequently observed in hypertrophic cardiomyopathy (HCM) and is associated with poor clinical outcome. Total atrial conduction time, estimated by tissue Doppler imaging (TDI), the so-called PA-TDI duration, reflects the left atrial (LA) structural and electrical remodelling. The aim of this study was to evaluate the association between PA-TDI and new-onset AF in patients with HCM., Methods and Results: From a large cohort of patients with HCM, 208 patients (64% male, mean age 53 ± 14 years) without AF were selected. PA-TDI duration was measured from the onset P wave on electrocardiogram to the peak A' wave of the lateral LA wall using TDI. The incidence of new-onset AF was 20% over a median follow-up of 7.3 (3.5-10.5) years. Patients with incident AF had longer PA-TDI duration when compared with patients without AF (133.7 ± 23.0 vs. 110.5 ± 30.0 ms, P < 0.001). PA-TDI duration was independently associated with new-onset AF (hazard ratio: 1.03, 95% confidence interval: 1.01-1.05, P < 0.001)., Conclusion: Prolonged PA-TDI duration was independently associated with new-onset AF in patients with HCM. This novel parameter could be useful to risk-stratify patients with HCM who are at risk of having AF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: Idiopathic ventricular fibrillation (IVF) is a rare cause of sudden cardiac arrest. Implantable cardioverter-defibrillator (ICD) implantation is currently the only treatment option. Limited data are available on the prevalence and complications of ICD therapy in these patients. We sought to investigate ICD therapy and its complications in patients with IVF., Methods and Results: Patients were selected from a national registry of IVF patients. Patients in whom no underlying diagnosis was found during follow-up were eligible for inclusion. Recurrence of ventricular arrhythmia (VA) was derived from medical and ICD records, electrogram records of ICD therapies were used to differentiate between appropriate or inappropriate interventions. Independent predictors for appropriate ICD shock were calculated using cox regression. In 217 IVF patients, recurrence of sustained VAs occurred in 66 patients (30%) during a median follow-up period of 6.1 years. Ten patients died (4.6%). Thirty-eight patients (17.5%) experienced inappropriate ICD therapy, and 32 patients (14.7%) had device-related complications. Symptoms before cardiac arrest [hazard ratio (HR): 2.51, 95% confidence interval (CI): 1.48-4.24], signs of conduction disease (HR: 2.27, 95% CI: 1.15-4.47), and carrier of the DPP6 risk haplotype (HR: 3.24, 1.70-6.17) were identified as independent predictors of appropriate shock occurrence., Conclusion: Implantable cardioverter-defibrillator therapy is an effective treatment in IVF, treating recurrences of potentially lethal VAs in approximately one-third of patients during long-term follow-up. However, device-related complications and inappropriate shocks were also frequent. We found significant predictors for appropriate ICD therapy. This may imply that these patients require additional management to prevent recurrent events., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Aims: Genetic, dilated cardiomyopathy (DCM) can be caused by a large variety of mutations. Mutation carriers are often asymptomatic until DCM is well established, presenting with heart failure, arrhythmias, or sudden cardiac death. Preventive strategies can only be applied if DCM can be detected early. Echocardiographic, left ventricular (LV) global longitudinal strain (GLS) is a promising tool for early diagnosis, i.e. before a decrease in LV ejection fraction (EF) has occurred. We, therefore, investigated the role of LV GLS as an early disease marker in genetic DCM., Methods and Results: Genetic DCM patients and genotyped family members were evaluated. The study population was grouped as (i) genotype-positive, phenotype-positive (GPFP) patients with a pathogenic mutation and LVEF <55% (ii) genotype-positive, phenotype-negative (GPFN) individuals with a pathogenic mutation and LVEF ≥55%, and (iii) genotype-negative, phenotype-negative (GNFN) individuals without a pathogenic mutation and LVEF ≥55%. One hundred and fifteen individuals (53 ± 15 years, 51% male) were analysed: 28 (24%) were classified as GNFN, 50 (44%) as GPFN, and 37 (32%) as GPFP. Various mutations were represented: 39 (34%) titin, 14 (12%) lamin A/C, 13 (11%) sarcomeric, and 21 (18%) less frequent mutations (grouped together). The mean LVEF was 58 ± 14% for all subjects. The mean LV GLS in the GNFN group was -21.7 ± 1.5% vs. -19.7 ± 3.5% for the GPFN group (P = 0.036). The mean LV GLS was -12.9 ± 4.3% for the GPFP category (P < 0.001 vs. GPFN and GNFN)., Conclusion: Decreased LV GLS discriminates GPFN individuals from normal controls, which may permit early institution of therapy for genetic DCM., (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: The number of implanted cardiac rhythm devices has rapidly increased in the past decade. Subsequently, the need for lead extraction has also increased. Several techniques of lead removal have been documented from manual traction of the lead to lead extraction assisted with mechanical or laser sheaths. The goal of this study was to review our experience with lead removal using manual traction without the assistance of extraction sheaths., Methods and Results: In the Leiden University Medical Center all leads are removed using manual traction without the assistance of extraction sheaths. We have retrospectively reviewed all lead removal procedures performed between 2000 and 2009. Procedures were reviewed for indication, success, complication rates, and mortality. In total, 279 lead removal procedures were included. During these procedures 445 leads were removed. Time since lead implantation: 4.2 ± 4.7 years. During extraction 53(11.9%) leads fractured, of which >50% could still be completely removed using a femoral approach. A longer implantation duration [odds ratio (OR) 1.16 per year, 95% confidence interval (CI) 1.09-1.23] and passive fixation (OR 2.52, 95%CI 1.17-5.45) significantly associated with the chance of lead fracture during lead removal. Clinical success, using the primary approach of manual traction from the pectoral area, was obtained in 228 (84.8%) procedures. Major complications occurred in 2(0.7%) and minor in 13(4.7%) procedures. One patient died within 24 h after the procedure due to septic shock. There was no further mortality within the first month after the procedure., Conclusion: Lead removal using manual traction, without the assistance of lead extraction sheaths, is clinically successful in ~85% of the lead extraction procedures. Concomitant morbidity and mortality are low. The highest clinical success (~95%) was observed in patients with leads implanted less than 2.6 years.

Aims: Myocardial excitability is known (amongst other reasons) to be related to the degree of ischaemia, contractile dysfunction and heart failure. It was hypothesized that the right ventricular (RV) stimulation threshold has prognostic value with respect to the occurrence of ventricular arrhythmias (VAs) and patient survival in recipients of an implantable cardioverter defibrillator (ICD)., Methods and Results: Ischaemic heart disease patients receiving an ICD at Leiden University Medical Center as primary prevention for sudden cardiac death were included in this study. Right ventricular thresholds were determined at ICD implant. Data were collected on VAs triggering ICD therapy and on all-cause mortality. A total of 689 consecutive patients were included (87% male, age 63 ± 11 years, left ventricular ejection fraction (LVEF) 29 ± 11%) and followed for a median of 28 months. Post-implant RV-threshold was 0.7 ± 0.5 volt (V) at 0.5 ms pulse duration. Best dichotomous separation was reached at a cut-off of 1 V. During follow-up, 167 (24%) patients received appropriate ICD therapy, 88 (13%) had appropriate shocks and 134 (19%) died. Cumulative appropriate shock incidence for patients with RV threshold ≥ 1 V (n = 166) was 16% at 1 year, 24% at 3 years and 34% at 5 years compared with 4, 11 and 17% for patients with an RV-threshold < 1 V (n = 523). Adjusted hazard ratio of RV threshold ≥ 1 V was 2.0 (95% CI: 1.4-2.9) for appropriate therapy, 3.3 (95% CI: 2.0-5.4) for appropriate shocks and 1.6 (95% CI: 1.1-2.5) for mortality., Conclusion: The RV stimulation threshold at ICD implant has a strong independent prognostic value for the occurrence of VAs triggering appropriate ICD therapy, appropriate shocks and mortality.

Aims: To assess the number of patients in daily clinical practice that meets criteria for implantation of an implantable cardioverter defibrillator (ICD) following acute myocardial infarction (AMI) when treated according to an aggressive treatment protocol., Methods and Results: Patients were treated according to the MISSION! protocol. The protocol encompasses pre-hospital, in-hospital, and outpatient clinical framework for the acute and chronic treatment of AMI patients and the decision making regarding primary prevention of sudden cardiac death (SCD). A total of 676 consecutive AMI patients (78% male, mean age 59 +/- 12 years) treated according to the MISSION! protocol were included in this analysis. Left ventricular ejection fraction at 3 months was 54 +/- 10%. Only 39 (6%) patients met criteria for implantation of an ICD <1 year post-MI. These patients suffered more extensive infarctions as indicated by higher peak troponin T values (mean 14.5 +/- 8.3 vs. 6.5 +/- 14.7 microg/L; P < 0.001) and had more left anterior descending artery related infarctions (79 vs. 46%; P < 0.001). Cumulative first appropriate therapy rate was 15% at 3 years follow-up. No SCD was observed in the study population., Conclusion: Aggressive treatment of AMI patients and close monitoring after the index event according to a standardized protocol, results in only a small number of patients becoming candidate for prophylactic ICD implantation. An easy-to-use protocol combining aggressive reperfusion, optimal medication, and a risk stratification algorithm tailored to fit within routine practice may help to maintain ICD implantation rates within manageable proportions.

Aims: To assess the long-term rate of mortality and the recurrence of potentially life-threatening ventricular arrhythmias in secondary prevention implantable cardioverter defibrillator (ICD) patients and to construct a model for baseline risk stratification., Methods and Results: Since 1996, all patients with ischaemic heart disease, receiving ICD therapy for secondary prevention of sudden death, were included in the current study. Patients were evaluated at implantation and during long-term follow-up. A total of 456 patients were included in the analysis and followed for 54 +/- 35 months. During follow-up, 100 (22%) patients died and ICD therapy was noted in 216 (47%) patients, of which 138 (30%) for fast, potentially life-threatening ventricular arrhythmia. Multivariate analysis revealed a history of atrial fibrillation or flutter (AF), ventricular tachycardia as presenting arrhythmia, and wide QRS and poor left ventricular ejection fraction as independent predictors of life-threatening ventricular arrhythmias. The strongest predictor was AF with a hazard ratio of 2.1 (95% confidence interval 1.3-3.2). On the basis of the available clinical data, it was not possible to identify a group which exhibited no risk on recurrence of potentially life-threatening ventricular arrhythmias., Conclusion: Ischaemic secondary prevention ICD recipients exhibit a high recurrence rate of potentially life-threatening ventricular arrhythmias. Factors that increase risk can be identified but, even with these factors, it was not possible to distinguish a recurrence-free group.