AimsSudden cardiac death (SCD) is challenging to predict. Electrocardiogram (ECG)-derived heart rate-corrected QT-interval (QTc) is used for SCD-risk assessment. QTc is preferably determined... Show moreAimsSudden cardiac death (SCD) is challenging to predict. Electrocardiogram (ECG)-derived heart rate-corrected QT-interval (QTc) is used for SCD-risk assessment. QTc is preferably determined manually, but vendor-provided automatic results from ECG recorders are convenient. Agreement between manual and automatic assessments is unclear for populations with aberrant QTc. We aimed to systematically assess pairwise agreement of automatic and manual QT-intervals and QTc.Methods and resultsA multi-centre cohort enriching aberrant QTc comprised ECGs of healthy controls and long-QT syndrome (LQTS) patients. Manual QT-intervals and QTc were determined by the tangent and threshold methods and compared to automatically generated, vendor-provided values. We assessed agreement globally by intra-class correlation coefficients and pairwise by Bland–Altman analyses and 95% limits of agreement (LoA). Further, manual results were compared to a novel automatic QT-interval algorithm. ECGs of 1263 participants (720 LQTS patients; 543 controls) were available [median age 34 (inter-quartile range 35) years, 55% women]. Comparing cohort means, automatic and manual QT-intervals and QTc were similar. However, pairwise Bland–Altman-based agreement was highly discrepant. For QT-interval, LoAs spanned 95 (tangent) and 92 ms (threshold), respectively. For QTc, the spread was 108 and 105 ms, respectively. LQTS patients exhibited more pronounced differences. For automatic QTc results from 440–540 ms (tangent) and 430–530 ms (threshold), misassessment risk was highest. Novel automatic QT-interval algorithms may narrow this range.ConclusionPairwise vendor-provided automatic and manual QT-interval and QTc results can be highly discrepant. Novel automatic algorithms may improve agreement. Within the above ranges, automatic QT-interval and QTc results require manual confirmation, particularly if T-wave morphology is challenging. Show less
Aims SCN5A mutations are associated with various cardiac phenotypes, including long QT syndrome type 3 (LQT3), Brugada syndrome (BrS), and cardiac conduction disease (CCD). Certain mutations, such... Show moreAims SCN5A mutations are associated with various cardiac phenotypes, including long QT syndrome type 3 (LQT3), Brugada syndrome (BrS), and cardiac conduction disease (CCD). Certain mutations, such as SCN5A-1795insD, lead to an overlap syndrome, with patients exhibiting both features of BrS/CCD [decreased sodium current (I-Na)] and LQT3 (increased late I-Na). The sodium channel blocker mexiletine may acutely decrease LQT3-associated late I-Na and chronically increase peak I-Na associated with SCN5A loss-of-function mutations. However, most studies have so far employed heterologous expression systems and high mexiletine concentrations. We here investigated the effects of a therapeutic dose of mexiletine on the mixed phenotype associated with the SCN5A-1795insD mutation in HEK293A cells and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods and results To assess only the chronic effects on trafficking, HEK293A cells transfected with wild-type (WT) SCN5A or SCN5A-1795insD were incubated for 48 h with 10 & mu;m mexiletine followed by wash-out, which resulted in an increased peak I-Na for both SCN5A-WT and SCN5A-1795insD and an increased late I-Na for SCN5A-1795insD. Acute re-exposure of HEK293A cells to 10 & mu;m mexiletine did not impact on peak I-Na but significantly decreased SCN5A-1795insD late I-Na. Chronic incubation of SCN5A-1795insD hiPSC-CMs with mexiletine followed by wash-out increased peak I-Na, action potential (AP) upstroke velocity, and AP duration. Acute re-exposure did not impact on peak I-Na or AP upstroke velocity, but significantly decreased AP duration. Conclusion These findings demonstrate for the first time the therapeutic benefit of mexiletine in a human cardiomyocyte model of SCN5A overlap syndrome. Show less
Sudden cardiac death and ventricular arrhythmias are a global health issue. Recently, a new guideline for the management of ventricular arrhythmias and prevention of sudden cardiac death has been... Show moreSudden cardiac death and ventricular arrhythmias are a global health issue. Recently, a new guideline for the management of ventricular arrhythmias and prevention of sudden cardiac death has been published by the European Society of Cardiology that serves as an update to the 2015 guideline on this topic. This review focuses on 10 novel key aspects of the current guideline: As new aspects, public basic life support and access to defibrillators are guideline topics. Recommendations for the diagnostic evaluation of patients with ventricular arrhythmias are structured according to frequently encountered clinical scenarios. Management of electrical storm has become a new focus. In addition, genetic testing and cardiac magnetic resonance imaging significantly gained relevance for both diagnostic evaluation and risk stratification. New algorithms for antiarrhythmic drug therapy aim at improving safe drug use. The new recommendations reflect increasing relevance of catheter ablation of ventricular arrhythmias, especially in patients without structural heart disease or stable coronary artery disease with only mildly impaired ejection fraction and haemodynamically tolerated ventricular tachycardias. Regarding sudden cardiac death risk stratification, risk calculators for laminopathies, and long QT syndrome are now considered besides the already established risk calculator for hypertrophic cardiomyopathy. Generally, ‘new’ risk markers beyond left ventricular ejection fraction are increasingly considered for recommendations on primary preventive implantable cardioverter defibrillator therapy. Furthermore, new recommendations for diagnosis of Brugada syndrome and management of primary electrical disease have been included. With many comprehensive flowcharts and practical algorithms, the new guideline takes a step towards a user-oriented reference book. Show less
Konemann, H.; Frommeyer, G.; Zeppenfeld, K.; Eckardt, L. 2022
The recently published guidelines of the European Society of Cardiology (ESC) on the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death is an update of... Show moreThe recently published guidelines of the European Society of Cardiology (ESC) on the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death is an update of the 2015 guideline. For the first time a new section is dedicated to public basic life support. In the acute treatment of ventricular arrhythmias electrical cardioversion is upgraded, and there is a new focus on the management of electrical storm. Recommendations for the comprehensive diagnostic evaluation of patients with first manifestations of ventricular arrhythmias structured according to common clinical scenarios are also new. Both genetic testing and cardiac magnetic resonance imaging are upgraded, not only for diagnostic evaluation but also for risk stratification. In the long-term management, recommendations for pharmacotherapy are aligned with current heart failure guidelines. Catheter ablation has gained relevance not only for recurrent ventricular tachycardia under amiodarone treatment and as an alternative to implantable cardioverter defibrillation (ICD) implantation in selected patients with coronary artery disease but also particularly in the treatment of idiopathic ventricular extrasystoles and tachycardia. The ICD treatment remains an essential component of primary and secondary prevention of sudden cardiac death. Of note, the recommendation on primary preventive ICD treatment for patients with dilated cardiomyopathy and left ventricular ejection fraction (LVEF) <= 35% has been downgraded. In addition to LVEF a combination of risk factors and risk calculators is included in the recommendations on primary prophylactic ICD implantation. Overall, due to numerous tables and practical algorithms, the guidelines have become a user-oriented reference book. Show less
Aims To develop a suite of quality indicators (QIs) for the management of patients with ventricular arrhythmias (VA) and the prevention of sudden cardiac death (SCD). Methods and results The... Show moreAims To develop a suite of quality indicators (QIs) for the management of patients with ventricular arrhythmias (VA) and the prevention of sudden cardiac death (SCD). Methods and results The Working Group comprised experts in heart rhythm management including Task Force members of the 2022 European Society of Cardiology (ESC) Clinical Practice Guidelines for the management of patients with VA and the prevention of SCD, members of the European Heart Rhythm Association, international experts, and a patient representative. We followed the ESC methodology for QI development, which involves (i) the identification of the key domains of care for the management of patients with VA and the prevention of SCD by constructing a conceptual framework of care, (ii) the development of candidate QIs by conducting a systematic review of the literature, (iii) the selection of the final set of QIs using a modified-Delphi method, and (iv) the evaluation of the feasibility of the developed QIs. We identified eight domains of care for the management of patients with VA and the prevention of SCD: (i) structural framework, (ii) screening and diagnosis, (iii) risk stratification, (iv) patient education and lifestyle modification, (v) pharmacological treatment, (vi) device therapy, (vii) catheter ablation, and (viii) outcomes, which included 17 main and 4 secondary QIs across these domains. Conclusion Following a standardized methodology, we developed 21 QIs for the management of patients with VA and the prevention of SCD. The implementation of these QIs will improve the care and outcomes of patients with VA and contribute to the prevention of SCD. Show less
Zeppenfeld, K.; Tfelt-Hansen, J.; Riva, M. de; Winkel, B.G.; Behr, E.R.; Blom, N.A.; ... ; ESC Scientific Document Group 2022
Aims This study was performed to develop and externally validate prediction models for appropriate implantable cardioverter-defibrillator (ICD) shock and mortality to identify subgroups with... Show moreAims This study was performed to develop and externally validate prediction models for appropriate implantable cardioverter-defibrillator (ICD) shock and mortality to identify subgroups with insufficient benefit from ICD implantation.Methods and results We recruited patients scheduled for primary prevention ICD implantation and reduced left ventricular function. Bootstrapping-based Cox proportional hazards and Fine and Gray competing risk models with likely candidate predictors were developed for all-cause mortality and appropriate ICD shock, respectively. Between 2014 and 2018, we included 1441 consecutive patients in the development and 1450 patients in the validation cohort. During a median follow-up of 2.4 (IQR 2.1-2.8) years, 109 (7.6%) patients received appropriate ICD shock and 193 (13.4%) died in the development cohort. During a median follow-up of 2.7 (IQR 2.0-3.4) years, 105 (7.2%) received appropriate ICD shock and 223 (15.4%) died in the validation cohort. Selected predictors of appropriate ICD shock were gender, NSVT, ACE/ARB use, atrial fibrillation history, Aldosterone-antagonist use, Digoxin use, eGFR, (N)OAC use, and peripheral vascular disease. Selected predictors of all-cause mortality were age, diuretic use, sodium, NT-pro-BNP, and ACE/ARB use. C-statistic was 0.61 and 0.60 at respectively internal and external validation for appropriate ICD shock and 0.74 at both internal and external validation for mortality.Conclusion Although this cohort study was specifically designed to develop prediction models, risk stratification still remains challenging and no large group with insufficient benefit of ICD implantation was found. However, the prediction models have some clinical utility as we present several scenarios where ICD implantation might be postponed. Show less
Nevvazhay, T.; Zeppenfeld, K.; Brouwer, C.; Hazekamp, M. 2020
Ventricular tachyarrhythmia (VT) is a major cause of late morbidity and mortality in patients who underwent surgical repair of tetralogy of Fallot. The majority of VTs are monomorphic macro... Show moreVentricular tachyarrhythmia (VT) is a major cause of late morbidity and mortality in patients who underwent surgical repair of tetralogy of Fallot. The majority of VTs are monomorphic macro-reentrant VT (MVT) and depend on slow conducting areas of diseased myocardium bordered by unexcitable tissue (anatomical isthmuses). Myocardial fibrosis due to surgical incisions, patch material and valve annuli are typical boundaries of anatomical isthmuses (AI). The conducting myocardium between the pulmonary valve and ventricular septum defect patch is called isthmus 3, and the majority of MVTs originate from this area. During pulmonary valve replacement, there is excellent exposure of isthmus 3. Importantly, after pulmonary valve replacement, the homograft may cover important parts of isthmus 3, which makes percutaneous catheter ablation at a later stage impossible. In all patients who need pulmonary valve replacement late after tetralogy of Fallot repair, preoperative electrophysiology study and electroanatomical mapping can identify patients with inducible MVT or slow conduction carrying high risk of MVT. In these patients, intraoperative cryoablation of isthmus 3 should be performed and bidirectional conduction block across the cryoablation line should be demonstrated by intraoperative differential pacing. Show less
Werf, C. van der; Lieve, K.V.; Bos, J.M.; Lane, C.M.; Denjoy, I.; Roses-Noguer, F.; ... ; Wilde, A.A. 2019
Pulmonary artery dissection is a rare entity, usually discovered post-mortem. In recent years, reported cases of living patients with a pulmonary artery dissection are growing and represent a... Show morePulmonary artery dissection is a rare entity, usually discovered post-mortem. In recent years, reported cases of living patients with a pulmonary artery dissection are growing and represent a challenging situation for clinicians. Show less
Aims Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for... Show moreAims Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients.Methods and results Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 +/- 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P < 0.001).Conclusion Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com). Show less
Sudden cardiac death (SCD) accounts for one fifth of global deaths, and occurs when a trigger (e.g. myocardial ischemia, premature ventricular contraction) interacts with an arrhythmic substrate (e... Show moreSudden cardiac death (SCD) accounts for one fifth of global deaths, and occurs when a trigger (e.g. myocardial ischemia, premature ventricular contraction) interacts with an arrhythmic substrate (e.g. myocardial scar, dilated cardiomyopathy). Multimodality imaging (echocardiographic, cardiac magnetic resonance and nuclear techniques) can potentially visualize many predisposing substrates and triggers. Implantable cardioverter-defibrillator (ICD) is the most effective approach to primary prevention of SCD, and current guidelines regarding ICD implantation are based on a left ventricular ejection fraction (LVEF) <= 35%. This practice is limited by a low sensitivity and specificity, and has limited value when applied to different etiologies. In this review, the role of multimodality imaging in SCD risk-stratification and the limitations of an LVEF-based approach, are discussed. Additional randomized, prospective data are eagerly awaited to inform on the role of imaging in SCD risk stratification, and ongoing/planned trials are subsequently discussed. (C) 2019 The Authors. Published by Elsevier Inc. Show less
Ebert, M.; Richter, S.; Dinov, B.; Zeppenfeld, K.; Hindricks, G. 2019
