KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern.

BACKGROUNDThe presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown.METHODSTo identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry.RESULTSWe identified a genome-wide significant (P < 5 × 10-8) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10-12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery.CONCLUSIONSIn this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies.FUNDINGThis project was funded by the German Center for Cardiovascular Research (DZHK Shared Expertise SE081 - STATS). For detailed funding information per study, see the Supplemental Acknowledgments.

Mapping and Ablation of Ventricular Fibrillation Associated With Early Repolarization Syndrome.

BACKGROUND: We conducted a multicenter study to evaluate mapping and ablation of ventricular fibrillation (VF) substrates or VF triggers in early repolarization syndromes (ERS) or J-wave syndrome (JWS). METHODS: We studied 52 patients with ERS (4 women; median age, 35 years) with recurrent VF episodes. Body surface electrocardiographic imaging and endocardial and epicardial electroanatomical mapping of both ventricles were performed during sinus rhythm and VF for localization of triggers, substrates, and drivers. Ablations were performed on VF substrates, defined as areas that had late depolarization abnormalities characterized by low-voltage fractionated late potentials, and VF triggers. RESULTS: Fifty-one of the 52 patients had detailed mapping that revealed 2 phenotypes: group 1 had late depolarization abnormalities predominantly at the right ventricular (RV) epicardium (n=40), and group 2 had no depolarization abnormalities (n=11). Group 1 can be subcategorized into 2 groups: Group 1A included 33 patients with ERS with Brugada electrocardiographic pattern, and group 1B included 7 patients with ERS without Brugada electrocardiographic pattern. Late depolarization areas colocalize with VF driver areas. The anterior RV outflow tract/RV epicardium and the RV inferior epicardium are the major substrate sites for group 1. The Purkinje network is the leading underlying VF trigger in group 2 that had no substrates. Ablations were performed in 43 patients: 31 and 5 group 1 patients had only VF substrate ablation and VF substrates plus VF trigger, respectively (mean, 1.4±0.6 sessions); 6 group 2 patients and 1 patient without group classification had only Purkinje VF trigger ablation (mean, 1.2±0.4 sessions). Ablations were successful in reducing VF recurrences (P<0.0001). After follow-up of 31±26 months, 39 (91%) had no VF recurrences. CONCLUSIONS: There are 2 phenotypes of ERS/J-wave syndrome: one with late depolarization abnormality as the underlying mechanism of high-amplitude J-wave elevation that predominantly resides in the RV outflow tract and RV inferolateral epicardium, serving as an excellent target for ablation, and the other with pure ERS devoid of VF substrates but with VF triggers that are associated with Purkinje sites. Ablation is effective in treating symptomatic patients with ERS/J-wave syndrome with frequent VF episodes.

Characterization and Management of Arrhythmic Events in Young Patients With Brugada Syndrome.

BACKGROUND: Information on young patients with Brugada syndrome (BrS) and arrhythmic events (AEs) is limited. OBJECTIVES: The purpose of this study was to describe their characteristics and management as well as risk factors for AE recurrence. METHODS: A total of 57 patients (age ≤20 years), all with BrS and AEs, were divided into pediatric (age ≤12 years; n = 26) and adolescents (age 13 to 20 years; n = 31). RESULTS: Patients' median age at time of first AE was 14 years, with a majority of males (74%), Caucasians (70%), and probands (79%) who presented as aborted cardiac arrest (84%). A significant proportion of patients (28%) exhibited fever-related AE. Family history of sudden cardiac death (SCD), prior syncope, spontaneous type 1 Brugada electrocardiogram (ECG), inducible ventricular fibrillation at electrophysiological study, and SCN5A mutations were present in 26%, 49%, 65%, 28%, and 58% of patients, respectively. The pediatric group differed from the adolescents, with a greater proportion of females, Caucasians, fever-related AEs, and spontaneous type-1 ECG. During follow-up, 68% of pediatric and 64% of adolescents had recurrent AE, with median time of 9.9 and 27.0 months, respectively. Approximately one-third of recurrent AEs occurred on quinidine therapy, and among the pediatric group, 60% of recurrent AEs were fever-related. Risk factors for recurrent AE included sinus node dysfunction, atrial arrhythmias, intraventricular conduction delay, or large S-wave on ECG lead I in the pediatric group and the presence of SCN5A mutation among adolescents. CONCLUSIONS: Young BrS patients with AE represent a very arrhythmogenic group. Current management after first arrhythmia episode is associated with high recurrence rate. Alternative therapies, besides defibrillator implantation, should be considered.

Proof of concept study of a novel pacemapping algorithm as a basis to guide ablation of ventricular arrhythmias.

Aims: To determine if a software algorithm can use an individualized distance-morphology difference model, built from three initial pacemaps, to prospectively locate the exit site (ES) of ventricular arrhythmias (VA). Methods and results: Consecutive patients undergoing ablation of VA from a single centre were recruited. During mapping, three initial pacing points were collected in the chamber of interest and the navigation algorithm applied to predict the ES, which was corroborated by conventional mapping techniques. Thirty-two patients underwent ES prediction over 35 procedures. Structural heart disease was present in 16 (7 ischaemic cardiomyopathy, 9 non-ischaemic cardiomyopathy), median ejection fraction 45% [Interquartile range (IQR) 26]. The remainder had normal hearts. The navigation algorithm was applied to 46 VA (24 left ventricle, 11 right ventricular outflow tract, 5 left ventricular outflow tract, 4 right ventricle, 2 epicardial) and successfully located the site of best pacemap match in 45 within a median area of 196.5 mm2 (IQR 161.3, range 46.6-1288.2 mm2). Conclusions: In a diverse population of patients with and without structural heart disease, the ES of VA can be accurately and reliably identified to within a clinically useful target area using a simple software navigation algorithm based on pacemapping.

Brugada syndrome: an update.

More than 20 years have passed since the description of Brugada syndrome as a clinical entity. The original case series depicted patients who all had coved ST-segment elevation in the right precordial leads, associated with a high risk of sudden death and no apparent structural heart disease. As subsequent registry data were published, it became apparent that the spectrum of risk is wide, with the majority of patients classified as low risk. Two consensus documents have been published that will continue to be updated. Despite intense research efforts, many controversies still exist over its pathophysiology and the risk stratification for sudden death. Management continues to be challenging with a lack of drug therapy and high complication rates from implantable cardioverter defibrillators. In this review, we highlight the current state-of-the-art therapies and their controversies.

Role of invasive EP testing in the evaluation and management of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an inheritable condition that may cause sudden death in the absence of significant symptoms or adverse morphological features. Therefore, there is a need for identification of those patients at sufficiently high risk to warrant prophylactic treatment. Risk stratification for primary prevention of sudden death has relied upon non-invasively derived markers of risk: syncope; a family history of premature sudden death; nonsustained ventricular tachycardia on Holter; abnormal blood pressure response to exercise; and severe left ventricular hypertrophy. The presence of two or more risk factors is associated with a 6-year sudden death survival rate of 72% (56-88%), justifying the consideration of prophylactic therapy. The 6-year sudden death survival rate in patients with one or no risk factors is 94% (91-98%). In these individuals the context and severity of the risk factor may guide the decision for prophylaxis; for example, a highly malignant family history carries greater justification than a large pedigree with only one sudden death. There is a need, however, for determining risk more accurately in those individuals with only one conventional risk factor. Programmed stimulation has been studied for its predictive value in primary prevention. 'Aggressive' protocols have been used and the most commonly induced arrhythmia is polymorphic ventricular tachycardia. These findings, however, are non-specific and of limited prognostic value. In addition the patients studied have been from selected high-risk populations without a low-risk cohort for comparison. Thus invasive EP studies appear to carry little advantage over non-invasive risk stratification. This is not surprising given that the mechanisms of cardiac arrest in HCM can be varied and may be modified by abnormal vascular responses and ischaemia. The relevance of invasively induced arrhythmias may therefore be limited. Other uses for electrophysiological study include the investigation and treatment of individuals with conduction disease and/or Wolff-Parkinson-White syndrome, atrial flutter and fibrillation and monomorphic ventricular tachycardia. Appropriate management may then involve radiofrequency ablation. A permanent pacemaker will be required if the atrio-ventricular node is ablated.