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

ABSTRACT: 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.

SUBMITTER: Teumer A

PROVIDER: S-EPMC6962032 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Teumer Alexander A Trenkwalder Teresa T Kessler Thorsten T Jamshidi Yalda Y van den Berg Marten E ME Kaess Bernhard B Nelson Christopher P CP Bastiaenen Rachel R De Bortoli Marzia M Rossini Alessandra A Deisenhofer Isabel I Stark Klaus K Assa Solmaz S Braund Peter S PS Cabrera Claudia C Dominiczak Anna F AF Gögele Martin M Hall Leanne M LM Ikram M Arfan MA Kavousi Maryam M Lackner Karl J KJ Müller Christian C Münzel Thomas T Nauck Matthias M Padmanabhan Sandosh S Pfeiffer Norbert N Spector Tim D TD Uitterlinden Andre G AG Verweij Niek N Völker Uwe U Warren Helen R HR Zafar Mobeen M Felix Stephan B SB Kors Jan A JA Snieder Harold H Munroe Patricia B PB Pattaro Cristian C Fuchsberger Christian C Schmidt Georg G Nolte Ilja M IM Schunkert Heribert H Pramstaller Peter P PP Wild Philipp S PS van der Harst Pim P Stricker Bruno H BH Schnabel Renate B RB Samani Nilesh J NJ Hengstenberg Christian C Dörr Marcus M Behr Elijah R ER Reinhard Wibke W

JCI insight 20191205 23

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 pot ...[more]

PMID: 31600170

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Project description:Background Early repolarization pattern (ERP) is considered a common training-related and benign ECG finding in young adult athletes. Few data exist on ERP in the pediatric athletes population. Therefore, we aimed to evaluate the ERP prevalence, characteristics, and prognosis in pediatric athletes aged ≤16 years. Methods and Results Eight-hundred eighty-six consecutive pediatric athletes engaged in 17 different sports (mean age, 11.7±2.5 years; 7-16 years) were enrolled and prospectively evaluated with medical history, physical examination, resting and exercise ECGs, and transthoracic echocardiography during their preparticipation screening. Known cardiovascular diseases associated with sudden cardiac death was considered exclusion criteria. Athletes were followed up yearly for 4 years. The prevalence of ERP was 117 (13.2%), equally distributed in both sexes (P=0.072), irrespectively of body mass index and classification of sports. The most common ERP localizations were inferolateral and inferior leads (53.8% and 27.3%, respectively). Notching J-point morphology was the most prevalent (70%), and rapidly ascending ST elevation (96%) was the most common ST-segment morphology. Athletes with ERP were older (P<0.001) had lower rest and recovery heart rates (P<0.001), increased precordial and limb R-wave voltages (P<0.001), increased R/S Sokolow index (P<0.001), and longer PR interval (P=0.006) in comparison with the athletes without ERP. Neither major cardiovascular nor arrhythmic events, nor sudden cardiac death were recorded over a median follow-up of 4.2 years. One hundred seventeen (80.3%) athletes with ERP exhibited a persistent ERP. ERP localization and J-point morphology changed during follow-up in 11 (11.7%) and 17 (18%) of athletes, respectively. Conclusions ERP is common in pediatric athletes. It was mostly located in the inferolateral leads and associated with concave ascending ST segment with other training-related ECG changes. The lack of either sudden cardiac death or cardiomyopathies linked to sudden cardiac death over follow-up suggests that in pediatric athletes, ERP may be considered a benign training-related ECG phenomenon with a potential dynamic pattern.

Project description:Background Dispersion and gradients in repolarization have been associated with life-threatening arrhythmias, but are difficult to quantify precisely from surface electrocardiography. The objective of this study was to evaluate electrocardiographic imaging (ECGI) to noninvasively detect repolarization-based abnormalities. Methods and Results Ex vivo data were obtained from Langendorff-perfused pig hearts (n=8) and a human donor heart. Unipolar electrograms were recorded simultaneously during sinus rhythm from an epicardial sock and the torso-shaped tank within which the heart was suspended. Regional repolarization heterogeneities were introduced through perfusion of dofetilide and pinacidil into separate perfusion beds. In vivo data included torso and epicardial potentials recorded simultaneously in anesthetized, closed-chest pigs (n=5), during sinus rhythm, and ventricular pacing. For both data sets, ECGI accurately reconstructed T-wave electrogram morphologies when compared with those recorded by the sock (ex vivo: correlation coefficient, 0.85 [0.52-0.96], in vivo: correlation coefficient, 0.86 [0.52-0.96]) and repolarization time maps (ex-vivo: correlation coefficient, 0.73 [0.63-0.83], in vivo: correlation coefficient, 0.76 [0.67-0.82]). ECGI-reconstructed repolarization time distributions were strongly correlated to those measured by the sock (both data sets, R2 ≥0.92). Although the position of the gradient was slightly shifted by 8.3 (0-13.9) mm, the mean, max, and SD between ECGI and recorded gradient values were highly correlated (R2=0.87, 0.75, and 0.86 respectively). There was no significant difference in ECGI accuracy between ex vivo and in vivo data. Conclusions ECGI reliably and accurately maps potentially critical repolarization abnormalities. This noninvasive approach allows imaging and quantifying individual parameters of abnormal repolarization-based substrates in patients with arrhythmogenesis, to improve diagnosis and risk stratification.

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

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

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