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Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.

ABSTRACT: The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

SUBMITTER: Young WJ

PROVIDER: S-EPMC10015012 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.

Young William J WJ Haessler Jeffrey J Benjamins Jan-Walter JW Repetto Linda L Yao Jie J Isaacs Aaron A Harper Andrew R AR Ramirez Julia J Garnier Sophie S van Duijvenboden Stefan S Baldassari Antoine R AR Concas Maria Pina MP Duong ThuyVy T Foco Luisa L Isaksen Jonas L JL Mei Hao H Noordam Raymond R Nursyifa Casia C Richmond Anne A Santolalla Meddly L ML Sitlani Colleen M CM Soroush Negin N Thériault Sébastien S Trompet Stella S Aeschbacher Stefanie S Ahmadizar Fariba F Alonso Alvaro A Brody Jennifer A JA Campbell Archie A Correa Adolfo A Darbar Dawood D De Luca Antonio A Deleuze Jean-François JF Ellervik Christina C Fuchsberger Christian C Goel Anuj A Grace Christopher C Guo Xiuqing X Hansen Torben T Heckbert Susan R SR Jackson Rebecca D RD Kors Jan A JA Lima-Costa Maria Fernanda MF Linneberg Allan A Macfarlane Peter W PW Morrison Alanna C AC Navarro Pau P Porteous David J DJ Pramstaller Peter P PP Reiner Alexander P AP Risch Lorenz L Schotten Ulrich U Shen Xia X Sinagra Gianfranco G Soliman Elsayed Z EZ Stoll Monika M Tarazona-Santos Eduardo E Tinker Andrew A Trajanoska Katerina K Villard Eric E Warren Helen R HR Whitsel Eric A EA Wiggins Kerri L KL Arking Dan E DE Avery Christy L CL Conen David D Girotto Giorgia G Grarup Niels N Hayward Caroline C Jukema J Wouter JW Mook-Kanamori Dennis O DO Olesen Morten Salling MS Padmanabhan Sandosh S Psaty Bruce M BM Pattaro Cristian C Ribeiro Antonio Luiz P ALP Rotter Jerome I JI Stricker Bruno H BH van der Harst Pim P van Duijn Cornelia M CM Verweij Niek N Wilson James G JG Orini Michele M Charron Philippe P Watkins Hugh H Kooperberg Charles C Lin Henry J HJ Wilson James F JF Kanters Jørgen K JK Sotoodehnia Nona N Mifsud Borbala B Lambiase Pier D PD Tereshchenko Larisa G LG Munroe Patricia B PB

Nature communications 20230314 1

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic meas ...[more]

PMID: 36918541

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Project description:Background: Hypothyroidism, the most common endocrine disease, induces cardiac electrical remodeling that creates a substrate for ventricular arrhythmias. Recent studies report that high thyrotropin (TSH) levels are related to cardiac electrical abnormalities and increased mortality rates. The aim of the present work was to investigate the direct effects of TSH on the heart and its possible causative role in the increased incidence of arrhythmia in hypothyroidism. Methods: A new rat model of central hypothyroidism (low TSH levels) was created and characterized together with the classical propylthiouracil-induced primary hypothyroidism model (high TSH levels). Electrocardiograms were recorded in vivo, and ionic currents were recorded from isolated ventricular myocytes in vitro by the patch-clamp technique. Protein and mRNA were measured by Western blot and quantitative reverse transcription polymerase chain reaction in rat and human cardiac myocytes. Adult human action potentials were simulated in silico to incorporate the experimentally observed changes. Results: Both primary and central hypothyroidism models increased the L-type Ca2+ current (ICa-L) and decreased the ultra-rapid delayed rectifier K+ current (IKur) densities. However, only primary but not central hypothyroidism showed electrocardiographic repolarization abnormalities and increased ventricular arrhythmia incidence during caffeine/dobutamine challenge. These changes were paralleled by a decrease in the density of the transient outward K+ current (Ito) in cardiomyocytes from animals with primary but not central hypothyroidism. In vitro treatment with TSH for 24 hours enhanced isoproterenol-induced spontaneous activity in control ventricular cells and diminished Ito density in cardiomyocytes from control and central but not primary hypothyroidism animals. In human myocytes, TSH decreased the expression of KCND3 and KCNQ1, Ito, and the delayed rectifier K+ current (IKs) encoding proteins in a protein kinase A-dependent way. Transposing the changes produced by hypothyroidism and TSH to a computer model of human ventricular action potential resulted in enhanced occurrence of early afterdepolarizations and arrhythmia mostly in primary hypothyroidism, especially under β-adrenergic stimulation. Conclusions: The results suggest that suppression of repolarizing K+ currents by TSH underlies most of the electrical remodeling observed in hypothyroidism. This work demonstrates that the activation of the TSH-receptor/protein kinase A pathway in the heart is responsible for the cardiac electrical remodeling and arrhythmia generation seen in hypothyroidism.

Dataset Information

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.

Publications

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.

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