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.

QRS-T Angles as Markers for Heart Sphericity in Subjects With Intrauterine Growth Restriction: A Simulation Study

“…A wider angle (greater than 100 degrees) is usually associated with changes in the Twave axis rather than QRS related and carries a considerably increased cardiac risk [30]. Reasons for θ RT angle changes are associated to changes in ventricular repolarization itself, or secondary to conduction abnormalities [31], [32]. A wide spatial θ RT angle has been demonstrated to be a predictor of sudden cardiac death in the general population (low risk) and in groups considered to be at higher risk (clinical population) and a strong predictor of all-cause mortality in postmenopausal women [30], [32], [33].…”

“…Both QRS and Twave angles changed from control to deformed simulations without considering ventricular conduction abnormalities in the deformed model. A recent genome-wide association study showed that ventricular conduction abnormalities are the most likely cause of QRS-T angle widening, being able to counteract the reduction in θ RT-XY [31]. As far as we know, there have been no studies indicating that conduction abnormalities occur as a result of IUGR.…”