Genome‐Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study)

Abstract

Background ECG global electrical heterogeneity (GEH) is associated with sudden cardiac death. We hypothesized that a genome‐wide association study would identify genetic loci related to GEH.Methods and ResultsWe tested genotyped and imputed variants in black (N=3057) and white (N=10 769) participants in the ARIC (Atherosclerosis Risk in Communities) study and CHS (Cardiovascular Health Study). GEH (QRS‐T angle, sum absolute QRST integral, spatial ventricular gradient magnitude, elevation, azimuth) was measured on 12‐lead ECGs. Linear regression models were constructed with each GEH variable as an outcome, adjusted for age, sex, height, body mass index, study site, and principal components to account for ancestry. GWAS identified 10 loci that showed genome‐wide significant association with GEH in whites or joint ancestry. The strongest signal (rs7301677, near TBX3) was associated with QRS‐T angle (white standardized β+0.16 [95% CI 0.13–0.19]; P=1.5×10−26), spatial ventricular gradient elevation (+0.11 [0.08–0.14]; P=2.1×10−12), and spatial ventricular gradient magnitude (−0.12 [95% CI −0.15 to −0.09]; P=5.9×10−15). Altogether, GEH‐SNPs explained 1.1% to 1.6% of GEH variance. Loci on chromosomes 4 (near HMCN2), 5 (IGF1R), 11 (11p11.2 region cluster), and 7 (near ACTB) are novel ECG phenotype‐associated loci. Several loci significantly associated with gene expression in the left ventricle (HMCN2 locus—with HMCN2;IGF1R locus—with IGF1R), and atria (RP11‐481J2.2 locus—with expression of a long non‐coding RNA and NDRG4).ConclusionsWe identified 10 genetic loci associated with ECG GEH. Replication of GEH GWAS findings in independent cohorts is warranted. Further studies of GEH‐loci may uncover mechanisms of arrhythmogenic remodeling in response to cardiovascular risk factors.

Vectorcardiogram in athletes: The Sun Valley Ski Study

“…The insulin‐like growth factor 1 ( IGF1 ) signaling pathway regulates exercise‐induced physiological cardiac hypertrophy and cardiac protection (Weeks et al, ). Tereshchenko et al recently identified a GEH‐associated genetic polymorphism in the intron of the IGF1 ‐receptor ( IGF1R ) gene (Tereshchenko et al, ). As demonstrated by an IGF1R locus‐associated GEH phenotype (Figure e in (Tereshchenko et al, )), physiological cardiac remodeling in the athlete's heart is characterized by sizable increase in SAI QRST and SVG magnitude with only mild increase in SVG azimuth and QRS‐T angle and simultaneous decrease in SVG elevation.…”

“…Tereshchenko et al recently identified a GEH‐associated genetic polymorphism in the intron of the IGF1 ‐receptor ( IGF1R ) gene (Tereshchenko et al, ). As demonstrated by an IGF1R locus‐associated GEH phenotype (Figure e in (Tereshchenko et al, )), physiological cardiac remodeling in the athlete's heart is characterized by sizable increase in SAI QRST and SVG magnitude with only mild increase in SVG azimuth and QRS‐T angle and simultaneous decrease in SVG elevation. Thus, GEH presentation can potentially distinguish athletes with physiological RV remodeling from those who are overtrained and are at risk to develop RV dysfunction.…”

Dynamic Predictive Accuracy of Electrocardiographic Biomarkers of Sudden Cardiac Death within a Survival Framework: The Atherosclerosis Risk in Communities (ARIC) study

“…26 Early cardiac development affects the generation of electrophysiological heterogeneities in the adult heart. 27 There may be a genetic basis for this phenomenon as GEH-associated genetic polymorphisms indicated the involvement of HAND1 and TBX3 genes, 4 both of which play a role in outflow tract development.…”

“…Many GEH-associated genetic loci are implicated in cardiac development. 4 Further studies of the underlying biology behind GEH-associated loci will help to uncover novel mechanisms of SCD and develop primary prevention strategies. A recent case-control genomewide association study (GWAS) of sudden cardiac arrest 32 did not identify any variants at genome-wide statistical significance.…”

“…3 The subsequent discovery of 10 genetic loci, associated with GEH at a genome-wide significance level confirmed the presence of several underlying mechanisms behind the GEH ECG phenotype. 4 We also developed a competing risk score of SCD and showed that the addition of GEH measures to clinical risk factors significantly improves reclassification of SCD risk. 3 The risk of SCD is known to be dynamic.…”