03005nas a2200325 4500008004100000022001400041245019900055210006900254260001500323300001200338490000800350520192200358100002202280700002402302700002402326700001902350700002002369700001902389700002602408700002202434700002702456700002202483700002402505700001902529700002202548700002202570700002302592700002802615856003602643 2016 eng d a1524-453900aGlobal Electric Heterogeneity Risk Score for Prediction of Sudden Cardiac Death in the General Population: The Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies.0 aGlobal Electric Heterogeneity Risk Score for Prediction of Sudde c2016 Jun 7 a2222-340 v1333 a

BACKGROUND: Asymptomatic individuals account for the majority of sudden cardiac deaths (SCDs). Development of effective, low-cost, and noninvasive SCD risk stratification tools is necessary.

METHODS AND RESULTS: Participants from the Atherosclerosis Risk in Communities study and Cardiovascular Health Study (n=20 177; age, 59.3±10.1 years; age range, 44-100 years; 56% female; 77% white) were followed up for 14.0 years (median). Five ECG markers of global electric heterogeneity (GEH; sum absolute QRST integral, spatial QRST angle, spatial ventricular gradient [SVG] magnitude, SVG elevation, and SVG azimuth) were measured on standard 12-lead ECGs. Cox proportional hazards and competing risks models evaluated associations between GEH electrocardiographic parameters and SCD. An SCD competing risks score was derived from demographics, comorbidities, and GEH parameters. SCD incidence was 1.86 per 1000 person-years. After multivariable adjustment, baseline GEH parameters and large increases in GEH parameters over time were independently associated with SCD. Final SCD risk scores included age, sex, race, diabetes mellitus, hypertension, coronary heart disease, stroke, and GEH parameters as continuous variables. When GEH parameters were added to clinical/demographic factors, the C statistic increased from 0.777 to 0.790 (P=0.008), the risk score classified 10-year SCD risk as high (>5%) in 7.2% of participants, 10% of SCD victims were appropriately reclassified into a high-risk category, and only 1.4% of SCD victims were inappropriately reclassified from high to intermediate risk. The net reclassification index was 18.3%.

CONCLUSIONS: Abnormal electrophysiological substrate quantified by GEH parameters is independently associated with SCD in the general population. The addition of GEH parameters to clinical characteristics improves SCD risk prediction.

1 aWaks, Jonathan, W1 aSitlani, Colleen, M1 aSoliman, Elsayed, Z1 aKabir, Muammar1 aGhafoori, Elyar1 aBiggs, Mary, L1 aHenrikson, Charles, A1 aSotoodehnia, Nona1 aBiering-Sørensen, Tor1 aAgarwal, Sunil, K1 aSiscovick, David, S1 aPost, Wendy, S1 aSolomon, Scott, D1 aBuxton, Alfred, E1 aJosephson, Mark, E1 aTereshchenko, Larisa, G uhttps://chs-nhlbi.org/node/713502814nas a2200313 4500008004100000022001400041245017100055210006900226260001600295490000600311520179000317100002802107700002202135700002402157700002002181700001902201700001902220700002302239700002202262700002402284700002202308700002702330700002202357700001902379700002302398700002402421700001902445856003602464 2018 eng d a2047-998000aGenome-Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study).0 aGenomeWide Associations of Global Electrical Heterogeneity ECG P c2018 Apr 050 v73 a

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 RESULTS: We 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 ) was associated with QRS-T angle (white standardized β+0.16 [95% CI 0.13-0.19]; =1.5×10), spatial ventricular gradient elevation (+0.11 [0.08-0.14]; =2.1×10), and spatial ventricular gradient magnitude (-0.12 [95% CI -0.15 to -0.09]; =5.9×10). Altogether, GEH-SNPs explained 1.1% to 1.6% of GEH variance. Loci on chromosomes 4 (near ), 5 (), 11 (11p11.2 region cluster), and 7 (near ) are novel ECG phenotype-associated loci. Several loci significantly associated with gene expression in the left ventricle ( locus-with ; locus-with ), and atria ( locus-with expression of a long non-coding RNA and ).

CONCLUSIONS: We 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.

1 aTereshchenko, Larisa, G1 aSotoodehnia, Nona1 aSitlani, Colleen, M1 aAshar, Foram, N1 aKabir, Muammar1 aBiggs, Mary, L1 aMorley, Michael, P1 aWaks, Jonathan, W1 aSoliman, Elsayed, Z1 aBuxton, Alfred, E1 aBiering-Sørensen, Tor1 aSolomon, Scott, D1 aPost, Wendy, S1 aCappola, Thomas, P1 aSiscovick, David, S1 aArking, Dan, E uhttps://chs-nhlbi.org/node/7672