Dataset Information

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 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 TBX3) was associated with QRS-T angle (white standardized ?+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). 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.

SUBMITTER: Tereshchenko LG

PROVIDER: S-EPMC6015433 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Tereshchenko Larisa G LG Sotoodehnia Nona N Sitlani Colleen M CM Ashar Foram N FN Kabir Muammar M Biggs Mary L ML Morley Michael P MP Waks Jonathan W JW Soliman Elsayed Z EZ Buxton Alfred E AE Biering-Sørensen Tor T Solomon Scott D SD Post Wendy S WS Cappola Thomas P TP Siscovick David S DS Arking Dan E DE

Journal of the American Heart Association 20180405 8

<h4>Background</h4>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.<h4>Methods and results</h4>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, ...[more]

PMID: 29622589

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Project description:BACKGROUND:Electric excitation initiates myocardial mechanical contraction and coordinates myocardial pumping. We hypothesized that ECG global electric heterogeneity (GEH) and its longitudinal changes are associated with cardiac structure and function. METHODS AND RESULTS:Participants from the ARIC study (Atherosclerosis Risk in Communities) (N=5114; 58% female; 22% blacks) with resting 12-lead ECGs (visits 1-5) and echocardiographic assessment of left ventricular (LV) ejection fraction, LV global longitudinal strain, LV mass index, LV end-diastolic volume index, and LV end-systolic volume index at visit 5 were included. Longitudinal analysis included ARIC participants (N=14 609) with measured GEH at visits 1 to 4. GEH was quantified by spatial ventricular gradient, QRS-T angle, and sum absolute QRS-T integral. Cross-sectional and longitudinal regressions were adjusted for manifest and subclinical cardiovascular disease. Having 4 abnormal GEH parameters was associated with a 6.4% (95% confidence interval, 5.5-7.3) LV ejection fraction decline, a 24.2 g/m2 (95% confidence interval, 21.5-26.9) increase in LV mass index, a 10.3 mL/m2 (95% confidence interval, 8.9-11.7) increase in LV end-diastolic volume index, and a 7.8 mL/m2 (95% confidence interval, 6.9-8.6) increase in LV end-systolic volume index. Altogether, clinical and ECG parameters accounted for approximately one third of LV volume and 20% of systolic function variability. The associations were significantly stronger in cardiovascular disease. Sum absolute QRS-T integral increased by 20 mV*ms for each 3-year period in participants who demonstrated LV dilatation at visit 5. Sudden cardiac death victims demonstrated rapid GEH worsening, whereas those with LV dysfunction demonstrated slow GEH worsening. Healthy aging was associated with a distinct pattern of spatial ventricular gradient azimuth decrement. CONCLUSIONS:GEH is a marker of subclinical abnormalities in cardiac structure and function.

Project description:<p>The Atherosclerosis Risk in Communities (ARIC) Study, sponsored by the National Heart, Lung and Blood Institute (NHLBI), is a prospective epidemiologic study conducted in four U.S. communities. The four communities are Forsyth County, NC; Jackson, MS; the northwest suburbs of Minneapolis, MN; and Washington County, MD. ARIC is designed to investigate the etiology and natural history of atherosclerosis, the etiology of clinical atherosclerotic diseases, and variation in cardiovascular risk factors, medical care and disease by race, gender, location, and date.</p> <p>ARIC includes two parts: the Cohort Component and the Community Surveillance Component. The Cohort Component began in 1987, and each ARIC field center randomly selected and recruited a cohort sample of approximately 4,000 individuals aged 45-64 from a defined population in their community. A total of 15,792 participants received an extensive examination, including medical, social, and demographic data. These participants were reexamined every three years with the first screen (baseline) occurring in 1987-89, the second in 1990-92, the third in 1993-95, and the fourth and last exam was in 1996-98. Follow-up occurs yearly by telephone to maintain contact with participants and to assess health status of the cohort.</p> <p>In the Community Surveillance Component, currently ongoing, these four communities are investigated to determine the community-wide occurrence of hospitalized myocardial infarction and coronary heart disease deaths in men and women aged 35-84 years. Hospitalized stroke is investigated in cohort participants only. Starting in 2006, the study conducts community surveillance of inpatient (ages 55 years and older) and outpatient heart failure (ages 65 years and older) for heart failure events beginning in 2005.</p> <p>ARIC is currently funded through January 31, 2012.</p> <p>This study is part of the Gene Environment Association Studies initiative (GENEVA, <a href="http://www.genevastudy.org" target="_blank">http://www.genevastudy.org</a>) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to atherosclerosis and cardiovascular disease through large-scale genome-wide association studies of well-characterized cohorts of adults in four defined populations. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center. Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.</p>

Project description:BACKGROUND:Previous studies suggest that heart failure (HF) is an independent risk factor for cognitive decline. A better understanding of the relationship between HF, cognitive status, and cognitive decline in a community-based sample may help clinicians understand disease risk. OBJECTIVE:To examine whether persons with HF have a higher prevalence of cognitive impairment and whether persons developing HF have more rapid cognitive decline. DESIGN:This observational cohort study of American adults in the Atherosclerosis Risk in Communities (ARIC) study has two components: cross-sectional analysis examining the association between prevalent HF and cognition using multinomial logistic regression, and change over time analysis detailing the association between incident HF and change in cognition over 15 years. PARTICIPANTS:Among visit 5 (2011-2013) participants (median age 75 years), 6495 had neurocognitive information available for cross-sectional analysis. Change over time analysis examined the 5414 participants who had cognitive scores and no prevalent HF at visit 4 (1996-1998). MEASUREMENTS:The primary outcome was cognitive status, classified as normal, mild cognitive impairment [MCI], and dementia on the basis of standardized cognitive tests (delayed word recall, word fluency, and digit symbol substitution). Cognitive change was examined over a 15-year period. Control variables included socio-demographic, vascular, and smoking/drinking measures. RESULTS:At visit 5, participants with HF had a higher prevalence of dementia (adjusted relative risk ratio [RRR] = 1.60 [95% CI 1.13, 2.25]) and MCI (RRR = 1.36 [1.12, 1.64]) than those without HF. A decline in cognition between visits 4 and 5 was - 0.07 standard deviation units [- 0.13, - 0.01] greater among persons who developed HF compared to those who did not. Results did not differ by ejection fraction. CONCLUSION:HF is associated with neurocognitive dysfunction and decline independent of other co-morbid conditions. Further study is needed to determine the underlying pathophysiology.

Project description:Carotid intima-media thickness has been reported to predict kidney function decline. However, whether carotid intima-media thickness is associated with a hard kidney end point, ESRD, has not been investigated.We studied 13,197 Atherosclerosis Risk in Communities participants at visit 1 (1987-1989) without history of cardiovascular disease, including coronary heart disease, stroke, and heart failure, at baseline and assessed whether carotid intima-media thickness measured by B-mode ultrasound is associated with ESRD risk using Cox proportional hazards models. Regarding carotid intima-media thickness parameters, we investigated the mean and maximum values of overall and segment-specific (common, bifurcation, and internal carotid arteries) measurements.Mean age was 54.0 (SD=5.7) years old, and there were 3373 (25.6%) blacks and 7370 (55.8%) women. During a median follow-up of 22.7 years, 433 participants developed ESRD (1.4/1000 person-years). After adjusting for shared risk factors for atherosclerosis and kidney disease, including baseline kidney function, carotid intima-media thickness was significantly associated with ESRD risk (hazard ratio [HR] between quartiles 4 and 1, 1.46; 95% confidence interval [95% CI], 1.02 to 2.08 for overall mean intima-media thickness and HR between quartiles 4 and 1, 1.75; 95% CI, 1.24 to 2.48 for overall maximum intima-media thickness). The associations were largely consistent in demographic and clinical subgroups. When we explored segment-specific intima-media thicknesses, the associations with ESRD were most robust for bifurcation carotid (e.g., adjusted HR between quartiles 4 and 1 of mean intima-media thickness, 1.49; 95% CI, 1.04 to 2.13 for bifurcation; adjusted HR between quartiles 4 and 1 of mean intima-media thickness, 1.36; 95% CI, 0.94 to 1.97 for common; and adjusted HR between quartiles 4 and 1 of mean intima-media thickness, 0.93; 95% CI, 0.67 to 1.29 for internal).Carotid intima-media thickness was independently associated with incident ESRD in the general population, suggesting the shared etiology of atherosclerosis and ESRD.

Project description:BACKGROUND AND PURPOSE:Cerebral microbleed (CMB) location (deep versus strictly lobar) may elucidate underlying pathology with deep CMBs being more associated with hypertensive vascular disease and lobar CMBs being more associated with cerebral amyloid angiopathy. The objective of this study was to determine whether neuroimaging signs of vascular disease and Alzheimer pathology are associated with different types of CMBs. METHODS:Among 1677 nondemented ARIC (Atherosclerosis Risk in Communities) participants (mean age=76±5 years; 40% men; 26% black) with 3-Tesla MRI scans at the fifth examination (2011-2013), we fit multinomial logistic regression models to quantify relationships of brain volumes (Alzheimer disease signature regions, total gray matter, frontal gray matter, and white matter hyperintensity volumes), infarct frequencies (lacunar, nonlacunar, and total), and apolipoprotein E (number of ?4 alleles) with CMB location (none, deep/mixed, or strictly lobar CMBs). Models were weighted for the sample selection scheme and adjusted for age, sex, education, hypertension, ever smoking status, diabetes mellitus, race site membership, and estimated intracranial volume (brain volume models only). RESULTS:Deep/mixed and strictly lobar CMBs had prevalences of 8% and 16%, respectively. Larger white matter hyperintensity burden, greater total infarct frequency, smaller frontal volumes (in women only), and smaller total gray matter volume were associated with greater risk of both deep and lobar CMBs relative to no CMBs. Greater white matter hyperintensity volume was also associated with greater risk of deep relative to lobar CMBs. Higher lacunar and nonlacunar infarct frequencies were associated with higher risk of deep CMBs, whereas smaller Alzheimer disease signature region volume and apolipoprotein E ?4 homozygosity were associated with greater risk of lobar CMBs. CONCLUSIONS:CMBs are a common vascular pathology in the elderly. Markers of hypertensive small-vessel disease may contribute to deep CMBs while cerebral amyloid angiopathy may drive development of lobar CMBs.

Dataset Information

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

Publications

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

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