Zhu Ming Zhang

Usefulness of T-axis deviation as an independent risk indicator for incident cardiac events in older men and women free from coronary heart disease (the Cardiovascular Health Study).

T-axis shift has been reported to be an indicator of increased mortality risk. We evaluated the association of spatial T-axis deviation with incident coronary heart disease (CHD) events in older men and women free from clinically overt CHD. Spatial T-axis deviation was measured from the standard 12-lead electrocardiogram of a subgroup of 4,173 subjects considered free of CHD at baseline in the Cardiovascular Health Study, a prospective cohort study of risk factors for CHD and stroke in older men and women. Cox regression analysis was used to evaluate the association of altered repolarization with the risk of incident CHD events. The prevalence of marked T-axis deviation (> or =45 degrees ) was 12%. During the median follow-up of 7.4 years, there were 161 CHD deaths, 743 deaths from all causes, and 679 incident CHD events. Adjusting for demographic and clinical risk factors, including other electrocardiographic abnormalities, there was a nearly twofold excess risk of CHD death, and approximately a 50% excess risk of incident CHD and all-cause mortality for those with marked T-axis deviation. From other electrocardiographic abnormalities, only QT prolongation was associated with excess risk for incident CHD comparable to that for abnormal T-axis deviation. These results suggest that T-axis deviation is an easily quantified marker for subclinical disease and an independent indicator for the risk of incident CHD events in older men and women free of CHD.

Atrial fibrillation and risk of ST-segment-elevation versus non-ST-segment-elevation myocardial infarction the Atherosclerosis Risk in Communities (ARIC) study

Background— It has recently been reported that atrial fibrillation (AF) is associated with an increased risk of myocardial infarction (MI). However, the mechanism underlying this association is currently unknown. Further study of the relationship of AF with the type of MI (ST-segment–elevation MI [STEMI] versus non–ST-segment–elevation MI [NSTEMI]) might shed light on the potential mechanisms. Methods and Results— We examined the association between AF and incident MI in 14u2009462 participants (mean age, 54 years; 56% women; 26% blacks) from the Atherosclerosis Risk in Communities (ARIC) study who were free of coronary heart disease at baseline (1987–1989) with follow-up through December 31, 2010. AF cases were identified from study visit ECGs and by review of hospital discharge records. Incident MI and its types were ascertained by an independent adjudication committee. Over a median follow-up of 21.6 years, 1374 MI events occurred (829 NSTEMIs, 249 STEMIs, 296 unclassifiable MIs). In a multivariable-adjusted model, AF (n=1545) as a time-varying variable was associated with a 63% increased risk of MI (hazard ratio,1.63; 95% confidence interval, 1.32–2.02). However, AF was associated with NSTEMI (hazard ratio, 1.80; 95% confidence interval, 1.39–2.31) but not STEMI (hazard ratio, 0.49; 95% confidence interval, 0.18–1.34; P for hazard ratio comparison=0.004). Combining the unclassifiable MI group with either STEMI or NSTEMI did not change this conclusion. The association between AF and MI, total and NSTEMI, was stronger in women than in men (P for interaction <0.01 for both). Conclusions— AF is associated with an increased risk of incident MI, especially in women. However, this association is limited to NSTEMI.

Long-term prognostic significance of isolated minor electrocardiographic T-wave abnormalities in middle-aged men free of clinical cardiovascular disease (The Multiple Risk Factor Intervention Trial [MRFIT])

1996;3:213–219. 5. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341: 410 –418. 6. Bloomfield Rubins H, Davenport J, Babikian V, Brass LM, Collins D, Wexler L, Wagner S, Papademetriou V, Rutan G, Robins SJ. Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). Circulation 2001;103:2828– 2833. 7. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, et al. Helsinki Heart Study: primaryprevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237–1245.

Ambient particulate air pollution and ectopy - The environmental epidemiology of arrhythmogenesis in women's health initiative study, 1999-2004

The relationships between ambient PM2.5 and PM10 and arrhythmia and the effect modification by cigarette smoking were investigated. Data from U.S. Environmental Protection Agency (EPA) air quality monitors and an established national-scale, log-normal kriging method were used to spatially estimate daily mean concentrations of PM at addresses of 57,422 individuals from 59 examination sites in 24 U.S. states in 1999–2004. The acute and subacute exposures were estimated as mean, geocoded address-specific PM concentrations on the day of, 0–2 d before, and averaged over 30 d before the electrocardiogram (ECG) (Lag0; Lag1; Lag2; Lag1–30). At the time of standard 12-lead resting ECG, the mean age (SD) of participants was 67.5 (6.9) yr (84% non-Hispanic White; 6% current smoker; 15% with coronary heart disease; 5% with ectopy). After the identification of significant effect modifiers, two-stage random-effects models were used to calculate center-pooled odds ratios and 95% confidence intervals (OR, 95% CI) of arrhythmia per 10 μg/m3 increase in PM concentrations. Among current smokers, Lag0 and Lag1 PM concentrations were significantly associated ventricular ectopy (VE)—the OR (95% CI) for VE among current smokers was 2 (1.32–3.3) and 1.32 (1.07–1.65) at Lag1 PM2.5 and PM10, respectively. The interactions between current smoking and acute exposures (Lag0; Lag1; Lag2) were significant in relationship to VE. Acute exposures were not significantly associated with supraventricular ectopy (SVE), or with VE among nonsmokers. Subacute (Lag1–30) exposures were not significantly associated with arrhythmia. Acute PM2.5 and PM10 exposure is directly associated with the odds of VE among smokers, suggesting that they are more vulnerable to the arrhythmogenic effects of PM.

Impact of ancestry and common genetic variants on QT interval in African Americans.

Background—Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval. Methods and Results—First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12 097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13 105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5×10–8) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2×10–15) and ATP1B1 (rs1320976, P=2×10–10). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10–5) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN. Conclusions—We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of Afr.

Ambient fine particulate matter exposure and myocardial ischemia in the Environmental Epidemiology of Arrhythmogenesis in the Women's Health Initiative (EEAWHI) study.

Background Ambient particulate matter (PM) air pollution is associated with coronary heart disease, but the pathways underlying the association remain to be elucidated. Methods We studied the association between PM and ischemia among 57,908 Women’s Health Initiative clinical trial participants from 1999–2003. We used the Minnesota Code criteria to identify ST-segment and T-wave abnormalities, and estimated T amplitude (microvolt) from resting, standard 12-lead electrocardiogram (ECG). We used U.S. Environmental Protection Agency’s monitor data to estimate concentrations of PM < 2.5 μm (PM2.5) at geocoded participant addresses over 6 days before the ECGs (lag0 through lag5). We excluded 2,379 women with ECG QRS duration ≥ 120 msec. Results Overall, 6% of the remaining 55,529 women (52–90 years of age; 83% non-Hispanic white) had ST abnormalities and 16% had T abnormalities. Lead-specific T amplitude was normally distributed (range of means from −14 to 349 μV). PM2.5 (mean ± SD) averaged over lag0–2 was 14 ± 7 μg/m3. In logistic and linear regression models adjusted for demographic, clinical, temporal, and climatic factors, a 10-μg/m3 increase in lag0–2 PM2.5 was associated with a 4% [95% confidence interval (CI), −3%, to 10%] increase in the odds of ST abnormality and a 5% (95% CI, 0% to 9%) increase in the odds of T abnormality. We observed corresponding decreases in T amplitude in all exam sites and leads except lead V1, reaching a minimum of −2 μV (95% CI, −5 to 0 μV) in lead V3. Conclusions Short-term PM2.5 exposure is associated with ECG evidence of myocardial ischemia among postmenopausal women. The principal manifestations include subclinical but potentially arrhythmogenic ST–T abnormalities and decreases in T amplitude.

Novel Loci Associated With PR Interval in a Genome-Wide Association Study of 10 African American Cohorts

Background—The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans. Methods and Results—We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (&lgr; range: 0.9–1.1), although not after genomic control correction was applied to the overall meta-analysis (&lgr;: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0×10−8), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0×10−8). Conclusions—This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

Advanced interatrial block and ischemic stroke The Atherosclerosis Risk in Communities Study

Objective: Given that recent reports have suggested left atrial disease to be an independent risk factor for ischemic stroke, we sought to examine if advanced interatrial block (aIAB) is an independent stroke risk factor. Methods: We examined the association between aIAB and incident ischemic stroke in 14,716 participants (mean age 54 ± 5.8 years; 55% female; 26% black) from the Atherosclerosis Risk in Communities Study (ARIC). Cases of aIAB were identified from digital ECGs recorded during the baseline ARIC visit (1987–1989) and the first 3 follow-up study visits (1990–1992, 1993–1995, and 1996–1998). Adjudicated ischemic stroke events were ascertained through December 31, 2010. Results: There were 266 (1.8%) participants who had evidence of aIAB. Over a median follow-up of 22 years, 916 (6.2%) ischemic stroke events were detected. The incidence rate (per 1,000 person-years) of ischemic stroke among those with aIAB (incidence rate 8.05, 95% confidence interval [CI] 5.7, 11.4) was more than twice the rate in those without aIAB (incidence rate 3.14, 95% CI 2.94, 3.35). In a multivariable Cox regression analysis adjusted for stroke risk factors and potential confounders, aIAB was associated with an increased risk of ischemic stroke (hazard ratio 1.63, 95% CI 1.13, 2.34). The results were consistent across subgroups of participants stratified by age, sex, and race. Conclusions: In the ARIC, aIAB was associated with incident ischemic stroke, which strengthens the hypothesis that left atrial disease should be considered an independent stroke risk factor.

Use of Hundreds of Electrocardiographic Biomarkers for Prediction of Mortality in Postmenopausal Women: The Women's Health Initiative

Background— Simultaneous contribution of hundreds of electrocardiographic (ECG) biomarkers to prediction of long-term mortality in postmenopausal women with clinically normal resting ECGs is unknown. Methods and Results— We analyzed ECGs and all-cause mortality in 33 144 women enrolled in the Womens Health Initiative trials who were without baseline cardiovascular disease or cancer and had normal ECGs by Minnesota and Novacode criteria. Four hundred and seventy-seven ECG biomarkers, encompassing global and individual ECG findings, were measured with computer algorithms. During a median follow-up of 8.1 years (range for survivors, 0.5 to 11.2 years), 1229 women died. For analyses, the cohort was randomly split into derivation (n=22 096; deaths, 819) and validation (n=11 048; deaths, 410) subsets. ECG biomarkers and demographic and clinical characteristics were simultaneously analyzed using both traditional Cox regression and random survival forest, a novel algorithmic machine-learning approach. Regression modeling failed to converge. Random survival forest variable selection yielded 20 variables that were independently predictive of long-term mortality, 14 of which were ECG biomarkers related to autonomic tone, atrial conduction, and ventricular depolarization and repolarization. Conclusions— We identified 14 ECG biomarkers from among hundreds that were associated with long-term prognosis using a novel random forest variable selection methodology. These biomarkers were related to autonomic tone, atrial conduction, ventricular depolarization, and ventricular repolarization. Quantitative ECG biomarkers have prognostic importance and may be markers of subclinical disease in apparently healthy postmenopausal women.

Electrocardiographic Predictors of Coronary Heart Disease and Sudden Cardiac Deaths in Men and Women Free From Cardiovascular Disease in the Atherosclerosis Risk in Communities Study

Background We evaluated predictors of coronary heart disease (CHD) death and sudden cardiac death (SCD) in the Atherosclerosis Risk in Communities (ARIC) study. Methods and Results The study population included 13 621 men and women 45 to 65 years of age free from manifest cardiovascular disease at entry. Hazard ratios from Cox regression with 95% confidence intervals were computed for 18 dichotomized repolarization‐related ECG variables. The average follow‐up was 14 years. Independent predictors of CHD death in men were TaVR‐ and rate‐adjusted QTend (QTea), with a 2‐fold increased risk for both, and spatial angles between mean QRS and T vectors and between Tpeak (Tp) and normal R reference vectors [θ(Rm|Tm) and θ(Tp|Tref), respectively], with a >1.5‐fold increased risk for both. In women, independent predictors of the risk of CHD death were θ(Rm|Tm), with a 2‐fold increased risk for θ(Rm|Tm), and θ(Tp|Tref), with a 1.7‐fold increased risk. Independent predictors of SCD in men were θ(Tp|Tref) and QTea, with a 2‐fold increased risk, and θ(Tinit|Tterm), with a 1.6‐fold increased risk. In women, θ(Tinit|Tterm) was an independent predictor of SCD, with a >3‐fold increased risk, and θ(Rm|Tm) and TV1 were >2‐fold for both. Conclusions θ(Rm|Tm) and θ(Tp|Tref), reflecting different aspects of ventricular repolarization, were independent predictors of CHD death and SCD, and TaVR and TV1 were also independent predictors. The risk levels for independent predictors for both CHD death and SCD were stronger in women than in men, and QTea was a significant predictor in men but not in women.