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1.  Evidence of Heterogeneity by Race/Ethnicity in Genetic Determinants of QT Interval 
Epidemiology (Cambridge, Mass.)  2014;25(6):790-798.
QT-interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations.
Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n=16,398), African (n=5,437), American Indian (n=5,032), Hispanic (n=1,143), and Asian (n=932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test.
Of 21 SNPs, seven showed consistent direction of effect across all five populations, and an additional nine had estimated effects that were consistent across four populations. Despite consistent direction of effect, nine of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity.
These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.
PMCID: PMC4380285  PMID: 25166880
2.  Use of statins and antihypertensive medications in relation to risk of longstanding persistent atrial fibrillation 
The Annals of pharmacotherapy  2015;49(4):378-386.
After an initial episode of atrial fibrillation (AF), patients may develop longstanding persistent or permanent AF.
We evaluated whether use of statins, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers is associated with lower risk of longstanding persistent AF after an initial AF episode.
We conducted a population-based inception cohort study of participants enrolled in Group Health, aged 30–84 with newly-diagnosed AF in 2001–2004. We included only participants whose initial AF episode terminated within six months of onset. We ascertained the primary outcome of longstanding persistent AF from medical records, electrocardiograms, and administrative data. We determined time-varying medication use from Group Health pharmacy data.
Among 1,317 participants with incident AF, 304 developed longstanding persistent AF. Our study suggests that current statin use vs. never use may be associated with lower risk for longstanding persistent AF. However, the association was not statistically significant when adjusted for age, sex, cardiovascular risk factors, and current use of antiarrhythmic medication (hazard ratio [HR] = 0.77; 95% confidence interval [CI]: 0.57, 1.03). In lagged analyses intended to reduce healthy user bias, current statin use one year prior vs. never use one year prior was not associated with risk for longstanding persistent AF (HR = 0.91; 95% CI: 0.67, 1.24). ACE inhibitor, ARB, and beta-blocker use were not associated with risk for longstanding persistent AF.
Current statin use may confer protection that wanes after discontinuing use. Alternatively, healthy user bias or chance may explain the association. The association of statin use with longstanding persistent AF warrants further investigation.
PMCID: PMC4562688  PMID: 25628466
antihypertensive agents; longstanding persistent atrial fibrillation; cohort studies; electrocardiography; hydroxymethylglutaryl-CoA reductase inhibitors; statins
3.  Genome-Wide Association Study of L-Arginine and Dimethylarginines Reveals Novel Metabolic Pathway for Symmetric Dimethylarginine 
Dimethylarginines (DMA) interfere with nitric oxide (NO) formation by inhibiting NO synthase (asymmetric dimethylarginine, ADMA) and L-arginine uptake into the cell (ADMA and symmetric dimethylarginine, SDMA). In prospective clinical studies ADMA has been characterized as a cardiovascular risk marker whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterise the environmental and genetic contributions to inter-individual variability of these biomarkers.
Methods and Results
This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (FHS (n=2992), GHS (n=4354) and MONICA/KORA F3 (n=581)) and identified replicated loci (DDAH1, MED23, Arg1 and AGXT2) associated with the inter-individual variability in ADMA, L-arginine and SDMA. Experimental in-silico and in-vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants and various cardiometabolic risk factors. AGXT2 variants were not associated with post-stroke survival in the Leeds study, nor were they associated with incident stroke in the CHARGE consortium.
These GWAS support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and L-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.
PMCID: PMC4797637  PMID: 25245031
biomarker; endothelial function; nitric oxide; Genome Wide Association Study
4.  Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium 
PLoS ONE  2016;11(3):e0144997.
Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.
We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10−6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.
In Stage I 15 loci passed the threshold of 5×10−6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10−3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10−9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10−3).
QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
PMCID: PMC4780701  PMID: 26950853
5.  Sustained Pre-hypertensive Blood Pressure and Incident Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis 
The association between sustained pre-hypertension and AF has not been thoroughly examined.
This study included 5,311 participants (mean age 62 ± 10 years; 47% male; 42.9% non-whites) from the Multi-Ethnic Study of Atherosclerosis. Sustained exposure was based on 2 or more visits within the same blood pressure category (optimal: <120/80 mm Hg; pre-hypertension: 120–139/80–89 mm Hg; hypertension: ≥140/90 mm Hg or antihypertensive medication use) during visits 1, 2, and 3. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association between blood pressure category and AF.
Over a median follow-up of 5.3 years, 182 (3.4%) participants developed AF. Pre-hypertension and hypertension were associated with an increased risk of AF compared with participants who had optimal blood pressure (optimal: HR=1.0, referent; pre-hypertension: HR=1.8, 95%CI=1.004, 3.2; hypertension: HR=2.6, 95%CI=1.6, 4.4).
Sustained pre-hypertension is associated with an increased risk of AF.
PMCID: PMC4369319  PMID: 25795549
blood pressure; atrial fibrillation; epidemiology; risk factors
6.  Mitral annular calcification and incident atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis 
Europace  2014;17(3):358-363.
The associations of mitral annular calcification (MAC) with atrial fibrillation (AF) risk factors and related outcomes suggest a possible association between MAC and AF. The aim of this study was to examine the association between MAC and AF in a racially and ethnically diverse population.
Methods and results
This analysis included 6641 participants (mean age 62 ± 10 years; 53% women; 27% Blacks; 22% Hispanics; 12% Chinese-Americans) from the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of clinical cardiovascular disease and AF at baseline. The presence of MAC was defined by cardiac computed tomography (CT) as an Agatston score >0. Atrial fibrillation was ascertained by hospital discharge records and from Medicare claims data until 31 December 2010. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between MAC and AF. At baseline, 619 (9.3%) participants had MAC. Over a median follow-up of 8.5 years, 308 (4.6%) participants developed AF. In a multivariable adjusted model, MAC was associated with an increased risk of AF (HR = 1.9, 95% CI = 1.5, 2.5). This association was consistent across subgroups of age, sex, race/ethnicity (Whites vs. non-Whites), hypertension, diabetes, and left atrial enlargement. The addition of MAC to the Framingham Heart Study and CHARGE AF risk scores for AF improved the C-statistics from 0.769 to 0.776 (P = 0.038) and 0.788 to 0.792 (P = 0.089), respectively.
The presence of MAC was predictive of incident AF in MESA. Potentially, these findings suggest a usefulness of cardiac CT to identify individuals at risk for AF.
PMCID: PMC4415068  PMID: 25341740
Mitral annulus calcification; Epidemiology; Atrial fibrillation
7.  Association between Left Atrial Abnormality on ECG and Vascular Brain Injury on MRI in the Cardiovascular Health Study 
Background and Purpose
Emerging evidence suggests that atrial disease is associated with vascular brain injury in the absence of atrial fibrillation (AF).
The Cardiovascular Health Study prospectively enrolled community-dwelling adults ≥65 years of age. Among participants who underwent MRI, we examined associations of ECG left atrial abnormality with brain infarcts and leukoaraiosis. P-wave terminal force in lead V1 (PTFV1) was the primary measure of left atrial abnormality; P-wave area and duration were secondary predictors. We excluded participants with AF before or on their index ECG. Primary outcomes were incident infarcts and worsening leukoaraiosis from initial to follow-up scan approximately 5 years later. Secondary outcomes were prevalent infarcts and degree of leukoaraiosis on initial MRI. Relative risk and linear regression models adjusted for vascular risk factors.
Among 3,129 participants with ≥1 scan, each SD increase in PTFV1 was associated with a 0.05-point (95% CI, 0.0003–0.10) higher baseline white matter grade on a 10-point scale. PTFV1 was associated with prevalent infarcts of any type (RR per SD, 1.09; 95% CI, 1.04–1.16), and more so with prevalent non-lacunar infarcts (RR per SD, 1.22; 95% CI, 1.08–1.38). Among 1,839 participants with 2 scans, PTFV1 was associated with worsening leukoaraiosis (RR per SD, 1.09; 95% CI, 1.01–1.18), but not incident infarcts (RR per SD, 1.06; 95% CI, 0.93–1.20). Sensitivity analyses adjusting for incident AF found similar results. P-wave area and duration were not associated with outcomes.
ECG left atrial abnormality is associated with vascular brain injury in the absence of documented AF.
PMCID: PMC4342300  PMID: 25677594
Arrhythmia; atrium; ECG; embolism; cerebrovascular disease/stroke
8.  Atrial fibrillation incidence and risk factors in relation to race/ethnicity and the population attributable fraction of atrial fibrillation risk factors: the Multi-Ethnic Study of Atherosclerosis 
Annals of epidemiology  2014;25(2):71-76.e1.
We studied incident atrial fibrillation (AF) in the prospective community-based Multi-Ethnic Study of Atherosclerosis (MESA). Reportedly, non-Hispanic blacks (NHBs) have a lower AF burden compared with their non-Hispanic white (NHW) counterparts. Information on the epidemiology of AF in Hispanic and Asian populations is much more limited.
We excluded participants with a history of AF at enrollment. A total of 6721 MESA participants were monitored for the first AF event ascertained according to hospital discharge International Classification of Diseases, Ninth Revision, codes. Age- and sex-adjusted incidence rates (IRs) of AF were calculated per 1000 person-years of observation. IR ratios were calculated using NHWs as the reference group. Age- and sex-adjusted population attributable fractions (PAFs) of established modifiable AF risk factors were ascertained.
In the MESA cohort, 47.2% was male; at baseline, 25.7% had hypertension; 12.5% had diabetes. Three hundred five incident hospitalized AF events occurred over a mean follow-up of 7.3 years. Age- and sex-adjusted IRs and IR ratios showed that overall AF incidence was significantly lower among Hispanics, NHBs and Chinese compared with NHWs (all P < .001). Among participants 65 years of age or greater, Hispanics, Chinese, and blacks had significantly lower AF incidence than NHWs (all P ≥ 01), but IRs were similar among participants under age 65 years. The PAF for smoking was 27% among NHBs but lower among other race–ethnic groups. Among NHWs, the PAF for hypertension was 22.2%, but this was higher among NHBs (33.1%), Chinese (46.3%), and Hispanics (43.9%).
Overall, the incidence of hospitalized AF was significantly lower in Hispanics, NHBs, and Chinese than in NHWs. A larger proportion of AF events appear to be attributable to hypertension among nonwhite populations compared with NHWs.
PMCID: PMC4559265  PMID: 25523897
Atrial fibrillation; epidemiology; Hispanics; Chinese
9.  Utility of lipoprotein particle measures for assessing coronary heart disease risk post-AHA/ACC guidelines: The Multi-Ethnic Study of Atherosclerosis 
The American College of Cardiology and American Heart Association have issued guidelines indicating that the contribution of apolipoprotein B-100 (ApoB) to cardiovascular risk assessment remains uncertain. The present analysis evaluates whether lipoprotein particle measures convey risk of coronary heart disease (CHD) in 4,679 Multi-Ethnic Study of Atherosclerosis (MESA) participants.
Approach and Results
Cox regression analysis was performed to determine associations between lipids or lipoproteins and primary CHD events. Following adjustment for non-lipid variables, lipoprotein particle levels in 4th quartiles were found to convey significantly greater risk of incident CHD compared to 1st quartile levels (hazard ratio (HR); 95% confidence interval (CI)): ApoB (HR: 1.84; CI: 1.25, 2.69), ApoB/ApoA-I (HR: 1.91; CI: 1.32, 2.76), total LDL-particles (LDL-P) (HR: 1.77; CI: 1.21, 2.58), and the LDL-P/HDL-P ratio (HR: 2.28; CI: 1.54, 3.37). Associations between lipoprotein particle measures and CHD were attenuated following adjustment for standard lipid panel variables. Using the AHA/ACC risk calculator as a baseline model for CHD risk assessment, significant net reclassification improvement (NRI) scores were found for ApoB/ApoA-I (0.18 p=0.007), and LDL-P/HDL-P (0.15, p<0.001). C-statistics revealed no significant increase in CHD event discrimination for any lipoprotein measure.
Lipoprotein particle measures ApoB/ApoA-I and LDL-P/HDL-P marginally improved NRI scores, but null findings for corresponding c-statistic are not supportive of lipoprotein testing. The attenuated associations of lipoprotein particle measures with CHD following adjustment for lipids indicate that their measurement does not detect risk that is unaccounted for by the standard lipid panel. However, the possibility that lipoprotein measures may identify CHD risk in a subpopulation of individuals with normal cholesterol but elevated lipoprotein particle numbers cannot be ruled out.
PMCID: PMC4304970  PMID: 25477346
10.  Association of Smoking, Alcohol, and Obesity with Cardiovascular Death and Ischemic Stroke in Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study and Cardiovascular Health Study (CHS) 
PLoS ONE  2016;11(1):e0147065.
Atrial fibrillation (AF) is associated with an increased risk of ischemic stroke and cardiovascular (CV) death. Whether modifiable lifestyle risk factors are associated with these CV outcomes in AF is unknown. Among Atherosclerosis Risk in Communities (ARIC) study and Cardiovascular Health Study (CHS) participants with incident AF, we estimated the risk of composite endpoint of ischemic stroke or CV death associated with candidate modifiable risk factor (smoking, heavy alcohol consumption, or high body mass index [BMI]), and computed the C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) of incorporating each factor into the CHA2DS2-VASc. Among 1222 ARIC (mean age: 63.4) and 756 CHS (mean age: 79.1) participants with incident AF, during mean follow-up of 6.9 years and 5.7 years, there were 332 and 335 composite events respectively. Compared with never smokers, current smokers had a higher incidence of the composite endpoint in ARIC [HR: 1.65 (1.21–2.26)] but not in CHS [HR: 1.05 (0.69–1.61)]. In ARIC, the addition of current smoking did not improve risk prediction over and above the CHA2DS2-VASc. No significant associations were observed with alcohol consumption or BMI with CVD outcomes in AF patients from either cohort. Smoking is associated with an increased risk of ischemic stroke or CV death in ARIC, which comprised mostly middle-aged to young-old (65–74 years), but not in CHS, which comprised mostly middle-old or oldest-old (≥75 years) adults with AF. However, addition of smoking to the CHA2DS2-VASc score did not improve risk prediction of these outcomes.
PMCID: PMC4710457  PMID: 26756465
11.  Brachial Flow-Mediated Dilation and Incident Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis 
It is unknown if endothelial dysfunction precedes atrial fibrillation (AF) development. The objective of this study was to examine the association of brachial flow-mediated dilation (FMD) with incident AF.
Approach and Results
A total of 2,936 participants (mean age 61 ± 9.9; 50% women; 66% non-whites) from the Multi-Ethnic Study of Atherosclerosis with available ultrasound brachial FMD measurements who were free of baseline AF were included in this analysis. Baseline (2000-2002) FMD was computed from the percent difference (%FMD) in brachial artery diameter and maximum diameter during measured vasodilator response. AF was ascertained from hospitalization data including Medicare claims during a median follow-up of 8.5 years. Probability-weighted Cox proportional-hazards regression was used to compute hazard ratios (HR) and 95% confidence intervals (95%CI) for the association between FMD as a continuous variable (%FMD values per 1-SD increase) and incident AF. Incident AF was detected in 137 (4.7%) participants. Those with %FMD values below the sex-specific median value (median %FMD; males=3.6%, females=4.2%) (Incidence rate per 1000 person-years=7.3, 95%CI=5.9, 9.0) were more likely to develop AF than persons whose %FMD values were above the median value (Incidence rate per 1000 person-years=4.5, 95%CI=3.4, 5.8) (log-rank p=0.0043). In a multivariable Cox regression analysis, 1-SD increase in %FMD values (SD=2.8%) was associated with less incident AF (HR=0.84, 95%CI=0.70, 0.99). These results were consistent across subgroups stratified by age, sex, and race/ethnicity.
Smaller brachial FMD values are associated with higher rates of AF, suggesting a role for endothelial dysfunction in AF pathogenesis.
PMCID: PMC4239189  PMID: 25341797
atrial fibrillation; endothelial dysfunction; epidemiology
12.  Telomere Length and the Risk of Atrial Fibrillation: Insights into the Role of Biological versus Chronological Aging 
Advanced age is the most important risk factor for atrial fibrillation (AF), however the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length (ATL) and LTL in cardiac surgery patients.
Methods and Results
Mean LTL and the TERT rs2736100 single nucleotide polymorphism (SNP) were assessed as predictors of incident AF in the Cardiovascular Health Study (CHS). Among the surgical patients, within subject comparison of ATL versus LTL was assessed. Among 1639 CHS participants, we observed no relationship between mean LTL and incident AF prior to and after adjustment for potential confounders (adjusted hazard ratio [HR] 1.09; 95% CI: 0.92–1.29, p=0.299); chronologic age remained strongly associated with AF in the same model. No association was observed between the TERT rs2736100 SNP and incident AF (adjusted HR: 0.95; 95% CI: 0.88–1.04, p=0.265). In 35 cardiac surgery patients (26 with AF), ATL was longer than LTL (1.19 ± 0.20 versus 1.02 ± 0.25 [T/S ratio], p< 0.001), a finding that remained consistent within the AF subgroup.
Our study revealed no evidence of an association between LTL and incident AF and no evidence of relative atrial cell telomere shortening in AF. Chronological aging independent of biological markers of aging is the primary risk factor for AF.
PMCID: PMC4294941  PMID: 25381796
atrial fibrillation; aging; genetics; telomere genetics
13.  Coronary Artery Calcium and Risk of Atrial Fibrillation (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2014;114(11):1707-1712.
Calcified coronary arteries are associated with the development of cardiovascular disease and stroke. It is currently unknown whether coronary artery calcium (CAC) is associated with an increased risk of atrial fibrillation (AF). We addressed this question in 6,641 participants (mean age 62 ± 10; 53% women; 62% non-whites) from the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of baseline clinical cardiovascular disease and AF. CAC measurements were assessed by cardiac computed tomography (CT) at study baseline. AF was ascertained by review of hospital discharge records and from Medicare claims data until December 31, 2010. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (95%CI) for the association between CAC and AF. During a median follow up of 8.5 years, 308 (4.6%) participants developed AF. In a model adjusted for socio-demographics, cardiovascular risk factors, and potential confounders, higher CAC scores were associated with an increased risk of AF (CAC=0: HR=1.0, referent; CAC=1–100: HR=1.4, 95%CI=1.01, 2.0; CAC=101–300: HR=1.6, 95%CI=1.1, 2.4; CAC>300: 2.1, 95%CI=1.4, 2.9). The addition of CAC to the Framingham Heart Study and the CHARGE AF risk scores yielded an integrated discrimination improvement (IDI) of 0.0033 (95%CI=0.0015, 0.0066) and 0.0028 (95%CI=0.0012, 0.0057) and with relative IDI of 0.10 (95%CI=0.061, 0.15) and 0.077 (95%CI=0.040, 0.11), respectively. In conclusion, CAC is independently associated with an increased risk of AF.
PMCID: PMC4253067  PMID: 25282316
coronary calcium; atrial fibrillation; epidemiology
14.  The QT Interval is Associated with Incident Cardiovascular Events in the Multi-Ethnic Study of Atherosclerosis 
Prolonged heart rate-corrected QT interval on the electrocardiogram (ECG) is associated with increased risk of myocardial infarction and cardiovascular disease (CVD)-related death in patients with prevalent coronary heart disease (CHD).
We sought to examine the prognostic association between the baseline QT interval and incident cardiovascular events in individuals without known prior CVD.
The corrected baseline 12-lead ECG QT interval duration (QTcorr) was determined by adjustment for age, sex, race/ethnicity, and RR interval duration in 6,273 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Cox proportional hazards models adjusting for demographic and clinical risk factors were used to examine the association of baseline QTcorr with incident cardiovascular events.
The mean age at enrollment was 61.7 ± 10 years, and 53.4% of participants were women. Cardiovascular events occurred in 291 participants over a mean follow-up of 8.0 ± 1.7 years. Each 10 ms increase in the baseline QTcorr was associated with incident heart failure (HR, 95% confidence interval (CI): 1.25 [1.14 to 1.37]), CVD events (HR, 95% CI: 1.12 [1.05 to 1.20]), and stroke (HR, 95% CI: 1.19 [1.07 to 1.32]) after adjustment for CVD risk factors and potential confounders. There was no evidence of interaction with sex or ethnicity.
The QT interval is associated with incident cardiovascular events in middle-aged and older adults without prior cardiovascular disease.
PMCID: PMC4254697  PMID: 25457400
Cardiovascular Disease; Coronary Heart Disease; Heart failure; Myocardial Infarction; QT interval; Stroke
15.  Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens 
JAMA internal medicine  2014;174(1):25-31.
Little is known about the comparative cardiovascular safety of oral hormone therapy (HT) products, which impedes women from making informed safety decisions about HT treatment of menopausal symptoms.
To compare the relative clinical cardiovascular safety of 2 commonly used oral estrogen drugs, conjugated equine estrogens (CEE) and estradiol (E2).
Population-based, case-control study from 2003 to 2009 comparing cardiovascular event risk associated with current CEE and E2 use.
Large health maintenance organization where the preferred formulary estrogen changed from CEE to E2 during the course of data collection.
384 postmenopausal women 30-79 years of age using oral HT.
Incident venous thrombosis (VT) was the primary clinical outcome and incident myocardial infarction (MI) and ischemic stroke were secondary outcomes. As validation, an intermediate clotting phenotype, endogenous thrombin potential-based normalized activated protein C sensitivity ratio (nAPCsr), was measured in plasma of controls.
We studied 68 VT, 67 MI, and 48 stroke cases, and 201 matched controls; all were current users of oral CEE or E2. In adjusted analyses, compared with current oral E2 use, current oral CEE use was associated with an increased VT risk (OR: 2.08; 95% CI: 1.02-4.27; p-value 0.045), an increased MI risk that did not reach statistical significance (OR: 1.87; 95% CI: 0.91-3.84; p=0.086), and was not associated with stroke risk (OR: 1.13; 95% CI: 0.55-2.31; p=0.736). Among controls (n=140), compared with E2 users, CEE users had higher nAPCsrs (p=0.0002), indicating a stronger clotting propensity.
In an observational study of oral HT users, CEE use was associated with a higher risk of incident VT and possibly MI than E2 use. This risk differential was supported by biologic data. These findings need replication and suggest that various oral estrogen drugs may be associated with different levels of cardiovascular risk.
PMCID: PMC4636198  PMID: 24081194
16.  Elevated hepatic enzymes and incidence of venous thromboembolism: a prospective study 
Annals of epidemiology  2014;24(11):817-821.e2.
Approximately 10 percent of the general population have elevated blood concentrations of hepatic enzymes, which are linked to increased coagulation markers. We tested whether elevated hepatic enzymes are associated with increased risk of venous thromboembolism (VTE).
We followed prospectively for VTE occurrence 12,604 adults with measurements of alanine transaminase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT).
AST and GGT above the laboratory normal were associated over two decades of follow-up with increased risk of total (n = 532) and provoked VTE (n = 332), but with not unprovoked VTE (n = 200). In a model adjusted for age, race, sex, hormone replacement, alcohol intake, diabetes, body mass index, estimated glomerular filtration rate, and C-reactive protein, the hazard ratios (95% CI) for high versus normal AST were 1.46 (1.00, 2.11) for total VTE and 1.83 (1.21, 2.79) for provoked VTE. For high GGT, the hazard ratios were 1.34 (1.06, 1.69) for total VTE and 1.43 (1.07, 1.91) for provoked VTE. When follow-up was limited to the first 10-years, associations were even stronger (hazard ratios ≈ 1.7 for total VTE).
Elevated concentrations of two hepatic enzymes (AST and GGT) in this general middle-aged population are associated with a modestly increased risk of VTE.
PMCID: PMC4254154  PMID: 25277506
Venous thrombosis; Pulmonary embolus; Cohort study; Liver enzymes; Risk factors
17.  Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium 
PLoS ONE  2015;10(10):e0140496.
Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.
Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).
Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10−8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.
PMCID: PMC4627813  PMID: 26516778
18.  Integrating Genetic, Transcriptional, and Functional Analyses to Identify Five Novel Genes for Atrial Fibrillation 
Circulation  2014;130(15):1225-1235.
Atrial fibrillation (AF) affects over 30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood.
Methods & Results
To identify new AF-related genes, we utilized a multifaceted approach, combining large-scale genotyping in two ethnically distinct populations, cis-eQTL mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501, RR=1.18, 95%CI 1.13 – 1.23, p=6.5×10−16), GJA1 (rs13216675, RR=1.10, 95%CI 1.06 – 1.14, p=2.2×10−8), TBX5 (rs10507248, RR=1.12, 95%CI 1.08 – 1.16, p=5.7×10−11), and CAND2 (rs4642101, RR=1.10, 95%CI 1.06 – 1.14, p=9.8×10−9). In Japanese, novel loci were identified near NEURL (rs6584555, RR=1.32, 95%CI 1.26–1.39, p=2.0×10−25) and CUX2 (rs6490029, RR=1.12, 95%CI 1.08–1.16, p=3.9×10−9). The top SNPs or their proxies were identified as cis-eQTLs for the genes CAND2 (p=2.6×10−19), GJA1 (p=2.66×10−6), and TBX5 (p=1.36×10−05). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively).
We have identified five novel loci for AF. Our results further expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.
PMCID: PMC4190011  PMID: 25124494
atrial fibrillation; genetics; epidemiology; expression; functional analysis; zebrafish
19.  B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies 
Europace  2014;16(10):1426-1433.
B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.
Methods and results
We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56–1.76], P < 0.0001 and 1.18 (95% CI, 1.11–1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ2 = 17.0; CRP, χ2 = 10.5; BNP and CRP, χ2 = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022–0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322–0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.
B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.
PMCID: PMC4197895  PMID: 25037055
Atrial fibrillation; Risk prediction; Epidemiology; Biomarker; B-type natriuretic peptide; C-reactive protein
20.  Multi-Ethnic Study of Atherosclerosis: Association between Left Atrial Function Using Tissue Tracking from Cine MR Imaging and Myocardial Fibrosis 
Radiology  2014;273(3):703-713.
Reduced regional and global functions of the left atrium are related to both regional replacement and diffuse myocardial fibrosis processes.
To investigate the association between left atrial (LAleft atrium) function and left ventricular myocardial fibrosis using cardiac magnetic resonance (MR) imaging in a multi-ethnic population.
Materials and Methods
For this HIPAA-compliant study, the institutional review board at each participating center approved the study protocol, and all participants provided informed consent. Of 2839 participants who had undergone cardiac MR in 2010–2012, 143 participants with myocardial scar determined with late gadolinium enhancement and 286 age-, sex-, and ethnicity-matched control participants were identified. LAleft atrium volume, strain, and strain rate were analyzed by using multimodality tissue tracking from cine MR imaging. T1 mapping was applied to assess diffuse myocardial fibrosis. The association between LAleft atrium parameters and myocardial fibrosis was evaluated with the Student t test and multivariable regression analysis.
The scar group had significantly higher minimum LAleft atrium volume than the control group (mean, 22.0 ± 10.5 [standard deviation] vs 19.0 ± 7.8, P = .002) and lower LAleft atrium ejection fraction (45.9 ± 10.7 vs 51.3 ± 8.7, P < .001), maximal LAleft atrium strain (Smaxmaximum LA strain) (25.4 ± 10.7 vs 30.6 ± 10.6, P < .001) and maximum LAleft atrium strain rate (SRmaxmaximum LA strain rate) (1.08 ± 0.45 vs 1.29 ± 0.51, P < .001), and lower absolute LAleft atrium strain rate at early diastolic peak (SRELA strain rate at early diastolic peak) (−0.77 ± 0.42 vs −1.01 ± 0.48, P < .001) and LAleft atrium strain rate at atrial contraction peak (SRALA strain rate at atrial contraction peak) (−1.50 ± 0.62 vs −1.78 ± 0.69, P < .001) than the control group. T1 time 12 minutes after contrast material injection was significantly associated with Smaxmaximum LA strain (β coefficient = 0.043, P = .013), SRmaxmaximum LA strain rate (β coefficient = 0.0025, P = .001), SRELA strain rate at early diastolic peak (β coefficient = −0.0016, P = .027), and SRALA strain rate at atrial contraction peakLA strain rate at atrial contraction peak (β coefficient −0.0028, P = .01) in the regression model. T1 time 25 minutes after contrast material injection was significantly associated with SRmaxmaximum LA strain rate (β coefficient = 0.0019, P = .016) and SRALA strain rate at atrial contraction peak (β coefficient = −0.0022, P = .034).
Reduced LAleft atrium regional and global function are related to both replacement and diffuse myocardial fibrosis processes.
Clinical trial registration no. NCT00005487
© RSNA, 2014
Online supplemental material is available for this article.
PMCID: PMC4314120  PMID: 25019562
21.  P-Wave Morphology and the Risk of Incident Ischemic Stroke in the Multi-Ethnic Study of Atherosclerosis 
Background and Purpose
Emerging data suggest that left atrial disease may cause ischemic stroke in the absence of atrial fibrillation or flutter (AF). If true, this condition may provide an etiology for many strokes currently classified as cryptogenic.
Among 6,741 participants in the Multi-Ethnic Study of Atherosclerosis who were free of clinically apparent cerebrovascular or cardiovascular disease (including AF) at baseline, we examined the association between markers of left atrial abnormality on a standard 12-lead electrocardiogram (ECG)—specifically, P-wave area, duration, and terminal force in lead V1 (PTFV1)—and the subsequent risk of ischemic stroke while accounting for incident AF.
During a median follow-up of 8.5 years, 121 participants (1.8%) suffered a stroke and 541 participants (8.0%) were diagnosed with AF. In Cox proportional hazards models adjusting for potential baseline confounders, PTFV1 was more strongly associated with incident stroke (hazard ratio [HR] per 1-SD increase, 1.21; 95% confidence interval [CI], 1.02–1.44) than with incident AF (HR per 1-SD, 1.11; 95% CI, 1.03–1.21). The association between PTFV1 and stroke was robust in numerous sensitivity analyses accounting for AF, including analyses that excluded those with any incident AF or modeled any incident AF as having been present from baseline.
We found an association between baseline P-wave morphology and incident stroke even after accounting for AF. This association may reflect an atrial cardiopathy that leads to stroke in the absence of AF.
PMCID: PMC4146624  PMID: 25052322
Arrhythmia; atrium; electrocardiography; embolism; stroke
22.  Use of Medicare Data to Identify Coronary Heart Disease Outcomes In the Women's Health Initiative (WHI) 
Data collected as part of routine clinical practice could be used to detect cardiovascular outcomes in pragmatic clinical trials, or in clinical registry studies. The reliability of claims data for documenting outcomes is unknown.
Methods and Results
We linked records of Women's Health Initiative (WHI) participants aged 65 years and older to Medicare claims data, and compared hospitalizations that had diagnosis codes for acute myocardial infarction (MI) or coronary revascularization with WHI outcomes adjudicated by study physicians. We then compared the hazard ratios for active versus placebo hormone therapy based solely on WHI adjudicated events with corresponding hazard ratios based solely on claims data for the same hormone trial participants.
Agreement between WHI adjudicated outcomes and Medicare claims was good for the diagnosis for MI (kappa = 0.71 to 0.74), and excellent for coronary revascularization (kappa=0.88 to 0.91). The hormone:placebo hazard ratio for clinical MI was 1.31 (95% confidence interval (CI) 1.03 to 1.67) based on WHI outcomes, and 1.29 (CI 1.00 to 1.68) based on Medicare data. The hazard ratio for coronary revascularization was 1.09 (CI 0.88 to 1.35) based on WHI outcomes and 1.10 (CI 0.89 to 1.35) based on Medicare data. The differences between hazard ratios derived from WHI and Medicare data were not significant in 1,000 bootstrap replications.
Medicare claims may provide useful data on coronary heart disease outcomes among patients aged 65 years and older in clinical research studies.
Clinical Trials Registration Information, Trial Number NCT00000611
PMCID: PMC4548886  PMID: 24399330
outcomes research; research design; randomized controlled trials
23.  Serial measures of cardiac troponin T levels by a highly sensitive assay and incident atrial fibrillation in a prospective cohort of ambulatory older adults 
Various mechanisms in cardiac remodeling related to atrial fibrillation (AF) lead to elevated circulating cardiac troponin levels, but little is known about such elevations upstream to AF onset.
The purpose of this study was to study the association between circulating troponin levels as assessed by a highly sensitive cardiac troponin T (hs-cTnT) assay and incident atrial fibrillation (AF).
In a large prospective cohort of ambulatory older adults [the Cardiovascular Health Study (CHS)], hs-cTnT levels were measured in sera that were collected at enrollment from 4262 participants without AF (2871 with follow-up measurements). Incident AF was identified by electrocardiograms during CHS visits, hospital discharge diagnoses, and Medicare files, including outpatient and physician claims diagnoses.
Over median follow-up of 11.2 years (interquartile range 6.1–16.5), 1363 participants (32.0%) developed AF. Higher baseline levels of hs-cTnT were associated with incident AF in covariate-adjusted analyses accounting for demographics, traditional risk factors, and incident heart failure in time-dependent analyzes (hazard ratio for 3rd tertile vs undetectable 1.75, 95% confidence interval 1.48–2.08). This association was statistically significant in analyses that additionally adjusted for biomarkers of inflammation and hemodynamic strain (hazard ratio for 3rd tertile vs undetectable 1.38, 95% confidence interval 1.16–1.65). Significant associations were also found when hs-cTnT levels were treated as a continuous variable and when examining change from baseline of hs-cTnT levels and incident AF.
The findings show a significant association of circulating troponin levels in ambulatory older adults with incident AF beyond that of traditional risk factors, incident heart failure, and biomarkers of inflammation and hemodynamic strain.
PMCID: PMC4546831  PMID: 25602173
Atrial fibrillation; Biomarker; Cardiac remodeling Aging
24.  Relation of Systolic, Diastolic, and Pulse Pressures and Aortic Distensibility with Atrial Fibrillation (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2014;114(4):587-592.
Previous research suggests that elevated pulse pressure (PP) is a risk factor for atrial fibrillation (AF) independently of mean arterial pressure (MAP). PP may serve as an indirect measure of aortic stiffness (reduced distensibility), but whether directly-measured aortic distensibility is related to risk of AF has not yet been studied. This analysis included 6,630 participants aged 45-84 years from the Multi-Ethnic Study of Atherosclerosis (MESA). At baseline, blood pressure (BP) and other relevant covariates were measured using standardized protocols. Magnetic resonance imaging-based aortic distensibility was measured in 3,441 participants. Incident AF was identified from hospitalization discharge codes and Medicare claims. Multivariable Cox models were used to estimate the association of BP components and aortic distensibility with AF risk. During a mean follow-up of 7.8 years, 307 AF events (137 among those with aortic distensibility measurements) were identified. In multivariable adjusted models simultaneously including MAP and PP, each 1-standard deviation increase in PP was associated with a 29% increased risk of AF (95% CI: 5%, 59%, p=0.02), with MAP not being associated with increased AF risk. Overall, aortic distensibility was not consistently associated with AF risk: after removing outliers, each 1-standard deviation increase in aortic distensibility was associated with a 9% increased risk of AF (95% CI: - 22%, 51%, p=0.63). In conclusion, in this large community-based cohort, we found that PP, but not MAP or aortic distensibility, was a significant risk factor for AF, emphasizing the importance of PP when assessing the risk of developing AF. Our results cast doubt upon the clinical utility of aortic distensibility as a predictor for the development of AF.
PMCID: PMC4119835  PMID: 24996553
blood pressure; atrial fibrillation; epidemiology
25.  Incidence of and Risk Factors for Sick Sinus Syndrome in the General Population 
Little is known about the incidence of and risk factors for sick sinus syndrome (SSS), a common indication for pacemaker implantation.
To describe the epidemiology of SSS.
This analysis included 20,572 participants (mean baseline age 59 years, 43% male) in the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS), who at baseline were free of prevalent atrial fibrillation and pacemaker therapy, had a heart rate of ≥50 bpm unless using beta blockers, and were identified as white or black race. Incident SSS cases were identified by hospital discharge ICD-9-CM code 427.81 and validated by medical record review.
During an average 17 years of follow-up, 291 incident SSS cases were identified (unadjusted rate 0.8 per 1,000 person-years). Incidence increased with age (HR 1.73, 95% CI: 1.47–2.05 per 5-year increment), and blacks had a 41% lower risk of SSS than whites (HR: 0.59, 95% CI: 0.37–0.98). Incident SSS was associated with greater baseline body mass index, height, NT-proBNP, and cystatin C, with longer QRS interval, with lower heart rate, and with prevalent hypertension, right bundle branch block, and cardiovascular disease. We project that the annual number of new SSS cases in the United States will increase from 78,000 in 2012 to 172,000 in 2060.
Blacks have a lower risk of SSS than whites, and several cardiovascular risk factors were associated with incident SSS. With the aging of the population, the number of Americans with SSS will increase dramatically over the next 50 years.
PMCID: PMC4139053  PMID: 25104519
Sick Sinus Syndrome; Tachy-brady syndrome; Pacemaker; Epidemiology

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