Search tips
Search criteria

Results 1-25 (71)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
Document Types
1.  Methylomics of gene expression in human monocytes 
Human Molecular Genetics  2013;22(24):5065-5074.
DNA methylation is one of several epigenetic mechanisms that contribute to the regulation of gene expression; however, the extent to which methylation of CpG dinucleotides correlates with gene expression at the genome-wide level is still largely unknown. Using purified primary monocytes from subjects in a large community-based cohort (n = 1264), we characterized methylation (>485 000 CpG sites) and mRNA expression (>48K transcripts) and carried out genome-wide association analyses of 8370 expression phenotypes. We identified 11 203 potential cis-acting CpG loci whose degree of methylation was associated with gene expression (eMS) at a false discovery rate threshold of 0.001. Most of the associations were consistent in effect size and direction of effect across sex and three ethnicities. Contrary to expectation, these eMS were not predominately enriched in promoter regions, or CpG islands, but rather in the 3′ UTR, gene bodies, CpG shores or ‘offshore’ sites, and both positive and negative correlations between methylation and expression were observed across all locations. eMS were enriched for regions predicted to be regulatory by ENCODE (Encyclopedia of DNA Elements) data in multiple cell types, particularly enhancers. One of the strongest association signals detected (P < 2.2 × 10−308) was a methylation probe (cg17005068) in the promoter/enhancer region of the glutathione S-transferase theta 1 gene (GSTT1, encoding the detoxification enzyme) with GSTT1 mRNA expression. Our study provides a detailed description of the epigenetic architecture in human monocytes and its relationship to gene expression. These data may help prioritize interrogation of biologically relevant methylation loci and provide new insights into the epigenetic basis of human health and diseases.
PMCID: PMC3836482  PMID: 23900078
2.  Prediction of mortality using a multi-bed vascular calcification score in the Diabetes Heart Study 
Cardiovascular Diabetology  2014;13(1):160.
Vascular calcified plaque, a measure of subclinical cardiovascular disease (CVD), is unlikely to be limited to a single vascular bed in patients with multiple risk factors. Consideration of vascular calcified plaque as a global phenomenon may allow for a more accurate assessment of the CVD burden. The aim of this study was to examine the utility of a combined vascular calcified plaque score in the prediction of mortality.
Vascular calcified plaque scores from the coronary, carotid, and abdominal aortic vascular beds and a derived multi-bed score were examined for associations with all-cause and CVD-mortality in 699 European-American type 2 diabetes (T2D) affected individuals from the Diabetes Heart Study. The ability of calcified plaque to improve prediction beyond Framingham risk factors was assessed.
Over 8.4 ± 2.3 years (mean ± standard deviation) of follow-up, 156 (22.3%) participants were deceased, 74 (10.6%) from CVD causes. All calcified plaque scores were significantly associated with all-cause (HR: 1.4-1.8; p < 1x10−5) and CVD-mortality (HR: 1.5-1.9; p < 1×10−4) following adjustment for Framingham risk factors. Associations were strongest for coronary calcified plaque. Improvement in prediction of outcome beyond Framingham risk factors was greatest using coronary calcified plaque for all-cause mortality (AUC: 0.720 to 0.757, p = 0.004) and the multi-bed score for CVD mortality (AUC: 0.731 to 0.767, p = 0.008).
Although coronary calcified plaque and the multi-bed score were the strongest predictors of all-cause mortality and CVD-mortality respectively in this T2D-affected sample, carotid and abdominal aortic calcified plaque scores also significantly improved prediction of outcome beyond traditional risk factors and should not be discounted as risk stratification tools.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-014-0160-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4266952  PMID: 25496604
Vascular calcified plaque; Mortality; Computed tomography; Type 2 diabetes
3.  Mediators of Atherosclerosis in South Asians Living in America (MASALA) study: Objectives, Methods, and Cohort Description 
Clinical cardiology  2013;36(12):713-720.
South Asians (individuals from India, Pakistani, Bangladesh, Nepal, and Sri Lanka) have high rates of cardiovascular disease which cannot be explained by traditional risk factors. There are no prospective cohort studies investigating antecedents of cardiovascular disease in South Asians.
The Mediators of Atherosclerosis in South Asians Living in America (MASALA) study is investigating the prevalence, correlates and outcomes associated with subclinical cardiovascular disease (CVD) in a population-based sample of South Asian men and women between ages 40 – 79 years from two U.S. clinical field centers. This cohort is similar in methods and measures to the Multi-Ethnic Study of Atherosclerosis to allow for efficient cross-ethnic comparisons. Measurements obtained at the baseline examination include sociodemographic information, lifestyle and psychosocial factors, standard CVD risk factors, oral glucose tolerance testing, electrocardiogram, assessment of microalbuminuria, ankle and brachial blood pressures, carotid intima media wall thickness using ultrasonagraphy, coronary artery calcium measurement and abdominal visceral fat using computed tomography. Blood samples will be assayed for biochemical risk factors.
Between October 2010 and March 2013 we enrolled 906 South Asians with mean age of 55±9 years, 46% women, 98% immigrants who have lived 27±11 years in the US.
The sociodemographic characteristics of this cohort are representative of US South Asians. Participants are being followed with annual telephone calls for identification of CVD events including acute myocardial infarction and other coronary heart disease, stroke, peripheral vascular disease, congestive heart failure, therapeutic interventions for CVD, and mortality.
PMCID: PMC3947423  PMID: 24194499
4.  Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins 
Postmus, Iris | Trompet, Stella | Deshmukh, Harshal A. | Barnes, Michael R. | Li, Xiaohui | Warren, Helen R. | Chasman, Daniel I. | Zhou, Kaixin | Arsenault, Benoit J. | Donnelly, Louise A. | Wiggins, Kerri L. | Avery, Christy L. | Griffin, Paula | Feng, QiPing | Taylor, Kent D. | Li, Guo | Evans, Daniel S. | Smith, Albert V. | de Keyser, Catherine E. | Johnson, Andrew D. | de Craen, Anton J. M. | Stott, David J. | Buckley, Brendan M. | Ford, Ian | Westendorp, Rudi G. J. | Eline Slagboom, P. | Sattar, Naveed | Munroe, Patricia B. | Sever, Peter | Poulter, Neil | Stanton, Alice | Shields, Denis C. | O’Brien, Eoin | Shaw-Hawkins, Sue | Ida Chen, Y.-D. | Nickerson, Deborah A. | Smith, Joshua D. | Pierre Dubé, Marie | Matthijs Boekholdt, S. | Kees Hovingh, G. | Kastelein, John J. P. | McKeigue, Paul M. | Betteridge, John | Neil, Andrew | Durrington, Paul N. | Doney, Alex | Carr, Fiona | Morris, Andrew | McCarthy, Mark I. | Groop, Leif | Ahlqvist, Emma | Bis, Joshua C. | Rice, Kenneth | Smith, Nicholas L. | Lumley, Thomas | Whitsel, Eric A. | Stürmer, Til | Boerwinkle, Eric | Ngwa, Julius S. | O’Donnell, Christopher J. | Vasan, Ramachandran S. | Wei, Wei-Qi | Wilke, Russell A. | Liu, Ching-Ti | Sun, Fangui | Guo, Xiuqing | Heckbert, Susan R | Post, Wendy | Sotoodehnia, Nona | Arnold, Alice M. | Stafford, Jeanette M. | Ding, Jingzhong | Herrington, David M. | Kritchevsky, Stephen B. | Eiriksdottir, Gudny | Launer, Leonore J. | Harris, Tamara B. | Chu, Audrey Y. | Giulianini, Franco | MacFadyen, Jean G. | Barratt, Bryan J. | Nyberg, Fredrik | Stricker, Bruno H. | Uitterlinden, André G. | Hofman, Albert | Rivadeneira, Fernando | Emilsson, Valur | Franco, Oscar H. | Ridker, Paul M. | Gudnason, Vilmundur | Liu, Yongmei | Denny, Joshua C. | Ballantyne, Christie M. | Rotter, Jerome I. | Adrienne Cupples, L. | Psaty, Bruce M. | Palmer, Colin N. A. | Tardif, Jean-Claude | Colhoun, Helen M. | Hitman, Graham | Krauss, Ronald M. | Wouter Jukema, J | Caulfield, Mark J.
Nature Communications  2014;5:5068.
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
Statins are effectively used to prevent and manage cardiovascular disease, but patient response to these drugs is highly variable. Here, the authors identify two new genes associated with the response of LDL cholesterol to statins and advance our understanding of the genetic basis of drug response.
PMCID: PMC4220464  PMID: 25350695
5.  Comparison of Novel Risk Markers for Improvement in Cardiovascular Risk Assessment in Intermediate Risk Individuals. The Multi-Ethnic Study of Atherosclerosis 
Risk markers including coronary artery calcium (CAC), carotid intima-media thickness (CIMT), ankle-brachial Index (ABI), brachial flow-mediated dilation (FMD), high sensitivity C -reactive protein (hs-CRP) and family history (FH) of coronary heart disease (CHD) have been reported to improve on the Framingham risk score (FRS) for prediction of CHD. However, there are no direct comparisons of these markers for risk prediction in a single cohort.
We compared improvement in prediction of incident CHD/cardiovascular disease (CVD) of these 6 risk markers within intermediate risk participants (5 % < FRS < 20%) in the Multi-Ethnic Study of Atherosclerosis (MESA).
Design, Setting and Participants
Of 6814 MESA participants from 6 US field centers, 1330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002; follow-up extended through May 2011. Probability- weighted Cox proportional hazard models were used to estimate hazard ratios (HR). Area under the receiver operator characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare incremental contributions of each marker when added to the FRS + race/ethnicity.
Main Outcome Measures
Incident CHD defined as MI, angina followed by revascularization, resuscitated cardiac arrest or CHD death. Incident CVD additionally included stroke or CVD death.
After median follow-up of 7.6 years (IQR 7.3 – 7.8 years), 94 CHD and 123 CVD events occurred. CAC, ABI, hs-CRP and FH were independently associated with incident CHD in multivariable analyses [HR (95%CI: 2.60(1.94-3.50), 0.79(0.66-0.95), 1.28(1.00-1.64) and 2.18(1.38-3.42) respectively]. CIMT and FMD were not associated with incident CHD in multivariable analyses [HR (95%CI) 1.17(0.95- 1.45) and 0.95(0.78 −1.14) respectively]. Although the addition of the markers individually to the FRS +race/ethnicity improved the AUC, CAC afforded the highest increment (0.623 vs. 0.784) while FMD afforded the least [0.623 vs. 0.639]. For incident CHD, the NRI with CAC was 0.659, FMD 0.024, ABI 0.036, CIMT 0.102, FH 0.160 and hs-CRP 0.079. Similar results were obtained for incident CVD.
CAC, ABI, hs-CRP and FH are independent predictors of incident CHD/CVD in intermediate risk individuals. CAC provides superior discrimination and risk reclassification compared with other risk markers.
PMCID: PMC4141475  PMID: 22910756
6.  Relation of Short-Term Heart Rate Variability to Incident Heart Failure (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2013;112(4):533-540.
Whether autonomic dysfunction predates the development of symptomatic heart failure (HF), or is simply a consequence of severe HF, is unknown. We hypothesized that reduced heart rate variability (HRV, a marker of abnormal autonomic function) at baseline is associated with incident HF in individuals free of clinically recognized cardiovascular disease. In the Multi- Ethnic Study of Atherosclerosis (MESA), a community-based study of subclinical cardiovascular disease in adults age 45–84 years, we measured HRV using a standard 30-second 12-lead electrocardiogram to measure the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive differences in R-R intervals (RMSSD). During a median follow-up of 7.6 years, 95 participants developed HF (incidence rate, 2.7/1000 person-years). After adjusting for age, sex, and ethnicity, hazard ratios for incident HF by RMSSD tertile were 2.4 (95% confidence interval [CI] 1.4–4.2) for the lowest tertile and 1.7 (95% CI 1.0–3.2) for the middle tertile (highest tertile = referent group; P for trend<0.001). The inverse association between RMSSD and incident HF persisted after adjustment for additional covariates, including diabetes, systolic blood pressure, heart rate, subclinical atherosclerosis, left ventricular endsystolic volume, interim myocardial infarction, and high sensitivity C-reactive protein (P for trend=0.009). A similarly significant inverse association was also observed for SDNN. In conclusion, baseline autonomic dysfunction is risk factor for the development of HF in a multiethnic cohort. These population-based findings implicate autonomic dysfunction in the pathogenesis of HF, and decreased short-term HRV may be a novel form of Stage B (asymptomatic) HF.
PMCID: PMC3735865  PMID: 23683953
autonomic nervous system; heart rate variability; heart failure; epidemiology
7.  Effect of Endurance Exercise Training on Endothelial function and Arterial Stiffness in Older Patients with Heart Failure and Preserved Ejection Fraction: A Randomized, Controlled, Single-Blind Trial 
To evaluate the effects of endurance exercise training (ET) on endothelial dependent flow-mediated arterial dilation (FMD) and carotid artery stiffness and their potential contributions to the training-related increase in peak exercise oxygen consumption (VO2) in older patients with heart failure with preserved ejection fraction (HFPEF).
Elderly HFFEF patients have severely reduced peak VO2 which improves with ET, however the mechanisms of this improvement are unclear. FMD and arterial distensibility are critical components of the exercise response and are reduced with aging. However, it's unknown whether these improve with ET in elderly HFPEF or contribute to the training-related improvement in peak VO2.
63 HFPEF patients (70±7 years) were randomized to 16 weeks of ET (walking, arm and leg ergometry, n=32) or attention control (CT; n=31). Peak VO2, brachial artery FMD in response to cuff ischemia, carotid artery distensibility by high-resolution ultrasound, LV function, and QOL were measured at baseline and follow-up.
ET increased peak VO2 (ET: 15.8±3.3 vs. CT: 13.8±3.1 ml/kg/min, p=0.0001) and QOL. However, brachial artery FMD (ET: 3.8±3.0% vs. CT: 4.3±3.5%, p=0.88), and carotid arterial distensibility (ET: 0.97±0.56 vs. CT: 1.07±0.34 × 10-3mm × mmHg-1 p=0.65) were unchanged. Resting LV systolic and diastolic function were unchanged by ET.
In elderly HFPEF patients, 16 weeks of ET improved peak VO2 without altering endothelial function or arterial stiffness. This suggests that other mechanisms, such as enhanced skeletal muscle perfusion and / or oxygen utilization, may be responsible for the ET-mediated increase in peak VO2 in older HFPEF patients.
PMCID: PMC3740089  PMID: 23665370
Heart Failure; Preserved ejection fraction; exercise; aging
8.  Atrial Fibrillation and the Risk of Myocardial Infarction 
JAMA internal medicine  2014;174(1):107-114.
Myocardial infarction (MI) is an established risk factor for atrial fibrillation (AF). However, the extent to which AF is a risk factor for MI has not been investigated.
To examine the risk of incident MI associated with AF.
A prospective cohort of 23 928 participants residing in the continental United States and without coronary heart disease at baseline were enrolled from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort between 2003 and 2007, with follow-up through December 2009.
Expert-adjudicated total MI events (fatal and nonfatal).
Over 6.9 years of follow-up (median 4.5 years), 648 incident MI events occurred. In a sociodemographic-adjusted model, AF was associated with about 2-fold increased risk of MI (hazard ratio [HR], 1.96 [95% CI, 1.52–2.52]). This association remained significant (HR, 1.70 [95% CI, 1.26–2.30]) after further adjustment for total cholesterol, high-density lipoprotein cholesterol, smoking status, systolic blood pressure, blood pressure–lowering drugs, body mass index, diabetes, warfarin use, aspirin use, statin use, history of stroke and vascular disease, estimated glomerular filtration rate, albumin to creatinine ratio, and C-reactive protein level. In subgroup analysis, the risk of MI associated with AF was significantly higher in women (HR, 2.16 [95% CI, 1.41–3.31]) than in men (HR, 1.39 [95% CI, 0.91–2.10]) and in blacks (HR, 2.53 [95% CI, 1.67–3.86]) than in whites (HR, 1.26 [95% CI, 0.83–1.93]); for interactions, P = .03 and P = .02, respectively. On the other hand, there were no significant differences in the risk of MI associated with AF in older (≥75 years) vs younger (<75 years) participants (HR, 2.00 [95% CI, 1.16–3.35] and HR, 1.60 [95% CI, 1.11–2.30], respectively); for interaction, P = .44.
AF is independently associated with an increased risk of incident MI, especially in women and blacks. These findings add to the growing concerns of the seriousness of AF as a public health burden: in addition to being a well-known risk factor for stroke, AF is also associated with increased risk of MI.
PMCID: PMC4115282  PMID: 24190540
9.  Relationship Between Brachial Flow - Mediated Dilation and Carotid Intima- Media Thickness in an Elderly Cohort: The Cardiovascular Health Study 
Atherosclerosis  2007;197(2):840-845.
The aim of this study was to determine the relationship between brachial flow-mediated dilation (FMD) and carotid intima-media thickness (IMT) in a large multi-ethnic elderly cohort.
Brachial flow-mediated dilation (FMD) is a physiologic measure and Carotid IMT is an anatomic structural measure of subclinical atherosclerosis. Both brachial FMD and carotid IMT have been associated with cardiovascular risk factors and cardiovascular events. The relationship between brachial FMD and carotid IMT is less clear especially in older adults.
Brachial FMD, carotid IMT and traditional cardiovascular risk factors were measured in 2338 adults, age 72–98 years who were participants in the Cardiovascular Health Study. The relationship between FMD and IMT was assessed both unadjusted and also after adjusting for age, gender, race/ethnicity. BMI, HDL, LDL, systolic and diastolic blood pressure, serum creatinine, current smoking, diabetes mellitus, hormone therapy and prior CVD.
Both brachial FMD and carotid IMT correlated significantly with age, HDL levels, waist/hip ratio, serum cholesterol and number of CV risk factors. Brachial FMD was not associated with CCA IMT in this elderly cohort (Pearson partial correlation coefficient= −0.0252, p=0.222). In the adjusted linear regression model with CCA IMT as the dependent variable, brachial FMD was also not associated with CCA IMT (beta coefficient= −0.006, p=0.470)
Brachial FMD and CCA IMT are not related in population-based older adults. Brachial FMD and CCA IMT may be distinct and independent stages in the complex atherosclerotic process.
PMCID: PMC4115586  PMID: 17804000
Brachial flow-mediated dilation; carotid intima-media thickness; endothelial function; atherosclerosis; elderly
Atherosclerosis  2007;197(2):768-776.
The association of brachial flow-mediated dilation (FMD) and cardiovascular disease (CVD) status is unclear especially in older adults whose FMD is greatly diminished. We assessed the association of FMD and the presence or absence of subclinical and clinical CVD in a population based cohort of older adults.
FMD was measured in 2971 adults aged 72–98 years (mean age 78.6 years) who participated in the Cardiovascular Health Study. Multiple linear regression analysis was used to examine the association between FMD and CVD status (clinical, subclinical and free of CVD). Out of 2791 with complete data, 82.7% were Caucasians and 59% females. 743 were classified as having clinical CVD, 607 as subclinical CVD and 1441 as neither clinical CVD nor subclinical CVD (CVD free). FMD was higher in the CVD free group compared with either the clinical (3.13 ± 0.05% vs 2.93 ± 0.07%, p=0.025) or the subclinical CVD group (3.13± 0.05% vs 2.95± 0.08%, p=0.05) after adjusting for covariates. There was no significant difference between the FMD of subjects with clinical and subclinical CVD (2.93 ± 0.07% vs 2.95 ± 0.08%, p=0.84). Similar but inverted associations were observed between height adjusted brachial artery diameter (BAD) and CVD status. However, FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD.
Among older adults, those with either clinical or subclinical CVD have lower FMD than CVD free subjects. BAD showed similar but inverted associations with CVD status in this cohort. FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD.
PMCID: PMC4115610  PMID: 17714717
Brachial flow-mediated dilation; brachial artery diameter; cardiovascular disease; elderly
11.  Knowledge-fused differential dependency network models for detecting significant rewiring in biological networks 
BMC Systems Biology  2014;8:87.
Modeling biological networks serves as both a major goal and an effective tool of systems biology in studying mechanisms that orchestrate the activities of gene products in cells. Biological networks are context-specific and dynamic in nature. To systematically characterize the selectively activated regulatory components and mechanisms, modeling tools must be able to effectively distinguish significant rewiring from random background fluctuations. While differential networks cannot be constructed by existing knowledge alone, novel incorporation of prior knowledge into data-driven approaches can improve the robustness and biological relevance of network inference. However, the major unresolved roadblocks include: big solution space but a small sample size; highly complex networks; imperfect prior knowledge; missing significance assessment; and heuristic structural parameter learning.
To address these challenges, we formulated the inference of differential dependency networks that incorporate both conditional data and prior knowledge as a convex optimization problem, and developed an efficient learning algorithm to jointly infer the conserved biological network and the significant rewiring across different conditions. We used a novel sampling scheme to estimate the expected error rate due to “random” knowledge. Based on that scheme, we developed a strategy that fully exploits the benefit of this data-knowledge integrated approach. We demonstrated and validated the principle and performance of our method using synthetic datasets. We then applied our method to yeast cell line and breast cancer microarray data and obtained biologically plausible results. The open-source R software package and the experimental data are freely available at
Experiments on both synthetic and real data demonstrate the effectiveness of the knowledge-fused differential dependency network in revealing the statistically significant rewiring in biological networks. The method efficiently leverages data-driven evidence and existing biological knowledge while remaining robust to the false positive edges in the prior knowledge. The identified network rewiring events are supported by previous studies in the literature and also provide new mechanistic insight into the biological systems. We expect the knowledge-fused differential dependency network analysis, together with the open-source R package, to be an important and useful bioinformatics tool in biological network analyses.
PMCID: PMC4131167  PMID: 25055984
Biological networks; Probabilistic graphical models; Differential dependency network; Network rewiring; Network analysis; Systems biology; Knowledge incorporation; Convex optimization
12.  Statin Therapy and Levels of Hemostatic Factors in a Healthy Population: the Multi-Ethnic Study of Atherosclerosis 
HMG CoA reductase inhibitors (statins) reduce risk of venous thromboembolism (VTE) in healthy people. Statins reduce levels of inflammation biomarkers, however the mechanism for reduction in VTE risk is unknown. In a large cohort of healthy people, we studied associations of statin use with plasma hemostatic factors related to VTE risk.
Cross-sectional analyses were performed in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of 6814 healthy men and women age 45–84, free of clinical cardiovascular disease at baseline; 1001 were using statins at baseline. Twenty-three warfarin users were excluded. Age, race, and sex-adjusted mean hemostatic factor levels were compared between statin users and nonusers, and multivariable linear regression models were used to assess associations of statin use with hemostasis factors, adjusted for age, race/ethnicity, education, income, hormone replacement therapy (in women), and major cardiovascular risk factors.
Participants using statins had lower adjusted levels of D-dimer (−9%), C-reactive protein (−21%) and factor VIII (−3%) than non-users (p<0.05). Homocysteine and von Willebrand factor were non-significantly lower with statin use. Higher fibrinogen (2%) and PAI-1 (22%) levels were observed among statin users than nonusers (p<0.05). Further adjustment for LDL and triglyceride levels did not attenuate the observed differences in these factors by statin use.
Findings of lower D-dimer, factor VIII and C-reactive protein levels with statin use suggest hypotheses for mechanisms whereby statins might lower VTE risk. A prospective study or clinical trial linking these biochemical differences to VTE outcomes in statin users and nonusers is warranted.
PMCID: PMC3702638  PMID: 23565981
statins; thrombosis; risk factor; blood coagulation; inflammation; fibrinolysis
13.  DNA Methylation in an Enhancer Region of the FADS Cluster Is Associated with FADS Activity in Human Liver 
PLoS ONE  2014;9(5):e97510.
Levels of omega-6 (n-6) and omega-3 (n-3), long chain polyunsaturated fatty acids (LcPUFAs) such as arachidonic acid (AA; 20∶4, n-6), eicosapentaenoic acid (EPA; 20∶5, n-3) and docosahexaenoic acid (DHA; 22∶6, n-3) impact a wide range of biological activities, including immune signaling, inflammation, and brain development and function. Two desaturase steps (Δ6, encoded by FADS2 and Δ5, encoded by FADS1) are rate limiting in the conversion of dietary essential 18 carbon PUFAs (18C-PUFAs) such as LA (18∶2, n-6) to AA and α-linolenic acid (ALA, 18∶3, n-3) to EPA and DHA. GWAS and candidate gene studies have consistently identified genetic variants within FADS1 and FADS2 as determinants of desaturase efficiencies and levels of LcPUFAs in circulating, cellular and breast milk lipids. Importantly, these same variants are documented determinants of important cardiovascular disease risk factors (total, LDL, and HDL cholesterol, triglycerides, CRP and proinflammatory eicosanoids). FADS1 and FADS2 lie head-to-head (5′ to 5′) in a cluster configuration on chromosome 11 (11q12.2). There is considerable linkage disequilibrium (LD) in this region, where multiple SNPs display association with LcPUFA levels. For instance, rs174537, located ∼15 kb downstream of FADS1, is associated with both FADS1 desaturase activity and with circulating AA levels (p-value for AA levels = 5.95×10−46) in humans. To determine if DNA methylation variation impacts FADS activities, we performed genome-wide allele-specific methylation (ASM) with rs174537 in 144 human liver samples. This approach identified highly significant ASM with CpG sites between FADS1 and FADS2 in a putative enhancer signature region, leading to the hypothesis that the phenotypic associations of rs174537 are likely due to methylation differences. In support of this hypothesis, methylation levels of the most significant probe were strongly associated with FADS1 and, to a lesser degree, FADS2 activities.
PMCID: PMC4026313  PMID: 24842322
14.  Usefulness of Biventricular Volume as a Predictor of Mortality in Patients with Diabetes Mellitus (From the Diabetes Heart Study) 
The American journal of cardiology  2013;111(8):1152-1158.
Individuals with type 2 diabetes mellitus (DM) are at increased risk of cardiovascular disease (CVD) and mortality. Beyond traditional CVD risk factors, novel measures reflecting additional aspects of disease pathophysiology, such as biventricular volume (BiVV), may be useful for risk stratification. This study examined the relationship between BiVV and risk for mortality in European Americans with type 2 DM from the Diabetes Heart Study. BiVV was calculated from 771 non-contrast computed tomography scans performed to image coronary artery calcified plaque (CAC). Relationships between BiVV and traditional CVD risk factors were examined. Cox proportional hazards regression was performed to determine risk for mortality (all-cause and CVD-mortality) associated with increasing BiVV. Area under the curve analysis was used to assess BiVV utility in risk prediction models. During 8.4 ± 2.4 years (mean ± SD) of follow-up, 23% of the sample were deceased. In unadjusted analyses, BiVV was significantly associated with increasing body mass index, height, CAC, history of hypertension and prior myocardial infarction (p<0.0001–0.012). BiVV was significantly associated with all-cause (HR: 2.45; CI: 1.06–5.67; p=0.036) and CVD-mortality (HR: 4.36; CI: 1.36–14.03; p=0.014) in models adjusted for other known CVD risk factors. Area under the curve increased from 0.76 to 0.78 (p=0.04) and 0.74 to 0.77 (p=0.02) for all-cause and CVD-mortality on inclusion of BiVV. In conclusion, in the absence of echocardiography or other noninvasive imaging modalities to assess ventricular volumes, or when such methods are contra-indicated, BiVV from computed tomography may be considered as a tool for stratification of high-risk individuals, such as those with type 2 DM.
PMCID: PMC3618594  PMID: 23351459
cardiovascular disease; heart size; diabetes; risk-prediction
15.  Coronary Calcium Score Predicts Cardiovascular Mortality in Diabetes 
Diabetes Care  2013;36(4):972-977.
In type 2 diabetes mellitus (T2DM), it remains unclear whether coronary artery calcium (CAC) provides additional information about cardiovascular disease (CVD) mortality beyond the Framingham Risk Score (FRS) factors.
A total of 1,123 T2DM participants, ages 34–86 years, in the Diabetes Heart Study followed up for an average of 7.4 years were separated using baseline computed tomography scans of CAC (0–9, 10–99, 100–299, 300–999, and ≥1,000). Logistic regression was performed to examine the association between CAC and CVD mortality adjusting for FRS. Areas under the curve (AUC) with and without CAC were compared. Net reclassification improvement (NRI) compared FRS (model 1) versus FRS+CAC (model 2) using 7.4-year CVD mortality risk categories 0% to <7%, 7% to <20%, and ≥20%.
Overall, 8% of participants died of cardiovascular causes during follow-up. In multivariate analysis, the odds ratios (95% CI) for CVD mortality using CAC 0–9 as the reference group were, CAC 10–99: 2.93 (0.74–19.55); CAC 100–299: 3.17 (0.70–22.22); CAC 300–999: 4.41(1.15–29.00); and CAC ≥1,000: 11.23 (3.24–71.00). AUC (95% CI) without CAC was 0.70 (0.67–0.73), AUC with CAC was 0.75 (0.72–0.78), and NRI was 0.13 (0.07–0.19).
In T2DM, CAC predicts CVD mortality and meaningfully reclassifies participants, suggesting clinical utility as a risk stratification tool in a population already at increased CVD risk.
PMCID: PMC3609509  PMID: 23230101
16.  Admixture Mapping of Coronary Artery Calcified Plaque in African Americans with Type 2 Diabetes 
The presence and severity of coronary artery calcified plaque (CAC) differs markedly between individuals of African and European descent, suggesting that admixture mapping (AM) may be informative for identifying genetic variants associated with subclinical cardiovascular disease (CVD).
Methods and Results
AM of CAC was performed in 1,040 unrelated African Americans with type 2 diabetes mellitus from the African American-Diabetes Heart Study (AA-DHS), Multi-Ethnic Study of Atherosclerosis (MESA), and Family Heart Study (FamHS) using the Illumina custom ancestry informative marker (AIM) panel. All cohorts obtained computed tomography scanning of the coronary arteries using identical protocols. For each AIM, the probability of inheriting 0, 1, and 2 copies of a European-derived allele was determined. Linkage analysis was performed by testing for association between each AIM using these probabilities and CAC, accounting for global ancestry, age, gender and study. Markers on 1p32.3 in the GLIS1 gene (rs6663966, LOD=3.7), 1q32.1 near CHIT1 (rs7530895, LOD=3.1), 4q21.2 near PRKG2 (rs1212373, LOD=3.0) and 11q25 in the OPCML gene (rs6590705, LOD=3.4) had statistically significant LOD scores, while markers on 8q22.2 (rs6994682, LOD=2.7), 9p21.2 (rs439314, LOD=2.7), and 13p32.1 (rs7492028, LOD=2.8) manifested suggestive evidence of linkage. These regions were uniformly characterized by higher levels of European ancestry associating with higher levels or odds of CAC. Findings were replicated in 1,350 AAs without diabetes and 2,497 diabetic European Americans from MESA and the Diabetes Heart Study.
Fine mapping these regions will likely identify novel genetic variants that contribute to CAC and clarify racial differences in susceptibility to subclinical CVD.
PMCID: PMC3578054  PMID: 23233742
ancestry; cardiovascular disease risk factors; type 2 diabetes; admixture mapping
17.  Associations among Lung Function, Arterial Elasticity and Circulating Endothelial and Inflammation Markers: the Multi-Ethnic Study of Atherosclerosis 
Hypertension  2013;61(2):542-548.
A parallel physiologic pathway for elastic changes is hypothesized for declines in arterial elasticity and lung function. Endothelial dysfunction and inflammation could potentially decrease elasticity of both vasculature and lung tissue. We examined biomarkers, large (LAE) and small (SAE) arterial elasticity, and forced vital capacity (FVC) in a period cross-sectional design in the Multi-Ethnic Study of Atherosclerosis, which recruited 1,823 women and 1,803 men, age range 45–84 years, black, white, Hispanic, and Chinese, free of clinically recognized CVD. Radial artery tonometric pulse waveform registration was performed and LAE and SAE were derived from diastole. Spirometric data and markers of endothelial dysfunction and inflammation (soluble intracellular adhesion molecule-1, fibrinogen, hs-C-reactive protein, and interleukin-6) were obtained. Mean LAE was 13.7 ± 5.5 ml/mmHgx10 and SAE was 4.6 ± 2.6 ml/mmHgx100. Mean FVC was 3,192 ± 956.0 mL and FEV1 was 2,386 ± 734.5 mL. FVC was about 40 ± 5 mL higher per SD of SAE, stronger in men than women. The association was slightly weaker with LAE, with no sex interaction. After regression adjustment for demographic, anthropometric, and cardiovascular risk factors, the biomarkers tended to be related to reduced SAE and FVC, particularly in men. These biomarker associations suggest important CVD risk alterations that occur concurrently with lower arterial elasticity and lung function. The observed positive association of SAE with FVC and with FEV1 in middle-aged to older free-living people is consistent with the hypothesis of parallel physiologic pathways for elastic changes in the vasculature and in lung parenchymal tissue.
PMCID: PMC3586233  PMID: 23283358
arterial stiffness; endothelial markers; inflammatory markers; large and small artery elasticity; lung function; MESA Study
18.  Relationship of Flow-Mediated Arterial Dilation and Exercise Capacity in Older Patients With Heart Failure and Preserved Ejection Fraction 
Older heart failure patients with preserved ejection fraction (HFpEF) have severely reduced exercise capacity and quality of life. Both brachial artery flow-mediated dilation (FMD) and peak exercise oxygen uptake (peak VO2) decline with normal aging. However, uncertainty remains regarding whether FMD is reduced beyond the degree associated with normal aging and if this contributes to reduced peak VO2 in elderly HFpEF patients.
Sixty-six older (70 ± 7 years) HFpEF patients and 47 healthy participants (16 young, 25 ± 3 years, and 31 older, 70 ± 6 years) were studied. Brachial artery diameter was measured before and after cuff occlusion using high-resolution ultrasound. Peak VO2 was measured using expired gas analysis during upright cycle exercise.
Peak VO2 was severely reduced in older HFpEF patients compared with age-matched healthy participants (15.2 ± 0.5 vs 19.6 ± 0.6 mL/kg/min, p < .0001), and in both groups, peak VO2 was reduced compared with young healthy controls (28.5 ± 0.8 mL/kg/min; both p < .0001). Compared with healthy young participants, brachial artery FMD (healthy young, 6.13% ± 0.53%) was significantly reduced in healthy older participants (4.0 ± 0.38; p < .0002) and in HFpEF patients (3.64% ± 0.28%; p < .0001). However, FMD was not different in HFpEF patients compared with healthy older participants (p = .86). Although brachial artery FMD was modestly related to peak VO2 in univariate analyses (r = .19; p = .048), it was not related in multivariate analyses that accounted for age, gender, and body size.
These results suggest that endothelial dysfunction may not be a significant independent contributor to the severely reduced exercise capacity in elderly HFpEF patients.
PMCID: PMC3598353  PMID: 22522508
Exercise capacity; Aging; Flow-mediated dilation; Heart failure with preserved ejection fraction; Endothelial function
19.  Diagnostic Time Course, Treatment, and In-Hospital Outcomes for STEMI Patients Presenting with Non-Diagnostic Initial ECG: A Report from the AHA Mission: Lifeline Program 
American heart journal  2012;165(1):50-56.
Prior studies indicate that a subset of patients diagnosed with ST-segment elevation myocardial infarction (STEMI) will have an initial non-diagnostic ECG during evaluation. However, the timing of diagnostic ECG changes in this group is unknown. Our primary aim was to describe the timing of ECG diagnosis of STEMI in patients whose initial ECG was non-diagnostic. Secondarily, we sought to compare the delivery of ACC/AHA guidelines-based care and in-hospital outcomes in this group compared to patients diagnosed with STEMI on initial ECG.
We analyzed data from 41,560 patients diagnosed with STEMI included in the NCDR® ACTION Registry®-GWTG™ from 01/2007 to 12/2010. We divided this study population into two groups: those diagnosed on initial ECG (N= 36,994) and those with an initial non-diagnostic ECG that were diagnosed on a follow-up ECG (N= 4,566).
In general, baseline characteristics and clinical presentations were similar between the two groups. For patients with an initial non-diagnostic ECG, 72.4% (N= 3,305)had an ECG diagnostic for STEMI within 90 minutes of their initial ECG. There did not appear to be significant differences in the administration of guidelines-recommended treatments for STEMI, in-hospital major bleeding (p 0.926), or death (p 0.475) between these groups.
In a national sample of patients diagnosed with STEMI, 11.0% had an initial non-diagnostic ECG. Of those patients, 72.4% had a follow-up diagnostic ECG within 90 minutes of their initial ECG. There did not appear to be clinically meaningful differences in guidelines-based treatment or major in-hospital outcomes between patients diagnosed with STEMI on an initial versus follow-up ECG.
PMCID: PMC3523309  PMID: 23237133
20.  Associations Between NOS1AP Single Nucleotide Polymorphisms (SNPs) and QT Interval Duration in Four Racial/Ethnic Groups in the Multi-Ethnic Study of Atherosclerosis (MESA) 
QT is a risk factor for sudden cardiac death (SCD). A genome wide association study identified NOS1AP variants associated with QT, which have been replicated in predominantly Caucasian (CAU) populations. We used MESA to examine association of QT with NOS1AP variants in an ethnically diverse cohort.
Twenty-eight tagging SNPs spanning NOS1AP were genotyped in 2847 MESA participants (approximately equal numbers of CAU, African-Americans (AFA), Hispanics (HIS) and Chinese (CHN)), age 45–84 years, without cardiovascular disease. QT was measured using 12-lead ECG. Associations between QT and NOS1AP variants were evaluated using linear regression, adjusted for heart rate, age, gender, and field center stratified by ancestry, using an additive inheritance model. Ancestry informative markers (AIMs) and principal components using AIMs were used as additional covariates.
More NOS1AP SNPs were associated with QT in CAU than the other races. In CAU, each copy of rs1932933 risk allele was associated with an increase in QT (4.9msec, p= 7.20×10-7). Significant associations in CAU and HIS were located at the 5′ end, while associations in CHN were located at the 3′ end.
NOS1AP variants were associated with QT in CAU, with weaker evidence for selected variants in HIS and CHN. Location of significant SNPs varied across ancestry. We identified possible novel associations at the 3′ end of NOS1AP, where we observed significant association with QT in CHN only. Genotyping within these regions may determine functional variants affecting QT and SCD risk. Further investigations are needed across ethnically diverse population cohorts.
PMCID: PMC3642094  PMID: 23347024
Genetics; Electrocardiography; Arrhythmia; Electrophysiology
21.  Carotid Arterial Stiffness and Its Relationship to Exercise Intolerance in Older Patients with Heart Failure and Preserved Ejection Fraction 
Hypertension  2012;61(1):112-119.
Heart failure with a preserved ejection fraction (HFpEF) is the dominant form of heart failure in the older population. The primary chronic symptom in HFpEF is severe exercise intolerance, however, its pathophysiology and therapy are not well understood. We tested the hypothesis that older patients with HFpEF have increased arterial stiffness beyond that which occurs with normal aging and that this contributes to their severe exercise intolerance.
Sixty-nine patients ≥ 60 years with HFpEF and 62 healthy volunteers (24 young healthy subjects ≤ 30 years (YHC) and 38 older healthy subjects ≥ 60 years old (OHC) were examined. Carotid arterial stiffness was assessed using high-resolution ultrasound and peak exercise oxygen consumption (VO2) was measured using expired gas analysis.
Peak VO2 was severely reduced in the HFpEF patients compared to OHC (14.1±2.9 vs. 19.7±3.7 ml/kg/min; p<0.001) and in both was reduced compared to YHC subjects, (32.0±7.2 ml/kg/min; both p<0.001). In HFpEF compared to OHC, carotid arterial distensibility was reduced (0.97±0.45 vs. 1.33±0.55 × 10−3 mmHg−1, p=0.008) and Young’s elastic modulus (YEM) was increased (1320±884 vs. 925±530 kPa, p<0.02). Carotid arterial distensibility was directly (0.28; p=0.02) and YEM was inversely (−0.32; p=0.01) related with peak VO2.
Carotid arterial distensibility is decreased in HFpEF beyond the changes due to normal aging and is related to peak VO2. This supports the hypothesis that increased arterial stiffness contributes to exercise intolerance in HFpEF and is a potential therapeutic target.
PMCID: PMC3712338  PMID: 23150511
Aging; heart failure with preserved ejection fraction; arterial stiffness; exercise capacity
22.  Prognosis of Individuals with Asymptomatic Left Ventricular Systolic Dysfunction in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Circulation  2012;126(23):2713-2719.
Limited data exist on the prevalence, associations and prognosis of individuals with asymptomatic left ventricular systolic dysfunction (ALVSD), especially in populations without prior clinical cardiovascular disease (CVD).
Methods and Results
Kaplan-Meier and Cox proportional hazard analyses were used to assess the association between ALVSD, defined as left ventricular ejection fraction less than 50%, and adjudicated incident congestive heart failure (CHF), all-cause mortality, and CVD events.
Out of 5004 participants, 112 participants had CHF, 321 had a CVD event, and 278 died after 9 years of follow-up. The overall prevalence of ALVSD was 1.7%, with a higher prevalence in African Americans (2.6%). ALVSD had worse cardiovascular risk profile and was also associated with increased risk in unadjusted and adjusted models for incident CHF [HR (95%): 12.0(7.04 – 20.3), p<0.0001 and 8.69(4.89 – 15.45), p<0.001 respectively], CVD [HR (95%):3.32(1.98 -5.58), p<0.001 and 2.21(1.30 – 3.73), p=0.003 respectively] and all-cause mortality [HR(95%):3.47(2.03 – 5.94), p<0.0001 and 2.00(1.13-3.54), p=0.017 respectively]. A 10% decrement in LVEF at baseline was associated with increase in risk in unadjusted and adjusted models for clinical CHF [HR (95%CI): 2.17(1.82 -2.63), p<0.0001 and 2.13(1.73 - 2.51), p<0.001 respectively] and all-cause mortality [HR (95%CI): 1.22(1.05 – 1.41), p=0.009 and 1.17(1.00 – 1.36), p=0.047 respectively]. Among the subset of participants with ALVSD, LVMI was particularly informative about risk for incident CHF (c- index = 0.74).
ALVSD is uncommon in individuals without prior clinical CVD, but is associated with high risk for CHF, CVD, and all-cause mortality. LVMI had good discrimination for incident CHF in MESA participants with ALVSD.
PMCID: PMC3533250  PMID: 23124035
heart failure; death; cardiovascular diseases; magnetic resonance imaging; population
23.  Vascular Responses to Long- and Short-Term Exposure to Fine Particulate Matter 
This study evaluated the association of long- and short-term air pollutant exposures with flow-mediated dilation (FMD) and baseline arterial diameter (BAD) of the brachial artery using ultrasound in a large multicity cohort.
Exposures to ambient air pollution, especially long-term exposure to particulate matter <2.5 μm in aerodynamic diameter (PM2.5), are linked with cardiovascular mortality. Short-term exposure to PM2.5 has been associated with decreased FMD and vasoconstriction, suggesting that adverse effects of PM2.5 may involve endothelial dysfunction. However, long-term effects of PM2.5 on endothelial dysfunction have not been investigated.
FMD and BAD were measured by brachial artery ultrasound at the initial examination of the Multi-Ethnic Study of Atherosclerosis. Long-term PM2.5 concentrations were estimated for the year 2000 at each participant’s residence (n = 3,040) using a spatio-temporal model informed by cohort-specific monitoring. Short-term PM2.5 concentrations were based on daily central-site monitoring in each of the 6 cities.
An interquartile increase in long-term PM2.5 concentration (3 μg/m3) was associated with a 0.3% decrease in FMD (95% confidence interval [CI] of difference: −0.6 to −0.03; p = 0.03), adjusting for demographic characteristics, traditional risk factors, sonographers, and 1/BAD. Women, nonsmokers, younger participants, and those with hypertension seemed to show a greater association of PM2.5 with FMD. FMD was not significantly associated with short-term variation in PM2.5 (−0.1% per 12 μg/m3 daily increase [95% CI: −0.2 to 0.04] on the day before examination).
Long-term PM2.5 exposure was significantly associated with decreased endothelial function according to brachial ultrasound results. These findings may elucidate an important pathway linking air pollution and cardiovascular mortality.
PMCID: PMC3665082  PMID: 23103035
air pollution; atherosclerosis; cardiovascular mortality; endothelial function; flow-mediated dilation; traffic
24.  Early Menopause Predicts Future Coronary Heart Disease and Stroke: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Menopause (New York, N.Y.)  2012;19(10):1081-1087.
Cardiovascular disease is the number one killer of women. Identifying women at risk of cardiovascular disease has tremendous public health importance. Early menopause is associated with increased cardiovascular disease events in some predominantly white populations, but not consistently. Our objective was to determine if a self-reported early menopause (menopause at an age <46) identifies women as at risk for future coronary heart disease or stroke.
The study population came from the Multi-Ethnic Study of Atherosclerosis, a longitudinal, ethnically diverse cohort study of US men and women aged 45 to 84 years enrolled in 2000–2002 and followed up until 2008. The association between a personal history of early menopause (either natural menopause or surgical removal of ovaries at an age <46) and future coronary heart disease and stroke was assessed in 2509 women (ages 45–84, 987 White, 331 Chinese, 641 Black, 550 Hispanic) from the Multi-Ethnic Study Atherosclerosis, who were free of cardiovascular disease at baseline.
693/2509 (28%) of women reported either surgical or natural early menopause. In survival curves, women with early menopause had worse coronary heart disease and stroke-free survival (log rank p=<0.008 and 0.0158). In models adjusted for age, race/ethnicity, Multi-Ethnic Study Atherosclerosis site and traditional cardiovascular disease risk factors, this risk for coronary heart disease and stroke remained (HR 2.08, 95% CI 1.17, 3.70 and 2.19, 95% CI 1.11, 4.32, respectively).
Early menopause is positively associated with coronary heart disease and stroke in a multiethnic cohort, independent of traditional cardiovascular disease risk factors.
PMCID: PMC3443540  PMID: 22692332
Early Menopause; Coronary Heart Disease; Stroke

Results 1-25 (71)