A high degree of inter-individual variability in plasma lipid level response to hormone therapy (HT) has been reported. Variations in the oestrogen receptor α gene (ESR1) and in genes involved in lipid metabolism may explain some of the variability in response to HT.
Postmenopausal Caucasian women (N=208) participating in a placebo-controlled randomized trial of 3.2 years of hormone therapy (HT).
Plasma triglycerides (TG), remnant lipoprotein cholesterol (RLP-C), and high-density lipoprotein cholesterol (HDL-C) levels and HDL subpopulations were assessed at baseline and at follow-up. Single nucleotide polymorphisms (SNPs) in ESR1 and in the ATP binding cassette A1 (ABCA1), cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC), lipoprotein lipase (LPL), and scavenger receptor class B type I (SRB1) genes were assessed for their association with baseline plasma levels and HT-related changes in levels of RLP-C and HDL subpopulations.
Carriers of the ESR1 PvuII or IVS1-1505 variants had lower plasma TG concentrations and higher plasma HDL-C and α-1 and preα-1 HDL particle levels at baseline and showed greater increases in HDL-C, apo A-I and α-1 particle levels after HT than wild-type carriers. Carriers of the N291S and D9N variants in the LPL gene had significantly higher remnant lipoproteins and lower α-2 HDL particle levels at baseline. The CETP TaqIB SNP was a significant determinant of baseline plasma HDL-C and HDL subpopulation profile.
SNPs in ESR1, CETP and LPL had significant effects on baseline plasma levels of TG-rich and HDL subpopulations. With the exception of ESR1 SNPs, variation in genes involved in lipid metabolism has a very modest effect on lipoprotein response to HT.
high-density lipoprotein; remnant lipoproteins; single nucleotide polymorphism hormone therapy
This study examined the effect of hormone therapy (HT) on the plasma concentration of remnant lipoprotein cholesterol (RLP-C) and high density lipoprotein (HDL) subpopulations and the contribution of HT-related changes in these lipoproteins to the progression of coronary heart disease (CHD) in postmenopausal women.
Study participants were 256 women who completed the Estrogen Replacement and Atherosclerosis (ERA) trial, a placebo-controlled, randomized trial that examined the effects of 3.2 years of conjugated equine estrogen (CEE, 0.625 mg/day) or CEE (0.625 mg/day) plus medroxyprogesterone acetate (MPA, 2.5 mg/day) on post-menopausal women with established coronary atherosclerosis. Quantitative coronary angiography and plasma RLP-C and HDL subpopulations were assessed at baseline and at follow-up.
Relative to placebo, both CEE and CEE+MPA caused a significant reduction in plasma RLP-C concentrations and a significant increase in α1 and α2 HDL subpopulations. However, in the HT-treated subjects, faster progression of coronary atherosclerosis was observed in women who experienced the greatest reductions in RLP-C and in preβ1 HDL subpopulations.
Our data suggest that individual variability in RLP-C and HDL subpopulation response to HT is a predictor of CHD progression. Lipoprotein response to HT may be an indirect marker of susceptibility to other harmful effect of HT in postmenopausal women with established CHD or an indication of formation of dysfunctional lipoproteins.
Lipoproteins; hormone therapy; coronary heart disease; angiography
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.
Early Menopause; Coronary Heart Disease; Stroke
AHA Scientific Statements; genetics
Anaemia is associated with an increased risk for morbidity and mortality in ST-elevation myocardial infarction (STEMI) patients. While several physiological mechanisms have been proposed to explain this association, decreased receipt of guidelines-based care may also contribute. We examined the relationship between admission haemoglobin (Hgb) level, receipt of ACC/AHA guidelines-based treatments, and in-hospital outcomes among STEMI patients. We also evaluated whether administration of these treatments modified the association between anaemia and in-hospital mortality in this group.
Methods and results:
We analysed data from 92,686 patients diagnosed with STEMI included in the NCDR ACTION Registry-GWTG database from January 2007 to March 2011. Patients were stratified by initial Hgb value: 83.1% (n=77,035) were classified as non-anaemic (Hgb >13.0 g/dl for men, >12.0 g/dl for women), 11.6% (n=10,710) as mildly anaemic (11.1−13.0 g/dl for men, 11.1−12.0 g/dl for women), 4.4% (n=4059) as moderately anaemic (9.1−11.0 g/dl), and 1.0% (n=882) as severely anaemic (<9.0 g/dl). Anaemia was associated with a significantly increased prevalence of other baseline comorbidities and decreased odds of receiving several class I recommended pharmacological treatments (heparin, beta-blockers, and angiotensin-converting enzyme inhibitors, p<0.01). The overall use of reperfusion therapy (fibrinolytic therapy and/or percutaneous coronary intervention) was also lower in anaemic vs. non-anaemic patients (p<0.01). Anaemia was associated higher in-hospital mortality risk, which remained significant after adjustment for use of guidelines-recommended therapies and interventions (p<0.01).
In a national sample of STEMI patients, anaemia on presentation was associated with decreased receipt of ACC/AHA guidelines-based care and higher in-hospital mortality. However, the higher mortality rates could not be fully explained by differences in in-hospital treatment.
Anaemia; guidelines; outcomes; ST-segment myocardial infarction (STEMI); treatment
To assess the cardiovascular risk of impaired fasting glucose (IFG).
The association between IFG, incident type 2 diabetes mellitus (T2DM) and cardiovascular (CV) events remains unclear.
The Multi-Ethnic Study of Atherosclerosis (MESA) included participants aged 45–84 free of clinical CV disease at baseline (2000–2002). T2DM was defined as fasting glucose >125mg/dl or anti-diabetes medication at baseline and follow-up exams, IFG as no T2DM and fasting glucose 100–125.mg/dl. Cox proportional hazard analysis was used to assess the association between IFG and incident DM and also with incident CV events.
Of 6753 participants included in these analyses 840 (12.7%) had T2DM, 940 (13.8%) had IFG at the baseline exam. During 7.5 years of follow-up there were 418 adjudicated CV events. T2DM was associated with an increased CV incidence in the univariate [hazard ratio (HR); 2.83(2.25–3.56), p<0.0001] and multivariable models (adjusted for demographics and traditional risk factors) [HR; 1.87(1.47 – 2.37), p<0.0001] compared with subjects without T2DM (IFG + NFG). IFG was associated with increased incidence of T2DM [HR; 13.2 (95%CI 10.8–16.2), p<0.001] that remained after adjusting for demographics, highest educational level, physical activity and BMI [HR; 10.5(8.4–13.1), p<0.001] compared to NFG. IFG was associated with incident CV events in the univariate [HR; 1.64(1.26 – 2.14), p=<0.001] but not in the full multivariable model [HR; 1.16(95% CI 0.88–1.52), p=0.3] compared with NFG.
Having IFG was not independently associated with an increased short-term risk for incident CV events. These data reiterate the importance of intervention in persons with IFG to reduce their incidence of T2DM.
Impaired fasting glucose; diabetes mellitus; cardiovascular events; population
We assessed the association between sleep apnea, snoring, incident cardiovascular (CV) events and all-cause mortality in the Multi Ethnic Study of Atherosclerosis (MESA) cohort.
Out of 5338 respondents to a sleep questionnaire administered during the second MESA exam period, 208 had physician-diagnosed sleep apnea (PDSA), 1452 were habitual snorers (HS) and 3678 were neither a habitual snorer nor had PDSA (normal participants). Cox proportional hazard analysis was used to assess the associations adjusting for age, gender, race/ethnicity, smoking, diabetes mellitus, total cholesterol, HDL, triglycerides, BMI, current alcohol use, benzodiazepine use, BP medications and statin use.
Over a 7.5 year average follow-up period, 310 adjudicated CV events including MI, stroke, angina, resuscitated cardiac arrest, stroke death and CVD death and 189 deaths occurred. Compared to HS, PDSA was associated with higher incident CV rates in both univariate and multivariable models [hazard ratio (95%); 1.89(1.22–2.93), p=0.004 and 1.91(1.20 –3.04), p=0.007 respectively]. PDSA was also associated with a higher death rates compared with HS [hazard ratio (95%); 2.13(1.25 – 3.63), p=0.006 and 2.70(1.52– 4.79), p=0.007 respectively]. Compared with normal participants, PDSA had higher incident CV event rates in both univariate and multivariable models [hazard ratio (95%); 2.23[1.39–3.60], p=0.001 and 2.16[1.30–3.58], p=0.003 respectively]. Similarly, PDSA had a higher death rate compared with normal participants in both the univariate and multivariable models [hazard ratio (95%CI); 2.44(1.36 – 4.37), p=0.003 and 2.71(1.45 – 5.08), p=0.002 respectively]. Habitual snorers had similar incident CV event rates and death rates in both univariate and multivariable models compared with normal participants.
PDSA but not habitual snoring was associated with high incident CV events and all-cause mortality in a multi-ethnic population based study of adults free of clinical CV disease at baseline.
Obstructive sleep apnea; habitual snorers; cardiovascular events; mortality; population
Little is known regarding the association of scavenger receptor class B type I (SCARB1) single nucleotide polymorphisms (SNPs) and subclinical atherosclerosis (SCA), particularly in subjects of different racial/ethnic backgrounds. We examined this relationship in the Multi-Ethnic Study of Atherosclerosis (MESA).
Methods and Results
Forty-three SCARB1 tagging SNPs were genotyped. Baseline examinations included fasting lipids and SCA phenotypes (coronary artery calcium [CAC], and common and internal carotid artery thickness [CCIMT and ICIMT]). Examining SNP associations with different SCA phenotypes across multiple racial/ethnic groups with adjustment for multiple covariates, we found the C allele of SNP rs10846744 was associated with higher CCIMT in African American (P=0.03), Chinese (P=0.02), European American (P=0.05), and Hispanic participants (P=0.03), and was strongly associated in pooled analyses (P=0.0002). The results also showed that the association of this SNP with CCIMT was independent of lipids and other well-established cardiovascular risk factors. Stratifying by sex, there appeared to be a strong association of rs10846744 with CCIMT in females, but no genotype-sex interactions were observed.
Variation in SCARB1 at rs10846744 was significantly associated with CCIMT across racial/ethnic groups in MESA.
genetics; atherosclerosis; cholesterol; lipids; prospective cohort study; genetic association
In diabetes, it remains unclear whether the coronary artery calcium (CAC) score provides additional information about total mortality risk beyond traditional risk factors.
RESEARCH DESIGN AND METHODS
A total of 1,051 participants, aged 34–86 years, in the Diabetes Heart Study (DHS) were followed for 7.4 years. Subjects were separated into five groups using baseline computed tomography scans and CAC scores (0–9, 10–99, 100–299, 300–999, and ≥1,000). Logistic regression was performed adjusting for age, sex, race, smoking, and LDL cholesterol to examine the association between CAC and all-cause mortality. Areas under the curve with and without CAC were compared. Natural splines using continuous measures of CAC were fitted to estimate the relationship between observed CAC and mortality risk.
A total of 17% (178 of 1,051) of participants died during the follow-up. In multivariate analysis, the odds ratios (95% CIs) for all-cause mortality, using CAC 0–9 as the reference group, were CAC 10–99: 1.40 (0.57–3.74); CAC 100–299: 2.87 (1.17–7.77); CAC 300–999: 3.04 (1.32–7.90); and CAC ≥1,000: 6.71 (3.09–16.87). The area under the curve without CAC was 0.68 (95% CI 0.66–0.70), and the area under the curve with CAC was 0.72 (0.70–0.74) (P = 0.0001). Using splines, the estimated risk (95% CI) of mortality for a CAC of 0 was 6.7% (4.6–9.7), and the risk increased nearly linearly, plateauing at CAC ≥1,000 (20.0% [15.7–25.2]).
In diabetes, CAC was shown to be an independent predictor of mortality. Participants with CAC (0–9) were at lower risk (0.9% annual mortality). The risk of mortality increased with increasing levels of CAC, plateauing at approximately CAC ≥1,000 (2.7% annual mortality). More research is warranted to determine the potential utility of CAC scans in diabetes.
Muscadine grape seeds have high concentrations of polyphenolic compounds with antioxidant and other properties that would be expected to have favorable effects on endothelial function.
To evaluate the effect of muscadine grape seed supplementation on endothelial function and cardiovascular risk factors in subjects with increased cardiovascular risk.
In a randomized, double-blind, placebo-controlled crossover trial, 50 adults with coronary disease or ≥1 cardiac risk factor received muscadine grape seed supplementation (1300 mg daily) and placebo for 4 weeks each, with a 4-week washout. Resting brachial diameter and brachial flow-mediated dilation (FMD) and biomarkers of inflammation, lipid peroxidation, and antioxidant capacity were determined at the beginning and end of each period and compared in mixed linear models.
There was no evidence of improved FMD (% change) with muscadine grape seed (muscadine grape seed: pre 5.2% ± 0.3%, post 4.6% ± 0.3%, p = 0.06; placebo: pre 5.3% ± 0.4%, post 5.2% ± 0.4%, p = 0.82; p for muscadine grape seed vs. placebo = 0.25). However, there was a significant increase in baseline diameter (mm) with muscadine grape seed supplementation (muscadine grape seed: pre 4.05 ± 0.09, post 4.23 ± 0.10, p = 0.002; placebo: pre 4.12 ± 0.11, post 4.12 ± 0.10, p = 0.93; p for muscadine grape seed vs. placebo = 0.026). All other biomarkers were not significantly altered by muscadine grape seed supplementation.
Four weeks of muscadine grape seed supplementation in subjects with increased cardiovascular risk did not produce a statistically significant increase in brachial flow-mediated vasodilation or a significant change in other biomarkers of inflammation, lipid peroxidation, or antioxidant capacity. However, the muscadine grape seed supplement did result in a significant increase in resting brachial diameter. The clinical significance of the effect on resting diameter is not yet established. More research is warranted to fully characterize the vascular effects of this and other grape-derived nutritional supplements and to determine whether these vascular effects translate into important clinical benefits.
endothelial function; cardiovascular disease; dietary supplements; antioxidants
Background. The NCEP metabolic syndrome (MetS) is a combination of dichotomized interrelated risk factors from predominantly Caucasian populations. We propose a continuous MetS score based on principal component analysis (PCA) of the same risk factors in a multiethnic cohort and compare prediction of incident CVD events with NCEP MetS definition. Additionally, we replicated these analyses in the Health, Aging, and Body composition (Health ABC) study cohort. Methods and Results. We performed PCA of the MetS elements (waist circumference, HDL, TG, fasting blood glucose, SBP, and DBP) in 2610 Caucasian Americans, 801 Chinese Americans, 1875 African Americans, and 1494 Hispanic Americans in the multiethnic study of atherosclerosis (MESA) cohort. We selected the first principal component as a continuous MetS score (MetS-PC). Cox proportional hazards models were used to examine the association between MetS-PC and 5.5 years of CVD events (n = 377) adjusting for age, gender, race, smoking and LDL-C, overall and by ethnicity. To facilitate comparison of MetS-PC with the binary NCEP definition, a MetS-PC cut point was chosen to yield the same 37% prevalence of MetS as the NCEP definition (37%) in the MESA cohort. Hazard ratio (HR) for CVD events were estimated using the NCEP and Mets-PC-derived binary definitions. In Cox proportional models, the HR (95% CI) for CVD events for 1-SD (standard deviation) of MetS-PC was 1.71 (1.54–1.90) (P < 0.0001) overall after adjusting for potential confounders, and for each ethnicity, HRs were: Caucasian, 1.64 (1.39–1.94), Chinese, 1.39 (1.06–1.83), African, 1.67 (1.37–2.02), and Hispanic, 2.10 (1.66-2.65). Finally, when binary definitions were compared, HR for CVD events was 2.34 (1.91–2.87) for MetS-PC versus 1.79 (1.46–2.20) for NCEP MetS. In the Health ABC cohort, in a fully adjusted model, MetS-PC per 1-SD (Health ABC) remained associated with CVD events (HR = 1.21, 95%CI 1.12–1.32) overall, and for each ethnicity, Caucasian (HR = 1.24, 95%CI 1.12–1.39) and African Americans (HR = 1.16, 95%CI 1.01–1.32). Finally, when using a binary definition of MetS-PC (cut point 0.505) designed to match the NCEP definition in terms of prevalence in the Health ABC cohort (35%), the fully adjusted HR for CVD events was 1.39, 95%CI 1.17–1.64 compared with 1.46, 95%CI 1.23–1.72 using the NCEP definition. Conclusion. MetS-PC is a continuous measure of metabolic syndrome and was a better predictor of CVD events overall and in individual ethnicities. Additionally, a binary MetS-PC definition was better than the NCEP MetS definition in predicting incident CVD events in the MESA cohort, but this superiority was not evident in the Health ABC cohort.
Type 2 diabetes mellitus is associated with dyslipidemia and with an increased risk of coronary heart disease (CHD). Our objective was to compare the effects of hormone replacement therapy (HRT) on plasma lipoproteins and coronary disease progression in postmenopausal women with and without diabetes. Study subjects were participants in the Estrogen Replacement and Atherosclerosis trial, a placebo-controlled, randomized trial of HRT (conjugated equine estrogen 0.625 mg/day with or without medroxyprogesterone acetate 2.5 mg/day) in postmenopausal women with established CHD (men age 65±7 y). Plasma remnant lipoprotein levels and HDL subpopulation levels were measured at baseline and year 1. Quantitative coronary angiography was assessed at baseline and at follow-up. At baseline, remnant lipoprotein levels were significantly higher and HDL-C levels significantly lower in diabetic women than in women without diabetes. HRT lowered remnant lipoproteins and increased HDL-C and large HDL particle levels in both groups. However, during HRT, levels of these parameters were still significantly worse in diabetic women than in non-diabetic women. A significant interaction between HRT and diabetes status, with greater increases in plasma atheroprotective HDL α1 particles in non-diabetic women than in diabetic women during HRT, was observed. CHD progressed significantly more in women with diabetes than in women without diabetes. Our findings indicate that diabetes attenuates the HRT-related increase in atheroprotective HDL α1 particles. Faster progression of coronary atherosclerosis in women with diabetes could be mediated in part by a worse lipoprotein profile in these women than in women without diabetes, both before and during HRT.
Hormone replacement therapy; diabetes mellitus; lipoproteins; cholesterol; triglycerides; coronary heart disease
Introduction. Reduced kidney function, approximated by elevated cystatin C, is associated with diastolic dysfunction, heart failure, and cardiovascular mortality; however, the precise mechanism(s) that account for these relationships remains unclear. Understanding the relationship between cystatin C and subclinical left ventricular (LV) remodeling, across ethnically diverse populations, may help explain the mechanisms underlying the association of kidney dysfunction with heart failure and cardiovascular mortality. Methods. Measures of cystatin C and LV parameters were obtained from the multi-ethnic study of atherosclerosis (MESA) cohort at baseline (N = 4, 970 with complete data on cystatin C and LV parameters). LV parameters; LV end-diastolic (LVEDV) and end-systolic volumes (LVESV), LV mass (LVM), concentricity (LV mass/LV end-diastolic volume), and LV ejection fraction (LVEF) were measured using magnetic resonance imaging. Nested linear models were used to examine the relationship between higher quartiles of cystatin C and LV parameters, with and without adjustment for demographics, height, and weight, and traditional cardiovascular risk factors. Similar analyses were performed stratified by ethnicity and gender. Results. A fully adjusted model demonstrated a linear relationship between higher quartiles of cystatin C and lower LVEDV, (Mean ± SE, 128 ± 0.7, 128 ± 0.7, 126 ± 0.7, 124 ± 0.8 mL; P = 0.0001). Associations were also observed between higher quartiles of cystatin C and lower LVESV (P = 0.04) and concentricity (P = 0.0001). In contrast, no association was detected between cystatin C and LVM or LVEF. In analyses stratified by race and gender, the patterns of association between cystatin C quartiles and LV parameters were qualitatively similar to the overall association. Conclusion. Cystatin C levels were inversely associated with LVEDV and LVESV with a disproportionate decrease in LVEDV compared to LVM in a multi-ethnic population. This morphometric pattern of concentric left ventricular remodeling, may in part explain the process by which kidney dysfunction leads to diastolic dysfunction, heart failure and cardiovascular mortality.
Background. There is an association between chronic kidney disease (CKD) and metabolic syndrome (MetS). We examined the joint association of CKD and MetS with incident cardiovascular (CVD) events in the Multiethnic Study of Atherosclerosis (MESA) cohort. Methods. We analyzed 2,283 Caucasians, 363 Chinese, 1,449 African-Americans, and 1,068 Hispanics in the MESA cohort. CKD was defined by cystatin C estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2 and MetS was defined by NCEP criteria. Cox proportional regression adjusting for age, ethnicity, gender, study site, education, income, smoking, alcohol use, physical activity, and total and LDL cholesterol was performed to assess the joint association of CKD and MetS with incident CVD events. Participants were divided into four groups by presence of CKD and/or MetS and compared to the group without CKD and MetS (CKD−/MetS−). Tests for additive and multiplicative interactions between CKD and MetS and prediction of incident CVD were performed. Results. During follow-up period of 5.5 years, 283 participants developed CVD. Multivariate Cox regression analysis demonstrated that CKD and MetS were independent predictors of CVD (hazard ratio, 2.02 for CKD, and 2.55 for MetS). When participants were compared to the CKD−/MetS− group, adjusted HR for the CKD+/MetS+ group was 5.56 (95% CI 3.72–8.12). There was no multiplicative interaction between CKD and MetS (P = 0.2); however, there was presence of additive interaction. The relative excess risk for additive interaction (RERI) was 2.73, P = 0.2, and the attributable portion (AP) was 0.49 (0.24–0.74). Conclusion. Our findings illustrate that the combination of CKD and MetS is a strong predictor of incident clinical cardiovascular events due to presence of additive interaction between CKD and MetS.
Interactions among genetic loci are believed to play an important role in disease risk. While many methods have been proposed for detecting such interactions, their relative performance remains largely unclear, mainly because different data sources, detection performance criteria, and experimental protocols were used in the papers introducing these methods and in subsequent studies. Moreover, there have been very few studies strictly focused on comparison of existing methods. Given the importance of detecting gene-gene and gene-environment interactions, a rigorous, comprehensive comparison of performance and limitations of available interaction detection methods is warranted.
We report a comparison of eight representative methods, of which seven were specifically designed to detect interactions among single nucleotide polymorphisms (SNPs), with the last a popular main-effect testing method used as a baseline for performance evaluation. The selected methods, multifactor dimensionality reduction (MDR), full interaction model (FIM), information gain (IG), Bayesian epistasis association mapping (BEAM), SNP harvester (SH), maximum entropy conditional probability modeling (MECPM), logistic regression with an interaction term (LRIT), and logistic regression (LR) were compared on a large number of simulated data sets, each, consistent with complex disease models, embedding multiple sets of interacting SNPs, under different interaction models. The assessment criteria included several relevant detection power measures, family-wise type I error rate, and computational complexity. There are several important results from this study. First, while some SNPs in interactions with strong effects are successfully detected, most of the methods miss many interacting SNPs at an acceptable rate of false positives. In this study, the best-performing method was MECPM. Second, the statistical significance assessment criteria, used by some of the methods to control the type I error rate, are quite conservative, thereby limiting their power and making it difficult to fairly compare them. Third, as expected, power varies for different models and as a function of penetrance, minor allele frequency, linkage disequilibrium and marginal effects. Fourth, the analytical relationships between power and these factors are derived, aiding in the interpretation of the study results. Fifth, for these methods the magnitude of the main effect influences the power of the tests. Sixth, most methods can detect some ground-truth SNPs but have modest power to detect the whole set of interacting SNPs.
This comparison study provides new insights into the strengths and limitations of current methods for detecting interacting loci. This study, along with freely available simulation tools we provide, should help support development of improved methods. The simulation tools are available at: http://code.google.com/p/simulation-tool-bmc-ms9169818735220977/downloads/list.
Background and Purpose
Retinal vascular caliber changes have been shown to predict stroke, but the underlying mechanism of this association is unknown. We examined the relationship between retinal vascular caliber with brachial flow-mediated dilation (FMD), a measure of systemic endothelial function.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a population-based study of persons 45 to 84 years of age residing in 6 US communities free of clinical cardiovascular disease at baseline. Brachial FMD data were collected at baseline (July 2000 to June 2002), and retinal vascular caliber was measured from digital retinal photographs at the second examination, immediately after the first (August 2002 to January 2004). Data were available for 2851 participants for analysis.
The mean brachial FMD was 4.39±2.79%. After adjusting for age and gender, brachial FMD was reduced in persons with wider retinal venular caliber (changes in FMD −0.25, 95% CI, −0.36, − 0.13; P<0.001, per SD increase in venular caliber). This relationship persists after adjusting for systolic blood pressure, serum total cholesterol, use of lipid-lowering and antihypertensive medication, body mass index, current smoking status, and hemoglobinA1C (−0.18; 95% CI −0.30, − 0.06; P=0.004, per SD increase in venular caliber). Brachial FMD was not associated with retinal arteriolar caliber.
Persons with wider retinal venules have reduced brachial FMD, independent of other vascular risk factors. This suggests that retinal venular caliber, previously shown to predict stroke, may be a marker of underlying systemic endothelial dysfunction.
epidemiology; vasodilation; imaging; endothelial function
Inflammatory markers predict coronary heart disease (CHD). However, associations with coronary artery calcium (CAC), a marker of subclinical CHD, are not established.
We examined cross-sectional associations of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with CAC presence (Agatston score > 0 by computed tomography) in 6,783 Multi-Ethnic Study of Atherosclerosis (MESA) participants.
In all participants, those in the highest, compared to lowest, quartile of CRP had a relative risk (RR, 95% confidence interval) of 1.13 (1.06-1.19; p<0.01) for CAC in age, sex and ethnicity adjusted models. For highest versus lowest quartiles, relative risks were 1.22 (1.15-1.30; p<0.01) for IL-6 and 1.18 (1.11-1.24; p<0.01) for fibrinogen. Adjusting for CHD risk factors (smoking, diabetes, blood pressure, obesity and dyslipidemia) attenuated RRs. RRs for CAC were 1.05 (0.99-1.12; p=0.63) for CRP, 1.12 (1.06-1.20; p<0.01) for IL-6 and 1.09 (1.02-1.16; p=0.01) for fibrinogen in multivariable adjusted models. Results were similar for men and women and across ethnic groups.
Inflammatory markers were weakly associated with CAC presence and burden in MESA. Our data support the hypothesis that inflammatory biomarkers and CAC reflect distinct pathophysiology.
Atherosclerosis; Calcium; Inflammation; Population
High plasma sphingomyelin level has been associated with subclinical atherosclerosis, coronary artery disease and worse prognosis in subjects with acute coronary syndromes. We assess the predictive value of plasma sphingomyelin levels for incident CHD events in the Multi Ethnic Study of atherosclerosis (MESA).
Method and Results
Plasma sphingomyelin was measured in 6809 out of 6814 subjects with mean age 62.2 ± 10.2 years, participating in the MESA study, a population based cohort study of adults free of clinical CVD at baseline recruited at six clinic sites in USA. The subjects consisted of 52.8% females, 38.5% Caucasian, 11.8% Chinese, 27.8% African Americans and 21.9% Hispanics. Cox proportional hazard analysis was used to examine the association between plasma sphingomyelin and five years of adjudicated incident CHD events including MI, resuscitated cardiac arrest, angina, CHD death and revascularization (CABG or PTCA). Mean (SD) plasma sphingomyelin level was 48 mg/dl (16.0). One hundred and eighty-nine subjects had an adjudicated CHD event during the five years of follow up. In the Kaplan meier analysis, subjects with plasma sphingomyelin level above the sex specific median had similar event free survival rate compared with subjects with plasma sphingomyelin level below or equal to the sex specific median (97.16% vs 97.0%, log rank p= 0.713). In the univariate Cox proportional hazard analysis, plasma sphingomyelin was not a predictor of incident CHD event [hazard ratio 0.992(0.982 – 1.004), p=0.09]. In our multistage multivariable Cox models, higher plasma sphingomyelin had modest negative association with incident CHD events when total cholesterol, HDL and triglycerides were included in the model [hazard ratio 0.985 (0.973 – 0.996), p=0.008] and also in our full model after adjusting for age, gender, total cholesterol, HDL, triglycerides, diabetes, cigarette smoking, systolic BP, diastolic BP, BP medication use, HMG CoA use [hazard ratio 0.984 (0.973 – 0.996), p=0.002]. In other models, plasma sphingomyelin was not associated with incident CHD events.
High plasma sphingomyelin level is not associated with increased risk of incident coronary heart disease in population based adults free of clinical cardiovascular disease at baseline.
Plasma sphingomyelin; prognosis; coronary heart disease events; epidemiology
Interleukin-10 (IL-10) is a cytokine with pleiotropic properties. Limited biochemical and clinical evidence suggest a link between IL-10 and coronary heart disease (CHD). However, more data are needed to clarify the relationship between IL-10 and risk for CHD events.
The present study was a secondary analysis of the Estrogen Replacement and Atherosclerosis (ERA) trial, a randomized clinical trial that examined the effects of hormone replacement therapy on post-menopausal women with known coronary atherosclerosis. IL-10 concentration, measured at baseline, was treated as both a continuous and categorical variable. Cox proportional hazards models were used to compute hazard ratios as estimates of relative risk for CHD events.
There were 71 events over an average 3.2 year follow-up. Incident rates were higher for individuals with IL-10 concentrations equal to or greater than the median level (1.04 pg/mL) compared to those individuals below the median level (30% vs. 18.5 %, p=0.02). The cumulative incidence of CHD events was significantly greater in individuals with IL-10 concentrations ≥1.04 pg/mL (p=0.01). A one standard deviation increase in baseline IL-10 concentration was associated with a 34% greater risk of a CHD event (HR 1.34 [1.06−1.68], p=0.01). This elevated risk was not altered by interleukin-6, C-reactive protein, or additional cardiovascular risk factors. IL-10 concentration and risk for CHD events was most pronounced in diabetics (HR 2.4 [1.46−3.83], p=0.0005).
In the ERA trial, elevated IL-10 concentration was associated with an increased risk for future cardiovascular events in post-menopausal women with established coronary atherosclerosis. Further study of the relationship between IL-10 and the pathogenesis and progression of atherosclerosis and cardiovascular events is warranted.
Interleukin-10; Coronary Heart Disease; Inflammation
To determine the effect of statins and hormone replacement therapy on submaximal exercise induced coronary artery blood flow in postmenopausal women without a history of coronary artery disease.
Hormone replacement or statin therapy in early postmenopausal women without coronary artery disease have been shown to enhance arterial endothelial function; we hypothesized that these agents would improve submaximal exercise induced coronary artery blood flow.
Sixty-four postmenopausal women, aged 50–65 years without documented coronary artery disease, were randomized in a double blinded, cross-over fashion to receive 8 weeks of hormone replacement therapy versus placebo, with or without 80 mg/day of atorvastatin. Prior to receipt of any therapy and after each treatment period, each woman underwent measures of coronary artery blood flow at rest and stress.
The combination of hormone replacement therapy and atorvastatin increased submaximal exercise induced coronary artery blood flow (p=0.04). In the subgroups of women compliant with treatment, resting coronary artery blood flow increased in those receiving hormone replacement therapy (p=0.03) or statin therapy (p=0.02).
In postmenopausal women aged 50–65 years without documented coronary artery disease, rest and submaximal exercise induced coronary artery blood flow improve after receipt of high dose atorvastatin and conjugated estrogen therapy.
estrogen; statins; exercise; magnetic resonance imaging; coronary artery flow
Evidence suggests that interleukin-1 receptor associated kinase-1 (IRAK1), fundamental in the toll-like receptor pathway (TLR), may play a more specific role in atherosclerosis.
Caucasian women (N=529) and men (N=467) from the Diabetes Heart Study (DHS) were genotyped at four loci within the IRAK1 gene located on the X chromosome. Generalized estimating equations (GEE1) were used to evaluate association with C-reactive protein (CRP) for both single SNP and haplotype analyses.
For each SNP genotyped, Caucasian women carrying one or two copies of the variant allele had greater CRP concentrations than those carrying the common genotype in both crude and adjusted models. There were 2 major haplotypes, CTTT (82%) and its complement, TCCG (13%). The presence of the TCCG haplotype was associated with greater CRP concentrations in Caucasian women (p=0.0004) and this relationship was maintained after adjustment for age, BMI, smoking, diabetes, and cholesterol-lowering therapy (p=0.003). There was no association between CRP and IRAK1 SNPs in Caucasian men.
Variation in the IRAK1 gene is associated with CRP concentration in Caucasian women in DHS. Further studies are needed to reproduce the current finding and to understand the biological relationship between IRAK1 and inflammation related to atherosclerosis.
Interleukin-1 receptor-associated kinase-1; IRAK1; C-reactive protein; CRP; innate immunity
Dietary patterns may influence cardiovascular disease risk through effects on inflammation and endothelial activation.
We examined relations between dietary patterns and markers of inflammation and endothelial activation.
At baseline, diet (food-frequency questionnaire) and concentrations of C-reactive protein (CRP), interleukin 6 (IL-6), homocysteine, soluble intercellular adhesion molecule-1 (sICAM-1), and soluble E selectin were assessed in 5089 nondiabetic participants in the Multi-Ethnic Study of Atherosclerosis.
Four dietary patterns were derived by using factor analysis. The fats and processed meats pattern (fats, oils, processed meats, fried potatoes, salty snacks, and desserts) was positively associated with CRP (P for trend < 0.001), IL-6 (P for trend < 0.001), and homocysteine (P for trend = 0.002). The beans, tomatoes, and refined grains pattern (beans, tomatoes, refined grains, and high-fat dairy products) was positively related to sICAM-1 (P for trend = 0.007). In contrast, the whole grains and fruit pattern (whole grains, fruit, nuts, and green leafy vegetables) was inversely associated with CRP, IL-6, homocysteine (P for trend ≤ 0.001), and sICAM-1 (P for trend = 0.034), and the vegetables and fish pattern (fish and dark-yellow, cruciferous, and other vegetables) was inversely related to IL-6 (P for trend = 0.009). CRP, IL-6, and homocysteine relations across the fats and processed meats and whole grains and fruit patterns were independent of demographics and lifestyle factors and were not modified by race-ethnicity. CRP and homocysteine relations were independent of waist circumference.
These results corroborate previous findings that empirically derived dietary patterns are associated with inflammation and show that these relations in an ethnically diverse population with unique dietary habits are similar to findings in more homogeneous populations.
Multi-Ethnic Study of Atherosclerosis; inflammation; endothelial activation; dietary patterns; factor analysis
Genetic variants in myocardial sodium and potassium channel genes are associated with prolonged QT interval and increased risk of sudden death. It is unclear whether these genetic variants remain relevant in subjects with underlying conditions such as diabetes that are associated with prolonged QT interval.
We tested single nucleotide polymorphisms (SNPs) in five candidate genes for association with QT interval in a family-based study of subjects with type 2 diabetes mellitus (T2DM). Thirty-six previously reported SNPs were genotyped in KCNQ1, HERG, SCN5A, KCNE1, and KCNE2 in 901 European Americans from 366 families. The heart rate-corrected (QTc) durations were determined using the Marquette 12SL program. Associations between the QTc interval and the genotypes were evaluated using SOLAR adjusting for age, gender, T2DM status, and body mass index.
Within KCNQ1 there was weak evidence for association between the minor allele of IVS12+14T>C and increased QTc (p=0.02). The minor allele of rs2236609 in KCNE1 trended toward significance with longer QTc (p=0.06), while the minor allele of rs1805123 in HERG trended toward significance with shorter QTc (p=0.07). However, no statistically significant associations were observed between the remaining SNPs and QTc variation.
We found weak evidence of association between three previously-reported SNPs and QTc interval duration. While it appears as though genetic variants in previously identified candidate genes may be associated with QT duration in subjects with diabetes, the clinical implications of these associations in diabetic subjects at high risk for sudden death remains to be determined.
QT interval; diabetes; association study; genetics; ion channels
Although brachial artery flow-mediated dilation (FMD) predicts recurrent cardiovascular events, its predictive value for incident cardiovascular disease (CVD) events in adults free of CVD is not well established. We assessed the predictive value of FMD for incident CVD events in the Multi Ethnic Study of Atherosclerosis (MESA).
Methods and Results
Brachial artery FMD was measured in a nested case- cohort sample of 3026 out of 6814 subjects (mean ± SD age 61.2 ± 9.9 years), in MESA, a population-based cohort study of adults free of clinical CV disease at baseline recruited at six clinic sites in the USA. The sample comprised 50.2% females, 34.3% Caucasian, 19.7% Chinese, 20.8% African Americans and 25.1% Hispanics. Probability-weighted Cox proportional hazard analysis was used to examine the association between FMD and five years of adjudicated incident CVD events, including incident myocardial infarction, definite angina, coronary revascularization (coronary artery bypass grafting, percutaneous transluminal coronary angioplasty or other revascularization), stroke, resuscitated cardiac arrest and CVD death.
Mean (SD) FMD of the cohort was 4.4 (2.8) %. In probability-weighted Cox models, FMD/unit SD was significantly associated with incident cardiovascular events in both the univariate(adjusted for age and gender) [hazard ratio; 0.79(95% CI, 0.65–0.97), p=0.01], after adjusting for the Framingham Risk Score (FRS) [hazard ratio; 0.80(95%CI, 0.62–0.97), p=0.025] and also in multivariable models [hazard ratio; 0.84(95%CI, 0.71–0.99), p=0.04] after adjusting for age, gender, diabetes mellitus, cigarette smoking status, systolic blood pressure, HDL, LDL, triglycerides, heart rate, statin use and blood pressure medication use. The c statistic (AUC) of FMD, FRS, FRS + FMD) were 0.65, 0.74 and 0.74 respectively. Compared with the FRS alone, the addition of FMD to the FRS net correctly re-classifies 52% of subjects with no incident CVD event, but net incorrectly reclassifies 23% of subjects with an incident CVD event; an overall net correct re-classification of 29% (p < 0.001).
Brachial FMD is a predictor of incident cardiovascular events in population based adults. Even though the addition of FMD to the FRS did not improve discrimination of subjects at risk of CVD events in ROC analysis, it did improve the classification of subjects as low, intermediate and high CVD risk compared to the FRS.
Endothelial dysfunction; brachial flow-mediated dilation; incident cardiovascular event; healthy adults
To determine whether middle-aged and older individuals with impaired fasting glucose (IFG), but no clinical evidence of cardiovascular disease, exhibit abnormal changes in proximal thoracic aortic stiffness or left ventricular (LV) mass when compared with healthy counterparts.
RESEARCH DESIGN AND METHODS
From the Multi-Ethnic Study of Atherosclerosis, 2,240 subjects with normal fasting glucose (NFG), 845 with IFG, and 414 with diabetes, all aged 45 to 85 years and without preexisting coronary artery disease, underwent MRI determinations of total arterial and proximal thoracic aortic stiffness and LV mass. The presence or absence of other factors known to influence arterial stiffness was assessed.
After adjustment for clinical factors known to modify arterial stiffness, proximal thoracic aortic stiffness was not increased in those with IFG compared with those with NFG (1.90 ± 0.05 versus 1.91 ± 0.04 10−3 mmHg−1, respectively, P = 0.83). After accounting for clinical factors known to influence LV mass, LV mass was increased in those with diabetes relative to those with NFG (150.6 ± 1.4 versus 145.8 ± 0.81 g, P < 0.0009) but not in those with IFG in comparison with NFG (145.2 ± 1.03 versus 145.8 ± 0.81 g, P = 0.56).
Middle-aged and older individuals with the pre-diabetes state of IFG do not exhibit abnormal proximal thoracic distensibility or LV hypertrophy relative to individuals with NFG. For this reason, an opportunity may exist in those with IFG to prevent LV hypertrophy and abnormal aortic stiffness that is observed in middle-aged and older individuals with diabetes.