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1.  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.
doi:10.1161/HYPERTENSIONAHA.111.00272
PMCID: PMC3586233  PMID: 23283358
arterial stiffness; endothelial markers; inflammatory markers; large and small artery elasticity; lung function; MESA Study
2.  Effect of exercise on abdominal fat loss in men and women with and without type 2 diabetes 
BMJ Open  2013;3(11):e003897.
Objective
To examine the effect of exercise on abdominal adipose tissue in adults with and without type 2 diabetes mellitus (T2DM).
Design
Post hoc analysis of two randomised controlled trials.
Setting
Outpatient secondary prevention programme in Baltimore, Maryland, USA.
Participants
97 men and women with prehypertension, stage 1 or medically controlled hypertension. 49% of the sample was also diagnosed with T2DM.
Intervention
All participants completed a 26-week (6.5 months) supervised aerobic and resistance exercise programme following American College of Sports Medicine guidelines.
Primary and secondary outcome measures
The main outcomes in this post hoc analysis were total abdominal adipose tissue (TAT), subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) measured by MRI. Secondary outcomes were to determine whether the magnitude of abdominal fat change differed by diabetes status in men and women and to identify the predictors of change in abdominal fat distribution with exercise.
Results
Overall, participants (mean age 61±6 years; 45% women) significantly improved peak oxygen uptake by 15% (p<0.01) and reduced weight by 2% (p<0.01). No change in SAT was observed after training. The reduction in VAT following exercise was attenuated in participants with T2DM (–3%) compared with participants who were non-T2DM (–18%, p<0.001 for the difference in change). The magnitude of VAT loss was associated with a decrease in body weight (r=0.50, p<0.001). After adjustment for weight change using regression analysis, diabetes status remained an independent predictor of the change in VAT.
Conclusions
Although participants with and without T2DM attained an exercise training effect as evidenced by increased fitness, VAT was unchanged in T2DM compared to those without T2DM, suggesting that these individuals may be resistant to this important benefit of exercise. The strategies for reducing cardiovascular disease risk in T2DM may be most effective when they include a weight loss component.
Clinical Trials Registration
Clinicaltrials.gov Registry NCT00212303.
doi:10.1136/bmjopen-2013-003897
PMCID: PMC3845055  PMID: 24282247
Preventive Medicine
3.  Effect of Exercise on Blood Pressure in Type 2 Diabetes: A Randomized Controlled Trial 
Journal of General Internal Medicine  2012;27(11):1453-1459.
BACKGROUND
Increased blood pressure (BP) in type 2 diabetes (T2DM) markedly increases cardiovascular disease morbidity and mortality risk compared to having increased BP alone.
OBJECTIVE
To investigate whether exercise reduces suboptimal levels of untreated suboptimal BP or treated hypertension.
DESIGN
Prospective, randomized controlled trial for 6 months.
SETTING
Single center in Baltimore, MD, USA.
PATIENTS
140 participants with T2DM not requiring insulin and untreated SBP of 120–159 or DBP of 85–99 mmHg, or, if being treated for hypertension, any SBP <159 mmHg or DBP < 99 mmHg; 114 completed the study.
INTERVENTION
Supervised exercise, 3 times per week for 6 months compared with general advice about physical activity.
MEASUREMENTS
Resting SBP and DBP (primary outcome); diabetes status, arterial stiffness assessed as carotid-femoral pulse-wave velocity (PWV), body composition and fitness (secondary outcomes).
RESULTS
Overall baseline BP was 126.8 ± 13.5 / 71.7 ± 9.0 mmHg, with no group differences. At 6 months, BP was unchanged from baseline in either group, BP 125.8 ± 13.2 / 70.7 ± 8.8 mmHg in controls; and 126.0 ± 14.2 / 70.3 ± 9.0 mmHg in exercisers, despite attaining a training effects as evidenced by increased aerobic and strength fitness and lean mass and reduced fat mass (all p < 0.05), Overall baseline PWV was 959.9 ± 333.1 cm/s, with no group difference. At 6-months, PWV did not change and was not different between group; exercisers, 923.7 ± 319.8 cm/s, 905.5 ± 344.7, controls.
LIMITATIONS
A completion rate of 81 %.
CONCLUSIONS
Though exercisers improve fitness and body composition, there were no reductions in BP. The lack of change in arterial stiffness suggests a resistance to exercise-induced BP reduction in persons with T2DM.
doi:10.1007/s11606-012-2103-8
PMCID: PMC3475835  PMID: 22610907
exercise training; diabetes; high blood pressure; randomized trial
4.  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.
Objective
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.
Methods
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.
Results
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).
Conclusions
Early menopause is positively associated with coronary heart disease and stroke in a multiethnic cohort, independent of traditional cardiovascular disease risk factors.
doi:10.1097/gme.0b013e3182517bd0
PMCID: PMC3443540  PMID: 22692332
Early Menopause; Coronary Heart Disease; Stroke
5.  Progression of coronary artery atherosclerosis in rheumatoid arthritis: comparison with participants from the Multi-Ethnic Study of Atherosclerosis 
Arthritis Research & Therapy  2013;15(5):R134.
Introduction
In cross-sectional studies, patients with rheumatoid arthritis (RA) have higher coronary artery calcium (CAC) than controls. However, their rate of progression of CAC and the predictors of CAC progression have heretofore remained unknown.
Methods
Incidence and progression of CAC were compared in 155 patients with RA and 835 control participants. The association of demographic characteristics, traditional cardiovascular risk factors, RA disease characteristics and selected inflammatory markers with incidence and progression of CAC were evaluated.
Results
The incidence rate of newly detected CAC was 8.2/100 person-years in RA and 7.3/100 person-years in non-RA control subjects [IRR 1.1 (0.7-1.8)]. RA patients who developed newly detectable CAC were older (59±7 vs. 55±6 years old, p=0.03), had higher triglyceride levels (137±86 vs. 97±60 mg/dL, p=0.03), and higher systolic blood pressure (129±17 vs. 117±15 mm Hg, p=0.01) compared to those who did not develop incident CAC. Differences in blood pressure and triglyceride levels remained significant after adjustment for age (p<=0.05). RA patients with any CAC at baseline had a median rate of yearly progression of 21 (7–62) compared to 21 (5–70) Agatston units in controls. No statistical differences between RA progressors and RA non-progressors were observed for inflammatory markers or for RA disease characteristics.
Conclusions
The incidence and progression of CAC did not differ between RA and non-RA participants. In patients with RA, incident CAC was associated with older age, higher triglyceride levels, and higher blood pressure, but not with inflammatory markers or RA disease characteristics.
doi:10.1186/ar4314
PMCID: PMC3978773  PMID: 24286380
6.  ENDOGENOUS SEX HORMONES, BLOOD PRESSURE CHANGE, AND RISK OF HYPERTENSION IN POSTMENOPAUSAL WOMEN: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS 
Atherosclerosis  2012;224(1):228-234.
Objective
Sex steroid hormones have been postulated to involve in blood pressure (BP) regulation. We examine the association of endogenous sex hormone levels with longitudinal change of BP and risk of developing hypertension in initially normotensive postmenopausal women.
Methods
We conducted prospective analysis among 619 postmenopausal women free of hypertension at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA). Change of BP and development of incident hypertension were assessed during a mean of 4.8 years follow-up.
Results
After adjusting for age, race/ethnicity, and lifestyle factors, baseline serum estradiol (E2), total and bioavailable testosterone (T), dehydroepiandrosterone (DHEA) were each positively and sex- hormone binding globulin (SHBG) was inversely associated with risk of hypertension. Additional adjustment for body mass index eliminated the associations for E2 and T but only attenuated the associations for DHEA and SHBG. The corresponding multivariable hazard ratios (95% CIs) in the highest quartile were 1.28 (0.83–1.97) for E2, 1.38 (0.89–2.14) for total T, 1.42 (0.90–2.23) for bioavailable T, 1.54 (1.02–2.31) for DHEA, and 0.48 (0.30–0.76) for SHBG. Adjustment for fasting glucose, insulin, and C-reactive protein further attenuated the association for DHEA but not SHBG. Associations of sex hormones with longitudinal BP change were similar.
Conclusion
In postmenopausal women, higher endogenous E2, T, and DHEA and lower SHBG were associated with higher incidence of hypertension and greater longitudinal rise in BP. The associations for E2, T, and DHEA were mostly explained by adiposity, while the association for SHBG was independent of measures of adiposity, insulin resistance, and systemic inflammation.
doi:10.1016/j.atherosclerosis.2012.07.005
PMCID: PMC3428144  PMID: 22862963
sex steroid hormones; hypertension; blood pressure; postmenopausal women; prospective study; epidemiology
7.  Association of Sex Hormones and SHBG with Depressive Symptoms in Post-menopausal Women: the Multi-Ethnic Study of Atherosclerosis 
Menopause (New York, N.y.)  2012;19(8):877-885.
Objective
Sex hormones are thought to play an important role in the pathophysiology of depressive disorders in women. This study assessed the associations of total testosterone (T), bioavailable T, estradiol (E2), dehydroepiandrosterone (DHEA) and sex hormone binding globulin (SHBG) with depressive symptoms stratified on postmenopausal stage to determine whether associations were strongest for early postmenopausal women.
Methods
Women (N=1824) free of depressive symptoms at baseline (2000–2002) in the Multi-Ethnic Study of Atherosclerosis were categorized into tertiles of years postmenopause: T1, 0–10 years; T2, 11–20 years; and T3, 21–58 years. Multivariable-adjusted relative risks (RR) and 95% confidence intervals were computed for the incidence of depressive symptoms, as defined by a score of 16 or higher on the Center for Epidemiologic Studies Depression scale at examination 3 (2004–2005).
Results
In analysis including all sex hormones, the RRs for incident depressive symptoms associated with 1 unit higher log(total T) was 0.57 (p=0.13), log(E2) was 0.78 (p=0.04), log(SHBG) was 1.84 (p=0.003) and log(DHEA) was 1.45 (p=0.08) in T1. Without adjustment for SHBG, the RR for log(bioavailable T) was 0.16 (p=0.04). However, in T2 and T3, there were no meaningful associations of hormone or SHBG levels with incident depressive symptoms. When stratified by HT use, results were consistent for HT users but attenuated for HT non-users.
Conclusions
In women early postmenopause, sex hormones were associated with incident depressive symptoms.
doi:10.1097/gme.0b013e3182432de6
PMCID: PMC3376685  PMID: 22415566
sex hormones; CES-D; depression; testosterone; estradiol; SHBG
8.  Bilateral Oophorectomy, Body Mass Index, and Mortality in U.S. Women Aged 40 Years and Older 
Bilateral oophorectomy is used as a risk reduction strategy in BRCA1/2 mutation carriers, although data on long-term side effects are not yet available. In the general population, oophorectomy, particularly at a young age, has been associated with increased overall and cardiovascular disease (CVD) mortality. The mechanisms for this association are not well understood. We examined the association between prior bilateral oophorectomy, obesity, and all-cause, cancer, and CVD mortality. Our study population included women ages 40 and above from the Third National Health and Nutrition Examination Survey (NHANES III), a nationally representative survey with enrollment from 1988 to 1994 and prospective mortality follow-up through December 31, 2006. We excluded women with a history of reproductive cancer or missing oophorectomy status, yielding a study population of 4,040. Cox proportional hazards modeling was used to estimate HR for all-cause and cause-specific mortality. In multivariate analyses, body mass index (BMI) significantly modified the association between oophorectomy and mortality (Pinteraction = 0.04). Women who were obese at the time of interview and who had an oophorectomy at less than 40 years were more than twice as likely to die [HR, 2.23; 95% confidence interval (CI), 1.25–3.98], particularly of CVD (HR, 2.77; 95% CI, 0.91–8.41), than nonobese women with intact ovaries. These associations persisted after excluding women who used estrogen therapy and women who had oophorectomy before 35 years of age. The joint effect of obesity and early oophorectomy on mortality was significantly greater than expected, given the independent effects of both exposures. Our results suggest that minimizing weight gain after oophorectomy and addressing cardiovascular risk factors could beneficially impact mortality.
doi:10.1158/1940-6207.CAPR-11-0430
PMCID: PMC3401905  PMID: 22556202
9.  Association of Baseline Sex Hormone Levels with Baseline and Longitudinal Changes in Waist-to-Hip Ratio : Multi-Ethnic Study of Atherosclerosis 
Objective
Waist-to-hip ratio (WHR) is strongly associated with prevalent atherosclerosis. We analyzed the associations of baseline serum levels of testosterone (T), estradiol (E2), sex hormone binding globulin (SHBG), and dehydroepiandrosterone (DHEA) with WHR in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort.
Subjects
Baseline data was available for 3144 men and 2038 postmenopausal women, who were non-users of hormone therapy, who were 45–84 years of age, and of White, Chinese, Black or Hispanic racial/ethnic groups. Of these, 2708 men and 1678 women also had longitudinal measurements of WHR measured at the second and/or the third study visits (median follow-up 578 days, and 1135 days, respectively).
Results
In cross-sectional analyses adjusted for age, race, and cardiovascular disease risk factors, T was negatively associated with baseline WHR in men, while in both sexes, E2 was positively associated and SHBG was negatively associated with WHR (all p<0.001). In longitudinal analyses, further adjusted for follow-up time and baseline WHR, baseline T was negatively associated with WHR at follow-up (p=0.001) in men, while in both sexes, E2 was positively associated (p=0.004), and SHBG was negatively associated with WHR (p<0.001). The longitudinal association of E2, but not T, was independent of SHBG. In both cross-sectional or longitudinal analyses, there were no associations between DHEA and WHR in either men or women.
Conclusion
Sex hormones are associated with WHR at baseline and also during follow-up above and beyond their baseline association. Future research is needed to determine if manipulation of hormones is associated with changes in central obesity.
doi:10.1038/ijo.2012.3
PMCID: PMC3342434  PMID: 22270378
Sex Hormones; epidemiology; waist to hip ratio
10.  Association of number of live births with left ventricular structure and function. The Multi-Ethnic Study of Atherosclerosis (MESA) 
American heart journal  2012;163(3):470-476.
Background
Pregnancy is associated with marked maternal cardiovascular/hemodynamic changes. A greater number of pregnancies may be associated with long-term subclinical changes in left ventricular (LV) remodeling.
Methods
Among 2,234 white, black, Hispanic, and Chinese women (mean age 62 years) in the MESA, we used linear regression to relate live births and cardiac magnetic resonance imaging LV measures. Covariates included age, ethnicity, height, income, education, birth country, smoking, menopause, and oral contraceptive duration. Models were additionally adjusted for potential mediators: systolic blood pressure, antihypertensive use, total/high-density lipoprotein cholesterol, triglycerides, diabetes, and body mass index. We performed sensitivity analyses excluding 763 women in the lowest socioeconomic group: annual income <$25,000 and lower high school level of education.
Results
With each live birth, LV mass increased 1.26 g; LV end-diastolic volume, 0.74 mL; and LV end-systolic volume, 0.45 mL; LV ejection fraction decreased 0.18% (P trend <0.05). Changes were most notable for the category of women with ≥5 pregnancies. Upon adjustment for potential biologic mediators, live births remained positively associated with LV mass and end-systolic volume. Live births remained significantly associated with LV end-systolic, end-diastolic volumes, and LV mass (P trend ≤0.02) after excluding women in the lowest socioeconomic group.
Conclusions
Number of live births is associated with key LV structural and functional measures in middle to older ages, even after adjustment for sociodemographic factors and cardiovascular disease risk factors. Hemodynamic changes during pregnancy may be associated with cardiac structure/function beyond childbearing years.
doi:10.1016/j.ahj.2011.12.011
PMCID: PMC3656723  PMID: 22424019
11.  Sex-Specific Association of Age with Carotid Artery Distensibility: Multi-Ethnic Study of Atherosclerosis 
Journal of Women's Health  2012;21(5):516-520.
Abstract
Background
Older women have a higher prevalence of systolic hypertension than do men; however, whether or not this relates to arterial properties, such as distensibility coefficient (DC), is not known. We examined whether the association of carotid artery DC with age differed by sex in the Multi-Ethnic Study of Atherosclerosis (MESA).
Methods
B-mode ultrasound-measured carotid diameters and brachial pressures were obtained from 6359 participants (53% female, 38% white, 12% Chinese, 27% black, 22% Hispanic, aged 45–85 years) of the MESA baseline examination. The within-individual slopes of 2log(diameter) vs. blood pressure fit using mixed models (MM) are interpreted as the DC, and interaction terms are interpreted as differences in DC. The MM calculation allows for correction of the confounding caused by the association of age, sex, and race with blood pressure, the denominator in the calculation of DC.
Results
DC was associated with age, sex, and race (all p<0.001). Women had a greater age-related lowering of DC compared to men (2.52×10−5 vs. 2.16×10−5/mm Hg lower DC per year of age, p=0.006). Mean diameter of carotid arteries was greater with age (p<0.001); this association also was significantly stronger in women compared to men (0.24% vs. 0.14% larger mean carotid diameter per year of age, p<0.001).
Conclusions
Greater stiffening and enlargement of arteries are seen in older women compared to older men. This implies that the afterload on the heart of older women is likely to be greater than that among older men.
doi:10.1089/jwh.2011.3220
PMCID: PMC3353825  PMID: 22393881
12.  Comparison of breast cancer recurrence risk and cardiovascular disease incidence risk among postmenopausal women with breast cancer 
The majority of breast cancers are diagnosed in postmenopausal women. Competing comorbidities, particularly cardiovascular disease (CVD), should be considered when individualizing adjuvant therapies for these women. We compared the 10-year predicted breast cancer recurrence risk with CVD risk among postmenopausal women with hormone receptor-positive (HR+), non-metastatic breast cancer. CVD risk factor data were prospectively collected from postmenopausal women with stage I-III, HR+ breast cancer initiating adjuvant aromatase inhibitor therapy. We compared predicted 10-year CVD risk, including the composite index heart age, computed from modified Framingham risk score, with predicted 10-year risk of breast cancer recurrence using Adjuvant! Online. We created multivariable logistic regression models to estimate the odds ratios (OR) and 95% confidence intervals (CI) for greater CVD risk than breast cancer recurrence risk. Among 415 women, mean age and heart age were 60 and 67 years, respectively. Overall, 43% of women had a predicted 10-year CVD risk equivalent to breast cancer recurrence risk and 37% had CVD risk higher than breast cancer recurrence risk. Predicted CVD risk was higher than breast cancer recurrence risk for stage I disease (OR: 6.1, 95% CI: 3.4–11.2) or heart age >65 (OR: 12.4, 95% CI: 7.0–22.6). The majority of postmenopausal women with HR+ early breast cancer had a predicted 10-year CVD risk that was equivalent to or higher than breast cancer recurrence risk. Physicians should weigh competing risks and offer early screening and cardiac prevention strategies for women at a greater risk for CVD.
doi:10.1007/s10549-011-1843-1
PMCID: PMC3582017  PMID: 22042368
Breast cancer risk; Cardiovascular disease risk; Adjuvant! Online; Modified Framingham risk score; Cancer survivorship
13.  Prevalence of Traditional Modifiable Cardiovascular Risk Factors in Patients with Rheumatoid Arthritis: Comparison with Control Subjects from the Multi-Ethnic Study of Atherosclerosis 
Objective
Despite the recognized risk of accelerated atherosclerosis in patients with rheumatoid arthritis (RA), little is known about cardiovascular risk management in contemporary cohorts of these patients. We tested the hypotheses that major modifiable cardiovascular risk factors were more frequent and rates of treatment, detection, and control were lower in patients with RA than in non-RA controls.
Methods
The prevalence of hypertension, diabetes, elevated low-density lipoprotein (LDL) cholesterol, elevated body mass index, smoking, moderate-high 10-year cardiovascular risk and the rates of underdiagnosis, therapeutic treatment, and recommended management were compared in 197 RA patients and 274 frequency-matched control subjects, and their associations with clinical characteristics were examined.
Results
Eighty percent of RA patients and 81% of control subjects had at least 1 modifiable traditional cardiovascular risk factor. Hypertension was more prevalent in the RA group (57%) than in controls [42%, P =0.001]. There were no statistically significant differences in the frequency of diabetes, elevated body mass index, smoking, intermediate-high 10-year coronary heart disease risk, or elevated LDL in patients with RA versus controls. Rates of newly identified diabetes, hypertension, and hyperlipidemia were similar in RA patients versus controls. Rates of therapeutic interventions were low in both groups but their use was associated with well-controlled blood pressure (OR = 4.55, 95% CI: 1.70, 12.19) and lipid levels (OR = 9.90, 95% CI: 3.30, 29.67).
Conclusions
Hypertension is more common in RA than in controls. Other traditional cardiovascular risk factors are highly prevalent, underdiagnosed, and poorly controlled in patients with RA, as well as controls.
doi:10.1016/j.semarthrit.2011.07.004
PMCID: PMC3538033  PMID: 22340996
rheumatoid arthritis; cardiovascular risk; epidemiology
14.  Association Between Sleep Apnea, Snoring, Incident Cardiovascular Events and All-Cause Mortality in an Adult Population. MESA 
Atherosclerosis  2011;219(2):963-968.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.atherosclerosis.2011.08.021
PMCID: PMC3255297  PMID: 22078131
Obstructive sleep apnea; habitual snorers; cardiovascular events; mortality; population
15.  Sex-Steroid Hormones and Electrocardiographic QT-Interval Duration: Findings From the Third National Health and Nutrition Examination Survey and the Multi-Ethnic Study of Atherosclerosis 
American Journal of Epidemiology  2011;174(4):403-411.
The association between physiologic levels of sex hormones and QT-interval duration in humans was evaluated using data from 727 men enrolled in the Third National Health and Nutrition Examination Survey and 2,942 men and 1,885 postmenopausal women enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). Testosterone, estradiol, and sex hormone-binding globulin levels were measured in serum and free testosterone was calculated from those values. QT interval was measured using a standard 12-lead electrocardiogram. In men from the Third National Health and Nutrition Survey, the multivariate adjusted differences in average QT-interval duration comparing the highest quartiles with the lowest quartiles of total testosterone and free testosterone were −8.5 ms (95% confidence interval (CI): −15.5, −1.4) and −8.0 ms (95% CI: −13.2, −2.8), respectively. The corresponding differences were −1.8 ms (95% CI: −3.8, −0.2), and −4.7 ms (95% CI: −6.7, −2.6), respectively, in men from MESA and −0.6 ms (95% CI: −3.0, 1.8) and 0.8 ms (95% CI: −1.6, 3.3), respectively, in postmenopausal women from MESA. Estradiol levels were not associated with QT-interval duration in men, but there was a marginally significant positive association in postmenopausal women. The findings suggest that testosterone levels may explain differences in QT-interval duration between men and women and could be a contributor to population variability in QT-interval duration among men.
doi:10.1093/aje/kwr172
PMCID: PMC3202165  PMID: 21768401
electrocardiography; estradiol; gonadal sex hormones; testosterone
17.  Sex Hormones Are Associated with Right Ventricular Structure and Function 
Rationale: Sex hormones have effects on the left ventricle, but hormonal influences on the right ventricle (RV) are unknown.
Objectives: We hypothesized that sex hormones would be associated with RV morphology in a large cohort free of cardiovascular disease.
Methods: Sex hormones were measured by immunoassay and RV ejection fraction (RVEF), stroke volume (RVSV), mass, end-diastolic volume, and end-systolic volume (RVESV) were measured by cardiac magnetic resonance imaging in 1,957 men and 1,738 postmenopausal women. The relationship between each hormone and RV parameter was assessed by multivariate linear regression.
Measurements and Main Results: Higher estradiol levels were associated with higher RVEF (β per 1 ln[nmol/L], 0.88; 95% confidence interval [CI], 0.32 to 1.43; P = 0.002) and lower RVESV (β per 1 ln[nmol/L], −0.87; 95% CI, −1.67 to −0.08; P = 0.03) in women using hormone therapy. In men, higher bioavailable testosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.97; 95% CI, 0.20 to 3.73; P = 0.03) and greater RV mass and volumes (P ≤ 0.01). Higher dehydroepiandrosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.37; 95% CI, 0.15 to 2.59; P = 0.03) and greater RV mass (β per 1 ln[nmol/L], 0.25; 95% CI, 0.00 to 0.49; P = 0.05) and volumes (P ≤ 0.001) in women.
Conclusions: Higher estradiol levels were associated with better RV systolic function in women using hormone therapy. Higher levels of androgens were associated with greater RV mass and volumes in both sexes.
doi:10.1164/rccm.201007-1027OC
PMCID: PMC3081282  PMID: 20889903
sex; sex hormones; right ventricle
18.  The association between non-subcutaneous adiposity and calcified coronary plaque: A substudy of the Multi-Ethnic Study of Atherosclerosis 
Background
Excessive non-subcutaneous fat deposition may impair the functions of surrounding tissues and organs through the release of inflammatory cytokines and free fatty acids.
Objective
We examined the cross-sectional association between non-subcutaneous adiposity and calcified coronary plaque, a non-invasive measure of coronary artery disease burden.
Design
Participants in the Multi-Ethnic Study of Atherosclerosis underwent CT assessment of calcified coronary plaque. We measured multiple fat depots in 398 white and black participants (47% men and 43% black), ages 47–86 years, from Forsyth County, NC during 2002–2005, using cardiac and abdominal CT scans. In addition to examining each depot separately, we also created a non-subcutaneous fat index using the standard scores of non-subcutaneous fat depots.
Results
A total of 219 participants (55%) were found to have calcified coronary plaque. After adjusting for demographics, lifestyle factors and height, calcified coronary plaque was associated with a one standard deviation increment in the non-subcutaneous fat index (OR = 1.41; 95% CI: 1.08, 1.84), pericardial fat (OR = 1.38; 95% CI: 1.04, 1.84), abdominal visceral fat (OR = 1.35; 95% CI: 1.03, 1.76), but not with fat content in the liver, intermuscular fat, or abdominal subcutaneous fat. The relation between non-subcutaneous fat index and calcified coronary plaque remained after further adjustment for abdominal subcutaneous fat (OR = 1.40; 95% CI: 1.00, 1.94). The relation did not differ by gender and ethnicity.
Conclusions
The overall burden of non-subcutaneous fat deposition, but not abdominal subcutaneous fat, may be a correlate of coronary atherosclerosis.
PMCID: PMC3282464  PMID: 18779279
19.  Abdominal Aortic Calcium and Multi-Site Atherosclerosis: The Multiethnic Study of Atherosclerosis 
Atherosclerosis  2011;214(2):436-441.
Background
Abdominal aortic calcification (AAC) is a measure of subclinical cardiovascular disease (CVD). Data are limited regarding its relation to other measures of atherosclerosis.
Methods
Among 1,812 subjects (49% female, 21% black, 14% Chinese, and 25% Hispanic) within the population-based Multiethnic Study of Atherosclerosis, we examined the cross-sectional relation of AAC with coronary artery calcium (CAC), ankle brachial index (ABI), and carotid intimal medial thickness (CIMT), as well as multiple measures of subclinical CVD.
Results
AAC prevalence ranged from 34% in those aged 45–54 to 94% in those aged 75–84 (p<0.0001), was highest in Caucasians (79%) and lowest in blacks (62%) (p<0.0001). CAC prevalence, mean maximum CIMT ≥ 1 mm, and ABI<0.9 was greater in those with vs. without AAC: CAC 60% vs 16%, CIMT 38% vs 7%, and ABI 5% vs 1% for women and CAC 80% vs 37%, CIMT 43% vs 16%, and ABI 4% vs 2% for men (p<0.01 for all except p<0.05 for ABI in men). The presence of multi-site atherosclerosis (≥ 3 of the above) ranged from 20% in women and 30% in men (p<0.001), was highest in Caucasians (28%) and lowest in Chinese (16%) and ranged from 5% in those aged 45–54 to 53% in those aged 75–84 (p<0.01 to p<0.001). Finally, increased AAC was associated with 2 to 3-fold relative risks for the presence of increased CIMT, low ABI, or CAC.
Conclusions
AAC is associated with an increased likelihood of other vascular atherosclerosis. Its additive prognostic value to these other measures is of further interest.
doi:10.1016/j.atherosclerosis.2010.09.011
PMCID: PMC3040451  PMID: 21035803
atherosclerosis; calcification; cardiovascular disease; epidemiology
20.  Stages of Systemic Hypertension and Blood Pressure as Correlates of Computed Tomography-Assessed Aortic Valve Calcium (From the Multi-Ethnic Study of Atherosclerosis) 
Hypertension has been identified as a risk factor for aortic valve calcium (AVC) but the magnitude of the risk relation with hypertension severity or whether age affects the strength of this risk association has not been studied. The relationship of hypertension severity, as defined by JNC-7 hypertension stages or blood pressure (BP), to CT-assessed AVC prevalence and severity was examined in 4,274 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) without treated hypertension. Analyses were stratified by age < or ≥ 65 years, were adjusted for common cardiovascular risk factors, and excluded those on antihypertensive medications. In age-stratified, adjusted analyses, Stage I/II hypertension was associated with prevalent AVC in those <65 but not in those ≥65 years of age [OR (95% CI): 2.31 (1.35, 3.94) vs. 1.33 (0.96, 1.85), P-interaction = 0.041]. Similarly, systolic BP and pulse pressure (PP) were more strongly associated with prevalent AVC in those <65 than those ≥65 years of age [OR (95% CI): 1.21 (1.08, 1.35) vs. 1.07 (1.01, 1.14) per 10 mmHg increase in systolic BP, Pinteraction = 0.006] and [OR (95% CI): 1.41 (1.21, 1.64) vs. 1.14 (1.05, 1.23) per 10 mmHg increase in PP]. No associations were found between either hypertension stage or BP and AVC severity. In conclusion, stage I/II hypertension, as well as higher systolic pressure and pulse pressure were associated with prevalent AVC. These risk associations were strongest in participants younger than age 65 years.
doi:10.1016/j.amjcard.2010.08.042
PMCID: PMC3032359  PMID: 21146685
Blood Pressure; Aortic Valve; Calcification
21.  Association of Endothelial and Oxidative Stress with Metabolic Syndrome and Subclinical Atherosclerosis: Multi-Ethnic Study of Atherosclerosis 
Objectives
A cluster of metabolic abnormalities termed metabolic syndrome (MetS) is associated with vascular endothelial dysfunction and oxidative internal milieu. We examined whether the association of MetS with subclinical atherosclerosis is explained by biomarkers of endothelial damage and oxidative stress.
Methods
MESA is a population based study of 45-84 year old individuals of four US ethnicities without clinical cardiovascular disease. A random sample of 997 MESA participants had data on the following biomarkers: von Willebrand Factor, soluble intercellular adhesion molecule-1 (sICAM1), CD40 ligand, soluble thrombomodulin, E-selectin, and oxidized LDL (oxLDL). We examined whether the associations of MetS with B-mode ultrasound-defined common and internal carotid intimal medial thickness (IMT) and coronary artery calcium (CAC) measured using computerized tomography were explained by the biomarkers using multiple regression methods.
Results
MetS was associated with higher levels of each of the biomarkers (p<0.001, CD40L suggestive association p=0.004), with greater IMT (p<0.001), and with greater extent of CAC in those in whom CAC was detectable (p=0.01). The association of MetS with measures of subclinical atherosclerosis remained unchanged after adjustment for the biomarkers. After adjusting for MetS, oxLDL was suggestively associated with greater prevalence of detectable CAC (p=0.005) and thicker internal carotid IMT (p=0.002), while sICAM-1was significantly associated with greater prevalence of detectable CAC (p=0.001).
Conclusions
The association of MetS with subclinical atherosclerosis was independent of its association with biomarkers of endothelial damage and oxidative stress, suggesting that metabolic abnormalities and oxidative endothelial damage may lead to atherosclerotic disease through distinct mechanisms.
doi:10.1038/ejcn.2011.47
PMCID: PMC3130805  PMID: 21505504
Metabolic syndrome; biomarkers; coronary artery atherosclerosis; carotid arteries
22.  Strategies and methods to study sex differences in cardiovascular structure and function: a guide for basic scientists 
Background
Cardiovascular disease remains the primary cause of death worldwide. In the US, deaths due to cardiovascular disease for women exceed those of men. While cultural and psychosocial factors such as education, economic status, marital status and access to healthcare contribute to sex differences in adverse outcomes, physiological and molecular bases of differences between women and men that contribute to development of cardiovascular disease and response to therapy remain underexplored.
Methods
This article describes concepts, methods and procedures to assist in the design of animal and tissue/cell based studies of sex differences in cardiovascular structure, function and models of disease.
Results
To address knowledge gaps, study designs must incorporate appropriate experimental material including species/strain characteristics, sex and hormonal status. Determining whether a sex difference exists in a trait must take into account the reproductive status and history of the animal including those used for tissue (cell) harvest, such as the presence of gonadal steroids at the time of testing, during development or number of pregnancies. When selecting the type of experimental animal, additional consideration should be given to diet requirements (soy or plant based influencing consumption of phytoestrogen), lifespan, frequency of estrous cycle in females, and ability to investigate developmental or environmental components of disease modulation. Stress imposed by disruption of sleep/wake cycles, patterns of social interaction (or degree of social isolation), or handling may influence adrenal hormones that interact with pathways activated by the sex steroid hormones. Care must be given to selection of hormonal treatment and route of administration.
Conclusions
Accounting for sex in the design and interpretation of studies including pharmacological effects of drugs is essential to increase the foundation of basic knowledge upon which to build translational approaches to prevent, diagnose and treat cardiovascular diseases in humans.
doi:10.1186/2042-6410-2-14
PMCID: PMC3292512  PMID: 22152231
animal models; estrogen; gender; genomics; sex chromosomes; sex steroid hormones; study design; testosterone
24.  Ageing, menopause, and ischaemic heart disease mortality in England, Wales, and the United States: modelling study of national mortality data  
Objectives To use changes in heart disease mortality rates with age to investigate the plausibility of attributing women’s lower heart disease mortality than men to the protective effects of premenopausal sex hormones.
Design Modelling study of longitudinal mortality data with models assuming (i) a linear association between mortality rates and age (absolute mortality) or (ii) a logarithmic association (proportional mortality). We fitted models to age and sex specific mortality rates in the census years 1950 to 2000 for three birth cohorts (1916-25, 1926-35, and 1936-45).
Data sources UK Office for National Statistics and the US National Center for Health Statistics.
Main outcome measure(s) Fit of models to data for England and Wales and for the US.
Results For England-Wales data, proportional increases in ischaemic heart disease mortality fitted the data better than absolute increases (improvement in deviance statistics: women, 58 logarithmic units; men, 37). We identified a deceleration in male mortality after age 45 years (decreasing from 30.3% to 5.2% per age-year, P=0.042), although the corresponding difference in women was non-significant (P=0.43, overall trend 7.9% per age-year, P<0.001). By contrast, female breast cancer mortality decelerated significantly after age 45 years (decreasing from 19.3% to 2.6% per age-year, P<0.001). We found similar results in US data.
Conclusions Proportional age related changes in ischaemic heart disease mortality, suggesting a loss of reparative reserve, fit longitudinal mortality data from England, Wales, and the United States better than absolute age related changes in mortality. Acceleration in male heart disease mortality at younger ages could explain sex differences rather than any menopausal changes in women.
doi:10.1136/bmj.d5170
PMCID: PMC3167164  PMID: 21896608
25.  Inflammation and the Incidence of Type 2 Diabetes 
Diabetes Care  2010;33(4):804-810.
OBJECTIVE
Many studies have documented associations between inflammation and type 2 diabetes incidence. We assessed potential variability in this association in the major U.S. racial/ethnic groups.
RESEARCH DESIGN AND METHODS
Incident type 2 diabetes was assessed among men and women aged 45–84 years without prior clinical cardiovascular disease or diabetes in the prospective Multi-Ethnic Study of Atherosclerosis. Interleukin (IL)-6, fibrinogen, and C-reactive protein (CRP) were measured at baseline (2000–2002); fasting glucose and diabetes medication use was assessed at baseline and three subsequent in-person exams through 2007. Type 2 diabetes was defined as use of diabetes drugs or glucose ≥126 mg/dl. Covariates included baseline demographics, clinic, smoking, alcohol, exercise, hypertension medication, systolic blood pressure, insulin resistance, and BMI. Cox proportional hazards regression was used to calculate hazard ratios (HRs) by quartiles of CRP, IL-6, and fibrinogen.
RESULTS
Among 5,571 participants (mean age 61.6 years, 53% female, 42.1% white, 11.5% Chinese, 25.7% black, and 20.7% Hispanic), 410 developed incident diabetes during a median follow-up time of 4.7 years (incidence 16.8 per 1,000 person-years). CRP, IL-6, and fibrinogen levels were associated with incident diabetes in the entire sample. After adjustment, the associations were attenuated; however, quartile 4 (versus quartile 1) of IL-6 (HR 1.5 [95% CI 1.1–2.2]) and CRP (1.7 [1.3–2.4]) remained associated with incident diabetes. In stratified analyses, similar associations were observed among white, black, and Hispanic participants.
CONCLUSIONS
Higher levels of inflammation predict short-term incidence of type 2 diabetes in a multiethnic American sample.
doi:10.2337/dc09-1679
PMCID: PMC2845031  PMID: 20097779

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