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1.  Is Cardiovascular Reactivity Associated With Atherosclerosis Among Hypertensives? 
Hypertension  2002;40(5):742-747.
Exaggerated cardiovascular reactivity to behavioral challenges among otherwise healthy individuals has been associated with carotid atherosclerosis. We evaluated whether a similar relationship exists among hypertensives, who are at a heightened atherosclerotic risk. Untreated, hypertensive men (n=251; age range, 40 to 70 years; 197 white, 54 black) completed a standardized battery of behavioral challenges while their blood pressure responses to the battery were measured. Mean and maximum carotid intima-media thickness and the occurrence of carotid plaques were subsequently determined using B-mode ultrasonography. Although greater systolic and diastolic responses to the battery were associated with greater mean and maximum intima-media thickness in univariate analyses (P<0.01), only diastolic reactivity showed a unique association with mean and maximum carotid intima-media thickness after multivariate adjustment for age, race, socioeconomic status, smoking and alcohol use, body mass index, lipid profile, glucose and insulin concentrations, and resting blood pressure (P<0.05). Carotid plaque occurrence was associated with greater systolic reactivity (P=0.05) and was marginally associated with greater diastolic reactivity (P=0.07) in univariate analyses, but neither systolic nor diastolic reactivity was uniquely associated with the presence of carotid plaques after multivariate risk-factor adjustment. Among hypertensives, exaggerated behaviorally evoked cardiovascular reactivity appears to be uniquely associated with greater carotid intima-media thickness but not with carotid plaque occurrence.
PMCID: PMC4896076  PMID: 12411471
atherosclerosis; cardiovascular reactivity; carotid intima-media thickness; carotid plaque; stress
2.  The impact of change in physical activity on change in arterial stiffness in overweight or obese sedentary young adults 
Arterial stiffness is associated with cardiovascular events and mortality. Lifestyle factors such as physical activity may reduce arterial stiffness. The purpose of this study is to determine the impact of change in physical activity (PA) on one-year change in arterial stiffness in 274 overweight/obese sedentary young adults. The Slow Adverse Vascular Effects of excess weight (SAVE) trial was a study evaluating the relationships between weight loss, dietary sodium, and vascular health. PA was measured with the ActiGraph AM7164 accelerometer. Intensity of activity was determined using established cutpoints. Arterial stiffness was assessed by brachial-ankle PWV (baPWV) using an automated device. Analysis of Covariance compared changes in total accelerometer counts, minutes/day in light intensity PA (LPA), and moderate-to-vigorous PA (MVPA), and sedentary time, by categories of change in baPWV. Models were adjusted for time since baseline visit, age, sex, race, homeostatis model of assessment of insulin resistance, mean arterial pressure, heart rate, and weight change. Total accelerometer counts and time spent in MVPA increased from baseline to 12 months while time spent in LPA significantly decreased. Mean baPWV was similar at each time point. Those that showed decreased baPWV also showed an increase in total accelerometer counts per day and time spent in MVPA in the fully adjusted models (p<0.001). Changes in sedentary time and time spent in LPA were not associated with changes in baPWV. These results indicate that even modest increases in MVPA can reduce arterial stiffness, a risk factor for future cardiovascular events.
PMCID: PMC4877277  PMID: 24879662
total movement; pulse wave velocity; accelerometer; obesity; intervention; vascular health
3.  Daily Psychological Demands Are Associated with Six-Year Progression of Carotid Artery Atherosclerosis: The Pittsburgh Healthy Heart Project 
Psychosomatic medicine  2012;74(4):432-439.
We examine associations between the perception of ongoing psychological demands by ecological momentary assessment (EMA) and 6-year changes in carotid artery atherosclerosis by ultrasonography.
270 initially healthy participants collected ambulatory blood pressure (ABP) and recorded their daily experiences, using electronic diaries, over two 3-day periods. Mean intima-medial thickness (IMT) and plaque were assessed in the carotid arteries using B-mode ultrasound at baseline and again during a 6-year follow-up (average follow-up duration 73 months).
Among those who had no exposure to antihypertensive medications over the course of follow-up (n = 192), daily psychological demands were associated with greater progression of IMT as well as plaque, after adjustment for demographic and risk factor covariates. Associations between demands and plaque change were partially accounted for by ABP differences among those reporting high demands. Among those who were employed at baseline (n=117), six-year IMT changes were more strongly associated with ratings of daily demands than with traditional measures of occupational stress.
These data support the role of psychological demands as a correlate of subclinical atherosclerotic progression, they point to ABP as a potential mechanism facilitating these effects, and they highlight the utility of EMA measures for capturing daily psychological demands with potential effects on health.
PMCID: PMC4869071  PMID: 22582340
Cardiovascular disease; intima medial thickness; ambulatory blood pressure; ecological momentary assessment; job stress; psychological stress
4.  Nulliparity is Associated with Less Healthy Markers of Subclinical Cardiovascular Disease In Overweight and Obese Young Women 
Obesity (Silver Spring, Md.)  2015;23(5):1085-1091.
Higher parity is associated with increased subclinical cardiovascular disease (CVD) in mid-life and older women, and with increased CVD risk overall. The relationship between parity, subclinical CVD, and infertility in overweight and obese young women has been infrequently evaluated.
Reproductive histories were obtained in 191 (73%) overweight and obese (BMI 25 – 39.9 kg/m2) young women participating in a weight loss trial. Baseline carotid intima-media thickness (IMT) and inter-adventitial diameter (IAD) were assessed via B-mode ultrasound. Linear regression was used to estimate the relationship between parity and carotid measures, adjusted for demographic, cardiovascular and reproductive risk factors.
Nulliparous women (n=70, age 34.9 ± 7.1) had increased common carotid IAD (.230 mm, SE .08, P = .003) and mean CCA IMT (.031 mm, SE .01, P = .007) compared with parous women (n=102, age 39.5 ± 4.9), persisting after adjustment for age, race, and CVD risk factors. No other reproductive factors were statistically significantly associated.
Nulliparity is associated with markers of less healthy carotid arteries in a sample of disease-free, overweight or obese 25-45 year-old women. This may represent a beneficial effect of pregnancy or indicate overall better health in overweight/obese women capable of childbearing.
PMCID: PMC4414732  PMID: 25866258
obesity; cardiovascular risk; women
5.  Longitudinal Assessment of the Menopausal Transition, Endogenous Sex Hormones, and Perception of Physical Functioning: The Study of Women’s Health Across the Nation 
To evaluate the longitudinal associations between menopausal status, related hormonal changes, and level of self-reported physical functioning.
Study included 2,495 women (age: 45–57 between 2000 and 2001) from the Study of Women’s Health Across the Nation. Physical functioning scale of the Medical Outcomes Study Short-Form (SF-36; score 0–100) was categorized as: no limitation (86–100), moderate limitation (51–85), and substantial limitation (0–50). Study variables were collected between 2000 (visit-04) and 2011 (visit-12) at five timepoints. Statistical models were adjusted for age at visit-04, time since visit-04, ethnicity, site, economic status, level and change in body mass index, level and change in physical activity, and presence of comorbid conditions.
In final models, natural and surgical postmenopausal women had significantly higher odds of functional limitation, compared with premenopausal women. Less reduction in estradiol and testosterone since visit-04 were significantly associated with lower odds of functional limitation, while greater increase in sex hormone-binding globulin was associated with higher odds of functional limitation.
Our findings suggest the menopause-related changes in endogenous sex hormones as a possible mechanism of action to explain the greater limitation in physical functioning reported in women at midlife.
PMCID: PMC4158400  PMID: 24465026
Physical function; Epidemiology; Functional performance; Geriatric endocrinology; Menopause.
6.  Incident Physical Disability in People with Lower Extremity Peripheral Arterial Disease: The Role of Cardiovascular Disease 
To evaluate the risk of incident physical disability and the decline in gait speed over a six year follow-up associated with a low ankle-arm index (AAI) in older adults.
Observational cohort study.
Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; or Allegheny County, Pennsylvania.
4705 older adults, 58% women and 17.6% black, participating in the Cardiovascular Health Study were included.
The AAI was measured in 1992–93 (baseline). Self-reported mobility disability, activities of daily living (ADL) and instrumental activities of daily living (IADL) disability and gait speed were recorded at baseline and at 1 year intervals over 6 years of follow-up. Mobility disability was defined as any difficulty walking ½ mile and ADL/IADL disability was defined as any difficulty with 11 specific ADL/IADL tasks. Individuals with mobility and/or ADL/IADL disability at baseline were excluded from the respective incident disability analyses.
Lower baseline AAI values were associated with increased risk of mobility disability and ADL/IADL disability. These associations were partially explained by clinical cardiovascular disease (CVD), diabetes and interim CVD events for mobility disability and by clinical CVD and diabetes for ADL/IADL disability. Individuals with AAI < 0.90 had on average a mean decrease in gait speed of 0.02 m/s/year or a decline of 0.12 m/s over the 6 year follow-up. This decrease was partly explained by prevalent CVD but not further attenuated by interim CVD events.
Low AAI serves as marker of future disability risk. Reduction of disability risk in patients with a low AAI should consider cardiovascular comorbidity and the prevention of additional disabling CVD events.
PMCID: PMC4509641  PMID: 18384579
Peripheral arterial disease; disability; cardiovascular disease
7.  Complement protein C3 and coronary artery calcium in middle-aged women with polycystic ovary syndrome and controls 
Circulating complement protein C3 (C3) levels have been associated with coronary artery calcification (CAC) in women with systemic lupus erythematosus, but have yet to be evaluated in women with polycystic ovary syndrome (PCOS). We aimed to determine whether C3 levels were elevated in women with PCOS compared to controls, and to quantify the association of C3 with cardiovascular disease (CVD) risk factors and CAC, and if PCOS modified this association. This cross-sectional analysis included 132 women with PCOS and 155 controls 35-62 years old from the third visit of a case-control study. CAC was measured during the study visit and circulating C3 was measured in stored sera. The presence of CAC and CAC categories (Agatston score 0, 1-9.9, and ≥10) were used for logistic and ordinal regression analysis, respectively. C3 levels were not significantly different between women with PCOS and controls. Among all women, C3 was associated with the presence of CAC and increasing CAC groups after adjusting for age, PCOS status, and insulin or BMI, all p<0.05. In addition, C3 was associated with the presence of CAC after adjusting for age, PCOS status, BMI, insulin and African American race, p=0.049. PCOS status did not modify these associations. In conclusion, circulating C3 levels may prove beneficial in identifying women at risk of CVD in women with PCOS and the general population.
PMCID: PMC4065194  PMID: 24592986
Polycystic ovary syndrome; subclinical cardiovascular disease; coronary artery calcium; inflammation; complement protein C3
8.  Associations between arterial stiffness and platelet activation in normotensive overweight and obese young adults 
Obese individuals have elevated platelet activation and arterial stiffness, but the strength and temporality of the relationship between these factors remain unclear. We aimed to determine the effect of increased arterial stiffness on circulating platelet activity in overweight/obese young adults. This analysis included 92 participants (mean age 40 years, 60 women) in the Slow Adverse Vascular Effects of excess weight (SAVE) trial, a clinical trial examining the effects of a lifestyle intervention with or without sodium restriction on vascular health in normotensive overweight/obese young adults. Carotid-femoral (cf), brachial-ankle (ba), and femoral-ankle (fa) pulse wave velocity (PWV) served as measures of arterial stiffness and were measured at baseline and 6, 12, and 24 months follow-up. Platelet activity was measured as plasma beta-thromboglobulin (β-TG) at 24 months. Higher plasma β-TG was correlated with greater exposure to elevated cfPWV (p=0.02) and baPWV (p=0.04) during the preceding two years. After adjustment for serum leptin, greater exposure to elevated baPWV remained significant (p=0.03) and exposure to elevated cfPWV marginally significant (p=0.054) in predicting greater plasma β-TG. Greater arterial stiffness, particularly central arterial stiffness, predicts greater platelet activation in overweight/obese individuals. This relationship might partly explain the association between increased arterial stiffness and incident atherothrombotic events.
PMCID: PMC3742736  PMID: 23654212
platelet activation; arterial stiffness; pulse wave velocity; obesity; weight loss
9.  Association of Total Marine Fatty Acids, Eicosapentaenoic and Docosahexaenoic Acids, With Aortic Stiffness in Koreans, Whites, and Japanese Americans 
American Journal of Hypertension  2013;26(11):1321-1327.
Few previous studies have reported the association of aortic stiffness with marine n-3 fatty acids (Fas) in the general population. The aim of this study was to determine the combined and independent associations of 2 major marine n-3 FAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), with aortic stiffness evaluated using carotid–femoral pulse wave velocity (cfPWV) in Korean, white, and Japanese American men.
A population-based sample of 851 middle-aged men (299 Koreans, 266 whites, and 286 Japanese Americans) was examined for cfPWV during 2002–2006. Serum FAs, including EPA and DHA, were measured as a percentage of total FAs using gas chromatography. Multiple regression analysis was used to examine the association of EPA and DHA with cfPWV after adjusting for blood pressure and other confounders.
Mean EPA and DHA levels were 1.9 (SD = 1.0) and 4.8 (SD = 1.4) for Koreans, 0.8 (SD = 0.6) and 2.4 (SD = 1.2) for whites, and 1.0 (SD = 1.0) and 3.2 (SD = 1.4) for Japanese Americans. Both EPA and DHA were significantly higher in Koreans than in the other 2 groups (P < 0.01). Multiple regression analyses in Koreans showed that cfPWV had a significant inverse association with total marine n-3 FAs and with EPA alone after adjusting for blood pressure and other potential confounders. In contrast, there was no significant association of cfPWV with DHA. Whites and Japanese Americans did not show any significant associations of cfPWV with total marine n-3 FAs, EPA, or DHA.
High levels of EPA observed in Koreans have an inverse association with aortic stiffness.
PMCID: PMC3790451  PMID: 23820020
aortic stiffness; blood pressure; carotid femoral pulse wave velocity; docosahexaenoic acid; eicosapentaenoic acid; fish oil; hypertension.
10.  Do Differences in Risk Factors Explain the Lower Rates of Coronary Heart Disease in Japanese Versus U.S. Women? 
Journal of Women's Health  2013;22(11):966-977.
Mortality from coronary heart disease (CHD) in women in Japan is one of the lowest in developed countries. In an attempt to shed some light on possible reasons of lower CHD in women in Japan compared with the United States, we extensively reviewed and analyzed existing national data and recent literature.
We searched recent epidemiological studies that reported incidence of acute myocardial infarction (AMI) and examined risk factors for CHD in women in Japan. Then, we compared trends in risk factors between women currently aged 50–69 years in Japan and the United States, using national statistics and other available resources.
Recent epidemiological studies have clearly shown that AMI incidence in women in Japan is lower than that reported from other countries, and that lipids, blood pressure (BP), diabetes, smoking, and early menopause are independent risk factors. Comparing trends in risk factors between women in Japan and the United States, current levels of serum total cholesterol are higher in women in Japan and levels have been similar at least since 1990. Levels of BP have been higher in in Japan for the past 3 decades. Prevalence of type 2 diabetes has been similar in Japanese and white women currently aged 60–69 for the past 2 decades. In contrast, rates of cigarette smoking, although low in women in both countries, have been lower in women in Japan.
Differences in risk factors and their trends are unlikely to explain the difference in CHD rates in women in Japan and the United States. Determining the currently unknown factors responsible for low CHD mortality in women in Japan may lead to new strategy for CHD prevention.
PMCID: PMC3820126  PMID: 24073782
11.  Perivascular Adipose Tissue of the Descending Thoracic Aorta is Associated with Systemic Lupus Erythematosus and Vascular Calcification in Women 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.09.004.
Women with systemic lupus erythematosus (SLE) have an increased risk of cardiovascular disease (CVD). Traditional CVD and SLE-disease related risk factors do not fully account for this increased risk. Perivascular adipose tissue (PVAT) is a visceral adipose depot in close proximity to blood vessels possibly influencing CVD. We hypothesized that women with SLE have an increased volume of descending thoracic aortic PVAT (aPVAT) associated with increased vascular calcification.
Using electron beam computed tomography, we quantified the aPVAT in clinically CVD-free SLE women (n=135) and age-/race-matched healthy controls (HC, n=152). Coronary artery calcification (CAC) and aortic calcification (AC) were quantified using Agatston scores and the aPVAT was quantified using standard Hounsfield Units (HU) for adipose tissue.
Women with SLE had greater median aPVAT (32.2 cm3 vs. HC aPVAT 28.6 cm3, p=0.0071) and greater median AC (26.0 vs HC AC 6.0, p=0.0013) than the healthy control women. Total aPVAT (per 25 cm3) remained significantly associated with SLE after adjusting for CVD risk factors (Odds Ratio 1.74 [95% Confidence Interval: 1.04-2.9], p=0.034), but was attenuated when adjusting for circulating inflammatory markers (p=0.34). In a logistic regression analysis, SLE aPVAT (per 25 cm3) was associated with AC (6.78 [2.0-23], p=0.0019), which remained significant after adjusting for circulating inflammatory markers (p=0.0074), and CAC (2.66 [1.4-5.0], p=0.0028).
Total aPVAT is greater in clinically CVD-free SLE women than in age-/race-matched controls and is associated with calcification in different vascular beds.
PMCID: PMC3831349  PMID: 24125423
atherosclerosis; adipose; systemic lupus erythematosus; calcification
12.  Relation of Carotid Intima-Media Thickness and Plaque With Incident Cardiovascular Events in Women With Systemic Lupus Erythematosus 
The American journal of cardiology  2013;112(7):1025-1032.
Patients with systemic lupus erythematosus (SLE) are at increased risk for cardiovascular (CV) disease. The aim of this study was to investigate the association between subclinical CV disease as measured by carotid intima-media thickness (IMT) and plaque using B-mode carotid ultrasound and incident CV events in a combined cohort of female patients with SLE. This was a prospective, 2-center observational study of 392 adult women with SLE and no previous CV events with a mean 8 years of follow-up. Incident CV events confirmed by clinicians were defined as angina, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, fatal cardiac arrest, transient ischemic attack, and cerebrovascular accident. Incident hard CV events excluded angina and transient ischemic attack. The mean age was 43.5 years, and most patients were Caucasian (77.3%). During follow-up, 38 patients had incident CV events, and 17 had incident hard CV events. Patients with incident hard CV events had higher mean carotid IMT (0.80 vs 0.64 mm, p <0.01) and presence of carotid plaque (76.5% vs 30.4%, p <0.01) compared with those without incident hard CV events. Baseline carotid IMT and presence of plaque were predictive of any incident hard CV event (hazard ratio 1.35, 95% confidence interval 1.12 to 1.64, and hazard ratio 4.26, 95% confidence interval 1.23 to 14.83, respectively), independent of traditional CV risk factors and medication use. In conclusion, in women with SLE without previous CV events, carotid IMT and plaque are predictive of future CV events. This suggests that carotid ultrasound may provide an additional tool for CV risk stratification in patients with SLE.
PMCID: PMC3779482  PMID: 23827400
13.  Prior Preterm Birth and Maternal Subclinical Cardiovascular Disease 4 to 12 Years After Pregnancy 
Journal of Women's Health  2013;22(10):835-843.
We considered that women with prior preterm birth (PTB) would have evidence of subclinical atherosclerosis, endothelial dysfunction, and arterial stiffness.
Four to 12 years after pregnancy, blood pressure and fasting lipids were analyzed, and women underwent evaluation, following standardized protocols, of carotid intima-media thickness (IMT), brachial flow-mediated dilation (FMD), and pulse wave velocity (PWV). Women with prior preterm (<37 weeks, n=181) or term births (>= 37 weeks, n=306) were compared. Those with preeclampsia or term small-for-gestational-age (SGA) births were excluded.
Women with a prior preterm vs. term birth had higher blood pressure, on average, and a more atherogenic lipid profile. They also had marginally higher IMT (0.579 standard error [SE] 0.005—vs. 0.567 [0.004] mm, p=0.06), adjusted for body size, demographics, and smoking. IMT differences were greater among those with non-preeclamptic-indicated PTB (0.034 mm, p=0.05) and PTB<34 weeks (0.024 mm, p=0.04) compared to those with term births. These differences appeared to be explained in part by the atherogenic lipid elevations in women with preterm birth. Women with prior PTB<34 weeks tended to have lower FMD, but results were not statistically significant. PWV did not differ according to PTB.
In the decade following pregnancy, women with non-preeclamptic-indicated PTB or PTB delivered before 34 weeks had higher blood pressure, atherogenic lipids, and IMT compared to women with term births. There may be subgroups of women with a prior PTB with excess cardiovascular risk that is detectable before overt clinical disease.
PMCID: PMC3787333  PMID: 24033091
14.  Favorable Effects of Insulin Sensitizers Pertinent to Peripheral Arterial Disease in Type 2 Diabetes 
Diabetes Care  2013;36(10):3269-3275.
The aim of this manuscript was to report the risk of incident peripheral arterial disease (PAD) in a large randomized clinical trial that enrolled participants with stable coronary artery disease and type 2 diabetes and compare the risk between assigned treatment arms.
The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial randomly assigned participants to insulin sensitization (IS) therapy versus insulin-providing (IP) therapy for glycemic control. Results showed similar 5-year mortality in the two glycemic treatment arms. In secondary analyses reported here, we examine the effects of treatment assignment on the incidence of PAD. A total of 1,479 BARI 2D participants with normal ankle-brachial index (ABI) (0.91–1.30) were eligible for analysis. The following PAD-related outcomes are evaluated in this article: new low ABI ≤0.9, a lower-extremity revascularization, lower-extremity amputation, and a composite of the three outcomes.
During an average 4.6 years of follow-up, 303 participants experienced one or more of the outcomes listed above. Incidence of the composite outcome was significantly lower among participants assigned to IS therapy than those assigned to IP therapy (16.9 vs. 24.1%; P < 0.001). The difference was significant in time-to-event analysis (hazard ratio 0.66 [95% CI 0.51–0.83], P < 0.001) and remained significant after adjustment for in-trial HbA1c (0.76 [0.59–0.96], P = 0.02).
In participants with type 2 diabetes who are free from PAD, a glycemic control strategy of insulin sensitization may be the preferred therapeutic strategy to reduce the incidence of PAD and subsequent outcomes.
PMCID: PMC3781574  PMID: 23735723
16.  Particle Numbers of Lipoprotein Subclasses and Arterial Stiffness among Middle-aged men from the ERA JUMP study 
Journal of human hypertension  2013;28(2):111-117.
We examined the association between serum lipoprotein subclasses and the three measures of arterial stiffness i.e. (i) carotid-femoral pulse wave velocity (cfPWV) which is a gold standard measure of central arterial stiffness, (ii) brachial-ankle PWV (baPWV) which is emerging as a combined measure of central and peripheral arterial stiffness, and (iii) femoral-ankle PWV (faPWV) which is a measure of peripheral arterial stiffness. Among a population-based sample of 701 apparently healthy Caucasian, Japanese American and Korean men aged 40–49 years, concentrations of lipoprotein particles were assessed by nuclear magnetic resonance (NMR) spectroscopy, and PWV was assessed with an automated waveform analyzer (VP2000, Omron, Japan). Multiple linear regressions were performed to analyze the association between each NMR lipoprotein subclasses and PWV measures, after adjusting for cardiovascular risk factors and other confounders. A cut-off of p<0.01 was used for determining significance. All PWV measures had significant correlations with total and small low-density lipoprotein particle number (LDL-P) (all p<0.0001) but not LDL-cholesterol (LDL-C) (all p>0.1), independent of race and age. In multivariate regression analysis, no NMR lipoprotein subclass was significantly associated with cfPWV (all p>0.01). However, most NMR lipoprotein subclasses had significant associations with both baPWV and faPWV (p<0.01). In this study of healthy middle-aged men, as compared to cfPWV, both baPWV and faPWV had stronger associations with particle numbers of lipoprotein subclasses. Our results may suggest that both baPWV and faPWV are related to arterial stiffness and atherosclerosis, whereas cfPWV may represent arterial stiffness alone.
PMCID: PMC3800263  PMID: 23823580
lipoproteins; lipoprotein fractions; pulse wave velocity; atherosclerosis
17.  Evidence for a Genetic Link Between Bone and Vascular Measures in African Ancestry Families 
Bone mineral density (BMD) has been inversely associated with subclinical and clinical cardiovascular disease (CVD) in population studies, but the potential mechanisms underlying this relationship are unclear. To test if there is a genetic basis underlying this association, we determined the phenotypic and genetic correlations between BMD and carotid artery ultrasound measures in families. Dual-energy X-ray absorptiometry and peripheral quantitative computed tomography were used to measure BMD in 461 African ancestry individuals belonging to 7 large, multigenerational families (mean family size 66; 3,414 total relative pairs). Carotid artery ultrasound was used to measure adventitial diameter (AD) and intima-media thickness (IMT). Phenotypic and genetic correlations between BMD and carotid measures were determined using pedigree-based maximum likelihood methods. We adjusted for potential confounding factors, including age, sex, body weight, height, menopausal status, smoking, alcohol intake, walking for exercise, diabetes, hypertension, serum lipid and lipoprotein levels, inflammation markers and kidney function. We found statistically significant phenotypic (ρ = −0.19) and genetic (ρG = −0.70) correlations (P < 0.05 for both) between lumbar spine BMD and AD in fully adjusted models. There was also a significant genetic correlation between trabecular BMD at the radius and IMT in fully adjusted models (ρG = −0.398; P < 0.05). Our findings indicate that the previously observed association between osteoporosis and CVD in population-based studies may be partly mediated by genetic factors and that the pleiotropic effects of these genes may operate independently of traditional risk pathways.
PMCID: PMC3720825  PMID: 23505032
bone mineral density; adventitial diameter; intima-media thickness; genetic correlation; African ancestry
Atherosclerosis  2007;197(2):768-776.
The association of brachial flow-mediated dilation (FMD) and cardiovascular disease (CVD) status is unclear especially in older adults whose FMD is greatly diminished. We assessed the association of FMD and the presence or absence of subclinical and clinical CVD in a population based cohort of older adults.
FMD was measured in 2971 adults aged 72–98 years (mean age 78.6 years) who participated in the Cardiovascular Health Study. Multiple linear regression analysis was used to examine the association between FMD and CVD status (clinical, subclinical and free of CVD). Out of 2791 with complete data, 82.7% were Caucasians and 59% females. 743 were classified as having clinical CVD, 607 as subclinical CVD and 1441 as neither clinical CVD nor subclinical CVD (CVD free). FMD was higher in the CVD free group compared with either the clinical (3.13 ± 0.05% vs 2.93 ± 0.07%, p=0.025) or the subclinical CVD group (3.13± 0.05% vs 2.95± 0.08%, p=0.05) after adjusting for covariates. There was no significant difference between the FMD of subjects with clinical and subclinical CVD (2.93 ± 0.07% vs 2.95 ± 0.08%, p=0.84). Similar but inverted associations were observed between height adjusted brachial artery diameter (BAD) and CVD status. However, FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD.
Among older adults, those with either clinical or subclinical CVD have lower FMD than CVD free subjects. BAD showed similar but inverted associations with CVD status in this cohort. FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD.
PMCID: PMC4115610  PMID: 17714717
Brachial flow-mediated dilation; brachial artery diameter; cardiovascular disease; elderly
19.  The Associations of Indices of Obesity with Lipoprotein Subfractions in Japanese American, African American and Korean Men 
Global heart  2013;8(3):273-280.
Both indices of obesity and lipoprotein subfractions contribute to coronary heart disease risk. However, associations between indices of obesity and lipoprotein subfractions remain undetermined across different ethnic groups. This study aims to examine the associations of indices of obesity in Japanese Americans (JA), African Americans (AA) and Koreans with lipoprotein subfractions.
A population-based sample of 230 JA, 91 AA, and 291 Korean men aged 40–49 was examined for indices of obesity, i.e., visceral and subcutaneous adipose tissue (VAT and SAT, respectively), waist circumference (WC), and body-mass index (BMI), and for lipoprotein subfractions by nuclear-magnetic-resonance spectroscopy. Multiple regression analyses were performed in each of the three ethnic groups to examine the associations of each index of obesity with lipoprotein.
VAT had significant positive associations with total and small low-density lipoprotein (LDL) and a significant negative association with large high-density lipoprotein (HDL) in all three ethnicities (p < 0.01). SAT, WC, and BMI had significant positive associations with total and small LDL in only JA and Koreans, while these indices had significant inverse associations with large HDL in all ethnic groups (p < 0.01). Compared to SAT, VAT had larger R2 values in the associations with total and small LDL and large HDL in all three ethnic groups.
VAT is significantly associated with total and small LDL and large HDL in all three ethnic groups. The associations of SAT, WC, and BMI with lipoprotein subfractions are weaker compared to VAT in all three ethnic groups.
PMCID: PMC4110345  PMID: 25068101
visceral adipose tissue; subcutaneous adipose tissue; body-mass index; waist circumference; lipoprotein subfractions
20.  The Prevalence of Aortic Calcification in Japanese Compared to White and Japanese-American Middle-Aged Men is Confounded by the Amount of Cigarette Smoking 
International journal of cardiology  2012;167(1):134-139.
Prevalence of coronary artery calcification (CAC) in Japanese men is lower than in white and Japanese-American men. It is unclear if aortic calcification (AC) strongly linked to smoking is also lower in Japanese men who have many times higher smoking prevalence compared to US men.
We conducted a population-based study of 903 randomly-selected men aged 40–49 years: 310 Japanese men in Kusatsu, Japan, 301 white men in Allegheny County, U.S., and 292 Japanese men in Hawaii, U.S. (2002–2006). The presence of AC was assessed by electron-beam tomography. AC was defined as Agatston aortic calcium scores (AoCaS) >0 and ≥100.
Japanese (35.8%) had significantly less AoCaS>0 compared to both white (68.8%, p<0.001) and Japanese-American (62.3%, p<0.001) but similar AoCaS≥100 (19.4%, 18.3%, 22.6%, respectively, p=0.392). Pack-years of smoking, which was highest in Japanese, was the most important single associate of AC in all populations. Additionally age, low-density-lipoprotein cholesterol (LDL-C), and triglycerides in Japanese; body-mass index (BMI) in white; and BMI, LDL-C, hypertension, diabetes, and lipid medications in Japanese-American were independent associates of AC. The risk of AC using either cut points adjusted for pack-years of smoking and additional risk factors was lower in Japanese compared to both white and Japanese-American. AC and CAC had moderately positive and significant correlations in Japanese (r=0.26), white (r=0.39), and Japanese-American (r=0.45).
Prevalence of AC defined both >0 and ≥100 was significantly lower in Japanese than in white and Japanese-American men after adjusting for cigarette smoking and additional risk factors
PMCID: PMC3328605  PMID: 22240754
Epidemiology; risk factors; atherosclerosis; aorta; calcification; electron-beam tomography; Caucasian; Japanese; Japanese American
21.  Inflammatory expression profiles in monocyte-to-macrophage differentiation in patients with systemic lupus erythematosus and relationship with atherosclerosis 
Arthritis Research & Therapy  2014;16(4):R147.
Our objectives were to examine mononuclear cell gene expression profiles in patients with systemic lupus erythematosus (SLE) and healthy controls and to compare subsets with and without atherosclerosis to determine which genes’ expression is related to atherosclerosis in SLE.
Monocytes were obtained from 20 patients with SLE and 16 healthy controls and were in vitro-differentiated into macrophages. Subjects also underwent laboratory and imaging studies to evaluate for subclinical atherosclerosis. Whole-genome RNA expression microarray was performed, and gene expression was examined.
Gene expression profiling was used to identify gene signatures that differentiated patients from controls and individuals with and without atherosclerosis. In monocytes, 9 out of 20 patients with SLE had an interferon-inducible signature compared with 2 out of 16 controls. By looking at gene expression during monocyte-to-macrophage differentiation, we identified pathways which were differentially regulated between SLE and controls and identified signatures based on relevant intracellular signaling molecules which could differentiate SLE patients with atherosclerosis from controls. Among patients with SLE, we used a previously defined 344-gene atherosclerosis signature in monocyte-to-macrophage differentiation to identify patient subgroups with and without atherosclerosis. Interestingly, this signature further classified patients on the basis of the presence of SLE disease activity and cardiovascular risk factors.
Many genes were differentially regulated during monocyte-to-macrophage differentiation in SLE patients compared with controls. The expression of these genes in mononuclear cells is important in the pathogenesis of SLE, and molecular profiling using gene expression can help stratify SLE patients who may be at risk for development of atherosclerosis.
PMCID: PMC4227297  PMID: 25011540
22.  Telomere length in patients with systemic lupus erythematosus and its associations with carotid plaque 
Rheumatology (Oxford, England)  2013;52(6):1101-1108.
Objective. To evaluate telomere length (TL) between patients with SLE and healthy controls and to test if TL is associated with carotid plaque.
Methods. A pilot study of 154 patients with SLE and 152 controls was performed from the SOLVABLE (Study of Lupus Vascular and Bone Long-Term Endpoints) cohort. Demographic and cardiovascular disease (CVD) factors were collected at baseline. The presence or absence of plaque was evaluated by B-mode US. Genomic DNA was isolated from whole peripheral blood. TL was quantified using real-time quantitative PCR.
Results. SLE women had a short TL compared with healthy controls (4.57 vs 5.44 kb, P = 0.03). SLE women showed shorter TL than controls across all age groups: <35 years (4.38 vs 6.37 kb), 35–44 years (4.52 vs 5.30 kb), 45–54 years (4.77 vs 5.68 kb) and ≥55 years (4.60 vs 4.71 kb). Among patients with SLE and carotid plaque there was a trend towards shorter TL at a younger age and it was significantly lower in the 35- to 44-year age group when compared with controls (P = 0.025). Multiple logistic regression analysis indicated a risk of carotid plaque with older age [odds ratio (OR) 1.09; 95% CI 1.06, 1.12] but not with TL (OR 1.05; 95% CI 0.97, 1.13).
Conclusion. SLE women had significantly shorter TL than controls. SLE women trended towards shorter TL at a younger age. When carotid plaque was identified, the younger SLE women had shorter TL. Only older age but not shorter TL was independently associated with carotid plaque. Additional studies are needed to confirm if TL is a novel biomarker for cardiovascular disease in SLE.
PMCID: PMC3651615  PMID: 23382361
systemic lupus erythematosus; cardiovascular disease; telomere length
23.  Adverse pregnancy outcomes and subsequent risk of cardiovascular disease in women with systemic lupus erythematosus 
Lupus Science & Medicine  2014;1(1):e000024.
Patients with systemic lupus erythematosus (SLE) are at increased risk for adverse pregnancy outcomes and cardiovascular disease (CVD). The objective of this exploratory study was to investigate the association between a history of adverse pregnancy outcomes and subsequent risk of subclinical CVD assessed by imaging studies and verified clinical CVD events in 129 women with SLE.
The occurrence of adverse pregnancy outcomes, specifically pre-eclampsia, preterm birth and low birth weight was ascertained by questionnaire. Subclinical CVD was assessed by coronary artery calcium (CAC) as measured by electron beam CT and carotid plaque measured by B mode ultrasound. Clinical CVD events were verified by medical record review. Logistic regression was used to estimate the association of pregnancy complications with occurrence of subclinical CVD and clinical CVD with a priori adjustment for age, which is associated with CVD and SLE disease duration as a measure of SLE disease burden.
Fifty-six women reported at least one pregnancy complication while 73 had none. Twenty-six women had at least one pregnancy complicated by pre-eclampsia and were more likely to have a CAC score greater than or equal to 10 (adjusted OR=3.7; 95% CI 1.2 to 11.9), but the presence of plaque was not associated with this pregnancy complication, OR=1.1, (95% CI 0.4 to 2.8). Low birth weight and preterm birth were not associated with CAC or plaque.
Patients with SLE with a history of pre-eclampsia had a higher rate of subclinical CVD as measured by CAC score. Future studies are needed to confirm the relationship between adverse pregnancy outcomes and subsequent subclinical CVD and clinical CVD events.
PMCID: PMC4213826  PMID: 25379191
Cardiovascular Disease; Systemic Lupus Erythematosus; Pregnancy; Pre-eclampsia
24.  Changes in serum aldosterone are associated with changes in obesity-related factors in normotensive overweight and obese young adults 
Recent data suggest excess circulating aldosterone promotes cardiometabolic decline. Weight loss may lower aldosterone levels, but little longitudinal data is available in normotensive adults. We aimed to determine if, independent of changes in sodium excretion, reductions in serum aldosterone are associated with favorable changes in obesity-related factors in normotensive overweight/obese young adults. We studied 285 overweight/obese young adult participants (body mass index (BMI) ≥ 25 and < 40 kg/m2, age 20–45 years) in a clinical trial examining the effects of a one year diet and physical activity intervention with or without sodium restriction on vascular health. Body weight, serum aldosterone, 24-hr sodium and potassium excretion, and obesity-related factors were measured at baseline, 6, 12, and 24 months. Weight loss was significant at 6 (7%), 12 (6%), and 24 months (4%) (all p<0.0001). Decreases in aldosterone were associated with decreases in C-reactive protein, leptin, insulin, homeostasis assessment of insulin resistance, heart rate, tonic cardiac sympathovagal balance, and increases in adiponectin (all p<0.05) in models adjusting for baseline age, sex, race, intervention arm, time since baseline, and sodium and potassium excretion. Weight loss and reductions in thigh intermuscular fat (IMAT) were associated with decreases in aldosterone in the subgroup (n=98) with metabolic syndrome (MetS) at baseline (MetS x weight loss p=0.04, MetS x change in IMAT p=0.04). Favorable changes in obesity-related factors are associated with reductions in aldosterone in young adults with no risk factors besides excess weight, an important finding given aldosterone’s emergence as an important cardiometabolic risk factor.
PMCID: PMC3766434  PMID: 23657296
aldosterone; obesity; adipokines; metabolic syndrome; adipose tissue
25.  Long-chain n-3 polyunsaturated fatty acids and incidence rate of coronary artery calcification in Japanese in Japan and United States whites – population-based prospective cohort study 
Heart (British Cardiac Society)  2013;100(7):569-573.
To determine whether serum levels of long-chain n-3 polyunsaturated fatty acids (LCn3PUFAs) contribute to the difference in incidence rate of coronary artery calcification (CAC) between Japanese in Japan and U.S. whites.
In a population-based prospective-cohort study, 214 Japanese and 152 white men aged 40–49 years at baseline (2002–2006) with coronary calcium score (CCS) = 0 were reexamined for CAC in 2007–2010. Among these, 175 Japanese and 113 whites participated in the follow-up exam. Incident cases were defined as participants with CCS ≥ 10 at follow-up. A relative risk regression analysis was used to model incidence rate ratio between Japanese and whites. The incidence rate ratio was first adjusted for potential confounders at baseline and then further adjusted for serum LCn3PUFAs at baseline.
Mean (standard deviation) serum percentage of LCn3PUFA was > 100% higher in Japanese than in whites (9.08 (2.49) versus 3.84 (1.79), respectively, p<0.01). Japanese had a significantly lower incidence rate of CAC compared to whites (0.9 versus 2.9/100 person-years, respectively, p < 0.01). Incidence rate ratio of CAC taking follow-up time into account between Japanese and white men was 0.321 (95% confidence interval (CI) 0.150, 0.690: p<0.01). After adjusting for age, systolic-blood pressure, low-density-lipoprotein cholesterol, diabetes, and other potential confounders, the ratio remained significant: 0.262 (95% CI: 0.094, 0.731, p=0.01). After further adjusting for LCn3PUFAs, however, the ratio was attenuated and became non-significant (0.376 (95% CI: 0.090, 1.572, p=0.18).
LCn3PUFAs significantly contributed to the difference in CAC incidence between Japanese and white men.
PMCID: PMC3949146  PMID: 24352736
long-chain n-3 fatty acids; coronary artery calcification; prospective cohort study; incidence; risk factors

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