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1.  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.
doi:10.3109/10641963.2013.789045
PMCID: PMC3742736  PMID: 23654212
platelet activation; arterial stiffness; pulse wave velocity; obesity; weight loss
2.  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.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
High levels of EPA observed in Koreans have an inverse association with aortic stiffness.
doi:10.1093/ajh/hpt107
PMCID: PMC3790451  PMID: 23820020
aortic stiffness; blood pressure; carotid femoral pulse wave velocity; docosahexaenoic acid; eicosapentaenoic acid; fish oil; hypertension.
3.  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.
Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1089/jwh.2012.4087
PMCID: PMC3820126  PMID: 24073782
4.  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.
Objective
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1016/j.atherosclerosis.2013.09.004
PMCID: PMC3831349  PMID: 24125423
atherosclerosis; adipose; systemic lupus erythematosus; calcification
5.  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.
doi:10.1016/j.amjcard.2013.05.040
PMCID: PMC3779482  PMID: 23827400
6.  Favorable Effects of Insulin Sensitizers Pertinent to Peripheral Arterial Disease in Type 2 Diabetes 
Diabetes Care  2013;36(10):3269-3275.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
doi:10.2337/dc12-2265
PMCID: PMC3781574  PMID: 23735723
7.  Prior Preterm Birth and Maternal Subclinical Cardiovascular Disease 4 to 12 Years After Pregnancy 
Journal of Women's Health  2013;22(10):835-843.
Abstract
Background
We considered that women with prior preterm birth (PTB) would have evidence of subclinical atherosclerosis, endothelial dysfunction, and arterial stiffness.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1089/jwh.2013.4248
PMCID: PMC3787333  PMID: 24033091
9.  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.
doi:10.1038/jhh.2013.60
PMCID: PMC3800263  PMID: 23823580
lipoproteins; lipoprotein fractions; pulse wave velocity; atherosclerosis
10.  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.
doi:10.1002/jbmr.1922
PMCID: PMC3720825  PMID: 23505032
bone mineral density; adventitial diameter; intima-media thickness; genetic correlation; African ancestry
11.  ASSOCIATION BETWEEN BRACHIAL ARTERY REACTIVITY AND CARDIOVASCULAR DISEASE STATUS IN AN ELDERLY COHORT: THE CARDIOVASCULAR HEALTH STUDY 
Atherosclerosis  2007;197(2):768-776.
BACKGROUND AND OBJECTIVES
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.
METHODS AND RESULTS
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.
CONCLUSION
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.
doi:10.1016/j.atherosclerosis.2007.07.013
PMCID: PMC4115610  PMID: 17714717
Brachial flow-mediated dilation; brachial artery diameter; cardiovascular disease; elderly
12.  The Associations of Indices of Obesity with Lipoprotein Subfractions in Japanese American, African American and Korean Men 
Global heart  2013;8(3):273-280.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.gheart.2013.07.001
PMCID: PMC4110345  PMID: 25068101
visceral adipose tissue; subcutaneous adipose tissue; body-mass index; waist circumference; lipoprotein subfractions
13.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
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
doi:10.1016/j.ijcard.2011.12.060
PMCID: PMC3328605  PMID: 22240754
Epidemiology; risk factors; atherosclerosis; aorta; calcification; electron-beam tomography; Caucasian; Japanese; Japanese American
14.  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.
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/ar4609
PMCID: PMC4227297  PMID: 25011540
15.  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.
doi:10.1093/rheumatology/kes424
PMCID: PMC3651615  PMID: 23382361
systemic lupus erythematosus; cardiovascular disease; telomere length
16.  Adverse pregnancy outcomes and subsequent risk of cardiovascular disease in women with systemic lupus erythematosus 
Lupus Science & Medicine  2014;1(1):e000024.
Background/objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1136/lupus-2014-000024
PMCID: PMC4213826  PMID: 25379191
Cardiovascular Disease; Systemic Lupus Erythematosus; Pregnancy; Pre-eclampsia
17.  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.
doi:10.1038/hr.2013.45
PMCID: PMC3766434  PMID: 23657296
aldosterone; obesity; adipokines; metabolic syndrome; adipose tissue
18.  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.
Objective
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.
Methods
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.
Results
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).
Conclusions
LCn3PUFAs significantly contributed to the difference in CAC incidence between Japanese and white men.
doi:10.1136/heartjnl-2013-304421
PMCID: PMC3949146  PMID: 24352736
long-chain n-3 fatty acids; coronary artery calcification; prospective cohort study; incidence; risk factors
19.  Do reports of sleep disturbance relate to coronary and aortic calcification in healthy middle-aged women?: Study of Women’s Health across the Nation 
Sleep medicine  2013;14(3):282-287.
Background
Poor sleep may be associated with the cardiovascular disease (CVD) morbidity and mortality. It is less clear if poor sleep is associated with subclinical CVD. We evaluated cross-sectional associations between self-reported sleep disturbance and duration and calcification in the coronary arteries (CAC) and aorta (AC) in healthy mid-life women.
Methods
512 black and white women enrolled in the SWAN Heart Study underwent a computed tomography protocol for measurement of CAC and AC and completed questionnaires about their sleep. Linear and partial proportional logit regression analyses adjusted for site, race, age, body mass index, and the Framingham risk score (model 1). Additional covariates of education, perceived health, hypnotic medication and alcohol use were evaluated (model 2), plus depressive symptoms (model 3).
Results
AC was related to higher levels of trouble falling asleep, waking earlier than planned, overall poor sleep quality, and cough/snoring and shorter sleep duration in linear regression analyses (model 1). Adjustment for additional covariates showed that poor sleep quality and waking earlier than planned remained associated with higher AC (models 2, 3). CAC was unrelated to sleep characteristics.
Conclusions
Poor sleep quality is related to AC in middle-aged women. Sleep quality should routinely be assessed in mid-life women.
doi:10.1016/j.sleep.2012.11.016
PMCID: PMC3582843  PMID: 23352420
sleep; insomnia; women; mid-life; calcification; aorta; cardiovascular risk factors
20.  Regional pulse wave velocities and their cardiovascular risk factors among healthy middle-aged men: a cross-sectional population-based study 
Background
Both carotid-femoral (cf) pulse wave velocity (PWV) and brachial-ankle (ba) PWV employ arterial sites that are not consistent with the path of blood flow. Few previous studies have reported the differential characteristics between cfPWV and baPWV by simultaneously comparing these with measures of pure central (aorta) and peripheral (leg) arterial stiffness, i.e., heart-femoral (hf) PWV and femoral-ankle (fa) PWV in healthy populations. We aimed to identify the degree to which these commonly used measures of cfPWV and baPWV correlate with hfPWV and faPWV, respectively, and to evaluate whether both cfPWV and baPWV are consistent with either hfPWV or faPWV in their associations with cardiovascular (CV) risk factors.
Methods
A population-based sample of healthy 784 men aged 40–49 (202 white Americans, 68 African Americans, 202 Japanese-Americans, and 282 Koreans) was examined in this cross-sectional study. Four regional PWVs were simultaneously measured by an automated tonometry/plethysmography system.
Results
cfPWV correlated strongly with hfPWV (r = .81, P < .001), but weakly with faPWV (r = .12, P = .001). baPWV correlated moderately with both hfPWV (r = .47, P < .001) and faPWV (r = .62, P < .001). After stepwise regression analyses with adjustments for race, cfPWV shared common significant correlates with both hfPWV and faPWV: systolic blood pressure (BP) and body mass index (BMI). However, BMI was positively associated with hfPWV and cfPWV, and negatively associated with faPWV. baPWV shared common significant correlates with hfPWV: age and systolic BP. baPWV also shared the following correlates with faPWV: systolic BP, triglycerides, and current smoking.
Conclusions
Among healthy men aged 40 – 49, cfPWV correlated strongly with central PWV, and baPWV correlated with both central and peripheral PWVs. Of the CV risk factors, systolic BP was uniformly associated with all the regional PWVs. In the associations with factors other than systolic BP, cfPWV was consistent with central PWV, while baPWV was consistent with both central and peripheral PWVs.
doi:10.1186/1471-2261-14-5
PMCID: PMC3893368  PMID: 24410766
Arterial stiffness; Aorta; Carotid arteries; Brachial artery; Femoral artery
21.  AORTIC PULSE WAVE VELOCITY PREDICTS FOCAL WHITE MATTER HYPERINTENSITIES IN A BIRACIAL COHORT OF OLDER ADULTS 
Hypertension  2012;61(1):160-165.
While the cross-sectional relationship of arterial stiffness with cerebral small vessel disease is consistently shown in middle-aged and young-old adults, its less clear if these associations remain significant over time in very old adults. We hypothesize that arterial stiffness is longitudinally associated with white matter characteristics and associations are stronger within watershed areas.
Neuroimaging was obtained in 2006–08 from 303 elderly (mean age 82.9 years, 59% women, 41% black) with pulse wave velocity measures in 1997–98. Multivariable regression models estimated the coefficients for pulse wave velocity (cm/sec) in relationship to presence, severity and spatial distribution of white matter hyperintensities, gray matter volume and fractional anisotropy from diffusion tensor, adjusting for demographic, cardiovascular risk factors and diseases from 1997–98 to 2006–08.
Higher pulse wave velocity in 1997–98 was associated with greater white matter hyperintensities volume in 2006–08 within the left superior longitudinal fasciculus (age and total brain white matter hyperintensities-adjusted p=0.023), but not with white matter hyperintensities in other tracts, or with fractional anisotropy or gray matter volume from total brain (p>0.2). Associations were stronger in blacks than in whites remaining significant in fully adjusted models.
Elderly with white matter hyperintensities in tracts related to processing speed and memory are more likely to have had higher pulse wave velocity values ten years prior, before neuroimaging data being available. Future studies should address whether arterial stiffness can serve as an early biomarker of covert brain structural abnormalities and whether early arterial stiffness control can promote successful brain aging, especially in black elderly.
doi:10.1161/HYPERTENSIONAHA.112.198069
PMCID: PMC3521843  PMID: 23172923
pulse wave velocity; small vessel disease; longitudinal; fractional anisotropy; community-dwelling elderly
22.  Progression Rates of Carotid Intima-media Thickness and Adventitial Diameter during the Menopausal Transition 
Menopause (New York, N.Y.)  2013;20(1):8-14.
Objectives
The authors assessed whether the levels and progression rates of carotid intima-media thickness (IMT) and adventitial diameter (AD) vary by menopausal stage.
Methods
249 Women (42–57 years old, premenopausal (49%) or early peri-menopausal (46%)) from the Study of Women’s Health Across the Nation were included in the current analysis. Participants were followed for up to 9 years (median=3.7 years) and had up to 5 carotid scans. Linear mixed models were used for analysis.
Results
The overall rate of change in IMT was 0.007 mm/year. Independent of age and race, progression rate of IMT increased substantially in late peri-menopausal stage (0.017 mm/year) compared to both premenopausal (0.007 mm/year) and early peri-menopausal (0.005 mm/year) stages; (P≤0.05). For AD, while the overall rate of change was negative (−0.009 mm/year), significant positive increases in the rate of change were observed in late peri-menopausal (0.024 mm/year) and postmenopausal (0.018 mm/year) stages compared to premenopausal stage (−0.032 mm/year); (P<0.05). In final models, postmenopausal stage was independently associated with higher levels of IMT and AD (P<0.05) compared to premenopausal stage.
Conclusions
During the menopausal transition, the carotid artery undergoes an adaptation that is reflected in adverse changes in IMT and AD. These changes may impact the vulnerability of the vessel to disease in older women.
doi:10.1097/gme.0b013e3182611787
PMCID: PMC3528819  PMID: 22990755
atherosclerosis; carotid intima-media thickness; epidemiology; menopause; risk factors
23.  Body Mass Index Following Natural Menopause and Hysterectomy with and without Bilateral Oophorectomy 
Objective
The directional and temporal nature of relationships between overweight and obesity and hysterectomy with or without oophorectomy is not well understood. Overweight and obesity may be both a risk factor for the indications for these surgeries and a possible consequence of the procedure. We used prospective data to examine whether body mass index (BMI) increased more following hysterectomy with and without bilateral oophorectomy compared to natural menopause among middle-aged women.
Methods
BMI was assessed annually for up to 10 years in the Study of Women’s Health Across the Nation (SWAN (n=1962). Piecewise linear mixed growth models were used to examine changes in BMI before and after natural menopause, hysterectomy with ovarian conservation, and hysterectomy with bilateral oophorectomy. Covariates included education, race/ethnicity, menopausal status, physical activity, self-rated health, hormone therapy use, antidepressant use, and age the visit prior to the final menstrual period (FMP; for natural menopause) or surgery (for hysterectomy/oophorectomy).
Results
By visit 10, 1780 (90.6%) women reached natural menopause, 106 (5.5%) reported hysterectomy with bilateral oophorectomy, and 76 (3.9%) reported hysterectomy with ovarian conservation. In fully adjusted models, BMI increased for all women from baseline to FMP or surgery (annual rate of change=.19 kg/m2 per year), with no significant differences in BMI change between groups. BMI also increased for all women following FMP, but increased more rapidly in women following hysterectomy with bilateral oophorectomy (annual rate of change=.21 kg/m2 per year) as compared to following natural menopause (annual rate of change=.08 kg/m2 per year, p=.03).
Conclusion
In this prospective examination, hysterectomy with bilateral oophorectomy was associated with greater increases in BMI in the years following surgery than following hysterectomy with ovarian conservation or natural menopause. This suggests that accelerated weight gain follows bilateral oophorectomy among women in midlife, which may increase risk for obesity-related chronic diseases.
doi:10.1038/ijo.2012.164
PMCID: PMC3530639  PMID: 23007036
menopause; oophorectomy; BMI; women’s health
24.  Effects of an intensive behavioral weight loss intervention consisting of caloric restriction with or without physical activity on common carotid artery remodeling in severely obese adults 
Metabolism: clinical and experimental  2012;61(11):1589-1597.
Objective
Obesity increases cardiovascular disease risk and adversely affects vascular structure and function. Few studies have evaluated the vascular effects of non-surgical weight reduction in the severely obese. We hypothesized that weight loss and improvements in cardiometabolic factors would reduce common carotid artery intima-media thickness (CIMT) and inter-adventitial diameter (AD) in severely obese adults.
Methods
We performed carotid ultrasound and measured cardiometabolic factors in 90 severely obese participants (body mass index (BMI)≥35 kg/m2, age 30–55) at baseline and 6 months in a randomized clinical trial of dietary intervention with (n=45) or without (n=45) physical activity.
Results
The achieved weight loss (mean=8%) did not differ significantly by intervention group (P=0.10) and resulted in a 0.07 mm mean decrease in AD (P=0.001). AD change was positively correlated with changes in BMI, waist circumference, abdominal visceral and subcutaneous fat, and body fat mass, and AD decreased more in men (P<0.05 for all). After multivariable adjustment, changes in BMI (P=0.03) and abdominal subcutaneous fat (P=0.04) were significant determinants of AD change. Although CIMT did not decrease significantly overall (−0.008 mm, P=0.16), individuals who lost at least 5% of their body weight experienced a significant mean reduction in CIMT of 0.02 mm (P=0.002). CIMT change was positively correlated with changes in BMI, waist circumference, fat-free mass, leptin, and insulin (P<0.05 for all). After multivariable adjustment, insulin reduction remained a significant determinant of CIMT decrease (P=0.03).
Conclusion
A6 month intensive behavioral intervention can significantly reverse metabolic and vascular abnormalities in severely obese adults.
doi:10.1016/j.metabol.2012.04.012
PMCID: PMC3419808  PMID: 22579053
Severe obesity; Carotid intima-media thickness; Carotid diameter; Lifestyle modification
25.  Endogenous Sex Hormones Impact the Progression of Subclinical Atherosclerosis in Women during the Menopausal Transition 
Atherosclerosis  2012;225(1):180-186.
Objective
To determine whether endogenous sex hormones (estradiol (E2), testosterone (T), sex hormone binding globulin (SHBG), and follicle-stimulating hormone (FSH)) are longitudinally associated with progression of atherosclerosis among women at midlife.
Methods
249 Pre- or early peri-menopausal women (42–57 years) from the Study of Women’s Health Across the Nation (SWAN) were followed for up to 9 years (median=3.7 years) and had up to 5 repeated measures of common carotid intima-media thickness (IMT) and adventitial diameter (AD). Linear mixed models were used for statistical analysis. Final models included age at baseline, time since baseline, cycle day of blood draw, race, income, SBP, BMI, insulin resistance index, lipids, C-reactive protein and co-morbidity.
Results
In final models for IMT, each one log unit decrease in SHBG was associated with a 0.005 mm/year increase in IMT progression (P=0.003). E2, T, and FSH were not associated with level or progression of IMT. For AD, each one log unit decrease in E2 was associated with a 0.012 mm/year increase in AD progression (P=0.04) and each one log unit increase in FSH was associated with a 0.016 mm/year increase in AD progression (P=0.003). T and SHBG were not associated with progression or level of AD.
Conclusions
Independent of SBP, BMI, lipids and other covariates, lower E2 and SHBG, and higher FSH were associated with increased subclinical atherosclerosis progression in women at midlife.
doi:10.1016/j.atherosclerosis.2012.07.025
PMCID: PMC3478422  PMID: 22981430
subclinical atherosclerosis; sex hormones; women

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