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1.  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
2.  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
3.  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
4.  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
5.  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.
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.
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).
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.
Poor sleep quality is related to AC in middle-aged women. Sleep quality should routinely be assessed in mid-life women.
PMCID: PMC3582843  PMID: 23352420
sleep; insomnia; women; mid-life; calcification; aorta; cardiovascular risk factors
6.  Regional pulse wave velocities and their cardiovascular risk factors among healthy middle-aged men: a cross-sectional population-based study 
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.
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.
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.
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.
PMCID: PMC3893368  PMID: 24410766
Arterial stiffness; Aorta; Carotid arteries; Brachial artery; Femoral artery
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.
PMCID: PMC3521843  PMID: 23172923
pulse wave velocity; small vessel disease; longitudinal; fractional anisotropy; community-dwelling elderly
8.  Progression Rates of Carotid Intima-media Thickness and Adventitial Diameter during the Menopausal Transition 
Menopause (New York, N.Y.)  2013;20(1):8-14.
The authors assessed whether the levels and progression rates of carotid intima-media thickness (IMT) and adventitial diameter (AD) vary by menopausal stage.
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.
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.
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.
PMCID: PMC3528819  PMID: 22990755
atherosclerosis; carotid intima-media thickness; epidemiology; menopause; risk factors
9.  Body Mass Index Following Natural Menopause and Hysterectomy with and without Bilateral Oophorectomy 
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.
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).
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).
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.
PMCID: PMC3530639  PMID: 23007036
menopause; oophorectomy; BMI; women’s health
10.  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.
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.
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.
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).
A6 month intensive behavioral intervention can significantly reverse metabolic and vascular abnormalities in severely obese adults.
PMCID: PMC3419808  PMID: 22579053
Severe obesity; Carotid intima-media thickness; Carotid diameter; Lifestyle modification
11.  Endogenous Sex Hormones Impact the Progression of Subclinical Atherosclerosis in Women during the Menopausal Transition 
Atherosclerosis  2012;225(1):180-186.
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.
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.
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.
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.
PMCID: PMC3478422  PMID: 22981430
subclinical atherosclerosis; sex hormones; women
12.  The Association of Menopausal Status with Physical Function: The Study of Women’s Health Across the Nation (SWAN) 
Menopause (New York, N.Y.)  2012;19(11):1186-1192.
To determine if post-menopausal status is associated with self-reported limitations in physical function.
SWAN is a multi-site, multi-ethnic, longitudinal study of midlife women. Women aged 45–57 years (N=2,566) completed the Medical Outcomes Study Short-Form Physical Function Scale at visit 4 (2000–2001); scores created a 3-category variable of physical function limitations: none (86–100), moderate (51–85) and substantial (0–50). Menopausal status in SWAN is a 5-category list variable based on menstrual bleeding patterns and gynecological surgery. Pre-and peri-menopausal women using hormones (n=284) or missing physical function scores (n=46) were excluded. Multinomial logistic regression was used to relate physical function and menopausal status adjusting for age, ethnicity, site, education, body mass index (BMI), self-reported diabetes, hypertension, arthritis, depressive symptoms, smoking and hormone use among postmenopausal women.
Of 2,236 women, 8% were pre-, 51% early peri-, 12% late peri-, 24% natural post-, and 5% surgical post-menopausal status. In the full model, substantial limitations in physical function were higher in post-menopausal compared to pre-menopausal women whether it occurred naturally (OR 3.82; 95% CI: 1.46–10.0) or surgically (OR 3.54; 95% CI: 1.15–10.84). These associations were attenuated by higher BMI and depressive symptoms, but remained significant. Moderate limitations in physical function were not significantly related to menopausal status.
Women with surgical or naturally occurring post-menopause reported greater limitations in physical function than pre-menopausal women, independent of age, only partly explained by higher BMI and depressive symptoms. This suggests that physiologic changes of menopause could contribute directly to limitations in physical function.
PMCID: PMC3526111  PMID: 22760087
Physical functioning; Functional limitations; Menopause; Menopausal status; SF-36
13.  Liver fat and SHBG affect insulin resistance in midlife women: The Study of Women’s Health Across the Nation (SWAN) 
Obesity (Silver Spring, Md.)  2013;21(5):1031-1038.
The liver is an insulin-responsive organ that contributes significantly to both whole body insulin sensitivity and availability of sex steroids through the production of sex hormone binding globulin (SHBG). Our objective was to explore whether lower SHBG was associated with ectopic liver fat and mediated its effect on insulin resistance in The Study of Women’s Health Across the Nation (SWAN). A subset of midlife African American and Caucasian women from SWAN (n=208; 50.9±0.18 yrs; 71% Caucasian) had computed tomography scans to quantify visceral, subcutaneous and liver fat. Blood samples were collected and assayed for hormonal and metabolic markers. The cohort, while overweight, was generally healthy, and both liver fat and SHBG were unaffected by menopausal stage or race. Both higher liver fat and lower SHBG levels were significantly associated with higher insulin concentrations after adjustment for adiposity (r=−0.25, p<0.001 and r=−0.18, p=0.01). SHBG and liver fat had additive effects on insulin concentrations such that women with the lowest SHBG and the highest fat levels had the highest values (interaction p=0.09). The association between SHBG and insulin was more apparent among women with fattier livers. SHBG and liver fat appear to have independent effects on insulin levels as adjustment for each other did not diminish the strength of either association (p=0.023 and 0.001 respectively). These results confirmed the strong independent associations between increased liver fat and decreased SHBG with increased metabolic risk in midlife women. Further these data underscore the need for additional research into the role of liver fat in modifying SHBG’s influence on insulin levels.
PMCID: PMC3695405  PMID: 23784907
liver fat; sex hormone binding globulin; perimenopause; ectopic fat; insulin resistance
14.  Reductions in arterial stiffness with weight loss in overweight and obese young adults: potential mechanisms 
Atherosclerosis  2012;223(2):485-490.
Arterial stiffness decreases with weight loss in overweight/obese young adults. We aimed to determine the mechanisms by which this occurs.
We evaluated carotid-femoral pulse wave velocity (cfPWV) and brachial-ankle pulse wave velocity (baPWV) in 344 young adults (23% male, BMI 25–40 kg/m2) at baseline, 6, and 12 months in a behavioral weight loss intervention. Linear mixed models were used to evaluate associations between weight loss and arterial stiffness and to examine whether improvements in obesity-related factors explained these associations.
At 6 months (7% mean weight loss), there was a significant median decrease of 47.5 cm/s in cfPWV (p<0.0001) and a mean decrease of 11.7 cm/s in baPWV (p=0.049). At 12 months (6% mean weight loss), only cfPWV remained reduced. In models adjusting for changes in mean arterial pressure and obesity-related factors, changes in BMI (p=0.01) and common carotid artery diameter (p=0.003) were positively associated with change in cfPWV. Reductions in heart rate (p<0.0001) and C-reactive protein (p=0.02) were associated with reduced baPWV and accounted for the association between weight loss and reduced baPWV.
Weight loss is associated with reduced cfPWV independently of changes in established hemodynamic and cardiometabolic risk factors, but its association with reduced baPWV is explained by concurrent reductions in heart rate and inflammation.
PMCID: PMC3411893  PMID: 22703865
arterial stiffness; obesity; lifestyle modification
15.  Ethnic difference in liver fat content: A cross-sectional observation among Japanese American in Hawaii, Japanese in Japan, and non-Hispanic whites in United States 
We recently reported that Japanese had higher liver fat at a lower level of BMI compared with non-Hispanic whites (NHW).
We hypothesize that ethnic difference in fat storage capacity contributes to this ethnic difference in liver fat.
To examine this, we assessed liver fat among 244 Japanese-American aged 40-49, using regional computed-tomography images, along with metabolic variables.
Despite the similar BMI between Japanese-Americans and NHW men, Japanese-Americans had more liver fat (liver to spleen attenuation ratio: 1.03 ± 0.22 for Japanese-Americans, and 1.07 ± 0.15 for NHW men; p<0.05) and tended to have a greater disposition for fatty liver with an increase in BMI than NHW, indicating a clear difference between the two groups. In addition, liver fat is less in Japanese-Americans compared with Japanese men (1.03 ± 0.22 vs. 1.01 ± 0.16; p<0.05), despite of a much higher BMI. These ethnic differences support the hypothesis that higher fat storage capacity indeed seems to be associated with less liver fat. In all the groups, liver fat content strongly correlated with triglycerides, homeostasis model assessment-insulin resistance, and C-reactive protein (CRP). Nevertheless, these metabolic variables were worse in Japanese-Americans, despite of less liver fat, compared with Japanese. Moreover, CRP levels were least among Japanese with highest liver fat, and highest among NHW men with least liver fat, despite of a strong positive association between CRP and fatty liver within each population.
Fat content in the liver is intermediate for Japanese-Americans compared with Japanese and NHW men, which supports the hypothesis of less fat storage capacity among Japanese, closely linked to ethnic difference in predisposition to fatty liver.
PMCID: PMC3664948  PMID: 23697588
Ethnicity; Fatty liver; Genetic; Environmental; CRP
16.  Aortic stiffness and calcification in men in a population-based international study 
Atherosclerosis  2012;222(2):473-477.
Aortic stiffness, a hallmark of vascular aging, is an independent risk factor of cardiovascular disease and all-cause mortality. The association of aortic stiffness with aortic calcification in middle-aged general population remains unknown although studies in patients with end-stage renal disease or elderly subjects suggest that aortic calcification is an important determinant of aortic stiffness. The goal of this study was to examine the association of aortic calcification and stiffness in multi-ethnic population-based samples of relatively young men.
We examined the association in 906 men aged 40–49 (81 Black Americans, 276 Japanese Americans, 258 White Americans and 291 Koreans). Aortic stiffness was measured as carotid-femoral pulse wave velocity (cfPWV) using an automated waveform analyzer. Aortic calcification from aortic arch to iliac bifurcation was evaluated using electron-beam computed tomography.
Aortic calcium score was calculated and was categorized into four groups: zero (n=303), 1–100 (n=411), 101–300 (n=110), and 401+ (n=82). Aortic calcification category had a significant positive association with cfPWV after adjusting for age, race, and mean arterial pressure (mean (standard error) of cfPWV (cm/second) from the lowest to highest categories: 836 (10), 850 (9), 877 (17) and 941 (19), p for trend <0.001). The significant positive association remained after further adjusting for other cardiovascular risk factors. The significant positive association was also observed in each race group.
The results suggest that aortic calcification can be one mechanism for aortic stiffness and that the association of aortic calcification with stiffness starts as early as the 40’s.
PMCID: PMC3361615  PMID: 22537531
aortic stiffness; aortic calcification; international multi-ethnic study
17.  Less subclinical atherosclerosis in Japanese men in Japan than in white men in the United States in the post World-War-II birth cohort 
American journal of epidemiology  2007;165(6):617-624.
Coronary heart disease (CHD) incidence and mortality remain very low in Japan despite major dietary changes and increases in CHD risk factors that should have resulted in substantial increase in CHD rates (Japanese paradox). Primary genetic effects are unlikely, given the substantial increase in CHD in migrant Japanese to the U.S. For men aged 40–49, levels of total cholesterol and blood pressure have been similar in Japan and the U.S. throughout their lifetime. The authors tested the hypothesis that levels of subclinical atherosclerosis, coronary artery calcification and intima-media thickness of the carotid artery (IMT), in men aged 40–49 are similar in Japan and the U.S. The authors conducted a population-based study of 493 randomly-selected men: 250 men in Kusatsu, Shiga, Japan, and 243 white men in Allegheny County, Pennsylvania, U.S. in 2002–2005. The Japanese had a less favorable profile of many risk factors than the whites. Prevalence ratio for the presence of coronary calcium score ≥10 in the Japanese compared to the whites was 0.52 (95% CI, 0.35, 0.76). Mean (SE) IMT was significantly lower in the Japanese (0.616 (0.005) versus 0.672 (0.005) mm, p<0.01). Both associations remained significant after adjusting for risk factors. The findings warrant further investigations.
PMCID: PMC3660737  PMID: 17244636
Atherosclerosis; epidemiology; men; risk factors
18.  Much lower prevalence of coronary calcium detected by electron-beam computed tomography among men aged 40-49 in Japan than in the US, despite a less favorable profile of major risk factors 
Since World War II (WWII), exposures to westernized lifestyle have occurred in many non-Western countries, including Japan. National surveys showed that risk factor profiles for atherosclerosis around 1990 were similar in men in the post WWII birth cohorts in the United States (US) and Japan. We compared the degree of coronary calcium and other factors in men in the post WWII birth cohort: men aged 40-49 between the US and Japan.
We conducted a cross sectional study examining randomly selected 100 men from Kusatsu, Japan, and 100 men from Allegheny County, US. Coronary calcium was assessed using electron-beam computed tomography.
Systolic blood pressure, total cholesterol, LDL-cholesterol and smoking rates were higher among the Japanese (122.6 ± 14.1 versus 113.7 ± 9.6 mmHg, p<0.01; 5.72 ± 0.90 versus 4.99 ± 0.81 mmol/l (220.9 ± 34.6 versus 192.8 ± 31.3 mg/dl), p<0.01; 3.52 ± 1.01 versus 3.10 ± 0.78 mmol/l (136.0 ± 39.0 versus 119.7 ± 30.0 mg/dl), p<0.01; and 48 versus 15%, p<0.01, respectively). Triglycerides and fibrinogen were similar. HDL-cholesterol was higher among the Japanese. Body mass index, fasting insulin, and C-reactive protein were higher among the Americans. Prevalence of coronary artery calcium score > 0 was strikingly lower among the Japanese than the Americans (13 % versus 47 %, p <0.01).
Much lower prevalence of coronary calcium despite a less favorable profile of many major independent risk factors in the Japanese might imply that there are strong protective factors against atherosclerosis in the Japanese. Further investigation is of critical importance.
PMCID: PMC3657559  PMID: 15563587
Subclinical atherosclerosis; electron-beam computed tomography; US; Japan; epidemiology; risk factors; post Word War II birth cohort; coronary calcium
19.  Systolic Blood Pressure and Incident Heart Failure in the Elderly 
Heart (British Cardiac Society)  2011;97(16):1304-1311.
The exact form of the association between systolic blood pressure (SBP) and heart failure (HF) risk in the elderly remains incompletely defined, especially in individuals not receiving antihypertensive medications. Our aim was to examine the association between SBP and HF risk in the elderly.
Competing-risks proportional hazards modeling of incident HF risk, utilizing 10-year follow-up data from two NIH-sponsored cohort studies; the Cardiovascular Health Study (inception: 1989-90 and 1992-93) and the Health ABC Study (inception: 1997-98).
Community-based cohorts.
4408 participants (age, 72.8 [4.9] years; 53.1% women, 81.7% white; 18.3% black) without prevalent HF and not receiving antihypertensive medications at baseline.
Main outcome measures
Incident HF, defined as first adjudicated hospitalisation for HF.
Over 10 years, 493 (11.1%) participants developed HF. Prehypertension (120-139 mmHg), stage 1 (140-159 mmHg), and stage 2 (≥160 mmHg) hypertension were associated with escalating HF risk; hazard ratios vs. optimal SBP (<120 mmHg) in competing-risks models controlling for clinical characteristics were 1.63 (95% CI, 1.23-2.16; P=0.001), 2.21 (95% CI, 1.65-2.96; P<0.001), and 2.60 (95% CI, 1.85-364; P<0.001), respectively. Overall 255 of 493 (51.7%) HF events occurred in participants with SBP <140 mm Hg at baseline. Increasing SBP was associated with higher HF risk in women than men; no race-SBP interaction was observed. In analyses with continuous SBP, HF risk had a continuous positive association with SBP to levels as low as 113 mmHg in men and 112 mmHg in women.
There is a continuous positive association between SBP and HF risk in the elderly for levels of SBP as low as <115 mmHg; over half of incident HF events occur in individuals with SBP <140 mmHg.
PMCID: PMC3652313  PMID: 21636845
epidemiology; hypertension; heart failure; risk stratification
20.  Association Between Depression and Vascular Disease in Systemic Lupus Erythematosus 
The Journal of rheumatology  2011;39(2):262-268.
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with increased prevalence of cardiovascular disease (CVD) and depression. Although depression may contribute to CVD risk in population-based studies, its influence on cardiovascular morbidity in SLE has not been evaluated. We evaluated the association between depression and vascular disease in SLE.
A cross-sectional study was conducted from 2002–2005 in 161 women with SLE and without CVD. The primary outcome measure was a composite vascular disease marker consisting of the presence of coronary artery calcium and/or carotid artery plaque.
In total, 101 women met criteria for vascular disease. In unadjusted analyses, several traditional cardiovascular risk factors, inflammatory markers, adiposity, SLE disease-related factors, and depression were associated with vascular disease. In the final multivariable model, the psychological variable depression was associated with nearly 4-fold higher odds for vascular disease (OR 3.85, 95% CI 1.37, 10.87) when adjusted for other risk factors of age, lower education level, hypertensive status, waist-hip ratio, and C-reactive protein.
In SLE, depression is independently associated with vascular disease, along with physical factors.
PMCID: PMC3632335  PMID: 22174200
21.  Pulse wave velocity is associated with muscle mass decline: Health ABC study 
Age  2011;34(2):469-478.
Age-related mechanisms that lead to sarcopenia are not entirely understood. Basal leg blood flow declines with aging by augmented sympathetic vasoconstriction and arterial stiffening, thus a dysfunction in blood vessel dynamics may have an independent role on sarcopenia. We determined whether pulse wave velocity (PWV), marker of arterial stiffness, was associated with skeletal muscle decline. Observational cohort study of older adults(70–79 years) living in Pittsburgh, PA, USA or Memphis, TN, USA. Analyses included 2,405 participants. Correlations among muscle parameters including skeletal muscle density and intermuscular adipose tissue using mid-thigh CT scans were assessed. Linear mixed models tested the association between the change in the sarcopenic index (SI) (assessed by dual energy X-ray absorptiometry) over time and baseline PWV independently of multiple confounders. SI was defined: appendicular lean mass/squared height and calculated at every follow-up (n = 6). Baseline PWV was significantly higher in black women compared to white women (930 ± 431 vs. 843 ± 366; p = 0.0001), while there were no significant differences between black and white men (943 ± 402 vs. 911 ± 375; p = 0.1786). Baseline analyses showed an independent negative association between PWV and muscle parameters after adjusting for confounders in both genders. The PWV-by-race interaction was significant in women and analyses are reported separately by race. Prospective mixed models showed that PWV was an independent determinant of the SI in all men (β = −0.1043; p = 0.0065) and in white women (β = −0.1091; p = 0.0192). In analyses examining the effect of arterial stiffness on limb lean mass over time, PWV correlated with lower leg (β = −0.2196; p = 0.0002)and arm mass (β = −0.0985; p = 0.0011) in all men and lower leg mass(β = −0.1608; p = 0.0027)in white women. In older persons, arterial stiffening is associated with skeletal muscle mass decline differently for race and gender.
PMCID: PMC3312626  PMID: 21479573
Aging; Sarcopenia; Pulse wave velocity; Vascular stiffness
22.  Vasomotor Symptoms and Lipid Profiles in Women Transitioning Through Menopause 
Obstetrics and Gynecology  2012;119(4):753-761.
To examine associations between vasomotor symptoms and lipids over 8 years, controlling for other cardiovascular risk factors, estradiol (E2) and follicle-stimulating hormone (FSH).
Study of Women’s Health Across the Nation participants (N=3201), aged 42–52 at entry, completed interviews on frequency of hot flushes and night sweats (none, 1–5 days, 6 days or more, in the past 2 weeks) physical measures (blood pressure, height, weight), and blood draws (low-density lipoprotein [LDL], high-density lipoprotein [HDL], apolipoproteinA-1, apolipoprotein B [apoB], lipoprotein(a), trigycerides, serum E2, FSH) yearly for 8 years. Relations between symptoms and lipids were examined in linear mixed models adjusting for cardiovascular risk factors, medications, and hormones.
Compared to no flushes, experiencing hot flushes was associated with significantly higher LDL [1–5 days: beta (β) (standard error (SE)) =1.48(.47), p<0.01; 6 days or more: β(SE)=2.13(.62), p<.001], HDL [1–5 days: β(SE)=.30(.18),; 6 days or more: β(SE)=.77(.24), p<.01], apolipoproteinA-1 [1–5 days: β(SE)=.92(.47), p<.10; 6 days or more: β(SE)=1.97(.62), p<.01], apolipoproteinB [1–5 days: β(SE)=1.41(.41), p<.001; 6 days or more: β(SE)=2.51(.54), p<.001], and triglycerides [1–5 days: percent change(95%CI)=2.91(1.41–4.43), p<.001; 6 days or more: percent change(95%CI)=5.90(3.86–7.97), p<.001] in multivariable models. Findings largely persisted adjusting for hormones. Estimated mean differences between hot flashes 6 days or more compared with no days ranged from less than 1 (HDL) to 10 mg/dL (triglycerides). Night sweats were similar. Associations were strongest for lean women.
Vasomotor symptoms were associated with higher LDL, HDL, apolipoproteinA-1, apolipoproteinB, and triglycerides. Lipids should be considered in links between hot flushes and cardiovascular risk.
PMCID: PMC3343636  PMID: 22433339
23.  Breastfeeding and Subsequent Maternal Visceral Adiposity 
Obesity (Silver Spring, Md.)  2011;19(11):2205-2213.
Women gain visceral fat during pregnancy. Studies examining the impact of breastfeeding on maternal body composition are inconclusive. We examined the extent to which breastfeeding was associated with visceral adiposity in a sample of US women. This was a cross-sectional analysis of 351 women aged 45–58 years, who were free of clinical cardiovascular disease and had not used oral contraceptives or hormone replacement therapy in the 3 months prior to enrollment in the Study of Women’s Health Across the Nation (SWAN)-Heart Study (2001–2003). History of breastfeeding was self-reported. Computed tomography was used to assess abdominal adiposity. Among premenopausal/early-peri-menopausal mothers, those who never breastfed had 28% greater visceral adiposity (95% confidence interval (CI): 11–49, P = 0.001), 4.7% greater waist-hip ratio (95% CI: 1.9–7.4, P < 0.001), and 6.49 cm greater waist circumference (95% CI: 3.71–9.26, P < 0.001) than mothers who breastfed all of their children for ≥3 months in models adjusting for study site; age; parity; years since last birth; socioeconomic, lifestyle, and family history variables; early adult BMI; and current BMI. In comparison to women who were nulliparous, mothers who breastfed all of their children for ≥3 months had similar amounts of visceral fat (P > 0.05). In contrast, premenopausal/early-peri-menopausal mothers who had never breastfed had significantly greater visceral adiposity (42% (95% CI: 17–70), P < 0.001), waist circumference (6.15 cm (95% CI: 2.75–9.56), P < 0.001), and waist-hip ratio (3.7% (95% CI: 0.69–6.8), P = 0.02) than nulliparous women. No significant relationships were observed among late peri-menopausal/postmenopausal women. In conclusion, until menopause, mothers who did not breastfeed all of their children for ≥3 months exhibit significantly greater amounts of metabolically active visceral fat than mothers who had breastfed all of their children for ≥3 months.
PMCID: PMC3610530  PMID: 21720436
24.  Progression of Coronary Artery Calcification in Black and White Women: Do the Stresses and Rewards of Multiple Roles Matter? 
Black women experience higher rates of cardiovascular disease (CVD) than white women, though evidence for racial differences in subclinical CVD is mixed. Few studies have examined multiple roles (number, perceived stress, and/or reward) in relation to subclinical CVD, or whether those effects differ by race.
To investigate the effects of multiple roles on 2-year progression of coronary artery calcification (CAC).
Subjects were 104 black and 232 white women (mean age 50.8 years). Stress and reward from four roles (spouse, parent, employee, caregiver) were assessed on 5-point scales. CAC progression was defined as an increase of ≥10 Agatston units.
White women reported higher rewards from their multiple roles than black women, yet black women showed cardiovascular benefits from role rewards. Among black women only, higher role rewards were related significantly to lower CAC progression, adjusting for BMI, blood pressure, and other known CVD risk factors. Blacks reported fewer roles but similar role stress as whites; role number and stress were unrelated to CAC progression.
Rewarding roles may be a novel protective psychosocial factor for progression of coronary calcium among black women.
PMCID: PMC3586734  PMID: 21901270
multiple roles; role stress; role reward; women; middle-aged; coronary artery calcium
25.  Racial Differences in the Association between Carotid Plaque and Aortic and Coronary Artery Calcification Among Women Transitioning the Menopause 
Menopause (New York, N.y.)  2012;19(2):157-163.
Carotid atherosclerosis is a marker for atherosclerotic disease in other vascular beds; however, racial differences in this association have not been fully examined. The purpose of this report is to evaluate racial differences in the relationship between carotid plaque and calcification in the aorta and coronary arteries among women transitioning the menopause.
540 African American and White women with a median age of 50 years were evaluated from the Study of Women’s Health Across the Nation. Carotid plaque (none versus any) was assessed with B-mode ultrasound and aortic (AC; 0, >0–100, >100) and coronary artery calcification (CAC; 0, >0–10, >10) with computed tomography.
For the total cohort, higher prevalence of plaque was significantly associated with higher levels of AC, but not CAC. The interaction of race and carotid plaque was significant in models with AC and CAC as dependent variables (p=0.03, 0.002, respectively). Among African Americans, there was an inverse relationship, although not significant, between carotid plaque and high AC (>100) (OR 0.75, 95%CI: 0.10–5.48), and between plaque and high CAC (>10) (OR 0.20, 95%CI: 0.03–1.52) in fully adjusted models. In contrast, for Whites, significant positive associations existed between carotid plaque and high AC (OR 4.12, 95%CI: 1.29–13.13) and borderline for high CAC (OR 1.83, 95%CI: 0.66–5.19).
This study demonstrated the presence of carotid plaque appeared to be a marker for AC and potentially CAC in White women during the menopause transition, but not African American middle-aged women.
PMCID: PMC3266995  PMID: 22037218
Atherosclerosis; Plaque; Carotid Arteries; Coronary Disease; African Americans and Calcium

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