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1.  THE ASSOCIATIONS OF ADIPOKINES WITH SELECTED MARKERS OF THE RENIN-ANGIOTENSINOGEN-ALDOSTERONE SYSTEM: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS 
Journal of human hypertension  2014;29(2):127-133.
Among obese individuals, increased sympathetic nervous system activity results in increased renin and aldosterone production, as well as renal tubular sodium reabsorption. This study determined the associations between adipokines and selected measures of the reninangiotensinogen-aldosterone system (RAAS). The sample was 1,970 men and women from the Multi-Ethnic Study of Atherosclerosis who were free of clinical cardiovascular disease at baseline and had blood assayed for adiponectin, leptin, plasma renin activity (PRA) and aldosterone. The mean age was 64.7 years and 50% were female. The mean (SD) PRA and aldosterone were 1.45 (0.56) ng/ml and 150.1 (130.5) pg/ml, respectively. After multivariable adjustment, a 1-SD increment of leptin was associated with a 0.55 ng/ml higher PRA and 8.4 pg/ml higher aldosterone (p < 0.01 for both). Although adiponectin was not significantly associated with PRA levels, the same increment in this adipokine was associated with lower aldosterone levels (−5.5 pg/ml, p = 0.01). Notably, the associations between aldosterone and both leptin and adiponectin were not materially changed with additional adjustment for PRA. Exclusion of those taking anti-hypertensive medications modestly attenuated the associations. The associations between leptin and both PRA and aldosterone were not different by gender but were significantly stronger among non-Hispanic Whites and Chinese Americans than African and Hispanic Americans (p < 0.01). The findings suggest that both adiponectin and leptin may relevant to blood pressure regulation via the RAAS, that the associations appear to be robust to anti-hypertension medication use and that the associations are likely different by ethnicity.
doi:10.1038/jhh.2014.40
PMCID: PMC4265023  PMID: 24919752
Adipokines; Renin; Aldosterone; Ethnicity
2.  Association of Subsyndromal and Depressive Symptoms with Inflammatory Markers among different Ethnic groups: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Journal of affective disorders  2014;164:165-170.
Objective
Depressive symptoms are associated with inflammation yet the association between inflammation and different levels of depression remains unclear. Therefore, we studied the association of subsyndromal and depressive symptoms with inflammatory markers in a large multi-ethnic cohort.
Methods
C-reactive protein (CRP) (n=6,269), interleukin-6 (IL-6) (n=6,135) and tumor necrosis factor-alpha (TNF-α) (n=1,830) were measured in selected participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Subsyndromal depressive symptoms were defined as a CES-D value from 8 to 15, depressive symptoms as a CES-D≥16 and normal as a CES-D≤7. Depressive states (subsyndromal and depressed) were entered into multivariable linear regression models incrementally adjusting for demographic, behavioral, biologic and comorbidities.
Results
Among 6,289 participants not taking antidepressants and free from CVD, the mean age was 62.2, while 52% were women, 36.4% were Caucasian, 28.9% African-American, 22.3% Hispanics and 12.4% Chinese-American. Of the total, 24.2% had subsyndromal depression and 11.8% had depressive symptoms. Compared to the non-depressed group and after controlling for demographics, there was no association between both subsyndromal and depressive symptoms with logCRP(β=−0.01, p=0.80 and β=−0.05, p=0.25; respectively), logIL-6(β=0.01, p=0.71 and β=−0.04, p=0.07; respectively) and logTNF-α(β=−0.03, p=0.29 and β=0.06, p=0.18; respectively). Moreover, fully adjusted models showed no significant associations for logIL-6 and logTNF-α and the different depressive categories. However, with full adjustment, we found a significant inverse association between depressive symptoms and lnCRP(β=−0.10; p=0.01) that was not present for subsyndromal depression (β=−0.05; p=0.11).
Conclusion
Among participants not taking anti-depressants, subsyndromal depression is not associated with inflammation. However, depressive symptoms measured by CES-D≥16 are associated with a lower inflammation (CRP).
doi:10.1016/j.jad.2014.04.018
PMCID: PMC4079665  PMID: 24856570
subsyndromal depression; inflammation; cardiovascular disease; depressive states
3.  Associations of Diabetes Mellitus and Other Cardiovascular Disease Risk Factors with Decline in the Ankle Brachial Index 
Objectives
We compared associations of diabetes mellitus (DM) and other cardiovascular disease (CVD) risk factors with decline in the ankle brachial index (ABI) over four years in participants with and without peripheral artery disease (PAD).
Methods
Five hundred sixty-six participants, 300 with PAD, were followed prospectively for four years.
Results
Mean (SD) baseline ABI values were 0.70 (0.13) for participants with both PAD and DM, 0.67 (0.14) for participants with only PAD, 1.10 (0.13) for participants with only DM, and 1.10 (0.10) for participants with neither PAD nor DM. After adjusting for age, gender, and baseline ABI, corresponding ABI change from baseline to 4-year follow-up were -0.02, -0.04, +0.05, and +0.05 respectively. Compared to participants with neither PAD nor DM, participants with only PAD showed significantly more ABI decline (P < .01), while the decline in participants with both PAD and DM was borderline non-significant (P = .06). After adjustments for baseline ABI, age, gender, African-American ethnicity, and other cardiovascular disease (CVD) risk factors; independent factors associated with ABI decline in participants with PAD in the lower ABI leg were older age and elevated D-dimer. DM was not related to ABI decline.
Conclusions
Despite being an important risk factor for PAD, DM was not independently associated with ABI decline. This could reflect the effect of DM promoting both PAD and lower extremity arterial stiffness, resulting in a small decline in the ABI over time. In conclusion, ABI change over time in persons with diabetes may not accurately reflect underlying atherosclerosis.
doi:10.1177/1358863X14554033
PMCID: PMC4515111  PMID: 25358555
Peripheral artery disease; Ankle brachial index; Diabetes
4.  Non-Steroidal Anti-Inflammatory Drugs and Cardiovascular Outcomes in Women: Results from the Women’s Health Initiative 
Background
Conclusive data regarding cardiovascular (CV) toxicity of non-steroidal anti-inflammatory drugs (NSAIDs) are sparse. We hypothesized that regular NSAID use is associated with increased risk for CV events in post-menopausal women, and that this association is stronger with greater cyclooxygenase (cox)-2 compared with cox-1 inhibition.
Methods and Results
Post-menopausal women enrolled in the Women’s Health Initiative (WHI) were classified as regular users or non-users of non-aspirin NSAIDs. Cox regression examined NSAID use as a time-varying covariate and its association with the primary outcome of total CV disease defined as CV death, nonfatal myocardial infarction, or nonfatal stroke. Secondary analyses considered the association of selective cox-2 inhibitors (e.g., celecoxib), non-selective agents with cox-2>cox-1 inhibition (e.g., naproxen), and non-selective agents with cox-1>cox-2 inhibition (e.g., ibuprofen) with the primary outcome. Overall, 160,801 participants were available for analysis (mean follow-up 11.2 years). Regular NSAID use at some point in time was reported by 53,142 participants. Regular NSAID use was associated with an increased hazard for CV events versus no NSAID use (HR=1.10[95% CI 1.06–1.15], Pitalic>0.001). Selective cox-2 inhibitors were associated with a modest increased hazard for CV events (HR=1.13[1.04–1.23], P=0.004; celecoxib only HR=1.13[1.01–1.27], P=0.031). Among aspirin users, concomitant selective cox-2 inhibitor use was no longer associated with increased hazard for CV events. There was an increased risk for agents with cox-2>cox-1 inhibition (HR=1.17[1.10–1.24], Pbold>0.001; naproxen only HR=1.22[1.12–1.34], P<0.001). This harmful association remained among concomitant aspirin users. We did not observe a risk elevation for agents with cox-1>cox-2 inhibition (HR=1.01[0.95–1.07], P=0.884; ibuprofen only HR=1.00[0.93–1.07], P=0.996).
Conclusions
Regular use of selective cox-2 inhibitors and non-selective NSAIDs with cox-2>cox-1 inhibition showed a modestly increased hazard for CV events. Non-selective agents with cox-1>cox-2 inhibition were not associated with increased CV risk.
Clinical Trial Registration
www.clinicaltrials.gov NCT00000611
doi:10.1161/CIRCOUTCOMES.113.000800
PMCID: PMC4151243  PMID: 25006185
non-steroidal anti-inflammatory drugs; coronary artery disease; myocardial infarction; stroke; cox inhibition
5.  Leptin-Mediated Increases in Catecholamine Signaling Reduce Adipose Tissue Inflammation via Activation of Macrophage HDAC4 
Cell metabolism  2014;19(6):1058-1065.
SUMMARY
Obesity promotes systemic insulin resistance through inflammatory changes that lead to the release of cytokines from activated macrophages. Although the mechanism is unclear, the second messenger cAMP has been found to attenuate macrophage activity in response to a variety of hormonal signals. We show that, in the setting of acute over-nutrition, leptin triggers catecholamine-dependent increases in cAMP signaling that reduce inflammatory gene expression via the activation of the histone deacetylase HDAC4. cAMP stimulates HDAC4 activity through the PKA-dependent inhibition of the salt inducible kinases (SIKs), which otherwise phosphorylate and sequester HDAC4 in the cytoplasm. Following its dephosphorylation, HDAC4 shuttles to the nucleus where it inhibits NFkB activity over pro-inflammatory genes. As variants in the HDAC4 gene are associated with obesity in humans, our results indicate that the cAMP-HDAC4 pathway functions importantly in maintaining insulin sensitivity and energy balance via its effects on the innate immune system.
doi:10.1016/j.cmet.2014.03.024
PMCID: PMC4207085  PMID: 24768298
6.  Association of Renin and Aldosterone With Ethnicity and Blood Pressure: The Multi-Ethnic Study of Atherosclerosis 
American Journal of Hypertension  2014;27(6):801-810.
BACKGROUND
Although variations in plasma renin activity (PRA) and aldosterone have been examined in whites and blacks, the association of these hormones with blood pressure in multiethnic populations has not been described.
METHODS
We measured PRA and aldosterone in 1,021 participants in the Multi-Ethnic Study of Atherosclerosis not taking antihypertensives and examined the association between ethnicity and PRA/aldosterone and the association between PRA/aldosterone with systolic blood pressure (SBP).
RESULTS
Average age was 62 (SD = 9) years, and 49% of participants were women. Median PRA was 0.51 (interquartile range (IQR) = 0.29–0.87) ng/ml/hour, and median aldosterone was 12.6 (IQR = 9.1–17.1) ng/dl. After age and sex adjustment, compared with whites, blacks had 28% lower PRA and 17.4% lower aldosterone, and Hispanics had 20.1% higher PRA but similar aldosterone levels. After multivariable adjustment, compared with whites, only Hispanic ethnicity independently associated with higher PRA (0.18ng/ml/hour; 95% confidence interval (CI) = 0.06–0.31). Blacks had lower aldosterone (−1.7ng/dl; 95% CI = −3.2 to −0.2) compared with whites. After multivariable adjustment, PRA was associated with lower SBP in whites (−3.2mm Hg; 95% CI = −5.2 to −1.2 per standardized unit PRA), Chinese (−3.5mm Hg; 95% CI = −6.2 to −0.80 per standardized unit), and Hispanics (−2.3mm Hg; 95% CI = −4.1 to −0.6 per standardized unit) but not blacks. Aldosterone was associated with higher SBP only in Hispanics (2.5mm Hg; 95% CI = 0.4–4.5 per SD).
CONCLUSIONS
Compared with whites, blacks have lower aldosterone and Hispanics have higher PRA. Aldosterone had significant associations with higher SBP in Hispanics compared with other groups, a finding that may suggest a different mechanism of hypertension.
doi:10.1093/ajh/hpt276
PMCID: PMC4017931  PMID: 24436325
black; blood pressure; Chinese; cross-sectional analysis; Hispanic; hypertension; white.
7.  Prevalence of Hypertension, Awareness, Treatment, and Control in the Hispanic Community Health Study/Study of Latinos 
American Journal of Hypertension  2014;27(6):793-800.
BACKGROUND
The prevention and control of hypertension is an essential component for reducing the burden of cardiovascular diseases. Here we describe the prevalence of hypertension in diverse Hispanic/Latino background groups and describe the proportion who are aware of their diagnosis, receiving treatment, and having their hypertension under control.
METHODS
The Hispanic Community Health Study/Study of Latinos is a longitudinal cohort study of 16,415 Hispanics/Latinos, aged 18–74 years from 4 US communities (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA). At baseline (2008–2011) the study collected extensive measurements and completed questionnaires related to research on cardiovascular diseases. Hypertension was defined as measured blood pressure ≥140/90mm Hg or use of antihypertensive medication.
RESULTS
The total age-adjusted prevalence of hypertension in this study was 25.5% as compared with 27.4% in non-Hispanic whites in the National Health and Nutrition Examination Survey. Prevalence of hypertension increased with increasing age groups and was highest in Cuban, Puerto Rican, and Dominican background groups. The percent with hypertension who were aware, being treated with medication, or had their hypertension controlled was lower compared with US non-Hispanic whites with hypertension and it was lowest in those without health insurance.
CONCLUSIONS
These findings indicate a significant deficit in treatment and control of hypertension among Hispanics/Latinos residing in the United States, particularly those without health insurance. Given the relative ease of identification of hypertension and the availability of low-cost medications, enabling better access to diagnostic and treatment services should reduce the burden of hypertension in Hispanic populations.
doi:10.1093/ajh/hpu003
PMCID: PMC4017932  PMID: 24627442
blood pressure; epidemiology; Hispanics; hypertension; Latinos; medically uninsured; socioeconomic status.
8.  EFFECT OF DIETARY MODIFICATION ON INCIDENT CAROTID ARTERY DISEASE IN POSTMENOPAUSAL WOMEN: RESULTS FROM THE WOMEN’S HEALTH INITIATIVE DIETARY MODIFICATION CLINICAL TRIAL 
Background and Purpose
Since the diagnosis and treatment of carotid artery disease may reduce the rate of stroke, the aim of this study was to determine whether a diet intervention was associated with incident carotid artery disease.
Methods
Participants were 48,835 postmenopausal women aged 50 to 79 years who were randomly assigned to either the intervention or comparison group in the WHI Diet Modification Trial. Incident carotid artery disease was defined as an overnight hospitalization with either symptoms or a surgical intervention to improve flow.
Results
After a mean follow-up of 8.3 years from 1994 – 2005, there were 297 (0.61%) incident carotid artery events. Contrasted to the comparison group, the risk of incident carotid disease did not differ from those assigned to the intervention group (HR: 1.08, 95% CI: 0.9 - 1.4). In secondary analysis, there was no significant effect of the intervention on the risk for incident carotid disease during the five years of post-intervention follow-up from 2005 to 2010 (1.24, 0.9 - 1.7) and no significant effect during cumulative follow-up from 1994 to 2010 (1.13, 0.9 – 1.4).
Conclusions
Among postmenopausal women, a dietary intervention aimed at reducing total fat intake and encouraging increased intake of fruit, vegetables and grains, did not significantly change the risk for incident carotid artery disease.
doi:10.1161/STROKEAHA.114.005096
PMCID: PMC4259099  PMID: 24743440
diet; carotid artery disease; trial; women
9.  Longitudinal Relationship of Low Leisure Satisfaction but not Depressive Symptoms With Systemic Low-Grade Inflammation in Dementia Caregivers 
Objectives.
This study aimed to further elucidate the biobehavioral mechanisms linking dementia caregiving with an increased cardiovascular disease risk. We hypothesized that both elevated depressive symptoms and a behavioral correlate of depression, low leisure satisfaction, are associated with systemic inflammation.
Method.
We studied 121 elderly Alzheimer’s disease caregivers who underwent 4 annual assessments for depressive symptoms, leisure satisfaction, and circulating levels of inflammatory markers. We used mixed-regression analyses controlling for sociodemographic and health-relevant covariates to examine longitudinal relationships between constructs of interest.
Results.
There were inverse relationships between total leisure satisfaction and tumor necrosis factor-α (TNF-α; p = .047), interleukin-8 (IL-8; p < .001), and interferon-γ (IFG; p = .020) but not with IL-6 (p = .21) and C-reactive protein (p = .65). Lower enjoyment from leisure activities was related to higher levels of TNF-α (p = .045), IL-8 (p < .001), and IFG (p = .002), whereas lower frequency of leisure activities was related only to higher IL-8 levels (p = .023). Depressive symptoms were not associated with any inflammatory marker (all p values > .17). Depressive symptoms did not mediate the relationship between leisure satisfaction and inflammation.
Discussion.
Lower satisfaction with leisure activities is related to higher low-grade systemic inflammation. This knowledge may provide a promising way of improving cardiovascular health in dementia caregivers through behavioral activation treatments targeting low leisure satisfaction.
doi:10.1093/geronb/gbt020
PMCID: PMC3983912  PMID: 23650246
Biomarkers; Blood coagulation; Cardiovascular disease; Depression; Inflammation; Psychological stress.
10.  Lower extremity peripheral artery disease in the absence of traditional risk factors. The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2010;214(1):169-173.
Objective
Lower-extremity peripheral artery disease (LE-PAD), is strongly related to traditional risk factors (smoking, hypertension, dyslipidemia, diabetes). We hypothesized that the prevalence of LE-PAD in the absence of traditional CVD risk factors is not negligible, and that this condition would remain associated with subclinical atherosclerosis in other territories.
Methods
In the Multi-Ethnic Study of Atherosclerosis, we classified participants without any traditional risk factor according to their ankle-brachial index (ABI) into 3 groups: low (<1.00), normal (1.00–1.30) and high (>1.30) ABI. Coronary or carotid artery diseases were defined by the presence of any coronary artery calcification (CAC score > 0) or carotid plaque, respectively.
Results
Among the 6814 participants, 1932 had no traditional risk factors. A low- and high ABI were found in 176 (9%) and 149 (7.8%) cases, respectively. Lower glomerular filtration rate (OR: 0.88/10 units, p = 0.04) and higher Interleukin-6 levels (OR: 1.42/natural-log unit, p = 0.02) were associated with low ABI. Past smoking (cessation > 10 years) and pulse pressure had borderline association with low ABI. In adjusted models, low-ABI was significantly associated with CAC prevalence (OR: 1.22, p < 0.03). No significant association was found with carotid plaque.
Conclusion
In the absence of traditional CVD risk factors, LE-PAD is still common and associated with coronary artery disease.
doi:10.1016/j.atherosclerosis.2010.10.011
PMCID: PMC4415364  PMID: 21067754
Atherosclerosis; Peripheral artery disease; Risk; Subclinical
11.  Comparison of Ordinal vs. Agatston Coronary Calcification Scoring for Cardiovascular Disease Mortality in Community-Living Individuals 
Objective
Coronary artery calcification (CAC) by the Agatston method predicts cardiovascular disease (CVD), but requires cardiac gated computed tomography (CT) scans, a procedure not covered by most insurance providers. An ordinal CAC score (scored 0-12 based on artery number and extent of calcification involvement) can be measured on standard chest CTs. However, the correlation of ordinal and Agatston CAC scores and the relative association with CVD mortality is uncertain, which we sought to determine.
Design
Nested case-control study
Setting
Community-living individuals undergoing “whole body” CT scans for preventive medicine.
Patients
4,544 consecutive patients with CT scans, were followed from 2000-2009. We selected cases who died of CVD (n=57) and age, sex, and CT slice-thickness matched each to 3 controls (N=171).
Interventions
Cardiac gated 3mm chest CTs and non-gated 6mm standard chest CTs.
Main outcome
CVD death over 9 years follow-up.
Results
The intra- and inter-reader kappa for the ordinal CAC score was 0.90 and 0.76 respectively. The correlation of Agatston and ordinal CAC scores was 0.72 (p< 0.001). In models adjusted for traditional CVD risk factors, the odds of CVD death per 1 SD greater CAC was 1.66 (1.03-2.68) using the ordinal CAC score and 1.57 (1.00-2.46) using the Agatston score.
Conclusions
A simple ordinal CAC score is reproducible, strongly correlated with Agatston CAC scores, and provides similar prediction for CVD death in predominantly Caucasian community-living individuals.
doi:10.1007/s10554-014-0392-1
PMCID: PMC4009350  PMID: 24610090
calcium; cardiovascular diseases; circulation; imaging; epidemiology
12.  The Adipokine Profile of Metabolically Benign Obese and At-Risk Normal Weight Postmenopausal Women: The Women’s Health Initiative Observational Study 
Obesity (Silver Spring, Md.)  2013;22(3):786-794.
Nearly a third of obese individuals, termed metabolically benign obese, have a low burden of adiposity-related cardiometabolic abnormalities, while a substantial proportion of normal weight individuals possess risk factors. In cross-sectional analyses of 699 normal weight and 1294 overweight/obese postmenopausal women enrolled in a nested case-control stroke study ancillary to the Women’s Health Initiative Observational Study, we compared levels of adiponectin, leptin, and resistin among metabolically benign normal weight, at-risk normal weight, metabolically benign obese, and at-risk obese women using components of the ATP III definition of the metabolic syndrome (metabolically benign: ≤1 of the 4 components; at-risk phenotype: ≥2 components or diabetes). Overall, 382/699 normal weight women (54.6%) and 328/1194 overweight/obese women (27.5%) were metabolically benign. Among normal weight women, at-risk women had higher leptin and lower adiponectin levels compared to metabolically benign women; multivariate-adjusted odds ratios were significant for having leptin (OR: 2.51; 95% CI: 1.28–5.01) and resistin (1.46; 1.03–2.07) in the top tertile and adiponectin in the bottom tertile (2.64; 1.81–3.84). Compared to metabolically benign overweight/obese women, at-risk obese women had higher odds of having leptin in the top tertile (1.62; 1.24–2.12) and adiponectin in the bottom tertile (2.78; 2.04–3.77). Overall, metabolically benign overweight/obese women had an intermediate adipokine profile (between at-risk obese and metabolically benign normal weight women), while at-risk normal weight women had a less favorable profile compared to metabolically benign normal weight women. As adiponectin was the only adipokine independent of BMI, it may be most likely to have a role in the etiological pathway of these phenotypes.
doi:10.1002/oby.20139
PMCID: PMC3883802  PMID: 24357553
postmenopausal women; adipose tissue; obesity; adipokines
13.  Associations of Physical Activity and Sedentary Behavior with Regional Fat Deposition 
Introduction
Increased sedentary behavior predicts greater cardiovascular morbidity and mortality, and does so independently of physical activity (PA). This association is only partially explained by BMI and overall body fat, suggesting mechanisms besides general increased adiposity. The purpose of this study was to explore associations of self-reported leisure PA and sitting time with regional fat depositions and abdominal muscle among community-dwelling older adults.
Methods
Participants were 539 diverse adults (mean age 65) who completed a study visit in 2001-2002. Areas of pericardial, intra-thoracic, subcutaneous, visceral, and intermuscular fat, as well as abdominal muscle, were measured using computed tomography. Leisure PA and sitting hours were entered simultaneously into multivariate regression models to determine associations with muscle and fat areas.
Results
After adjusting for demographics, smoking, diabetes, hypertension, triglycerides, and cholesterol, greater PA was associated with less intra-thoracic, visceral, subcutaneous, and intermuscular fat (for all p < .05), while greater sedentary time was associated with greater pericardial and intra-thoracic fat (for both p < .05). After further adjusting for BMI, each hour of weekly PA was associated with 1.85 cm2 less visceral fat (p < .01), but was not associated with other fat depositions. Conversely, each hour of daily sitting was associated with 2.39cm2 more pericardial fat (p < .05), but was not associated with any other fat depositions. There were no associations with abdominal muscle area. Adjusting for common inflammatory markers had little effect. Associations between fat and PA were stronger for men.
Conclusions
Sitting and physical activity have distinct associations with regional fat deposition in older adults. The association between sitting and pericardial fat could partially explain the link between sitting and coronary heart disease.
doi:10.1249/MSS.0b013e3182a77220
PMCID: PMC3916942  PMID: 23924920
sitting; body composition; visceral fat; pericardial fat; cardiovascular disease
14.  Testing Departure from Additivity in Tukey’s Model using Shrinkage: Application to a Longitudinal Setting 
Statistics in medicine  2014;33(29):5177-5191.
While there has been extensive research developing gene-environment interaction (GEI) methods in case-control studies, little attention has been given to sparse and efficient modeling of GEI in longitudinal studies. In a two-way table for GEI with rows and columns as categorical variables, a conventional saturated interaction model involves estimation of a specific parameter for each cell, with constraints ensuring identifiability. The estimates are unbiased but are potentially inefficient because the number of parameters to be estimated can grow quickly with increasing categories of row/column factors. On the other hand, Tukey’s one degree of freedom (df) model for non-additivity treats the interaction term as a scaled product of row and column main effects. Due to the parsimonious form of interaction, the interaction estimate leads to enhanced efficiency and the corresponding test could lead to increased power. Unfortunately, Tukey’s model gives biased estimates and low power if the model is misspecified. When screening multiple GEIs where each genetic and environmental marker may exhibit a distinct interaction pattern, a robust estimator for interaction is important for GEI detection. We propose a shrinkage estimator for interaction effects that combines estimates from both Tukey’s and saturated interaction models and use the corresponding Wald test for testing interaction in a longitudinal setting. The proposed estimator is robust to misspecification of interaction structure. We illustrate the proposed methods using two longitudinal studies — the Normative Aging Study and the Multi-Ethnic Study of Atherosclerosis.
doi:10.1002/sim.6281
PMCID: PMC4227925  PMID: 25112650
adaptive shrinkage estimation; gene-environment interaction; longitudinal data; Tukey’s one df test for non-additivity
15.  Bone mineral density and atherosclerosis: The Multi-Ethnic Study of Atherosclerosis, Abdominal Aortic Calcium Study 
Atherosclerosis  2009;209(1):283-289.
Context
Molecular and cell biology studies have demonstrated an association between bone and arterial wall disease, but the significance of a population-level association is less clear and potentially confounded by inability to account for shared risk factors.
Objective
To test population-level associations between atherosclerosis types and bone integrity.
Main Outcome Measures
Volumetric trabecular lumbar bone mineral density (vBMD), ankle-brachial index (ABI), intima-media thickness of the common carotid (CCA-IMT) and internal carotid (ICA-IMT) arteries, and carotid plaque echogenicity.
Design, Setting and Participants
A random subset of participants from the Multi-Ethnic Study of Atherosclerosis (MESA) assessed between 2002 and 2005.
Results
904 post-menopausal female (62.4 years; 62% non-white; 12% ABI<1; 17% CCA-IMT>1mm; 33% ICA-IMT>1mm) and 929 male (61.4 years; 58% non-white; 6% ABI<1; 25% CCA-IMT>1mm; 40% ICA-IMT>1mm) were included. In serial, sex-specific regression models adjusting for age, ethnicity, body mass index, dyslipidemia, hypertension, smoking, alcohol consumption, diabetes, homocysteine, interleukin-6, sex hormones, and renal function, lower vBMD was associated with lower ABI in men (p for trend <0.01) and greater ICA-IMT in men (p for trend <0.02). CCA-IMT was not associated with vBMD in men or women. Carotid plaque echogenicity was independently associated with lower vBMD in both men (trend p=0.01) and women (trend p<0.04). In all models, adjustment did not materially affect results.
Conclusions
Lower vBMD is independently associated with structural and functional measures of atherosclerosis in men and with more advanced and calcified carotid atherosclerotic plaques in both sexes.
doi:10.1016/j.atherosclerosis.2009.09.011
PMCID: PMC4254856  PMID: 19819456
16.  Null Association between Abdominal Muscle and Calcified Atherosclerosis in Community-Living Persons Without Clinical Cardiovascular Disease: the Multi-Ethnic Study of Atherosclerosis 
Metabolism: clinical and experimental  2013;62(11):10.1016/j.metabol.2013.06.001.
Objective
Detrimental effects of lean muscle loss have been hypothesized to explain J-shaped relationships of body mass index (BMI) with cardiovascular disease (CVD), yet associations of muscle mass with CVD are largely unknown. We hypothesized that low abdominal lean muscle area would be associated with greater calcified atherosclerosis, independent of other CVD risk factors.
Materials/Methods
We investigated 1020 participants from the Multi-Ethnic Study of Atherosclerosis who were free of clinical CVD. Computed tomography (CT) scans at the 4th and 5th lumbar disk space were used to estimate abdominal lean muscle area. Chest and abdominal CT scans were used to assess coronary artery calcification(CAC), thoracic aortic calcification (TAC), and abdominal aortic calcification (AAC).
Results
The mean age was 64±10 years, 48% were female, and mean BMI was 28±5 kg/m2. In models adjusted for demographics, physical activity, caloric intake, and traditional CVD risk factors, there was no inverse association of abdominal muscle mass with CAC(Prevalence Ratio [PR] 1.02 [95% CI 0.95,1.10]), TAC (PR 1.13 [95%CI 0.92, 1.39]) or AAC (PR 0.99 [95%CI 0.94, 1.04]) prevalence. Similarly, there was no significant inverse relationship between abdominal lean muscle area and CAC, TAC, and AAC severity.
Conclusion
In community-living individuals without clinical CVD, greater abdominal lean muscle area is not associated with less calcified atherosclerosis.
doi:10.1016/j.metabol.2013.06.001
PMCID: PMC3740763  PMID: 23916063
Cardiovascular Disease; atherosclerosis; lean muscle
17.  Influence of Urine Creatinine Concentrations on the Relation of Albumin-Creatinine Ratio With Cardiovascular Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Higher urine albumin-creatinine ratio (ACR) is associated with cardiovascular disease (CVD) events, an association that is stronger than that between spot urine albumin on its own and CVD. Urine creatinine is correlated with muscle mass, and low muscle mass is also associated with CVD. Whether low urine creatinine in the denominator of the ACR contributes to the association of ACR with CVD is uncertain.
Study Design
Prospective cohort study.
Setting & Participants
6,770 community-living individuals without CVD.
Predictors
Spot urine albumin, the reciprocal of the urine creatinine concentration (1/UCr), and ACR.
Outcome
Incident CVD events.
Results
During a mean of 7.1 years’ follow-up, 281 CVD events occurred. Geometric means for spot urine creatinine, urine albumin and ACR were 95 ± 2 (SD) mg/dl, 0.7 ± 3.7 mg/dl and 7.0 ± 3.1 mg/g. Adjusted HRs per 2-fold higher increment in each urinary measures with CVD events were similar (1/UCr: 1.07 [95% CI, 0.94-1.22]; urine albumin: 1.08 [95% CI, 1.01-1.14]; and ACR: 1.11 [95% CI, 1.04-1.18]). Urine creatinine was lower in older, female, and low weight individuals. ACR ≥10 mg/g was more strongly associated with CVD events in individuals with low weight (HR for lowest vs. highest tertile: 4.34 vs. 1.97; p for interaction=0.006). Low weight also modified the association of urine albumin with CVD (p for interaction=0.06), but 1/urine creatinine did not (p for interaction=0.9).
Limitations
We lacked 24-hour urine data.
Conclusions
While ACR is more strongly associated with CVD events among persons with low body weight, this association is not driven by differences in spot urine creatinine. Overall, the associations of ACR with CVD events appear to be driven primarily by urine albumin and less by urine creatinine.
doi:10.1053/j.ajkd.2013.05.010
PMCID: PMC3783582  PMID: 23830183
18.  The Association Between Physical Activity and Both Incident Coronary Artery Calcification and Ankle Brachial Index Progression: The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2013;230(2):278-283.
Objective
Both coronary artery calcification (CAC) and the ankle brachial index (ABI) are measures of subclinical atherosclerotic disease. The influence of physical activity on the longitudinal change in these measures remains unclear. To assess this we examined the association between these measures and self-reported physical activity in the Multi-Ethnic Study of Atherosclerosis (MESA).
Methods
At baseline, the MESA participants were free of clinically evident cardiovascular disease. We included all participants with an ABI between 0.90 and 1.40 (n=5656). Predictor variables were based on self-reported measures with physical activity being assessed using the Typical Week Physical Activity Survey from which metabolic equivalent-minutes/week of activity were calculated. We focused on physical activity intensity, intentional exercise, sedentary behavior, and conditioning. Incident peripheral artery disease (PAD) was defined as the progression of ABI to values below 0.90 (given the baseline range of 0.90 to 1.40). Incident CAC was defined as a CAC score >0 Agatston units upon follow up with a baseline score of 0 Agatston units.
Results
Mean age was 61 years, 53% were female, and mean body mass index was 28 kg/m2. After adjusting for traditional cardiovascular risk factors and socioeconomic factors, intentional exercise was protective for incident peripheral artery disease (Relative Risk (RR)= 0.85, 95% Confidence Interval (CI): 0.74 to 0.98). After adjusting for traditional cardiovascular risk factors and socioeconomic factors, there was a significant association between vigorous PA and incident CAC (RR=0.97, 95% CI: 0.94 to 1.00). There was also a significant association between sedentary behavior and increased amount of CAC among participants with CAC at baseline (Δlog(Agatston Units +25)=0.027, 95% CI 0.002, 0.052).
Conclusions
These data suggest that there is an association between physical activity/sedentary behavior and the progression of two different measures of subclinical atherosclerotic disease.
doi:10.1016/j.atherosclerosis.2013.07.045
PMCID: PMC4085097  PMID: 24075757
Ankle Brachial Index; Coronary Artery Calcification; Physical Activity; Epidemiology; Prospective Cohort Study
19.  Residential Proximity to Major Roadways and Prevalent Hypertension Among Postmenopausal Women: Results From the Women's Health Initiative San Diego Cohort 
Background
Living near major roadways has been linked with increased risk of cardiovascular events and worse prognosis. Residential proximity to major roadways may also be associated with increased risk of hypertension, but few studies have evaluated this hypothesis.
Methods and Results
We examined the cross‐sectional association between residential proximity to major roadways and prevalent hypertension among 5401 postmenopausal women enrolled into the San Diego cohort of the Women's Health Initiative. We used modified Poisson regression with robust error variance to estimate the association between prevalence of hypertension and residential distance to nearest major roadway, adjusting for participant demographics, medical history, indicators of individual and neighborhood socioeconomic status, and for local supermarket/grocery and fast food/convenience store density. The adjusted prevalence ratios for hypertension were 1.22 (95% CI: 1.07, 1.39), 1.13 (1.00, 1.27), and 1.05 (0.99, 1.12) for women living ≤100, >100 to 200, and >200 to 1000 versus >1000 m from a major roadway (P for trend=0.006). In a model treating the natural log of distance to major roadway as a continuous variable, a shift in distance from 1000 to 100 m from a major roadway was associated with a 9% (3%, 16%) higher prevalence of hypertension.
Conclusions
In this cohort of postmenopausal women, residential proximity to major roadways was positively associated with the prevalence of hypertension. If causal, these results suggest that living close to major roadways may be an important novel risk factor for hypertension.
doi:10.1161/JAHA.113.000727
PMCID: PMC4323802  PMID: 25274494
environment; hypertension; traffic pollution; women
20.  Association of Obesity and Kidney Function Decline among Non-Diabetic Adults with eGFR > 60 ml/min/1.73m2: Results from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Obesity is associated with higher end-stage renal disease incidence, but associations with earlier forms of kidney disease remain incompletely characterized.
Methods
We studied the association of body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) with rapid kidney function decline and incident chronic kidney disease in 4573 non-diabetic adults with eGFR ≥ 60 ml/min/1.73m2 at baseline from longitudinal Multi-Ethnic Study of Atherosclerosis cohort. Kidney function was estimated by creatinine and cystatin C. Multivariate analysis was adjusted for age, race, baseline eGFR, and hypertension.
Results
Mean age was 60 years old, BMI 28 kg/m2, baseline eGFRCr 82 and eGFRCys 95 ml/min/1.73m2. Over 5 years of follow up, 25% experienced rapid decline in renal function by eGFRCr and 22% by eGFRCys. Incident chronic kidney disease (CKD) developed in 3.3% by eGFRCys, 11% by eGFRCr, and 2.4% by both makers. Compared to persons with BMI < 25, overweight (BMI 25 – 30) persons had the lowest risk of rapid decline by eGFRCr (0.84, 0.71 – 0.99). In contrast, higher BMI categories were associated with stepwise higher odds of rapid decline by eGFRCys, but remained significant only when BMI ≥ 35 kg/m2 (1.87, 1.41 – 2.48). Associations of BMI with incident CKD were insignificant after adjustment. Large WC and WHR were associated with increased risk of rapid decline only by eGFRCys, and of incident CKD only when defined by both filtration markers.
Conclusions
Obesity may be a risk factor for kidney function decline, but associations vary by filtration marker used.
PMCID: PMC4157691  PMID: 25210651
Kidney Function Decline; MESA; Obesity; Waist Circumference; Waist-to-Hip Ratio
21.  Abdominal Aortic Calcium, Coronary Artery Calcium, and Cardiovascular Morbidity and Mortality in the Multi-Ethnic Study of Atherosclerosis 
Objective
To evaluate the predictive value of abdominal aortic calcium (AAC) for incident cardiovascular disease (CVD) independent of coronary artery calcium (CAC).
Approach and Results
We evaluated the association of AAC with CVD in 1974 men and women aged 45 to 84 years randomly selected from the Multi-Ethnic Study of Atherosclerosis participants who had complete AAC and CAC data from computed tomographic scans. AAC and CAC were each divided into following 3 percentile categories: 0 to 50th, 51st to 75th, and 76th to 100th. During a mean of 5.5 years of follow-up, there were 50 hard coronary heart disease events, 83 hard CVD events, 30 fatal CVD events, and 105 total deaths. In multivariable-adjusted Cox models including both AAC and CAC, comparing the fourth quartile with the ≤50th percentile, AAC and CAC were each significantly and independently predictive of hard coronary heart disease and hard CVD, with hazard ratios ranging from 2.4 to 4.4. For CVD mortality, the hazard ratio was highly significant for the fourth quartile of AAC, 5.9 (P=0.01), whereas the association for the fourth quartile of CAC (hazard ratio, 2.1) was not significant. For total mortality, the fourth quartile hazard ratio for AAC was 2.7 (P=0.001), and for CAC, it was 1.9, P=0.04. Area under the receiver operating characteristic curve analyses showed improvement for both AAC and CAC separately, although improvement was greater with CAC for hard coronary heart disease and hard CVD, and greater with AAC for CVD mortality and total mortality. Sensitivity analyses defining AAC and CAC as continuous variables mirrored these results.
Conclusions
AAC and CAC predicted hard coronary heart disease and hard CVD events independent of one another. Only AAC was independently related to CVD mortality, and AAC showed a stronger association than CAC with total mortality.
doi:10.1161/ATVBAHA.114.303268
PMCID: PMC4153597  PMID: 24812323
aortic diseases; calcium; cardiovascular diseases; diagnostic imaging; epidemiology
22.  Association between higher levels of sexual function, activity, and satisfaction and self-rated successful aging in older postmenopausal women 
Objectives
To determine if measures of successful-aging are associated with sexual activity, satisfaction, and function in older post-menopausal women.
Design
Cross-sectional study using self-report surveys; analyses include chi-square and t-tests and multiple linear regression analyses.
Setting
Community-dwelling older post-menopausal women in the greater San Diego Region.
Participants
1,235 community-dwelling women aged 60-89 years participating at the San Diego site of the Women's Health Initiative.
Measurements
Demographics and self-report measures of sexual activity, function, and satisfaction and successful aging.
Results
Sexual activity and functioning (desire, arousal, vaginal tightness, use of lubricants, and ability to climax) were negatively associated with age, as were physical and mental health. In contrast, sexual satisfaction and self-rated successful aging and quality of life remained unchanged across age groups. Successful aging measures were positively associated with sexual measures, especially self-rated quality of life and sexual satisfaction.
Conclusions
Self-rated successful aging, quality of life, and sexual satisfaction appear to be stable in the face of declines in physical health, some cognitive abilities, and sexual activity and function and are positively associated with each other across ages 60-89 years.
doi:10.1111/j.1532-5415.2011.03495.x
PMCID: PMC4151627  PMID: 21797827
Sexual Activity; Sexual Satisfaction; Sexual Function; Post-menopausal Women; Self-Rated Successful aging
23.  Relation of Leptin to Left Ventricular Hypertrophy (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2013;112(5):726-730.
Increasing adiposity increases the risk for left ventricular hypertrophy. Adipokines are hormone-like substances from adipose tissue that influence several metabolic pathways relevant to LV hypertrophy. Data was from participants enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent magnetic resonance imaging of the heart and who also had fasting venous blood assayed for 4 distinct adipokines (adiponectin, leptin, tumor necrosis factor – alpha and resistin). 1,464 MESA participants had complete data. The mean age was 61.5 years, the mean body mass index was 27.6 kg/m2 and 49% were female. With adjustment for age, sex, race, height and weight, multivariable linear regression modeling revealed that a 1-SD increment in leptin was significantly associated with smaller LV mass (ß: −4.66 % predicted, p-value: < 0.01), LV volume (−5.87 % predicted, < 0.01), stroke volume (−3.23 ml, p < 0.01) and cardiac output (−120 mL/min, p = 0.01) as well as a lower odds ratio for the presence of LV hypertrophy (OR: 0.65, p < 0.01), but a higher ejection fraction (0.44%, p = 0.05). Additional adjustment for the traditional cardiovascular disease (CVD) risk factors, insulin resistance, physical activity, education, income, inflammatory biomarkers, other selected adipokines and pericardial fat did not materially change the magnitude or significance of the associations. The associations between the other adipokines and LV structure and function were inconsistent and largely non-significant. In conclusion, the results indicate that higher levels of leptin are associated with more favorable values of several measures of LV structure and function.
doi:10.1016/j.amjcard.2013.04.053
PMCID: PMC3745795  PMID: 23711806
leptin; left ventricle; hypertrophy; mass
24.  Changes in Physical Activity and Body Composition in Postmenopausal Women over Time 
Purpose
Higher physical activity (PA) has been associated with greater attenuation of body-fat gain and preservation of lean mass across the lifespan. These analyses aimed to determine relationships of change in PA to changes in fat and lean body mass in a longitudinal prospective study of postmenopausal women.
Methods
Among 11,491 women enrolled at three Women’s Health Initiative (WHI) clinical centers were selected to undergo dual-energy x-ray absorptiometry (DXA), 8,352 had baseline body composition measurements, with at least one repeated measure at yr 1, 3, and 6. PA data were obtained by self-report at baseline, 3 and 6 yr of follow-up. Time-varying PA impact on change in lean and fat mass during the six-yr study period for age groups (50–59y, 60–69y, 70–79y) was estimated using mixed effects linear regression.
Results
Baseline PA and body composition differed significantly among the three age groups. The association of change in fat mass from baseline and time-varying PA differed across the three age groups (p=0.0006). In women aged 50–59, gain in fat mass from baseline was attenuated with higher levels of physical activity. Women aged 70–79 lost fat mass at all PA levels. In contrast, change in lean mass from baseline and time-varying PA did not differ by age group (p=0.1935).
Conclusions
The association between PA and change in fat mass varies by age group, with younger, but not older, women benefitting from higher levels of aerobic PA. Higher levels of aerobic activity are not associated with changes in lean mass, which tends to decrease in older women regardless of activity level. Greater attention to resistance training exercises may be needed to prevent lean mass loss as women age.
doi:10.1249/MSS.0b013e31828af8bd
PMCID: PMC3715578  PMID: 23439422
lean mass changes; exercise; aging; women; sarcopenia
25.  Associations Between Nocturnal Blood Pressure Dipping and the Metabolic Syndrome in High- Vs. Low-Acculturated Mexican American Women 
American Journal of Hypertension  2013;26(8):1030-1036.
BACKGROUND
Less nocturnal blood pressure (BP) dipping has been associated with greater odds for the metabolic syndrome (MetS), a constellation of risk factors associated with cardiovascular disease (CVD). Little work has examined this association in Hispanics, who have elevated rates of MetS, or investigated differences in this relationship by level of acculturation. The purpose of this study was to examine the association between BP dipping and MetS in Hispanic women and to determine if this association is moderated by acculturation status.
METHODS
Two hundred eighty-six Mexican American women underwent assessment of MetS components (BP, waist circumference, fasting glucose, high-density lipoprotein cholesterol, and triglycerides) and completed a 36-hour ambulatory BP monitoring protocol, during which systolic BP (SBP) and diastolic BP readings were obtained. Nocturnal BP dipping was calculated as the percentage difference between average daytime and nighttime BP. Acculturation was defined by the language (Spanish, English) in which participants preferred to complete study instruments.
RESULTS
Although no significant main effects for BP dipping or acculturation emerged for MetS, the SBP dipping by acculturation interaction was significantly related to MetS (P < 0.01). Simple slope analyses revealed that less SBP dipping related to greater odds of MetS in high-acculturated women, but SBP dipping and MetS were unrelated in low-acculturated women.
CONCLUSIONS
The strength of the association between BP dipping and CVD risk (as measured by MetS) appears to vary by acculturation in Hispanic women. Future studies should explore mechanisms behind the BP dipping and CVD risk association and relevant modifying factors.
doi:10.1093/ajh/hpt061
PMCID: PMC3706207  PMID: 23645325
acculturation; blood pressure; blood pressure dipping; Hispanic; hypertension; metabolic syndrome.

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