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Journal of human hypertension  2013;27(10):617-622.
Adipokines are secreted from adipose tissue, influence energy homeostasis and may contribute to the association between obesity and hypertension. Among 1,897 participants enrolled in the Multi-Ethnic Study of Atherosclerosis, we examined associations between blood pressure and leptin, tumor necrosis factor – α [TNFα], resistin and total adiponectin. The mean age and body mass index was 64.7 years and 28.1 respectively, and 50% were female. After adjustment for risk factors, a 1-standard deviation increment higher leptin level was significantly associated with higher systolic (5.0 mmHg), diastolic (1.9), mean arterial (2.8) and pulse pressures (3.6), as well as a 34% higher odds for being hypertensive (p < 0.01 for all). These associations were not materially different when the other adipokines, as well as body mass index, waist circumference or waist to hip ratio, were additionally added to the model. Notably, the associations between leptin and hypertension were stronger in men, but were not different by race/ethnic group, body mass index or smoking status. Adiponectin, resistin and TNFα were not independently associated with blood pressure or hypertension. Higher serum leptin, but not adiponectin, resistin or TNFα, is associated with higher levels of all measures of blood pressure, as well as a higher odds of hypertension, independent of risk factors, anthropometric measures and other selected adipokines.
PMCID: PMC3735864  PMID: 23535989
adipokine; leptin; blood pressure; hypertension; ethnicity
2.  The Relationship between Urban Sprawl and Coronary Heart Disease in Women 
Health & place  2012;20:51-61.
Studies have reported relationships between urban sprawl, physical activity, and obesity, but—to date—no studies have considered the relationship between sprawl and coronary heart disease (CHD) endpoints. In this analysis, we use longitudinal data on post-menopausal women from the Women’s Health Initiative (WHI) Clinical Trial to analyze the relationship between metropolitan statistical area (MSA)-level urban compactness (the opposite of sprawl) and CHD endpoints including death, any CHD event, and myocardial infarction. Models control for individual and neighborhood sociodemographic characteristics. Women who lived in more compact communities at baseline had a lower probability of experiencing a CHD event and CHD death or MI during the study follow-up period. One component of compactness, high residential density, had a particularly noteworthy effect on outcomes. Finally, exploratory analyses showed evidence that the effects of compactness were moderated by race and region.
PMCID: PMC3594054  PMID: 23376728
Urban Sprawl; Coronary Heart Disease; Neighborhoods; Women’s Health
3.  Subthreshold Depression and Successful Aging in Older Women 
Subthreshold Depression (StD) is common in older adults and is associated with poor self-rated health. However, the impact of StD on broader indicators of successful aging, such as positive psychological constructs, cognitive functioning, or quality of well-being, has not been assessed. We compared persons with scores above and below a predetermined threshold on the Center for Epidemiological Studies Scale for Depression (CESD) to non-depressed persons (ND) on measures of multiple domains associated with successful aging.
Cross sectional survey-based psychological assessments.
1,979 community-dwelling older women participating in the Women’s Health Initiative study.
ND was defined as a CESD score below 8, StD as a score between 8 and 15, and CESD Depression (CD) as a score of 16 or above. The study questionnaire consisted of multiple self-reported measures of positive psychological functioning (e.g., optimism, resilience), cognitive functioning and complaints, and quality of well-being. We also obtained a history of diagnosis, treatment, and hospitalization related to mental health problems.
20.2% of women met CES-D criteria for StD and 7% for CD. Women with StD had worse self-rated successful aging, worse physical and emotional functioning, lower optimism, more negative attitudes toward aging, lower personal mastery and self-efficacy, and greater anxiety and hostility than ND women, but scored better on all these measures than women with CD. StD subjects also had higher self-reported rates of previous diagnosis, treatment, and hospitalization for mental health problems than the ND group. StD subjects with depressed mood and/or anhedonia were largely similar to those without these symptoms.
Mild-moderate levels of depressive symptoms that likely fall under a general category of StD were common, and were associated with worse functioning on virtually every component of successful aging that we examined. StD represents a clinical entity that may affect the longitudinal course of successful aging for large numbers of persons and is a potential target for clinical intervention.
PMCID: PMC3937985  PMID: 20224518
4.  Associations of pericardial and intra-thoracic fat with coronary calcium presence and progression in a multi-ethnic study 
Obesity (Silver Spring, Md.)  2013;21(8):1704-1712.
Body mass index (BMI) may not accurately or adequately reflect body composition or its role in the development of cardiovascular disease (CVD). Ectopic adipose depots may provide a more refined representation of the role of adiposity in CVD. Thus, we examined the association of pericardial and intra-thoracic fat with coronary artery calcium (CAC). Nearly 600 white men and women, as well as Filipina women and African-American women, all without known CVD, had abdominal and chest computed tomography (CT) scans at two time points about four years apart from which CAC presence, severity and progression, as well as pericardial and intra-thoracic fat volumes were obtained. Logistic and linear regression models with staged adjustment were used to assess associations of pericardial and intra-thoracic fat with CAC presence, severity and progression. After adjustment for age, BMI, sex/ethnic group, ever smoking, and lipids, each standard deviation higher increment of intra-thoracic fat, but not pericardial fat, was significantly associated with 3.84-fold higher odds of prevalent CAC (95% CI (1.54, 9.58), p=0.004) and a 38.4% higher CAC score (95% CI (3.5%, 90.0%), p=0.03). Neither pericardial nor intra-thoracic fat were associated with CAC progression. Contrary to previous reports, pericardial fat was not associated with the presence, severity or progression of CAC. We did, however, demonstrate a significant association between intra-thoracic fat and both the presence and severity of CAC. Studies measuring fat in the thoracic cavity may consider defining intra-thoracic fat as a separate entity from pericardial fat.
PMCID: PMC3748173  PMID: 23666866
5.  A Meta-Analysis Identifies New Loci Associated with Body Mass index in Individuals of African Ancestry 
Monda, Keri L. | Chen, Gary K. | Taylor, Kira C. | Palmer, Cameron | Edwards, Todd L. | Lange, Leslie A. | Ng, Maggie C.Y. | Adeyemo, Adebowale A. | Allison, Matthew A. | Bielak, Lawrence F. | Chen, Guanji | Graff, Mariaelisa | Irvin, Marguerite R. | Rhie, Suhn K. | Li, Guo | Liu, Yongmei | Liu, Youfang | Lu, Yingchang | Nalls, Michael A. | Sun, Yan V. | Wojczynski, Mary K. | Yanek, Lisa R. | Aldrich, Melinda C. | Ademola, Adeyinka | Amos, Christopher I. | Bandera, Elisa V. | Bock, Cathryn H. | Britton, Angela | Broeckel, Ulrich | Cai, Quiyin | Caporaso, Neil E. | Carlson, Chris | Carpten, John | Casey, Graham | Chen, Wei-Min | Chen, Fang | Chen, Yii-Der I. | Chiang, Charleston W.K. | Coetzee, Gerhard A. | Demerath, Ellen | Deming-Halverson, Sandra L. | Driver, Ryan W. | Dubbert, Patricia | Feitosa, Mary F. | Freedman, Barry I. | Gillanders, Elizabeth M. | Gottesman, Omri | Guo, Xiuqing | Haritunians, Talin | Harris, Tamara | Harris, Curtis C. | Hennis, Anselm JM | Hernandez, Dena G. | McNeill, Lorna H. | Howard, Timothy D. | Howard, Barbara V. | Howard, Virginia J. | Johnson, Karen C. | Kang, Sun J. | Keating, Brendan J. | Kolb, Suzanne | Kuller, Lewis H. | Kutlar, Abdullah | Langefeld, Carl D. | Lettre, Guillaume | Lohman, Kurt | Lotay, Vaneet | Lyon, Helen | Manson, JoAnn E. | Maixner, William | Meng, Yan A. | Monroe, Kristine R. | Morhason-Bello, Imran | Murphy, Adam B. | Mychaleckyj, Josyf C. | Nadukuru, Rajiv | Nathanson, Katherine L. | Nayak, Uma | N’Diaye, Amidou | Nemesure, Barbara | Wu, Suh-Yuh | Leske, M. Cristina | Neslund-Dudas, Christine | Neuhouser, Marian | Nyante, Sarah | Ochs-Balcom, Heather | Ogunniyi, Adesola | Ogundiran, Temidayo O. | Ojengbede, Oladosu | Olopade, Olufunmilayo I. | Palmer, Julie R. | Ruiz-Narvaez, Edward A. | Palmer, Nicholette D. | Press, Michael F. | Rampersaud, Evandine | Rasmussen-Torvik, Laura J. | Rodriguez-Gil, Jorge L. | Salako, Babatunde | Schadt, Eric E. | Schwartz, Ann G. | Shriner, Daniel A. | Siscovick, David | Smith, Shad B. | Wassertheil-Smoller, Sylvia | Speliotes, Elizabeth K. | Spitz, Margaret R. | Sucheston, Lara | Taylor, Herman | Tayo, Bamidele O. | Tucker, Margaret A. | Van Den Berg, David J. | Velez Edwards, Digna R. | Wang, Zhaoming | Wiencke, John K. | Winkler, Thomas W. | Witte, John S. | Wrensch, Margaret | Wu, Xifeng | Yang, James J. | Levin, Albert M. | Young, Taylor R. | Zakai, Neil A. | Cushman, Mary | Zanetti, Krista A. | Zhao, Jing Hua | Zhao, Wei | Zheng, Yonglan | Zhou, Jie | Ziegler, Regina G. | Zmuda, Joseph M. | Fernandes, Jyotika K. | Gilkeson, Gary S. | Kamen, Diane L. | Hunt, Kelly J. | Spruill, Ida J. | Ambrosone, Christine B. | Ambs, Stefan | Arnett, Donna K. | Atwood, Larry | Becker, Diane M. | Berndt, Sonja I. | Bernstein, Leslie | Blot, William J. | Borecki, Ingrid B. | Bottinger, Erwin P. | Bowden, Donald W. | Burke, Gregory | Chanock, Stephen J. | Cooper, Richard S. | Ding, Jingzhong | Duggan, David | Evans, Michele K. | Fox, Caroline | Garvey, W. Timothy | Bradfield, Jonathan P. | Hakonarson, Hakon | Grant, Struan F.A. | Hsing, Ann | Chu, Lisa | Hu, Jennifer J. | Huo, Dezheng | Ingles, Sue A. | John, Esther M. | Jordan, Joanne M. | Kabagambe, Edmond K. | Kardia, Sharon L.R. | Kittles, Rick A. | Goodman, Phyllis J. | Klein, Eric A. | Kolonel, Laurence N. | Le Marchand, Loic | Liu, Simin | McKnight, Barbara | Millikan, Robert C. | Mosley, Thomas H. | Padhukasahasram, Badri | Williams, L. Keoki | Patel, Sanjay R. | Peters, Ulrike | Pettaway, Curtis A. | Peyser, Patricia A. | Psaty, Bruce M. | Redline, Susan | Rotimi, Charles N. | Rybicki, Benjamin A. | Sale, Michèle M. | Schreiner, Pamela J. | Signorello, Lisa B. | Singleton, Andrew B. | Stanford, Janet L. | Strom, Sara S. | Thun, Michael J. | Vitolins, Mara | Zheng, Wei | Moore, Jason H. | Williams, Scott M. | Zhu, Xiaofeng | Zonderman, Alan B. | Kooperberg, Charles | Papanicolaou, George | Henderson, Brian E. | Reiner, Alex P. | Hirschhorn, Joel N. | Loos, Ruth JF | North, Kari E. | Haiman, Christopher A.
Nature genetics  2013;45(6):690-696.
Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.
PMCID: PMC3694490  PMID: 23583978
6.  Leisure Activities, Caregiving Demands, and Catecholamine Levels in Dementia Caregivers 
Psychology & health  2011;27(10):1134-1149.
This study examined whether satisfaction from leisure activities moderates the relationship between caregiving demands (i.e., hours per day spent caring for a spouse with dementia) and resting levels of the catecholamines norepinephrine (NE) and epinephrine (EPI). Spousal caregivers (N=107; mean age 73.95±8.12 years) were assessed in home for plasma levels of NE and EPI, amount of care provided, and leisure satisfaction. Regression was used to determine whether leisure satisfaction moderated the relationship between hours providing care per day and catecholamine levels. A significant interaction was found between hours caregiving and leisure satisfaction for NE, but not for EPI. Post hoc regressions were conducted for both NE and EPI. At low leisure satisfaction, time spent caring for a spouse was positively associated with plasma NE (β = .41; p = .005) and EPI (β = .44; p = .003). In contrast, at high levels of satisfaction, time caregiving was not significantly associated with plasma NE (β = −.08; p = .57) or EPI (β = .23; p = .12). These findings suggest that leisure satisfaction may protect caregivers from increases in catecholamines, which have been implicated in cardiovascular risk. Further support for these findings may impact psychological treatments for distressed caregivers.
PMCID: PMC3346846  PMID: 22149759
leisure satisfaction; leisure activities; catecholamine; dementia caregiving; cardiovascular disease
7.  Associations of BMI and insulin resistance with leptin, adiponectin, and the leptin to adiponectin ratio across ethnic groups: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Annals of epidemiology  2012;22(10):705-709.
Associations of adiponectin and leptin and their ratio with BMI and HOMA-IR have been investigated in different ethnic groups but variability in both assays and statistical methods have made cross-study comparisons difficult. We examined associations among these variables across four ethnic groups in a single study.
Adiponectin and leptin were measured in a subset of MESA participants. We calculated associations (using both partial correlations and adjusted linear regression) in each ethnic group and then compared the magnitude of these associations across groups.
After excluding individuals with type 2 diabetes there were 714 White, 219 Chinese, 332 African American, and 405 Hispanic individuals, in the study sample. Associations of BMI with adiponectin and leptin differed significantly (P < 0.05) across the ethnic groups in regression analyses, while associations of HOMA-IR with adiponectin and leptin did not differ across ethnic groups. The leptin to adiponectin ratio was not associated with a greater amount of adiposity or HOMA-IR variance than leptin or adiponectin in any ethnic group.
Given the consistency of HOMA-IR and adipokine associations, the differing means of adiponectin and leptin across ethnic groups may help to explain ethnic differences in mean insulin resistance.
PMCID: PMC3459265  PMID: 22929534
8.  Relationships of Coronary Heart Disease with 27-Hydroxycholesterol, Low Density Lipoprotein Cholesterol, and Menopausal Hormone Therapy 
Circulation  2012;126(13):1577-1586.
Menopausal hormone therapy (MHT) increases risk of coronary heart disease (CHD) in older women with elevated low-density lipoprotein (LDLC) levels. The endogenous estrogen receptor antagonist 27-hydroxycholesterol (27OHC) is correlated with LDLC levels and may block beneficial effects of estrogen on the cardiovascular system.
Methods and Results
We conducted a nested case-control study in the Women’s Health Initiative trials of 350 CHD cases and 813 matched controls to explore potential mediation by 27OHC of the dependence of the CHD risk elevation with MHT on LDLC. Baseline levels of 27OHC were not associated with CHD risk when LDLC was included in the multivariable models. The odds ratio for CHD associated with increased LDLC was 1.15 (95% confidence interval 1.08, 1.23) and was unchanged at 1.14 (1.07, 1.22) when 27OHC was added to the model. Baseline 27OHC did not interact with MHT on CHD risk (p = 0.81). In contrast, LDLC levels modified the effect of MHT on CHD risk (p for interaction = 0.02), and adding 27OHC did not affect this result. Using log scales the MHT effect on CHD increased linearly with increasing level of baseline LDLC, with a transition from no risk to increased risk at approximately 3.36 mmol/L (130 mg/dl).
27OHC does not independently increase risk of CHD, does not modify the increased risk of CHD due to MHT, and does not mediate the interaction of LDLC with MHT. Measuring blood lipids may aid in counseling individual women about initiating MHT and cardiovascular risk mitigation.
PMCID: PMC3482942  PMID: 22932256
acute coronary syndrome; atherosclerosis; estrogen; low-density lipoprotein (LDL)-cholesterol; pathophysiology
9.  Prevalence of Major Cardiovascular Risk Factors and Cardiovascular Diseases Among Hispanic/Latino Individuals of Diverse Backgrounds in the United States 
Major cardiovascular diseases (CVDs) are leading causes of mortality among US Hispanic and Latino individuals. Comprehensive data are limited regarding the prevalence of CVD risk factors in this population and relations of these traits to socioeconomic status (SES) and acculturation.
To describe prevalence of major CVD risk factors and CVD (coronary heart disease [CHD] and stroke) among US Hispanic/Latino individuals of different backgrounds, examine relationships of SES and acculturation with CVD risk profiles and CVD, and assess cross-sectional associations of CVD risk factors with CVD.
Design, Setting, and Participants
Multicenter, prospective, population-based Hispanic Community Health Study/Study of Latinos including individuals of Cuban (n =2201), Dominican (n = 1400), Mexican (n=6232), Puerto Rican (n=2590), Central American (n=1634), and South American backgrounds (n = 1022) aged 18 to 74 years. Analyses involved 15 079 participants with complete data enrolled between March 2008 and June 2011.
Main Outcome Measures
Adverse CVD risk factors defined using national guidelines for hypercholesterolemia, hypertension, obesity, diabetes, and smoking. Prevalence of CHD and stroke were ascertained from self-reported data.
Age-standardized prevalence of CVD risk factors varied by Hispanic/Latino background; obesity and current smoking rates were highest among Puerto Rican participants (for men, 40.9% and 34.7%; for women, 51.4% and 31.7%, respectively); hypercholesterolemia prevalence was highest among Central American men (54.9%) and Puerto Rican women (41.0%). Large proportions of participants (80% of men, 71% of women) had at least 1 risk factor. Age- and sex-adjusted prevalence of 3 or more risk factors was highest in Puerto Rican participants (25.0%) and significantly higher (P<.001) among participants with less education (16.1%), those who were US-born (18.5%), those who had lived in the United States 10 years or longer (15.7%), and those who preferred English (17.9%). Overall, self-reported CHD and stroke prevalence were low (4.2% and 2.0% in men; 2.4% and 1.2% in women, respectively). In multivariate-adjusted models, hypertension and smoking were directly associated with CHD in both sexes as were hypercholesterolemia and obesity in women and diabetes in men (odds ratios [ORs], 1.5–2.2). For stroke, associations were positive with hypertension in both sexes, diabetes in men, and smoking in women (ORs, 1.7–2.6).
Among US Hispanic/Latino adults of diverse backgrounds, a sizeable proportion of men and women had adverse major risk factors; prevalence of adverse CVD risk profiles was higher among participants with Puerto Rican background, lower SES, and higher levels of acculturation.
PMCID: PMC3777250  PMID: 23117778
10.  Renal artery calcification and mortality among clinically asymptomatic adults 
To assess the associations between renal artery calcification (RAC) and mortality in a healthy outpatient cohort without known cardiovascular disease (CVD).
Studies in individuals with known diabetes and kidney disease have suggested that RAC confers additional mortality risk independent of coronary artery calcification, but this has not been explored in healthier populations.
We assessed RAC by CT scan in 4450 healthy outpatients without known CVD. We used Cox proportional-hazards models to examine the association of RAC with mortality.
The mean age of participants was 57; 42.6% were women. RAC was present in 622 of 4,450 (14%) participants. Over a median follow-up of 8.2 years, 178 deaths occurred. After adjustment for age, gender, diabetes, smoking, cholesterol and family history of CVD, the presence of RAC conferred a more than 60% increased hazard for all-cause mortality (HR 1.63, 95% CI 1.17–2.29). Adjustment for calcification in other vascular beds attenuated this association (HR 1.40, 95% CI 0.99–1.97). Adjustment for hypertension, a potential mediator of the association, did not substantially change the results (HR 1.44, 95% CI, 1.02–2.03). Adding RAC to a model including Framingham risk and CAC improved the predictive ability of the model, from 0.73 to 0.77 (p 0.0002); the net reclassification index was 14.4% for addition of RAC. Results for cardiovascular mortality were not significant, limited by a small number of cardiovascular deaths.
We found that RAC is associated with an increased risk of subsequent all-cause mortality in healthy outpatient individuals, independent of traditional cardiac risk factors. The risk was modestly attenuated by adjustment for vascular calcification in other vascular beds, suggesting partial confounding by systemic calcified atherosclerosis. The effect did not appear to be mediated by hypertension.
PMCID: PMC3684424  PMID: 22939556
11.  Genetic Associations with Valvular Calcification and Aortic Stenosis 
The New England journal of medicine  2013;368(6):503-512.
Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.
We determined genomewide associations with the presence of aorticvalve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.
One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aorticvalve calcification (odds ratio per allele, 2.05; P = 9.0×10−10), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aorticvalve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5×10−8 and P = 1.8×10−8, respectively), but the findings were not replicated consistently.
Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aorticvalve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
PMCID: PMC3766627  PMID: 23388002
12.  Extremes of an Aromatase Index Predict Increased 25-year Risk of Cardiovascular Mortality in Older Women 
Clinical endocrinology  2012;77(3):391-398.
Peripheral conversion of androgens to estrogens via aromatase is the primary source of estrogen in postmenopausal women and may play a role in cardiovascular health.
Participants, Measurements
The association of an index of aromatase activity (AROM), the serum estrone to androstenedione ratio, with 25 year cardiovascular (CVD) mortality was examined in 819 postmenopausal non-estrogen using women (mean age at baseline=72).
Overall, 247 deaths were attributed to CVD. The median AROM value was 60 (95% range 17–129). AROM was positively correlated with age (r=0.28) and BMI (r=0.22) (P<0.001). The age-adjusted risk for CVD mortality was significantly elevated for women in the lowest (HR=2.01, 95%CI 1.31–3.12) and highest (HR=1.51, 95%CI 1.02–2.22) quintiles of AROM, compared to the middle quintile. This U-shaped association persisted after additional adjustment for BMI, waist-to-hip ratio, exercise, smoking, alcohol use and traditional CVD risk factor covariates. There was a significant interaction of AROM and BMI (P=.001) such that high AROM was associated with a 63% reduction in risk of CVD death for women with low BMI (<22 kg/m2), but with 2.1 to 2.5-fold increased risk in women with mid-range (22–<25 kg/m2) and high (≥25 kg/m2) BMI. Estradiol did not influence AROM associations and was not independently related to CVD death.
These results suggest that aromatase is a novel endocrine factor predictive of CVD mortality among postmenopausal women. If confirmed, additional studies are needed to determine whether extremes of aromatase reflect genetic influences or underlying disease processes.
PMCID: PMC3298636  PMID: 22066939
cardiovascular mortality; aromatase; women; epidemiology; aging
13.  Association between Annual Visit-to-Visit Blood Pressure Variability and Stroke in Postmenopausal Women: Data from the Women's Health Initiative 
Hypertension  2012;60(3):625-630.
Accumulating evidence suggests that increased visit-to-visit variability (VVV) of blood pressure is associated with stroke. No study has examined the association between VVV of blood pressure and stroke in postmenopausal women, and scarce data exists as to whether this relation is independent of the temporal trend of blood pressure. We examined the association of VVV of blood pressure with stroke in 58,228 postmenopausal women enrolled in the Women's Health Initiative. Duplicate blood pressure readings, which were averaged, were taken at baseline and at each annual visit. VVV was defined as the standard deviation about the participant's mean systolic blood pressure (SBP) across visits (SD), and about the participant's regression line with SBP regressed across visits (SDreg). Over a median follow-up of 5.4 years, 997 strokes occurred. In an adjusted model including mean SBP over time, the hazard ratios (95% CI) of stroke for higher quartiles of SD of SBP compared to the lowest quartile (referent) were 1.39 (1.03-1.89) for quartile 2, 1.52 (1.13-2.03) for quartile 3, and 1.72 (1.28-2.32) for quartile 4 (P trend<0.001). The relation was similar for SDreg of SBP quartiles in a model that additionally adjusted for the temporal trend in SBP (P trend<0.001). The associations did not differ by stroke type (ischemic vs. hemorrhagic). There was a significant interaction between mean SBP and SDreg on stroke with the strongest association seen below 120 mmHg. In postmenopausal women, greater VVV of SBP was associated with increased risk of stroke, particularly in the lowest range of mean SBP.
PMCID: PMC3427141  PMID: 22753206
hypertension; blood pressure; stroke; postmenopause; women
14.  Influence of Patients’ Coronary Artery Calcium on Subsequent Medication Use Patterns 
To determine whether information on the presence and extent of coronary artery calcium (CAC) is associated with the likelihood of physicians’ prescribing preventive therapies.
In a longitudinal design, asymptomatic participants (N=510) were evaluated by computed tomography for CAC. Changes to medications were at the discretion of the patient’s primary care provider, who received the CT report.
In multivariable analysis, the likelihood of patients reporting that their primary care physician prescribed preventive therapies was significantly associated with the presence and extent of CAC.
This study suggests that physicians’ prescribing practices are influenced by patients’ CAC scores obtained via CT.
PMCID: PMC3753401  PMID: 22584090
coronary calcium; computed tomography; physician prescribing practices; preventive therapies
15.  A Longitudinal Analysis of the Relations Among Stress, Depressive Symptoms, Leisure Satisfaction, and Endothelial Function in Caregivers 
Health Psychology  2012;31(4):433-440.
Stress and depressive symptoms have been associated with impaired endothelial function as measured by brachial artery flow-mediated dilation (FMD), possibly through repeated and heightened activation of the sympathetic nervous system (SNS). Behavioral correlates of depression, such as satisfaction with leisure activities (i.e., leisure satisfaction), may also be associated with endothelial function via their association with depressive symptoms. This study examined the longitudinal associations between stress, depressive symptoms, leisure satisfaction, and endothelial function as measured by FMD.
Participants were 116 elderly Alzheimer’s caregivers (mean age = 74.3 ± 8.1; 68% female; 87% Caucasian) who underwent three yearly assessments of FMD, stress, depressive symptoms, and leisure satisfaction. Mixed regression analyses were used to examine longitudinal relationships between constructs of interest.
A significant and positive association was found between leisure satisfaction and FMD (p = .050), whereas a negative relationship was found for stress (p = .017). Depressive symptoms were not associated with FMD (p = .432). Time (p < .001) and the number of years caregiving (p = .027) were also significant predictors of FMD, suggesting that FMD decreased over time and was worse the longer a participant had been a caregiver prior to study enrollment.
These results suggest that behavioral correlates of depression (i.e., engagement in pleasurable activities) may be related to endothelial function in caregivers, and behavioral treatments for depression may be particularly useful in improving cardiovascular outcomes in caregivers.
PMCID: PMC3393823  PMID: 22486550
Behavioral Activation; Depression; Flow-Mediated Dilation; Stress
16.  Inflammatory Markers and the Risk of Hip Fracture: The Women's Health Initiative 
Journal of Bone and Mineral Research  2012;27(5):1167-1176.
Cytokines play a major role in bone remodeling in vitro and in animal models, with evidence supporting the involvement of inflammatory markers in the pathogenesis of osteoporosis. However, less is known about the longitudinal association of inflammatory markers with hip fracture. We tested whether high receptor levels of pro-inflammatory cytokines are associated with an increased risk of hip fracture in older women. We used a nested case-control study design from the Women's Health Initiative Observational Study (WHI-OS) and selected 400 cases with physician adjudicated incident hip fractures and 400 age, race, and date of blood draw matched controls. Participants were chosen from 39,795 postmenopausal women without previous hip fractures, not using estrogens or other bone-active therapies. Incident hip fractures (median follow-up 7.1 years) were verified by review of radiographs and confirmed by blinded central adjudicators. Hip fractures with a pathological cause were excluded. In multivariable models, the risk of hip fracture for subjects with the highest levels of inflammatory markers (quartile 4) compared with those with lower levels (quartiles 1, 2, and 3) was 1.43 (95% CI, 0.98 to 2.07) for IL-6 SR and 1.41 (95% CI, 0.97 to 2.05) for TNF SR1 and 1.57 (95% CI, 1.09 to 2.25) for TNF SR2. In subjects with all three markers in the highest quartile, the risk ratio of fracture was 2.27 (95% CI to 1.04 to 4.93) in comparison with subjects with 0 or 1 elevated marker(s) (p trend = 0.042). Elevated levels of inflammatory markers for all 3 cytokine soluble receptors were associated with an increased risk of hip fractures in older women. Future clinical trials should test whether interventions to decrease inflammatory marker levels reduces hip fractures.
PMCID: PMC3361578  PMID: 22392817
Inflammation; hip fractures; cytokines; women; osteoporosis; nested case-control
17.  Genetic determinants of the ankle-brachial index: A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium 
Atherosclerosis  2012;222(1):138-147.
Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ~50,000 SNPs across ~2100 candidate genes to identify genetic variants for ABI.
Methods and results
We studied subjects of European ancestry from 8 studies (n = 21,547, 55% women, mean age 44–73 years) and African American ancestry from 5 studies (n = 7267, 60% women, mean age 41–73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI > 1.40) and PAD (defined as ABI < 0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p < 2 × 10−6 to denote statistical significance.
In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β = −0.007, p = 6.02 × 10−7) and rs290481 in TCF7L2 (β = −0.008, p = 7.01 × 10−7) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p = 4.99 × 10−5) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n = 15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p = 0.75; rs290481, p = 0.19) and in the combined discovery and replication analysis the SNP–ABI associations were no longer significant (rs2171209, p = 1.14 × 10−3; rs290481, p = 8.88 × 10−5). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance.
Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.
PMCID: PMC3596171  PMID: 22361517
Ankle brachial index; Peripheral artery disease; Genetics; Candidate gene array; Meta-analysis; Ethnicity
18.  Relationship between chronic stress and carotid intima-media thickness (IMT) in elderly Alzheimer’s disease caregivers 
Stress (Amsterdam, Netherlands)  2011;15(2):121-129.
The stress associated with providing care for a spouse diagnosed with Alzheimer’s disease can have adverse effects on cardiovascular health. One potential explanation is that chronic caregiving stress may contribute to the development of atherosclerosis. The purpose of this study was to determine if the duration that one has provided care is associated with degree of atherosclerotic burden, as measured by carotid artery intima-media thickness (IMT). One hundred and ten Alzheimer caregivers (mean age 74 ± 8 years, 69% female) underwent in-home assessment of carotid artery IMT via B-mode ultrasonography. Data regarding medical history, blood pressure, and multiple indicators of caregiving stress were also collected. Multiple regression indicated that duration of care was positively associated with IMT measured in the internal/bifurcation segments of the carotid artery (β = 0.202, p = 0.044) independent of risk factors such as age, gender, body mass index, smoking history, sleep quality, hypertension status, and caregiving stressors. Duration of care was positively associated with IMT in the common carotid artery, but the relationship was not significant. These findings provide more evidence of the link between chronic caregiving stress and cardiovascular disease and suggest that enduring the experience of caregiving over a period of years might be associated with atherosclerotic burden.
PMCID: PMC3223262  PMID: 21790484
Alzheimer’s disease; Atherosclerosis; Caregiving; Chronic Stress; Coronary Heart Disease; Intima-media thickness
19.  Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies 
Murabito, Joanne M. | White, Charles C. | Kavousi, Maryam | Sun, Yan V. | Feitosa, Mary F. | Nambi, Vijay | Lamina, Claudia | Schillert, Arne | Coassin, Stefan | Bis, Joshua C. | Broer, Linda | Crawford, Dana C. | Franceschini, Nora | Frikke-Schmidt, Ruth | Haun, Margot | Holewijn, Suzanne | Huffman, Jennifer E. | Hwang, Shih-Jen | Kiechl, Stefan | Kollerits, Barbara | Montasser, May E. | Nolte, Ilja M. | Rudock, Megan E. | Senft, Andrea | Teumer, Alexander | van der Harst, Pim | Vitart, Veronique | Waite, Lindsay L. | Wood, Andrew R. | Wassel, Christina L. | Absher, Devin M. | Allison, Matthew A. | Amin, Najaf | Arnold, Alice | Asselbergs, Folkert W. | Aulchenko, Yurii | Bandinelli, Stefania | Barbalic, Maja | Boban, Mladen | Brown-Gentry, Kristin | Couper, David J. | Criqui, Michael H. | Dehghan, Abbas | Heijer, Martin den | Dieplinger, Benjamin | Ding, Jingzhong | Dörr, Marcus | Espinola-Klein, Christine | Felix, Stephan B. | Ferrucci, Luigi | Folsom, Aaron R. | Fraedrich, Gustav | Gibson, Quince | Goodloe, Robert | Gunjaca, Grgo | Haltmayer, Meinhard | Heiss, Gerardo | Hofman, Albert | Kieback, Arne | Kiemeney, Lambertus A. | Kolcic, Ivana | Kullo, Iftikhar J. | Kritchevsky, Stephen B. | Lackner, Karl J. | Li, Xiaohui | Lieb, Wolfgang | Lohman, Kurt | Meisinger, Christa | Melzer, David | Mohler, Emile R | Mudnic, Ivana | Mueller, Thomas | Navis, Gerjan | Oberhollenzer, Friedrich | Olin, Jeffrey W. | O’Connell, Jeff | O’Donnell, Christopher J. | Palmas, Walter | Penninx, Brenda W. | Petersmann, Astrid | Polasek, Ozren | Psaty, Bruce M. | Rantner, Barbara | Rice, Ken | Rivadeneira, Fernando | Rotter, Jerome I. | Seldenrijk, Adrie | Stadler, Marietta | Summerer, Monika | Tanaka, Toshiko | Tybjaerg-Hansen, Anne | Uitterlinden, Andre G. | van Gilst, Wiek H. | Vermeulen, Sita H. | Wild, Sarah H. | Wild, Philipp S. | Willeit, Johann | Zeller, Tanja | Zemunik, Tatijana | Zgaga, Lina | Assimes, Themistocles L. | Blankenberg, Stefan | Boerwinkle, Eric | Campbell, Harry | Cooke, John P. | de Graaf, Jacqueline | Herrington, David | Kardia, Sharon L. R. | Mitchell, Braxton D. | Murray, Anna | Münzel, Thomas | Newman, Anne | Oostra, Ben A. | Rudan, Igor | Shuldiner, Alan R. | Snieder, Harold | van Duijn, Cornelia M. | Völker, Uwe | Wright, Alan F. | Wichmann, H.-Erich | Wilson, James F. | Witteman, Jacqueline C.M. | Liu, Yongmei | Hayward, Caroline | Borecki, Ingrid B. | Ziegler, Andreas | North, Kari E. | Cupples, L. Adrienne | Kronenberg, Florian
Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
Methods and Results
Continuous ABI and PAD (ABI≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ~2.5 million SNPs in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed-effects inverse variance weighted meta-analyses. There were a total of 41,692 participants of European ancestry (~60% women, mean ABI 1.02 to 1.19), including 3,409 participants with PAD and with GWAS data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β= −0.006, p=2.46x10−8). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16,717). The association for rs10757269 strengthened in the combined discovery and replication analysis (p=2.65x10−9). No other SNP associations for ABI or PAD achieved genome-wide significance. However, two previously reported candidate genes for PAD and one SNP associated with coronary artery disease (CAD) were associated with ABI : DAB21P (rs13290547, p=3.6x10−5); CYBA (rs3794624, p=6.3x10−5); and rs1122608 (LDLR, p=0.0026).
GWAS in more than 40,000 individuals identified one genome-wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for CAD are associated with ABI.
PMCID: PMC3303225  PMID: 22199011
cohort study; genetic association; genome-wide association study; meta-analysis; peripheral vascular disease
20.  Effect of Chronic Dementia Caregiving and Major Transitions in the Caregiving Situation on Kidney Function: A Longitudinal Study 
Psychosomatic Medicine  2012;74(2):214-220.
To estimate the glomerular filtration rate (GFR) in relation to the chronic stress of dementia caregiving and major transitions in the caregiving situation.
We longitudinally assessed 119 elderly spousal Alzheimer’s disease (AD) caregivers and 58 non-caregiving controls for a period of up to three years (mean of 2.8 assessments per participant). Random regression models with fixed and time-variant effects for psychosocial factors, risk factors of chronic kidney disease, and caregiving transitions were used to evaluate changes over time in estimated GFR.
The change in GFR did not differ between caregivers and controls during follow-up (p=.77). Further analyses revealed that GFR declined disproportionately following placement of the spouse in a nursing home at 3 months post-placement (−4.9±2.2 mL/min/1.73m2; p=.03). Post hoc analyses showed that this effect was stronger in caregivers with hypertension compared to those without hypertension (−5.7±3.1 vs. −2.4±3.4 mL/min), as well as in caregivers with diastolic BP levels at 1 standard deviation above the mean than in those with diastolic BP levels at 1 standard deviation below the mean (−8.3±2.9 vs. −1.4±2.7 mL/min).
Kidney function did not differ between caregivers and controls over time. However, GFR had impaired at 3 months after a major caregiving transition. As the effect of placement of the AD spouse on the decline in GFR was moderated by BP, it might be confined to caregivers who experience increased sympathetic activation post-placement.
PMCID: PMC3384744  PMID: 22286846
Blood pressure; caregivers; dementia; kidney disease; psychological stress
21.  Sedentary Behavior and Adiposity-Associated Inflammation The Multi-Ethnic Study of Atherosclerosis 
Sedentary behavior is associated with adiposity and cardiometabolic risk.
To determine the associations between sedentary behavior and measures of adiposity-associated inflammation.
Between 2002 and 2005, a total of 1543 Multi-Ethnic Study of Atherosclerosis participants completed detailed health history questionnaires, underwent physical measurements and had blood assayed for adiponectin, leptin, tumor necrosis factor – alpha (TNF - α) and resistin. Analyses included linear regression completed in 2010. The mean age was 64.3 years and nearly 50% were female. Forty-one percent were non-Hispanic white, 24% Hispanic-American, 20% African-American, and 14% Chinese-American.
In linear regression analyses and with adjustment for age, gender, ethnicity, education, BMI, smoking, alcohol consumption, hypertension, diabetes mellitus, dyslipidemia, hormone therapy and waist circumference, sedentary behavior was associated with higher natural log (“ln”) of leptin and ln TNF - α but a lower ln adiponectin-to-leptin ratio (β = 0.07, β = 0.03 and –0.07, p < 0.05 for all). Compared to the first tertile, and after the same adjustment, the second and third tertiles of sedentary behavior were associated with higher levels of ln leptin (β = 0.11and β = 0.12, respectively; p < 0.05 for both) but lower levels of the adiponectin-to-leptin ratio (β = –0.09 and –0.11, respectively; p < 0.05 for both).
Sedentary behavior is associated with unfavorable levels of adiposity-associated inflammation.
PMCID: PMC3244676  PMID: 22176840
22.  A Prospective Study of Serum 25-Hydroxyvitamin D Levels, Blood Pressure, and Incident Hypertension in Postmenopausal Women 
American Journal of Epidemiology  2011;175(1):22-32.
In randomized trials, the effect of vitamin D supplementation on blood pressure has been equivocal, while most prospective cohort studies have shown that the risk of incident hypertension is lower in people with higher levels of 25-hydroxyvitamin D (25(OH)D). The authors examined the association between levels of 25(OH)D and changes in blood pressure and incident hypertension in 4,863 postmenopausal women recruited into the Women’s Health Initiative between 1993 and 1998. Over 7 years, there were no significant differences in the adjusted mean change in systolic or diastolic blood pressure by quartile of 25(OH)D. The covariate-adjusted risk of incident hypertension was slightly lower in the upper 3 quartiles of 25(OH)D compared with the lowest quartile, but this was statistically significant only in the third quartile (hazard ratio = 0.67, 95% confidence interval: 0.46, 0.96). There was no significant linear or nonlinear trend in the risk of incident hypertension by untransformed or log-transformed continuous values of 25(OH)D. In postmenopausal women in this study, serum levels of 25(OH)D were not related to changes in blood pressure, and evidence for an association with lower risk of incident hypertension was weak.
PMCID: PMC3291161  PMID: 22127681
blood pressure; calcifediol; hypertension; prospective studies; vitamin D
23.  Effect of Alzheimer Caregiving on Circulating Levels of C-reactive Protein and Other Biomarkers Relevant to Cardiovascular Disease Risk: A Longitudinal Study 
Gerontology  2011;58:354-365.
Providing care to a spouse with Alzheimer’s disease (AD) may contribute to cardiovascular disease (CVD). The acute phase reactant C-reactive protein is a well-established biomarker of an increased CVD risk.
To investigate the hypothesis that dementia caregiving is associated with elevated circulating levels of CRP and possibly other biomarkers of CVD risk.
We examined 118 elderly spousal Alzheimer caregivers and 51 non-caregiving controls about once a year for up to three years. Random regression models with fixed and time-variant effects for a range of covariates known to affect biomarker levels were used to evaluate changes in CRP and in twelve additional measures of inflammation, cellular adhesion, endothelial function, and hemostasis in relation to caregiving status, years of caregiving, and major transitions in the caregiving situation.
During the study period longer duration of caregiving was associated with elevated CRP levels (p=0.040) and caregivers showed greater tumor necrosis factor alpha (TNF-α) levels than controls (p=0.048). Additionally, three months after the death of the AD spouse, caregivers showed a significant drop in CRP levels (p=0.003) and also in levels of soluble intercellular adhesion molecule (sICAM)-1 (p=0.008).
Duration of caregiving, and being a caregiver per se, were both associated with chronic low-grade inflammation as indicated by elevated CRP and TNF-α levels, respectively. Conversely, death of the AD spouse was associated with lower CRP and sICAM-1 levels. The findings indicate that chronic caregiving of those with dementia may result in increased inflammation and thereby, possibly increased CVD risk.
PMCID: PMC3425376  PMID: 22133914
Alzheimer disease; biomarkers; cardiovascular disease; caregiver; cytokines; inflammation; psychological stress
24.  Emotional and cognitive health correlates of leisure activities in older Latino and Caucasian women 
Psychology, health & medicine  2011;16(6):661-674.
This study examined differences in the frequency of leisure activity participation and relationships to depressive symptom burden and cognition in Latino and Caucasian women. Cross-sectional data were obtained from a demographically matched subsample of Latino and Caucasian (n = 113 each) post-menopausal women (age ≥60), interviewed in 2004–06 for a multi-ethnic cohort study of successful aging in San Diego County. Frequencies of engagement in 16 leisure activities and associations between objective cognitive performance and depressive symptom burden by ethnicity were identified using bivariate and linear regression, adjusted for physical functioning and demographic covariates. Compared to Caucasian women, Latinas were significantly more likely to be caregivers and used computers less often. Engaging in organized social activity was associated with fewer depressive symptoms in both groups. Listening to the radio was positively correlated with lower depressive symptom burden for Latinas, and better cognitive functioning in Caucasians. Cognitive functioning was better in Latinas who read and did puzzles. Housework was negatively associated with Latinas’ emotional health and Caucasians’ cognitive functioning. Latino and Caucasian women participate in different patterns of leisure activities. Additionally, ethnicity significantly affects the relationship between leisure activities and both emotional and cognitive health.
PMCID: PMC3134532  PMID: 21391135
25.  Cardiometabolic Effects in Caregivers of Nursing Home Placement and Death of their Alzheimer Spouse 
Alzheimer’s Disease (AD) caregiving stress may contribute to increased cardiovascular disease risk in spousal caregiving through physiological changes characteristic of the metabolic syndrome (MetS).
We tested the hypothesis that cardiometabolic risk is attenuated when caregivers are relieved from caregiving stress when the caregiving recipient transitions out of the home.
Longitudinal study.
Subjects’ homes.
One hundred and nineteen spousal caregivers of a patient with AD and 55 non-caregiving controls (mean age 75±8 years of entire sample, 68% women).
Participants underwent up to three yearly assessments of MetS factors related to adiposity, dyslipidemia, hypertension, and hyperglycemia. Changes in the total number of MetS factors (range 0–5) at 3 months after caregiver transitions were evaluated using random regression models with fixed and time-variant effects for sociodemographic and health-related covariates.
Compared to non-caregivers, caregivers had a greater number of MetS factors over time (1.78±0.13 vs. 1.36±0.18, p=0.008), which, after the death of the spouse, dropped by 0.46±0.16 (p=0.003) being no longer different from non-caregivers; this effect was most prominently related to decreases in triglycerides (−22.2±11.0 mg/dl, p=0.032), systolic BP (−6.2±2.6 mmHg, p=0.019), and diastolic BP (−3.4±1.5 mmHg, p=0.026). Placement of the spouse decreased the number of MetS factors only in caregivers with lower levels of depressive symptoms (−0.48±0.18, p=0.010) and sleeping difficulties (−0.42±0.18, p=0.021), but not in caregivers with higher levels in these measures at post-placement.
Elevated cardiometabolic risk in caregivers decreased to the level of non-caregivers within three months of death of the AD spouse. Placement, a transition in the course of dementia caregiving, however, did not benefit cardiovascular health in highly distressed caregivers.
PMCID: PMC3384995  PMID: 22091921
Cardiovascular disease; caregivers; dementia; metabolic syndrome; psychological stress

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