Showing papers by "Howard N. Hodis published in 2012"

Biomarkers of Microbial Translocation and Macrophage Activation: Association With Progression of Subclinical Atherosclerosis in HIV-1 Infection

Abstract: (See the editorial commentary by Crowe and Hoy, on pages 1491–3.) With improved survival, cardiovascular disease has become an increasingly important cause of morbidity and mortality among persons infected with human immunodeficiency virus (HIV) type 1 [1], underscoring the need to better understand the contributors to cardiovascular disease risk. Evidence from clinical studies supports a link between endotoxemia and the development of atherosclerosis and metabolic complications in humans [2, 3]. HIV pathogenesis is characterized by a chronic state of immune activation, which is an independent predictor of disease progression in untreated persons [4]. Although bacterial translocation from the gut has been implicated as a possible cause of this immune activation and thus disease progression [4, 5], its role in the progression of atherosclerosis in HIV-infected persons receiving antiretroviral therapy (ART) remains largely unknown. Previous studies have shown increased serum lipopolysaccharide (LPS) levels in persons with viremia compared with healthy volunteers [6, 7]. LPS is thought to induce systemic immune activation by binding to CD14+ monocytes and macrophages, which consequently produce soluble CD14 (sCD14) [8–10]. Thus, levels of LPS and sCD14 have been used as biomarkers of bacterial translocation and macrophage activation, respectively, but have not been previously studied in of the context of atherosclerosis in HIV infection [5]. In addition, the effect of ART, including protease inhibitor (PI) drugs, on levels of these biomarkers remains largely unknown. Measurement of carotid artery intima-media thickness (CIMT) using noninvasive B-mode ultrasound is well documented as a measure of subclinical atherosclerosis [11–13], and we used the yearly rate of change in CIMT (ΔCIMT) as the primary end point for this study. Serum sCD14 and LPS levels were determined on cryopreserved samples, and these biomarkers were compared between HIV-infected individuals receiving PI-based treatment, HIV-infected individuals receiving non–PI-based treatment, and HIV-uninfected individuals. The effects of HIV infection and PI treatment on levels of these serum biomarkers over time were evaluated. Finally, we examined the association between baseline serum sCD14 and LPS with the progression of atherosclerosis as evaluated by the yearly rate of change in CIMT in each of these groups.

Long-term soy isoflavone supplementation and cognition in women A randomized, controlled trial

Abstract: Objective: To determine the cognitive effects of long-term dietary soy isoflavones in a daily dose comparable to that of traditional Asian diets. Methods: In the double-blind Women9s Isoflavone Soy Health trial, healthy postmenopausal women were randomly allocated to receive daily 25 g of isoflavone-rich soy protein (91 mg of aglycone weight of isoflavones: 52 mg of genistein, 36 mg of daidzein, and 3 mg glycitein) or milk protein−matched placebo. The primary cognitive endpoint compared between groups at 2.5 years was change from baseline on global cognition, a composite of the weighted sum of 14 neuropsychological test score changes. Secondary outcomes compared changes in cognitive factors and individual tests. Results: A total of 350 healthy postmenopausal women aged 45–92 years enrolled in this trial; 313 women with baseline and endpoint cognitive test data were included in intention-to-treat analyses. Adherence in both groups was nearly 90%. There was no significant between-group difference on change from baseline in global cognition (mean standardized improvement of 0.42 in the isoflavone group and 0.31 in the placebo group; mean standardized difference 0.11, 95% confidence interval [CI] −0.13 to 0.35). Secondary analyses indicated greater improvement on a visual memory factor in the isoflavone group (mean standardized difference 0.33, 95% CI 0.06–0.60) but no significant between-group differences on 3 other cognitive factors or individual test scores, and no significant difference within a subgroup of younger postmenopausal women. Conclusion: For healthy postmenopausal women, long-term dietary soy isoflavone supplementation in a dose comparable to that of traditional Asian diets has no effect on global cognition but may improve visual memory. Classification of evidence: This study provides Class I evidence that long-term dietary supplementation with isoflavone-rich soy protein does not improve global cognition of healthy postmenopausal women.

Cytomegalovirus Immunoglobulin G Antibody Is Associated With Subclinical Carotid Artery Disease Among HIV-Infected Women

Abstract: Background. Cytomegalovirus (CMV) infection has been implicated in immune activation and accelerated progression of immunodeficiency from human immunodeficiency virus (HIV) coinfection. We hypothesized that CMV is associated with vascular disease in HIV-infected adults. Methods. In the Women’s Interagency HIV Study, we studied 601 HIV-infected and 90 HIV-uninfected participants. We assessed the association of CMV immunoglobulin G (IgG) level with carotid artery intima-media thickness, carotid artery distensibility, Young’s elastic modulus, and blood pressures. Multivariable models adjusted for age, race/ethnicity, smoking, diabetes, and body mass index. Results. Mean CMV IgG levels were higher in HIV-infected women compared with HIV-uninfected women (P< .01). Among HIV-infected women, higher CMV IgG level was associated with decreased carotid artery distensibility (P< .01) and increased Young’s modulus (P= .02). Higher CMV IgG antibody level was associated with increased prevalence of carotid artery lesions among HIV-infected women who achieved HIV suppression on antiretroviral therapy, but not among viremic or untreated HIV-infected women. Adjustment for Epstein–Barr virus antibody levels and C-reactive protein levels had no effect on the associations between CMV IgG levels and vascular parameters. Conclusions. Cytomegalovirus antibody titers are increased in HIV-infected women and associated with subclinical cardiovascular disease. Host responses to CMV may be abnormal in HIV infection and associated with clinical disease.

The timing hypothesis for coronary heart disease prevention with hormone therapy: past, present and future in perspective

Abstract: Over the past decade, two informative events in primary prevention of coronary heart disease (CHD) have occurred for women's health. The first concerns hormone replacement therapy (HRT) where data have come full circle from presumed harm to consistency with observational data that HRT initiation in close proximity to menopause significantly reduces CHD and overall mortality. The other concerns sex-specific efficacy of CHD primary prevention therapies where lipid-lowering and aspirin therapy have not been conclusively shown to significantly reduce CHD and, more importantly, where there is lack of evidence that either therapy reduces overall mortality in women. Cumulated data support a 'window-of-opportunity' for maximal reduction of CHD and overall mortality and minimization of risks with HRT initiation before 60 years of age and/or within 10 years of menopause and continued for 6 years or more. There is a substantial increase in quality-adjusted life-years over a 5-30-year period in women who initiate HRT in close proximity to menopause, supporting HRT as a highly cost-effective strategy for improving quality-adjusted life. Although primary prevention therapies and HRT contrast in their efficacy to significantly reduce CHD and especially overall mortality in postmenopausal women, the magnitude and types of risks associated with HRT are similar to those associated with other medications commonly used in women's health. The cumulated data highlight the importance of studying the HRT cardioprotective hypothesis in women representative of those from whom the hypothesis was generated.

Potential cardiovascular disease risk markers among HIV-infected women initiating antiretroviral treatment

Abstract: BACKGROUND Inflammation and hemostasis perturbation may be involved in vascular complications of HIV infection. We examined atherogenic biomarkers and subclinical atherosclerosis in HIV-infected adults before and after beginning highly active antiretroviral therapy (HAART). METHODS In the Women's Interagency HIV Study, 127 HIV-infected women studied pre and post HAART were matched to HIV-uninfected controls. Six semiannual measurements of soluble CD14, tumor necrosis factor (TNF) alfa, soluble interleukin (IL) 2 receptor, IL-6, IL-10, monocyte chemoattractant protein 1, D-dimer, and fibrinogen were obtained. Carotid artery intima-media thickness was measured by B-mode ultrasound. RESULTS Relative to HIV-uninfected controls, HAART-naive HIV-infected women had elevated levels of soluble CD14 (1945 vs 1662 ng/mL, Wilcoxon signed rank P < 0.0001), TNF-α (6.3 vs 3.4 pg/mL, P < 0.0001), soluble IL-2 receptor (1587 vs 949 pg/mL, P < 0.0001), IL-10 (3.3 vs 1.9 pg/mL, P < 0.0001), monocyte chemoattractant protein 1 (190 vs 163 pg/mL, P < 0.0001), and D-dimer (0.43 vs 0.31 μg/mL, P < 0.01). Elevated biomarker levels declined after HAART. Although most biomarkers normalized to HIV-uninfected levels, in women on effective HAART, TNF-α levels remained elevated compared with HIV-uninfected women (+0.8 pg/mL, P = 0.0002). Higher post-HAART levels of soluble IL-2 receptor (P = 0.02), IL-6 (P = 0.05), and D-dimer (P = 0.03) were associated with increased carotid artery intima-media thickness. CONCLUSIONS Untreated HIV infection is associated with abnormal hemostasis (eg, D-dimer), proatherogenic (eg, TNF-α), and antiatherogenic (eg, IL-10) inflammatory markers. HAART reduces most inflammatory mediators to HIV-uninfected levels. Increased inflammation and hemostasis are associated with subclinical atherosclerosis in recently treated women. These findings have potential implications for long-term risk of cardiovascular disease in HIV-infected patients, even with effective therapy.

Equol production changes over time in postmenopausal women.

Abstract: Equol (EQ) is produced by intestinal bacteria from the soy isoflavone daidzein (DE) in 30%-60% of the population and is believed to provide benefits from soy intake. A robust EQ status definition is lacking, and it is uncertain whether EQ is formed consistently within an individual and ceases upon oral antibiotic treatment. In a randomized, double-blind, placebo-controlled soy intervention trial with 350 postmenopausal women, DE and EQ were analyzed by liquid chromatography/tandem mass spectrometry at baseline and every 6 months over 2.5 years in overnight urine, spot urine and plasma. Equol production changes and status (remaining an EQ producer or nonproducer or changing towards an EQ producer or nonproducer) were assessed. Equol status was determined most dependably by overnight urine applying as cutoff a ratio of EQ/DE≥0.018 with a DE threshold ≥2 nmol/mg creatinine: the soy and placebo groups had approximately 30% consistent EQ producers during the study, but 14% and 35%, respectively, changed EQ status (mean 1.4-1.7 times), while 27% and 17%, respectively, had antibiotic treatment (P<.01 for inverse association). No significant trend in change of EQ production or status was observed when overnight urine was limited to collections closest to before and after antibiotic treatment. Similarly, antibiotic type or class, duration, dose or time between antibiotic treatment and overnight urine collection showed no consistent influence on EQ production. Equol production can markedly change intraindividually over 2.5 years, and antibiotic treatment impacts it inconsistently. Factors other than antibiotic treatment must be considered as causes for EQ production changes.

Associations Among Vascular Risk Factors, Carotid Atherosclerosis, and Cortical Volume and Thickness in Older Adults

Abstract: Background and Purpose—The purpose of this study was to investigate whether the Framingham Cardiovascular Risk Profile and carotid artery intima-media thickness are associated with cortical volume and thickness. Methods—Consecutive subjects participating in a prospective cohort study of aging and mild cognitive impairment enriched for vascular risk factors for atherosclerosis underwent structural MRI scans at 3-T and 4-T MRI at 3 sites. Freesurfer (Version 5.1) was used to obtain regional measures of neocortical volumes (mm3) and thickness (mm). Multiple linear regression was used to determine the association of Framingham Cardiovascular Risk Profile and carotid artery intima-media thickness with cortical volume and thickness. Results—One hundred fifty-two subjects (82 men) were aged 78 (±7) years, 94 had a clinical dementia rating of 0, 58 had a clinical dementia rating of 0.5, and the mean Mini-Mental State Examination was 28 ± 2. Framingham Cardiovascular Risk Profile score was inversely associated wit...

Childhood Air Pollutant Exposure and Carotid Artery Intima-Media Thickness in Young Adults

Abstract: Background—Exposure to ambient air pollutants increases risk for cardiovascular health outcomes in adults. The contribution of childhood air pollutant exposure to cardiovascular health has not been thoroughly evaluated. Methods and Results—The Testing Responses on Youth study consists of 861 college students recruited from the University of Southern California in 2007 to 2009. Participants attended 1 study visit during which blood pressure, heart rate, and carotid artery intima-media thickness (CIMT) were assessed. Self-administered questionnaires collected information about health and sociodemographic characteristics, and a 12-hour fasting blood sample was drawn for lipid and biomarker analyses. Residential addresses were geocoded and used to assign cumulative air pollutant exposure estimates based on data derived from the U.S. Environmental Protection Agency's Air Quality System database. The associations between CIMT and air pollutants were assessed using linear regression analysis. Mean CIMT was 603 μ...

Vitamin D levels and markers of arterial dysfunction in HIV.

Abstract: HIV-infected patients have low vitamin D levels as well as an increase in cardiovascular (CVD) risk. We examined the relationship between vitamin D and three markers of arterial dysfunction among HIV-infected individuals on stable antiretroviral (ARV) therapy. Levels of 25-hydroxyvitamin D [25(OH)D] were assessed by chemiluminescent immunoassay (DiaSorin) in 100 enrollees into the Hawaii Aging with HIV-Cardiovascular Cohort Study, a cohort of HIV-infected subjects age ≥40 years on stable (≥6 months) ARV therapy. The relationships between 25(OH)D levels and brachial artery flow-mediated dilation (FMD), right common carotid artery intima-media thickness (cIMT), and coronary artery calcium (CAC) were examined. Analytical methods included Pearson's correlations, Kruskal–Wallis tests, relative risks, and linear regression models. The cohort was 86% male and 60% white with a median age of 52 years and CD4 of 510 cells/mm3. The median (Q1, Q3) level of 25(OH)D was 27.9 ng/ml (21.8, 38.3). There were 72 ...

Associations between retinol-binding protein 4 and cardiometabolic risk factors and subclinical atherosclerosis in recently postmenopausal women: cross-sectional analyses from the KEEPS study

Abstract: Background: The published literature regarding the relationships between retinol-binding protein 4 (RBP4) and cardiometabolic risk factors and subclinical atherosclerosis is conflicting, likely due, in part, to limitations of frequently used RBP4 assays. Prior large studies have not utilized the gold-standard western blot analysis of RBP4 levels. Methods: Full-length serum RBP4 levels were measured by western blot in 709 postmenopausal women screened for the Kronos Early Estrogen Prevention Study. Cross-sectional analyses related RBP4 levels to cardiometabolic risk factors, carotid artery intima-media thickness (CIMT), and coronary artery calcification (CAC). Results: The mean age of women was 52.9 (± 2.6) years, and the median RBP4 level was 49.0 (interquartile range 36.9-61.5) μg/mL. Higher RBP4 levels were weakly associated with higher triglycerides (age, race, and smokingadjusted partial Spearman correlation coefficient = 0.10; P=0.01), but were unrelated to blood pressure, cholesterol, C-reactive protein, glucose, insulin, and CIMT levels (all partial Spearman correlation coefficients ≤0.06, P>0.05). Results suggested a curvilinear association between RBP4 levels and CAC, with women in the bottom and upper quartiles of RBP4 having higher odds of CAC (odds ratio [95% confidence interval] 2.10 [1.07-4.09], 2.00 [1.02-3.92], 1.64 [0.82-3.27] for the 1 st ,3 rd , and 4 th RBP4 quartiles vs. the 2 nd quartile). However, a squared RBP4 term in regression modeling was non-significant (P=0.10). Conclusions: In these healthy, recently postmenopausal women, higher RBP4 levels were weakly associated with elevations in triglycerides and with CAC, but not with other risk factors or CIMT. These data using the gold standard of RBP4 methodology only weakly support the possibility that perturbations in RBP4 homeostasis may be an additional risk factor for subclinical coronary atherosclerosis.

Abstract P313: De-Conditioning Adversely Affects Subclinical Atherosclerosis in a Unique Cohort of Spinal Cord Injury

Abstract: Introduction: Physical activity is presumed to improve cardiovascular disease (CVD), of which carotid artery intima-media thickness (CIMT) is a common indicator. Individuals with spinal cord injury (SCI) have limited mobility and therefore an expected increased risk for CVD. The purpose of this study was to determine which CVD risk factors predict CIMT among women with SCI, with the ultimate goal of targeting therapy to improve CVD in this population. Methods: One hundred twenty-two women with SCI who attended an outpatient SCI clinic and met inclusion and exclusion criteria participated in this study. SCI was categorized into 1 of 4 categories: complete tetraplegia, incomplete tetraplegia, complete paraplegia, and incomplete paraplegia. Maximum heart rate and VO2 max were obtained using bicycle ergometry with ventilatory gas exchange and continuous electrocardiogram. Hierarchical regression was used to predict CIMT, with the first block including demographic variables (age, race, smoking status) and the second block including physiologic variables (total cholesterol, heart rate, VO2 max, BMI, fasting serum glucose, hemoglobin A1c, and blood pressure). Results: Similar findings were observed for left and right CIMT, therefore only results from right CIMT are reported. The overall model was significant, F(16,46)=8.53, p=.000. Adjusted R square was .54 for the first block of variables and increased significantly (p=.006) to .66 when the second block of variables was added. Significant predictors at alpha=.05 included age (beta=.51, t=4.79, p=.000) and max/peak heart rate (beta=−.336, t=−2.39, p=.02). At alpha=.10, A1c was significant (beta=.187, t=1.99, p=.053). Conclusions: Although low aerobic conditioning is a purported CVD risk factor, quantitative measurements of such lack a demonstrable relationship with subclinical atherosclerosis (CIMT), perhaps because of its reduced importance relative to other CVD risk factors in a mobile population. We found expected relationships with CIMT in our SCI population (i.e., age), however we also found a quantitative measure of aerobic conditioning (max/peak heart rate) to be associated with CIMT. Our data indicate that SCI individuals may bear a greater CVD burden from cardiac de-conditioning than the general population and that investigation of a cohort with mobility limitation may provide a unique opportunity to study the impact of physical conditioning on CVD risk.