Showing papers by "Howard N. Hodis published in 2013"

Pioglitazone Slows Progression of Atherosclerosis in Prediabetes Independent of Changes in Cardiovascular Risk Factors

Abstract: Objective— To determine whether changes in standard and novel risk factors during the Actos Now for Prevention of Diabetes trial explained the slower rate of carotid intima media thickness (CIMT) progression with pioglitazone treatment in persons with prediabetes. Methods and Results— CIMT was measured in 382 participants at the beginning and up to 3 additional times during follow-up of the Actos Now for Prevention of Diabetes trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly ( P =0.01) lower with pioglitazone treatment (4.76×10 –3 mm/year; 95% CI: 2.39×10 –3 –7.14×10 –3 mm/year) compared with placebo (9.69×10 –3 mm/year; 95% CI: 7.24×10 –3 –12.15×10 –3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA 1c , fasting insulin, Matsuda insulin sensitivity index, adiponectin, and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo ( P Conclusion— Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia, and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.

Cognition, mood, and physiological concentrations of sex hormones in the early and late postmenopause

Abstract: Variations in the hormonal milieu after menopause may influence neural processes concerned with cognition, cognitive aging, and mood, but findings are inconsistent In particular, cognitive effects of estradiol may vary with time since menopause, but this prediction has not been assessed directly using serum hormone concentrations We studied 643 healthy postmenopausal women not using hormone therapy who were recruited into early (<6 y after menopause) and late (10+ y after menopause) groups Women were administered a comprehensive neuropsychological battery and assessed with the Center for Epidemiologic Studies Depression Scale They provided serum for free estradiol, estrone, progesterone, free testosterone, and sex hormone binding globulin measurements Cognitive outcomes were standardized composite measures of verbal episodic memory, executive functions, and global cognition Covariate-adjusted linear regression analyses were conducted for each hormone separately and after adjustment for other hormone levels Endogenous sex steroid levels were unassociated with cognitive composites, but sex hormone binding globulin was positively associated with verbal memory Results for early and late groups did not differ significantly, although progesterone concentrations were significantly positively associated with verbal memory and global cognition in early group women Hormone concentrations were not significantly related to mood Results fail to support the hypothesis that temporal proximity to menopause modifies the relation between endogenous serum levels of estradiol and verbal memory, executive functions, or global cognition Physiological variations in endogenous postmenopausal levels of sex steroid hormones are not substantially related to these aspects of cognition or mood; positive associations for progesterone and sex hormone binding globulin merit additional study

Characterization of Vascular Disease Risk in Postmenopausal Women and Its Association with Cognitive Performance

Abstract: Objectives: While global measures of cardiovascular (CV) risk are used to guide prevention and treatment decisions, these estimates fail to account for the considerable interindividual variability in pre-clinical risk status. This study investigated heterogeneity in CV risk factor profiles and its association with demographic, genetic, and cognitive variables. Methods: A latent profile analysis was applied to data from 727 recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Women were cognitively healthy, within three years of their last menstrual period, and free of current or past CV disease. Education level, apolipoprotein E e4 allele (APOE4), ethnicity, and age were modeled as predictors of latent class membership. The association between class membership, characterizing CV risk profiles, and performance on five cognitive factors was examined. A supervised random forest algorithm with a 10-fold cross-validation estimator was used to test accuracy of CV risk classification. Results: The best-fitting model generated two distinct phenotypic classes of CV risk 62% of women were ‘‘low-risk’’ and 38% ‘‘high-risk’’. Women classified as low-risk outperformed high-risk women on language and mental flexibility tasks (p=0.008) and a global measure of cognition (p=0.029). Women with a college degree or above were more likely to be in the low-risk class (OR=1.595, p=0.044). Older age and a Hispanic ethnicity increased the probability of being at high-risk (OR=1.140, p=0.002; OR=2.622, p=0.012; respectively). The prevalence rate of APOE-e4 was higher in the high-risk class compared with rates in the low-risk class. Conclusion: Among recently menopausal women, significant heterogeneity in CV risk is associated with education level, age, ethnicity, and genetic indicators. The model-based latent classes were also associated with cognitive function. These differences may point to phenotypes for CV disease risk. Evaluating the evolution of phenotypes could in turn clarify preclinical disease, and screening and preventive strategies. ClinicalTrials.gov NCT00154180

Ultrasonographic measures of cardiovascular disease risk in antiretroviral treatment-naive individuals with HIV infection.

Abstract: Cardiovascular disease (CVD) is a leading cause of mortality among individuals with human immunodeficiency virus (HIV) infection [1,2]. Although there is evidence that HIV-infected individuals are at increased CVD risk, most of the studies evaluating the associations between HIV-infection and CVD have been conducted in individuals receiving antiretroviral therapy (ART). Several commonly used ART agents have been associated with increased risk for myocardial infarction and metabolic abnormalities that increase CVD risk, such as dyslipoproteinemia and insulin resistance [3–5]. Given the relatively low CVD risk in most HIV-infected individuals in the United States and the confounding effects of ART on CVD risk, it is unclear if HIV infection or its treatment notably increases CVD risk. Prior to the era of active ART, HIV infection also was associated with premature coronary heart disease and atherogenic dyslipoproteinemia, characterized by hypertriglyceridemia and small low-density lipoproteins, as well as increased serological markers of inflammation [6]. However, studies characterizing CVD risk factors in ART-naive patients tended to be small, included highly selected patients who mostly were of white ethnicity, and no longer reflect the general health and diversity of modern patients considering initiation of ART. Furthermore, subclinical arterial disease has not been well-characterized in HIV-infected patients not on ART. The purpose of this report is to evaluate the associations between traditional CVD risk factors, inflammatory markers, and markers of HIV disease activity with ultrasonographic measures of CVD risk (carotid artery intima-media thickness [CIMT] and brachial artery flow-mediated vasodilation [FMD]), in patients with HIV who are not receiving ART. CIMT and FMD respectively are measures of arterial structure and function that independently predict future CVD events in individuals without known CVD [7–13].

The Timing Hypothesis and Hormone Replacement Therapy: A Paradigm Shift in the Primary Prevention of Coronary Heart Disease in Women. Part 1: Comparison of Therapeutic Efficacy

Abstract: The long-held belief that outcome data from intervention trials in men are generalizable to women has created the framework in which the primary prevention of coronary heart disease (CHD) in women is viewed, but over the past decade, data have accumulated to refute such a supposition of generalizability. These lines of evidence concern the sex-specific efficacy of CHD primary prevention therapies and timing of postmenopausal hormone replacement therapy (HRT) initiation according to age and time since menopause as modifiers of efficacy and risk. Although the standard primary prevention therapies of statins and aspirin reduce CHD in men, neither therapy reduces CHD and, more importantly, mortality in women under primary prevention conditions. Nonetheless, HRT significantly reduces CHD and mortality in primary prevention when it is initiated in women who are younger than 60 or are less than 10 years since menopause. Herein, the efficacy of the commonly used therapies for the primary prevention of CHD in women, statins, aspirin, and postmenopausal HRT is discussed. The comparative risks of these therapies will be discussed in Part 2 of this series.

Effect of isoflavone soy protein supplementation on endometrial thickness, hyperplasia, and endometrial cancer risk in postmenopausal women: a randomized controlled trial.

Abstract: Objective To determine whether long-term isoflavone soy protein (ISP) supplementation affects endometrial thickness and rates of endometrial hyperplasia and cancer in postmenopausal women.

The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. Part 2: comparative risks.

Abstract: A major misperception concerning postmenopausal hormone replacement therapy (HRT) is that the associated risks are large in magnitude and unique to HRT, but over the past 10 years, sufficient data have accumulated so that the magnitude and perspective of risks associated with the primary coronary heart disease prevention therapies of statins, aspirin, and postmenopausal HRT have become more fully defined. Review of randomized controlled trials indicates that the risks of primary prevention therapies and other medications commonly used in women's health are of similar type and magnitude, with the majority of these risks categorized as rare to infrequent (<1 event per 100 treated women). Evidence-based data show that the risks of postmenopausal HRT are predominantly rare (<1 event per 1,000 treated women) and certainly no greater than other commonly used medications in women's health, including statins and aspirin. These risks, including breast cancer, stroke, and venous thromboembolism are common across medications and are rare, and even rarer when HRT is initiated in women younger than 60 or who are less than 10 years since menopause. In Part 1 of this series, the sex-specificity of statins and aspirin and timing of initiation of HRT as modifiers of efficacy in women were reviewed. Herein, the comparative risks of primary prevention therapies in women are discussed.

Gonadotropin and sex steroid levels in HIV-infected premenopausal women and their association with subclinical atherosclerosis in HIV-infected and -uninfected women in the women's interagency HIV study (WIHS).

Abstract: Background: HIV-infected women may experience prolonged amenorrhea, suggesting altered gonadotropin and sex hormone levels. However, the impact of these endocrine disruptions on atherosclerosis has not been evaluated in women living with, or at risk for, HIV infection. We investigated the association of sex hormone and gonadotropin concentrations with subclinical atherosclerosis in HIV-infected and -uninfected premenopausal women in the Women's Interagency HIV Study. Methods: Using B-mode ultrasound, the common carotid artery intima-media thickness and distensibility were measured once. Cycle-specific FSH, total estradiol (E2), and inhibin-B concentrations were measured in 584 (414 HIV infected, 170 HIV uninfected) women. Random concentrations of total T, dehydroepiandrosterone sulphate, and SHBG were measured in 1094 (771 HIV infected, 323 HIV uninfected) women. The endocrine analytes were measured at or before the ultrasound visit. Sex hormones, FSH, and SHBG concentrations were compared between HIV-inf...

Genetic polymorphisms associated with carotid artery intima-media thickness and coronary artery calcification in women of the Kronos Early Estrogen Prevention Study.

Abstract: Menopausal hormone treatment (MHT) may limit progression of cardiovascular disease (CVD) but poses a thrombosis risk. To test targeted candidate gene variation for association with subclinical CVD ...

Dysfunctional HDL and progression of atherosclerosis in HIV-1-infected and -uninfected adults

Abstract: Background: HDL function rather than absolute level may be a more accurate indicator for risk of developing atherosclerosis. Dysfunctional HDL has increased redox activity and reduced antioxidant properties, but it is unknown whether abnormal HDL function is associated with progression of atherosclerosis in HIV-1-infected subjects. Findings: We retrospectively measured serum HDL function in 91 subjects from a prospective 3-year study of carotid artery intima-media thickness (CIMT), which enrolled triads of risk factor-matched persons that were HIV-1-uninfected (n=36) or HIV-1+ with (n=29) or without (n=26) protease inhibitor (PI)-based therapy for ≥ 2 years. HDL function was assessed using a biochemical assay that measures the oxidation of dihydrorhodamine 123 (DHR oxidation rate, DOR), in which higher DOR readout corresponds to dysfunctional HDL phenotype. There were no significant associations between DOR and HIV-1 infection. In univariate analysis of 55 HIV-1-infected subjects, greater waist circumference and lower serum HDL were significantly associated with higher baseline levels of DOR (p=0.01). These subjects had significant increases in levels of DOR over time (3 years) that were associated with white race (p=0.03), higher nadir CD4 count (p 0.1) (DOR), were significantly associated (p=0.02) with progression of CIMT. Conclusion: In a small matched cohort study of HIV-1-infected subjects who had a low cardiovascular risk profile, HDL function changed over time and was independently associated with anthropometric parameters of obesity but not with progression of CIMT.

Perturbations of circulating levels of RANKL-osteoprotegerin axis in relation to lipids and progression of atherosclerosis in HIV-infected and -uninfected adults: ACTG NWCS 332/A5078 Study.

Abstract: The receptor activator of the NF-κB ligand (RANKL)-osteoprotegerin (OPG) axis has been shown to play a role in the inflammatory process of atherogenesis and may be regulated by changes in levels of cholesterol. However, the interplay between HIV-1 infection, lipids, the RANKL-OPG axis, and atherosclerosis is poorly defined. Serum RANKL, OPG, and RANKL/OPG ratio were retrospectively assessed for 91 subjects from a 3-year study of carotid artery intima-media thickness (CIMT), which enrolled triads of risk factor-matched persons that were HIV-1 uninfected (n=36) or HIV-1+ with (n=29) or without (n=26) continuous protease inhibitor (PI)-based therapy for ≥2 years. Associations of serum RANKL, OPG, and RANKL/OPG ratio to the primary outcomes of levels of circulating lipids and atherosclerosis progression were determined using multivariate regression models. Serum RANKL and RANKL/OPG ratio were significantly lower in HIV-infected versus HIV-uninfected subjects (p<0.01). Multivariate models for HIV-1+ s...

Ectopic fat and adipokines in metabolically benign overweight/obese women: The kronos early estrogen prevention study

Abstract: Objective It is unclear why despite a comparable cardiometabolic risk profile, “metabolically benign” overweight/obese individuals show an elevated risk of cardiovascular disease compared to normal weight individuals. Design and Methods In cross-sectional analyses, we compared levels of ectopic fat (epicardial, pericardial, and hepatic fat) and adipokines (leptin, soluble leptin receptor, and high molecular weight [HMW] adiponectin) among metabolically benign (MBO) and at-risk overweight/obese (ARO), and metabolically benign normal weight (MBNW) women, screened for the Kronos Early Estrogen Prevention Study. We defined “metabolically benign” with ≤ 1, and “at-risk” with ≥2 components of the metabolic syndrome. Results Compared to MBO women, ARO women had significantly elevated odds of being in the top tertile of epicardial fat (OR: 1.76, 95% CI: 1.04-2.99), hepatic fat (OR: 1.90, 95% CI:1.12-3.24) and leptin (OR: 2.15, 95% CI: 1.23-3.76), and the bottom tertile of HMW-adiponectin (OR: 2.90, 95% CI: 1.62-5.19). Compared to MBNW women, MBO women had significantly higher odds of being in the top tertile of epicardial fat (OR: 5.17, 95% CI: 3.22-8.29), pericardial fat (OR: 9.27, 95% CI: 5.52-15.56) and hepatic fat (OR: 2.72, 95% CI: 1.77-4.19) and the bottom tertile of HMW adiponectin levels (OR: 2.51, 95% CI: 1.60-3.94). Conclusions Levels of ectopic fat and the adverse adipokine profile increase on a continuum of BMI, suggesting that the metabolically benign phenotype may be a transient state.

Treatment-related changes in serum lipids and inflammation: clinical relevance remains unclear. Analyses from the Women's Interagency HIV study.

Abstract: Among 127 HIV-infected women, the magnitude of HDLc increases after HAART initiation predicted the magnitude of concurrent decreases in inflammation biomarkers. After HAART initiation, changes in LDLc and inflammation were unrelated. In the same population, predicted risk of coronary heart disease based upon levels of standard clinical risk factors was similar before and after HAART treatment. Thus, it remains unknown whether short-term treatment-related changes in standard risk factors may appreciably change risk of CVD.

Response to Letter Regarding Article, “Childhood Air Pollutant Exposure and Carotid Artery Intima–Media Thickness in Young Adults”

Abstract: We thank Wang et al for their commentary regarding our recently published article relating childhood O3 exposure to carotid intima–media thickness (CIMT) in adulthood.1 The authors suggest that adjustment for additional clinical information may strengthen our conclusion regarding O3 as a novel predictor of CIMT. Specifically, they suggest we include data on childhood dietary patterns, adolescent blood pressure (BP), and glucose tolerance testing. Although we agree that these data are relevant clinical parameters when assessing cardiovascular disease risk and atherosclerosis, it is unlikely that they will act as confounders of our observed association with O3 if they are not related to exposure. First, the evaluation of elementary and lifetime diet, as suggested by the authors, is a daunting task, and one highly susceptible to recall bias. Most food frequency questionnaires are designed to address recall only …