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1.  Body Composition and Metabolic Changes in HIV-Infected Patients 
The Journal of Infectious Diseases  2012;205(Suppl 3):S383-S390.
As antiretroviral therapy has decreased human immunodeficiency virus (HIV)–associated mortality, cardiometabolic abnormalities have become increasingly apparent in HIV-infected individuals. Many patients treated for HIV infection exhibit body composition changes, including peripheral fat atrophy and visceral lipohypertrophy. In addition, HIV-infected individuals demonstrate a higher prevalence of dyslipidemia, insulin resistance and diabetes, and cardiovascular risk, compared with the general population. Although antiretroviral therapy appears to contribute to some of the cardiometabolic abnormalities in HIV infection, HIV itself, immunologic factors, and lifestyle factors are also important mediators of cardiovascular risk. Treatment strategies for body composition changes and cardiometabolic abnormalities in HIV infection include lifestyle modification, lipid-lowering agents, insulin sensitizers, and treatments to reverse endocrine abnormalities in HIV, including growth hormone–releasing hormone. None of these strategies has comprehensively addressed the abnormalities experienced by this population, however, and further research is needed into combined strategies to improve body composition and ameliorate cardiovascular risk.
PMCID: PMC3349298  PMID: 22577212
2.  Circulating Branched-chain Amino Acid Concentrations Are Associated with Obesity and Future Insulin Resistance in Children and Adolescents 
Pediatric obesity  2012;8(1):52-61.
Branched-chain amino acid (BCAA) concentrations are elevated in response to overnutrition, and can affect both insulin sensitivity and secretion. Alterations in their metabolism may therefore play a role in the early pathogenesis of type 2 diabetes in overweight children.
To determine whether pediatric obesity is associated with elevations in fasting circulating concentrations of branched-chain amino acids (isoleucine, leucine, and valine), and whether these elevations predict future insulin resistance.
Research Design and Methods
Sixty-nine healthy subjects, ages 8 to18 years, were enrolled as a cross-sectional cohort. A subset who were pre- or early-pubertal, ages 8 to 13 years, were enrolled in a prospective longitudinal cohort for 18 months (n=17 with complete data).
Elevations in the concentrations of BCAA’s were significantly associated with BMI Z-score (Spearman’s Rho 0.27, p=0.03) in the cross-sectional cohort. In the subset of subjects followed longitudinally, baseline BCAA concentrations were positively associated with HOMA-IR measured 18 months later after controlling for baseline clinical factors including BMI Z-score, sex, and pubertal stage (p=0.046).
Elevations in the concentrations of circulating branched-chain amino acids are significantly associated with obesity in children and adolescents, and may independently predict future insulin resistance.
PMCID: PMC3519972  PMID: 22961720
branched-chain amino acids; insulin resistance; pediatric obesity; metabolomics; type 2 diabetes
3.  Associations of Cardiovascular Risk Factors with Two Surrogate Markers of Subclinical Atherosclerosis: Endothelial Function and Carotid Intima Media Thickness 
Atherosclerosis  2011;217(2):437-440.
Endothelial function and carotid intima media thickness (cIMT) were investigated in a cohort of 54 healthy adults without known cardiovascular disease.
Pulse wave amplitude was determined with peripheral arterial tonometry (PAT) to obtain the reactive hyperemia (RH)-PAT ratio. Ultrasound was used to determine cIMT.
cIMT and RH-PAT were significantly associated (rho = −0.35, P = 0.02) in univariate analysis. RH-PAT was significantly associated with age, triglycerides, fasting glucose, HDL, WHR, waist circumference and VAT. cIMT was associated with age, smoking history, fasting glucose, systolic blood pressure, diastolic blood pressure and LDL. In multivariate regression analyses, triglyceride level (P = 0.04) remained a significant determinant of RH-PAT whereas systolic blood pressure (P = 0.02) and smoking pack-year history (P = 0.046) were significant determinants of cIMT.
Determinants of cIMT and RH-PAT were different, dominated by triglyceride and abdominal adiposity measures for RH-PAT but traditional risk factors including blood pressure, glucose, smoking and LDL for cIMT.
PMCID: PMC3146552  PMID: 21570076
Endothelial function; carotid intima media thickness; atherosclerosis
4.  Receptor activator of nuclear factor kappa β ligand (RANKL) and its relationship to coronary atherosclerosis in HIV patients 
HIV-infected individuals have an increased prevalence of coronary artery disease (CAD). Receptor activator of nuclear factor kappa β ligand (RANKL) and osteoprotegerin (OPG) have been postulated as mediators of vascular calcification. 78 HIV-infected men and 32 healthy controls without history of CAD were prospectively recruited to undergo cardiac computed tomography (CT) and CT angiography to assess coronary artery calcium and plaque burden. sRANKL was lower in HIV-infected individuals than controls (2.52 [1.08, 3.98] vs. 3.33 [2.44, 4.64] pg/ml, P=0.01, median [IQR] respectively). sRANKL was negatively associated with the number of coronary segments with plaque (Spearman ρ=−0.41, P<0.001) and Agatston calcium score (ρ=−0.30, P<0.01) in HIV-infected individuals even after adjusting for traditional cardiovascular risk factors.
PMCID: PMC3766949  PMID: 22842843
atherosclerosis; receptor activator of nuclear factor kappa β ligand; osteoprotegerin; coronary artery disease; HIV
5.  Relationship Between Neck Circumference and Cardiometabolic Parameters in HIV-Infected and non–HIV-Infected Adults 
Diabetes Care  2011;34(4):1026-1031.
Upper body fat is associated with increased cardiometabolic risk. More recently, neck circumference (NC) and/or neck fat have been associated with hyperlipidemia, impaired glucose homeostasis, and hypertension. The objective of this study was to determine whether this relationship is evident in HIV-infected individuals, who often exhibit changes in relative fat distribution, and to determine whether NC is independently associated with carotid intima-media thickness (cIMT) in HIV and non–HIV-infected patients.
Body composition, including anthropometrics, visceral adipose tissue assessment by CT, and metabolic parameters, including lipids, cIMT, and oral glucose tolerance test, were measured in 174 men and women with HIV infection and 154 non–HIV-infected subjects. NC was measured in triplicate inferior to the laryngeal prominence.
In univariate analysis, NC was significantly and positively related to blood pressure, hemoglobin A1c, glucose, and insulin and significantly and negatively related to HDL cholesterol in HIV-infected individuals and HIV-negative control subjects. NC was significantly associated with cIMT in univariate regression analysis among HIV-infected (r = 0.21, P = 0.006) and non–HIV-infected (r = 0.31, P = 0.0001) patients. This relationship remained significant among non–HIV-infected patients (R2 = 0.45, P < 0.001) but not HIV-infected patients in multivariate modeling controlling for age, sex, race, smoking hypertension, glucose, and lipids.
Among both HIV and non–HIV-infected patients, increased NC is strongly associated with decreased HDL and impaired glucose homeostasis. Among non–HIV-infected subjects, NC also predicts increased cIMT when controlling for traditional risk factors.
PMCID: PMC3064017  PMID: 21378212
7.  Effects of Etanercept in Patients With the Metabolic Syndrome 
Archives of internal medicine  2006;166(8):902-908.
Adipose-derived cytokines, including tumor necrosis factor α, may contribute to the inflammation that occurs in the metabolic syndrome. We investigated the effects of inhibition of tumor necrosis factor α with etanercept in patients with the metabolic syndrome.
Fifty-six subjects with the metabolic syndrome were randomized to administration of either etanercept or identical placebo, 50 mg subcutaneously once a week for 4 weeks. The C-reactive protein level was the primary end point. Effects on other inflammatory markers (including fibrinogen, interleukin 6, and adiponectin), insulin sensitivity, lipid levels, and body composition were also determined.
Baseline characteristics were similar between the groups. Two subjects dropped out of each group, and etanercept was well tolerated throughout the study. The C-reactive protein levels decreased significantly in the treated compared with the placebo group (−2.4 ± 0.4 vs 0.5 ± 0.7 mg/L; P<.001). Adiponectin levels rose significantly in the etanercept group compared with the placebo group (0.8 ± 0.4 vs −0.3 ± 0.3 µg/mL; P=.03). Fibrinogen levels decreased (−68 ± 16 vs −2 ± 31 mg/dL [−2.0 ± 0.47 vs −0.06 ± 0.91 µmol/L]; P=.04) and interleukin 6 levels tended to decrease (−1.2 ± 0.8 vs 0.5 ± 0.5 ng/L; P=.07) in the etanercept-treated subjects compared with placebo, respectively. No changes occurred in body composition parameters or insulin sensitivity, but high-density lipoprotein levels tended to decrease in the etanercept group (−1 ± 1 vs 2 ± 1 mg/dL [−0.03 ± 0.03 vs 0.05 ± 0.03 mmol/L]; P=.06) compared with the placebo group.
Etanercept reduces C-reactive protein levels and tends to improve other inflammatory cardiovascular risk indexes in patients with the metabolic syndrome. Etanercept may interrupt the inflammatory cascade that occurs with abdominal obesity. Further, longer-term studies are needed to determine the effects of tumor necrosis factor α inhibition on cardiovascular disease in patients with the metabolic syndrome.
PMCID: PMC3196549  PMID: 16636217
8.  Relationship between Monocyte/Macrophage Activation Marker Soluble CD163 and Insulin Resistance in Obese and Normal-Weight Subjects 
Clinical endocrinology  2012;77(3):385-390.
The relationship of monocyte/macrophage activation to insulin resistance in obesity is unknown.
To investigate a marker of macrophage activation, soluble CD163 (sCD163), in relationship to insulin resistance and metabolic parameters in obese and normal-weight subjects.
Design and Participants
95 healthy subjects (65 obese and 30 normal-weight) were studied. Plasma concentrations of sCD163 were assessed, as well as markers of glucose homeostasis, anthropometrics, cytokines, and adipokines. The relationships between sCD163 and these parameters were investigated, and multiple regression modeling assessing the contribution of sCD163 to insulin resistance (HOMA-IR) was performed.
sCD163 was significantly increased in obese subjects compared to normal-weight controls [974 (657, 1272) ng/ml vs. 599 (423, 892) ng/ml, median (IQR); p < 0.0001]. sCD163 was strongly associated with HOMA-IR (Spearman's rho = 0.37, p = 0.0003) and other metabolic parameters. In multiple regression modeling for log HOMA-IR, sCD163 remained significantly associated (p = 0.005) controlling for known mediators of insulin resistance including age, gender, visceral adiposity, and inflammatory markers (model R2 = 0.54, p < 0.0001). Additional nested multiple regression models for log HOMA-IR showed that sCD163 added more than other adipokines and inflammatory markers to the prediction of HOMA-IR.
Monocyte/macrophage activation, as reflected by sCD163 levels, is strongly associated with HOMA-IR in normal-weight and obese subjects after controlling for known mediators of insulin resistance. Moreover, sCD163 adds to standard risk markers for predicting insulin resistance. These data suggest that monocyte/macrophage activation may be an important determinant of insulin resistance in obesity.
PMCID: PMC3660104  PMID: 22098563
sCD163; monocyte/macrophage activation; insulin resistance
9.  Effects of TNF-alpha antagonism on E-selectin in obese subjects with metabolic dysregulation 
Clinical endocrinology  2010;73(1):48-54.
Endothelial adhesion molecules like E-selectin play an important role in leukocyte recruitment and development of atherosclerotic plaque. E-selectin is increased in obesity, yet little is known regarding the specific factors contributing to elevated E-selectin in obesity and whether tumor necrosis factor alpha (TNF-alpha) increases E-selectin in vivo in this population. The objectives of this study were to: 1) determine the body composition, metabolic and inflammatory factors associated with increased E-selectin, and 2) determine the role of TNF-alpha in the physiological regulation of E-selectin by antagonism of TNF-alpha with etanercept among obese subjects.
E-selectin levels, body composition, metabolic parameters and inflammatory cytokines were assessed in 51 obese subjects and 37 non-obese healthy controls. Obese subjects were randomized to etanercept 50 mg weekly or placebo for four weeks. Changes in E-selectin were compared between treatment groups.
Obese subjects had higher E-selectin than non-obese controls (47.4 [32.7 – 58.8] vs. 27.2 [20.3 – 42.1] ng/mL, obese vs. non-obese, p<0.0001). E-selectin was significantly associated with multiple body composition measures and metabolic parameters, along with specific measures of TNF-alpha activation, including soluble tumor necrosis factor receptors 1 (p=0.03) and 2 (p=0.02). In multivariate modeling, visceral adipose tissue, but not other measures of body composition, remained significantly associated with E-selectin. Among obese subjects, treatment with etanercept significantly decreased E-selectin (−5.7 ± 8.7 vs. 0.5 ± 6.0 ng/mL, etanercept vs. placebo, p=0.005).
E-selectin is increased in obesity, in relationship to increased visceral adiposity and markers of TNF-alpha activation. TNF-alpha antagonism with etanercept reduces E-selectin in obese subjects, providing evidence that the systemic circulatory release of E-selectin is regulated at least in part by TNF-alpha in obesity.
PMCID: PMC2891313  PMID: 19878508
obesity; inflammation; tumor necrosis factor-alpha; E-selectin
10.  Comparison of Ischemic Stroke Incidence in HIV-Infected and Non-HIV-Infected Patients in a U.S. Health Care System 
Cardiovascular disease is increased among HIV-infected patients, but little is known regarding ischemic stroke rates. We sought to compare stroke rates and determine stroke risk factors in HIV versus non-HIV patients.
An HIV cohort and matched non-HIV comparator cohort seen between 1996 and 2009 were identified from a Boston health care system. The primary endpoint was ischemic stroke, defined using International Classification of Diseases (ICD) codes. Unadjusted stroke incidence rates were calculated. Cox proportional hazards modeling was used to determine adjusted hazard ratios (HR).
The incidence rate of ischemic stroke was 5.27 per 1000 person years (PY) in HIV compared with 3.75 in non-HIV patients, with an unadjusted HR of 1.40 (95% confidence interval [CI] 1.17-1.69, P<0.001). HIV remained an independent predictor of stroke after controlling for demographics and stroke risk factors (1.21, 1.01-1.46, P=0.043). The relative increase in stroke rates (HIV vs. non-HIV) was significantly higher in younger HIV patients (incidence rate ratio 4.42, 95% CI 1.56-11.09 age 18-29; 2.96, 1.69-4.96 age 30-39; 1.53, 1.06-2.17 age 40-49), and in women (HR 2.16 [1.53-3.04] for women vs. 1.18 [0.95-1.47] for men). Among HIV patients, increased HIV RNA (HR 1.10, 95% CI 1.04-1.17, P=0.001) was associated with an increased risk of stroke.
Stroke rates were increased among HIV-infected patients, independent of common stroke risk factors, particularly among young patients and women.
PMCID: PMC3670086  PMID: 22580566
HIV; stroke; cerebrovascular; cardiovascular; vascular risk factors
11.  Arterial inflammation in patients with HIV 
Cardiovascular disease is increased in HIV patients, but the specific mechanisms are unknown.
To assess arterial wall inflammation in HIV, using 18fluorine-2-deoxy-D-glucose Positron Emission Tomography (18FDG-PET), in relationship to traditional and non-traditional risk markers, including sCD163, a marker of macrophage activation.
Design, Setting, and Participants
81 participants were investigated in a cross-sectional study from November 2009 to July 2011. 27 HIV-infected participants without known cardiac disease underwent cardiac 18FDG-PET and coronary CT imaging for coronary calcium (CAC). Two separate non-HIV control groups were compared. One control group (n=27) was matched to the HIV group for age, gender and Framingham Risk Score (FRS) and had no known atherosclerotic disease (FRS-Matched Controls). The second control group (n=27) was matched on gender and selected based on the presence of known atherosclerotic disease (Atherosclerotic Controls).
Main Outcome Measure
Arterial inflammation was prospectively determined as the ratio of FDG uptake in the arterial wall of the ascending aorta/blood background, as the target to background ratio (TBR).
HIV participants demonstrated well-controlled HIV disease (CD4 641±288 cells/mm3, HIV RNA <48 [<48, <48] copies/mL). All were receiving ART (duration 12±4 yrs). The mean Framingham Risk Score (FRS) was low in both HIV and FRS-Matched Controls (6.4 (4.8–8.0) vs. 6.6 (4.9–8.2), P=0.87). Arterial inflammation in the aorta (Aortic TBR) was higher in the HIV vs. FRS-Matched Control Participants (2.23 (2.07–2.40) vs. 1.89 (1.80–1.97), P<0.001), but was similar compared to Atherosclerotic Controls (2.23 (2.07–2.40) vs. 2.13 (2.03–2.23), P=0.29). Aortic TBR remained significantly higher in the HIV group vs. the FRS-Matched Controls after adjusting for traditional cardiovascular risk factors (P=0.002) and in stratified analyses among participants with undetectable viral load, zero calcium, FRS<10, and LDL< 100 mg/dL (2.59 mmol/L) (all P<0.01). Aortic TBR was associated with sCD163 (P=0.04) but not with CRP (P=0.65) or D-Dimer (P=0.08) among HIV-infected patients.
Persons infected with HIV, compared to non-infected controls with similar cardiac risk factors, had signs of increased arterial inflammation which was associated with circulating markers of macrophage activation.
PMCID: PMC3724172  PMID: 22820791
12.  Effects of Aging and Smoking on Carotid Intima Media Thickness in HIV-infection 
AIDS (London, England)  2013;27(1):49-57.
To investigate the effects of aging and smoking on carotid intima-media thickness (cIMT) among patients with and without HIV.
Data from a community sample of HIV-infected and HIV-uninfected participants were analyzed. Carotid intima-media thickness was measured via carotid ultrasound and smoking history was obtained via patient interview.
Data on 166male and female participants with stable HIV-infection and 152 healthy HIV-uninfected participants were analyzed. Among the HIV-infected and HIV-uninfected participants, a significant association was observed between age and cIMT [r=0.51, P<0.0001 (HIV), r=0.39, P<0.0001, (non-HIV)], and between smoking burden and cIMT [r=0.42, P<0.0001 (HIV), r=0.24, P=0.003 (non-HIV)]. In multivariate regression modeling among all participants (HIV and non-HIV), a significant three-way interaction was observed between age, smoking burden, and HIV status with respect to cIMT (P<0.010), controlling for gender, race and traditional cardiovascular disease (CVD) risk factors, such that increased cIMT was associated with increased smoking burden and age to a greater degree among HIV-infected vs. HIV-uninfected participants. Among HIV-infected participants a significant interaction between smoking burden and age with respect to cIMT was seen (P=0.027), controlling for race, gender, CVD risk factors, immunological function and antiretroviral therapy use.
A significant interaction between HIV, age and smoking on cIMT was observed, suggesting that HIV-infection modifies the relationship of age and smoking on cIMT in this population. These findings emphasize the need to encourage smoking cessation in this population, due to its deleterious effect on subclinical atherosclerosis in older HIV-infected patients.
PMCID: PMC3690796  PMID: 22874518
HIV; Aging; Cardiovascular Diseases; Smoking
13.  Effects of Tesamorelin on Inflammatory Markers in HIV Patients with Excess Abdominal Fat: Relationship with Visceral Adipose Reduction 
AIDS (London, England)  2011;25(10):1281-1288.
To report the effects of tesamorelin, a growth hormone releasing hormone analogue, on inflammatory and fibrinolytic markers and to relate these effects to changes in visceral adipose tissue (VAT).
Design and Methods
410 HIV-infected patients with abdominal adiposity were randomized to 2 mg tesamorelin (n=273) or placebo (n=137) subcutaneously daily for 26 weeks. Circulating PAI-1 antigen, tPA antigen, CRP, and adiponectin were assessed.
At baseline, VAT was significantly associated with PAI-1 antigen (ρ = 0.36, P < 0.001), tPA antigen (ρ = 0.29, P < 0.001), CRP (ρ = 0.18, P < 0.001), and adiponectin (ρ = −0.22, P < 0.001). Treatment with tesamorelin resulted in a significant decrease from baseline in tPA antigen (−2.2±2.5 vs. −1.6±2.9 ng/mL, tesamorelin vs. placebo, P < 0.05). Changes in PAI-1 antigen were not significant in the tesamorelin group compared to placebo. Among patients receiving tesamorelin, changes in inflammatory markers were associated with change in VAT (PAI-1 antigen: ρ = 0.16, P = 0.02; tPA antigen: ρ = 0.16, P = 0.02; adiponectin: ρ = −0.27, P < 0.001), and these associations remained significant when controlling for changes in IGF-1.
In HIV patients with abdominal adiposity, tesamorelin may have a modest beneficial effect on adiponectin and fibrinolytic markers in association with changes in VAT. Further studies are needed to determine the clinical significance of these changes. These data further highlight the deleterious role of excessive VAT and the utility of strategies to improve VAT in this population.
PMCID: PMC3673013  PMID: 21516030
tesamorelin; GHRH; HIV; intra-abdominal fat; adiponectin; tissue plasminogen activator; plasminogen activator inhibitor 1
14.  Reduction in Visceral Adiposity Is Associated With an Improved Metabolic Profile in HIV-Infected Patients Receiving Tesamorelin 
Following treatment with the growth hormone–releasing hormone analogue tesamorelin, patients who experience reduced visceral adiposity have improved lipid levels and relatively unchanged glucose homeostasis, whereas patients who do not experience decreased visceral fat have worsened glucose homeostasis and unchanged lipid levels.
Background. Tesamorelin, a growth hormone–releasing hormone analogue, decreases visceral adipose tissue (VAT) by 15%–20% over 6–12 months in individuals with human immunodeficiency virus (HIV)–associated abdominal adiposity, but it is unknown whether VAT reduction is directly associated with endocrine and metabolic changes.
Methods. In 2 phase III, randomized, double-blind studies, men and women with HIV-associated abdominal fat accumulation were randomly assigned (ratio, 2:1) to receive tesamorelin or placebo for 26 weeks. At week 26, patients initially receiving tesamorelin were randomly assigned to continue receiving tesamorelin or to receive placebo for an additional 26 weeks. In per-protocol analysis of 402 subjects initially randomly assigned to receive tesamorelin, those with ≥8% reduction in VAT were defined a priori as responders per the statistical analysis plan. Post hoc analyses were performed to assess differences between responders and nonresponders.
Results. Compared with tesamorelin nonresponders, responders experienced greater mean (±SD) reduction in triglyceride levels (26 weeks: −0.6 ± 1.7 mmol/L vs −0.1 ± 1.2 mmol/L [P = .005]; 52 weeks: −0.8 ± 1.8 mmol/L vs 0.0 ± 1.1 mmol/L [P = .003]) and attenuated changes in fasting glucose levels (26 weeks: 1 ± 16 mg/dL vs 5 ± 14 mg/dL [P = .01]; 52 weeks: −1 ± 14 mg/dL vs 8 ± 17 mg/dL [P < .001]), hemoglobin A1c levels (26 weeks: 0.1 ± 0.3% vs 0.3 ± 0.4% [P < .001]; 52 weeks: 0.0 ± 0.3% vs 0.2 ± 0.5% [P = .003]), and other parameters of glucose homeostasis. Similar patterns were seen for adiponectin levels, with significant improvement in responders vs nonresponders. Changes in lipid levels and glucose homeostasis were significantly associated with percentage change in VAT.
Conclusions. In contrast to nonresponders, HIV-infected patients receiving tesamorelin with ≥8% reduction in VAT have significantly improved triglyceride levels, adiponectin levels, and preservation of glucose homeostasis over 52 weeks of treatment. Registration. NCT00123253, NCT00435136, NCT00608023.
PMCID: PMC3348954  PMID: 22495074
16.  Increased Epicardial Adipose Tissue Volume in HIV-Infected Men and Relationships to Body Composition and Metabolic Parameters 
AIDS (London, England)  2010;24(13):2127-2130.
Epicardial fat accumulation may have important clinical consequences, yet little is known regarding this depot in HIV patients. We compared epicardial fat volume in 78 HIV-infected men and 32 HIV-negative controls. Epicardial fat volume was higher in HIV than control subjects (p=0.04). In HIV patients, epicardial fat volume was strongly associated with visceral adipose tissue area (VAT)(ρ = 0.76, p<0.0001), fasting glucose (ρ = 0.41, p=0.001) and insulin (ρ = 0.44, p=0.0003). Relationships with glucose and insulin remained significant controlling for age, race, BMI, adiponectin, VAT, and antiretroviral therapy. Epicardial fat may be an important fat depot in HIV-infected patients.
PMCID: PMC3620604  PMID: 20588167
HIV; epicardial fat; visceral fat; glucose; atherosclerosis
17.  Increased Skeletal Muscle Phosphocreatine Recovery after Sub-maximal Exercise is Associated with Increased Carotid Intima-Media Thickness 
Atherosclerosis  2010;215(1):214-217.
The association between skeletal muscle mitochondrial function and CVD risk in healthy subjects is unknown.
Forty subjects were evaluated for CVD risk with lipid profile, oral glucose tolerance test and measurement of carotid intima-media thickness (cIMT). Skeletal muscle mitochondrial function was determined by phosphocreatine recovery after sub-maximal exercise with 31Phosphorous-MRS and represented as τPCr.
τPCr was positively associated with age (r=+0.41; P=0.009) and cIMT (r=+0.50; P=0.001) on univariate analyses. In multivariate regression analysis controlling for age, the association between τPCr and cIMT remained significant (β=0.003; P=0.03). This association remained significant after controlling for traditional risk factors for CVD including age, gender, tobacco use, BMI, blood pressure, cholesterol and fasting glucose in a combined model (β=0.003; P=0.04; R2 for overall model: 0.53; P=0.008 for overall model).
These data suggest a novel association between skeletal muscle τPCr and increased cIMT, independent of age or traditional CVD risk factors.
PMCID: PMC3057276  PMID: 21185022
MRS; spectroscopy; mitochondria; cardiovascular risk
18.  Association of Immunologic and Virologic Factors with Myocardial Infarction Rates in a U.S. Health Care System 
The effects of immunologic and virologic factors on AMI rates in HIV patients are unclear.
HIV-infected patients in a U.S. health care system were assessed for AMI.
Of 6,517 HIV patients, 273 (4.2%) had an AMI. In a model adjusting for cardiovascular risk factors, antiretroviral medications, and HIV parameters, CD4 count less than 200/mm3 (OR 1.74, 95% CI 1.07-2.81, P=0.02) predicted AMI. Increased HIV viral load was associated with AMI accounting for CVD risk factors and antiretroviral medications but was not significant when CD4 count was considered.
Immunologic control appears to be the most important HIV-related factor associated with AMI.
PMCID: PMC3036774  PMID: 20827215
HIV; myocardial infarction; immune function; cardiovascular risk factors
19.  The relationship between reduced testosterone, stimulated growth hormone secretion and increased carotid intima-media thickness in obese men 
Clinical endocrinology  2010;73(5):622-629.
Obesity is associated with reduced testosterone and growth hormone (GH). However, the interrelationship between these axes and their independent contributions to cardiovascular risk is unknown. The objectives of this study were to determine (1) the association between testosterone and GH in obesity, (2) whether excess adiposity mediates this association and (3) the relative contribution of reduced testosterone and GH to increased carotid intima-media thickness (cIMT) in obesity.
Fifty obese men were studied with GH-releasing hormone–arginine testing, and morning free testosterone (FT) was measured by equilibrium dialysis. Metabolic, anthropometric and cardiovascular risk indices, including cIMT were measured. Twenty-six normal weight men served as controls.
Obese subjects demonstrated lower mean (±SEM) peak stimulated GH (5·9 ± 0·6 vs 36·4 ± 3·9 µg/l; P < 0·0001) and FT (0·41 ± 0·03 vs 0·56 ± 0·03 nmol/l; P = 0·0005) compared to controls. GH was significantly associated with FT (r = +0·44; P < 0·0001) and both were inversely related to visceral adipose tissue (VAT) (GH: r = −0·65; P < 0·0001; FT: r = −0·51; P < 0·0001). In multivariate regression analysis controlling for VAT, FT was no longer related to GH. Both GH and FT were associated with cIMT in univariate analysis. However, in multivariate modelling including traditional cardiovascular risk markers, GH (β = 0·003; P = 0·04) but not FT (P = 0·35) was associated with cIMT.
These results demonstrate a strong relationship between FT and GH in obesity and suggest that this relationship is more a function of excess adiposity rather than a direct relationship. While reduced FT and GH are both related to increased cIMT, the relationship with reduced GH remains significant controlling for reduced FT and traditional cardiovascular disease risk markers.
PMCID: PMC3225917  PMID: 20681993
20.  Determinants of Skeletal Loss and Recovery in Anorexia Nervosa 
Anorexia nervosa (AN) is complicated by severe bone loss. The effects of persistent undernutrition and consequent neuroendocrine dysfunction on bone mass and the factors influencing skeletal recovery have not been well characterized.
The objective of the study was to determine the rate of bone loss at the spine and hip in women with AN and whether resumption of menstrual function and/or improvement in weight are determinants of skeletal recovery in AN.
The study had a longitudinal design.
The study was conducted at a clinical research center.
Study Participants
Participants included 75 ambulatory women with AN.
Main Outcome Measures
Bone mineral density (BMD) and body composition were measured with dual x-ray absorptiometry.
In women not receiving oral contraceptives, those who did not improve weight or resume menses had a mean annual rate of decline of 2.6% at the spine and 2.4% at the hip. Those who resumed menses and improved weight had a mean annual increase of 3.1% at the posteroanterior spine and 1.8% at the hip. Women who recovered menses demonstrated a mean increase of posteroanterior spine but not hip BMD, independent of weight gain. Women who improved weight, regardless of whether they recovered menstrual function, demonstrated a mean increase of hip, but not spine, BMD. Increase in fat-free mass was a more significant determinant of increased BMD than weight or fat mass gain. In women receiving oral contraceptives, there was no increase in BMD at any site despite a mean 11.7% weight increase.
These data suggest that rapid bone loss, at an average annual rate of about 2.5%, occurs in young women with active AN. Resumption of menstrual function is important for spine BMD recovery, whereas weight gain is critical for hip BMD recovery. We did not observe an increase in BMD with weight gain in women receiving oral contraceptives. Therefore, improvements in reproduction function and weight, with increases in lean body mass a critical component, are both necessary for skeletal recovery in women with AN.
PMCID: PMC3220933  PMID: 16735492
21.  Effects of Obesity, Body Composition, and Adiponectin on Carotid Intima-Media Thickness in Healthy Women 
Increased common carotid intima-media thickness (IMT) is predictive of coronary artery disease and stroke.
In this study, we investigated common carotid IMT by obesity category in a cohort of healthy women without previously known cardiovascular disease.
Design, Setting, Participants, and Main Outcome Measures
One hundred healthy women (aged 24-59 yr) from the general community enrolled in an observational study conducted at an academic medical center participated in the study. B-mode ultrasound imaging of the common carotid arteries was used to measure common carotid IMT in 99 subjects. Fat distribution was determined by computed tomography. Hormonal and inflammatory parameters related to cardiovascular disease and obesity were measured.
IMT was higher in obese [body mass index (BMI) ≥ 30 kg/m2], compared with overweight women (BMI ≥ 25 and < 30 kg/m2) [0.69 mm, interquartile range (IQR) 0.60-0.75 mm] vs. 0.62 mm [IQR 0.56-0.68 mm), P = 0.044] and in comparison with lean women (BMI < 25 kg/m2) [0.69 mm (IQR 0.60-0.75 mm) vs. 0.59 mm (IQR 0.54-0.67 mm), P = 0.016]. In multivariate modeling, age (beta = 0.0050 mm change in IMT per year of age, P = 0.003), smoking (beta = 0.0044 mm change in IMT per pack-year, P = 0.046), and sc abdominal adiposity (beta = 0.00026 mm change in IMT per square centimeter, P = 0.010) were positively associated with IMT, whereas adiponectin (beta =–0.0042 mm change in IMT per milligram per liter, P = 0.045) was negatively associated with IMT. Visceral adiposity (beta = 0.00048 mm change in IMT per square centimeter, P = 0.092) was not significantly associated with IMT after adjusting for age, race, smoking, sc abdominal adiposity, and adiponectin.
Obesity is associated with increased common carotid IMT in young and middle-aged women. Adiponectin and sc abdominal adiposity are associated with carotid IMT in this population.
PMCID: PMC3210448  PMID: 16522690
22.  Effects of a nucleoside reverse transcriptase inhibitor, stavudine, on glucose disposal and mitochondrial function in muscle of healthy adults 
Mitochondrial dysfunction may contribute to the development of insulin resistance and type 2 diabetes. Nucleoside reverse transcriptase inhibitors (NRTIs), specifically stavudine, are known to alter mitochondrial function in human immunodeficiency virus (HIV)-infected individuals, but the effects of stavudine on glucose disposal and mitochondrial function in muscle have not been prospectively evaluated. In this study, we investigated short-term stavudine administration among healthy control subjects to determine effects on insulin sensitivity. A secondary aim was to determine the effects of stavudine on mitochondrial DNA (mtDNA) and function. Sixteen participants without personal or family history of diabetes were enrolled. Subjects were randomized to receive stavudine, 30 – 40 mg, twice a day, or placebo for 1 mo. Insulin sensitivity determined by glucose infusion rate during the hyperinsulinemic euglycemic clamp was significantly reduced after 1-mo exposure in the stavudine-treated subjects compared with placebo (−0.8 ± 0.5 vs. +0.7 ± 0.3 mg· kg−1 · min−1, P = 0.04, stavudine vs. placebo). In addition, muscle biopsy specimens in the stavudine-treated group showed significant reduction in mtDNA/nuclear DNA (−52%, P = 0.005), with no change in placebo-treated subjects (+8%, P = 0.9). 31P magnetic resonance spectroscopy (MRS) studies of mitochondrial function correlated with insulin sensitivity measures (r2 = 0.5, P = 0.008). These findings demonstrate that stavudine administration has potent effects on insulin sensitivity among healthy subjects. Further studies are necessary to determine whether changes in mtDNA resulting from stavudine contribute to effects on insulin sensitivity.
PMCID: PMC3206591  PMID: 17284576
human immunodeficiency virus; insulin resistance; magnetic resonance spectroscopy
23.  Effects of TNF-α neutralization on adipocytokines and skeletal muscle adiposity in the metabolic syndrome 
In a prior study, we have shown that tumor necrosis factor (TNF)-α neutralization improves inflammatory markers and total adiponectin in patients with the metabolic syndrome, without improving insulin sensitivity. In this study, we sought to extend our understanding of the effects of TNF-α neutralization in this human model of obesity by investigating the responses of high-molecular-weight (HMW) adiponectin, resistin, leptin, and muscle adiposity to etanercept in patients with the metabolic syndrome. Fifty-six men and women with the metabolic syndrome enrolled in a double-blind randomized placebo-controlled trial. Circulating concentrations of total and HMW adiponectin, resistin, and leptin were determined at baseline and after 4 wk of treatment with etanercept. Muscle adiposity was measured by computed tomography (CT). Although etanercept increased total adiponectin concentration, the HMW form, which is thought to mediate insulin sensitivity, was unchanged. Thus the ratio of HMW to total adiponectin decreased following etanercept treatment compared with placebo (−0.03 ± 0.03 vs. 0.06 ± 0.03, P = 0.02). Resistin tended to decrease in the etanercept-treated group compared with placebo (−0.6 ± 0.7 vs. 1.2 ± 0.7 ng/ml, P = 0.06), whereas leptin was not altered. Etanercept decreased muscle attenuation on CT [−0.61 ± 0.64 Hounsfield units (HU) vs. 1.54 ± 0.77 HU in placebo, P = 0.04], suggesting an increase in muscle adiposity. Together, these results demonstrate that neutralization of TNF-α in obese humans results in differential effects on critical adipokines and body composition indexes. These findings may help to explain the lack of effect on insulin sensitivity and extend our knowledge of the biological effects of TNF-α neutralization in obesity.
PMCID: PMC3196534  PMID: 17374698
tumor necrosis factor-α; adiponectin; resistin; muscle adiposity; metabolic syndrome
24.  Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men 
AIDS (London, England)  2010;24(2):243-253.
The degree of subclinical coronary atherosclerosis in HIV-infected patients is unknown. We investigated the degree of subclinical atherosclerosis and the relationship of traditional and nontraditional risk factors to early atherosclerotic disease using coronary computed tomography angiography.
Design and methods
Seventy-eight HIV-infected men (age 46.5 ± 6.5 years and duration of HIV 13.5 ± 6.1 years, CD4 T lymphocytes 523 ± 282; 81% undetectable viral load), and 32 HIV-negative men (age 45.4 ± 7.2 years) with similar demographic and coronary artery disease (CAD) risk factors, without history or symptoms of CAD, were prospectively recruited. 64-slice multidetector row computed tomography coronary angiography was performed to determine prevalence of coronary atherosclerosis, coronary stenosis, and quantitative plaque burden.
HIV-infected men demonstrated higher prevalence of coronary atherosclerosis than non-HIV-infected men (59 vs. 34%; P = 0.02), higher coronary plaque volume [55.9 (0–207.7); median (IQR) vs. 0 (0–80.5) μl; P = 0.02], greater number of coronary segments with plaque [1 (0–3) vs. 0 (0–1) segments; P = 0.03], and higher prevalence of Agatston calcium score more than 0 (46 vs. 25%, P = 0.04), despite similar Framingham 10-year risk for myocardial infarction, family history of CAD, and smoking status. Among HIV-infected patients, Framingham score, total cholesterol, low-density lipoprotein, CD4/CD8 ratio, and monocyte chemoattractant protein 1 were significantly associated with plaque burden. Duration of HIV infection was significantly associated with plaque volume (P = 0.002) and segments with plaque (P = 0.0009) and these relationships remained significant after adjustment for age, traditional risk factors, or duration of antiretroviral therapy. A total of 6.5% (95% confidence interval 2–15%) of our study population demonstrated angiographic evidence of obstructive CAD (>70% luminal narrowing) as compared with 0% in controls.
Young, asymptomatic, HIV-infected men with long-standing HIV disease demonstrate an increased prevalence and degree of coronary atherosclerosis compared with non-HIV-infected patients. Both traditional and nontraditional risk factors contribute to atherosclerotic disease in HIV-infected patients.
PMCID: PMC3154841  PMID: 19996940
atherosclerosis; cardiovascular risk factors; coronary artery disease; coronary computed tomography angiography; HIV
25.  Increased Aldosterone Among HIV-Infected Women with Visceral Fat Accumulation 
AIDS (London, England)  2009;23(17):2366-2370.
Increased aldosterone has been associated with obesity and the metabolic syndrome in non HIV-infected patients, but aldosterone has not been investigated among HIV-infected patients with increased visceral adipose tissue (VAT). 24-hour urine aldosterone was assessed among age and BMI-matched HIV-infected women with increased VAT, HIV-infected women without increased VAT and healthy controls. 24-hour urine aldosterone was higher in HIV-infected women with increased VAT and was associated with systolic blood pressure, VAT, and hemoglobin A1c. Increased aldosterone may contribute to the detrimental effects of excess visceral adiposity on blood pressure and glucose homeostasis among HIV patients.
PMCID: PMC2921849  PMID: 19770620
Aldosterone; Lipodystrophy; HIV; Visceral Fat

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