Background. Little is known about coronary plaque in human immunodeficiency virus (HIV)–infected women.
Methods. Sixty HIV-infected and 30 non–HIV-infected women without symptoms or history of cardiovascular disease were recruited to assess coronary plaque with coronary computed tomographic angiography and immune activation. Data from 102 HIV-infected men and 41 non–HIV-infected male controls were compared.
Results. HIV-infected women demonstrated significantly higher percentages of segments with noncalcified plaque (mean ± SD, 74% ± 28% vs 23% ± 39% compared to female control subjects; median [interquartile range], 75% [63%–100%] vs 0% [0%–56%]; P = .007) and more segments with noncalcified plaque (mean ± SD, 0.92 ± 1.48 vs 0.40 ± 1.44; median [interquartile range], 0 [0–2] vs 0 [0–0]; P = .04). Immune activation parameters, including soluble CD163 (sCD163; P = .006), CXCL10 (P = .002), and percentages of CD14+CD16+ monocytes (P = .008), were higher in HIV-infected women than in female control subjects, but no differences were seen in general inflammatory markers. Among HIV-infected women with noncalcified coronary plaque, sCD163 levels were significantly higher than in HIV-infected women without noncalcified plaque (P = .04). In multivariate modeling for sCD163 levels among male and female subjects, significant effects of HIV (P < .0001), age (P = .002), and sex (P = .0002) were seen.
Conclusions. Young, asymptomatic, HIV-infected women, demonstrate increased noncalcified coronary plaque and increased immune activation, particularly monocyte activation. Independent effects of sex, HIV status, and aging on immune activation may contribute to cardiovascular disease in this population.
Clinical Trials Registration. NCT00455793.
HIV; atherosclerosis; cardiovascular disease; non-calcified coronary plaque; immune activation; age
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.
HIV; Aging; Cardiovascular Diseases; Smoking
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.
Clinicaltrials.gov Registration. NCT00123253, NCT00435136, NCT00608023.
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.
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.
Endothelial function; carotid intima media thickness; atherosclerosis
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.
RESEARCH DESIGN AND METHODS
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.
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.
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.
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.
obesity; inflammation; tumor necrosis factor-alpha; E-selectin
To determine the effects of switching from lopinavir/ritonavir (LPV/r) to atazanavir/ritonavir (ATV/r) on muscle glucose uptake, glucose homeostasis, lipids, and body composition.
Fifteen HIV-infected men and women on a regimen containing LPV/r and with evidence of hyperinsulinemia and/or dyslipidemia were randomized to continue LPV/r or to switch to ATV/r (ATV 300mg and ritonavir 100mg daily) for six months. The primary endpoint was change in thigh muscle glucose uptake as measured by positron emission tomography (PET). Secondary endpoints included abdominal visceral adipose tissue, fasting lipids and safety parameters. The difference over time between treatment groups (treatment effect of ATV/r relative to LPV/r) was determined by repeated measures ANCOVA.
After six months, anterior thigh muscle glucose uptake increased significantly (treatment effect +18.2 ± 5.9 μmol/kg/min, ATV/r vs. LPV/r, p=0.035), and visceral adipose tissue (VAT) area decreased significantly in subjects who switched to ATV/r (treatment effect -31 ± 11cm2, ATV/r vs. LPV/r, p=0.047). Switching to ATV/r significantly decreased triglyceride (treatment effect -182 ± 64 mg/dL, ATV/r vs. LPV/r, p=0.02) and total cholesterol (treatment effect -23 ± 8 mg/dL, ATV/r vs. LPV/r, p=0.01), whereas HDL and LDL did not change significantly. Fasting glucose also decreased significantly following switch to ATV/r (treatment effect -15 ± 4 mg/dL, ATV/r vs. LPV/r, p=0.002).
Switching from LPV/r to ATV/r significantly increases glucose uptake by muscle, decreases abdominal visceral adipose tissue, improves lipid parameters and decreases fasting glucose over 6 months.
HIV; lipodystrophy; atazanavir; lopinavir; glucose; intra-abdominal fat; lipids
The purpose of this study was to evaluate the relationship of respiratory quotient (RQ), a surrogate marker of substrate oxidation, as well as body composition and dietary intake to resting energy expenditure (REE) among HIV-infected patients in the current era of HAART and among non HIV-infected control subjects. Resting energy expenditure (REE) is increased in HIV-infected patients, but little is known regarding the potential contribution of altered substrate metabolism, body composition and dietary intake to increased energy expenditure in this population. RQ, REE, body composition and dietary intake parameters were assessed in 283 HIV-infected patients and 146 community-derived HIV-negative controls that were evaluated for metabolic studies between 1998 and 2005. RQ was lower (0.83±0.00 vs. 0.85±0.01, P=0.005) whereas REE adjusted for fat free mass (FFM) was higher (31.8±0.3 vs. 29.8±0.3 kcal/d/kg, P=<0.0001) in HIV-infected compared to control subjects. In multivariate modeling among HIV-infected patients, including age, gender and parameters of immune function, FFM (beta=24.811334, P <0.0001), visceral adiposity (beta=0.7182746, P=0.008), and total body fat (beta=8.0506839, P=0.041) were positively associated with REE, whereas RQ was negatively associated with REE (beta= −528.4808, P=0.024). Overall r2=0.705, P<0.0001 for the model. In control subjects, by contrast, only visceral adiposity (beta = 1.0612073, P=0.004), total body fat (beta = 15.805547, P=0.010), and FFM (beta = 22.613005, P <0.0001) were significant predictors of REE, and there was no relationship with RQ. Overall r2=0.825, P<0.0001 for the model. These data suggest that alterations in substrate metabolism may contribute to increased REE in HIV-infected patients compared to control subjects.
HIV; resting energy expenditure; lipid oxidation; substrate metabolism; RQ
Metabolic changes and smoking are common among HIV patients and may confer increased cardiovascular risk.
The aim of the study was to determine acute myocardial infarction (AMI) rates and cardiovascular risk factors in HIV compared with non-HIV patients in two tertiary care hospitals.
Design, Setting, and Participants
We conducted a health care system-based cohort study using a large data registry with 3,851 HIV and 1,044,589 non-HIV patients. AMI rates were determined among patients receiving longitudinal care between October 1, 1996, and June 30, 2004.
Main Outcome Measures
The primary outcome was myocardial infarction, identified by International Classification of Diseases coding criteria.
AMI was identified in 189 HIV and 26,142 non-HIV patients. AMI rates per 1000 person-years were increased in HIV vs. non-HIV patients [11.13 (95% confidence interval [CI] 9.58–12.68) vs. 6.98 (95% CI 6.89–7.06)]. The HIV cohort had significantly higher proportions of hypertension (21.2 vs. 15.9%), diabetes (11.5 vs. 6.6%), and dyslipidemia (23.3 vs. 17.6%) than the non-HIV cohort (P < 0.0001 for each comparison). The difference in AMI rates between HIV and non-HIV patients was significant, with a relative risk (RR) of 1.75 (95% CI 1.51–2.02; P < 0.0001), adjusting for age, gender, race, hypertension, diabetes, and dyslipidemia. In gender-stratified models, the unadjusted AMI rates per 1000 person-years were higher for HIV patients among women (12.71 vs. 4.88 for HIV compared with non-HIV women), but not among men (10.48 vs. 11.44 for HIV compared with non-HIV men). The RRs (for HIV vs. non-HIV) were 2.98 (95% CI 2.33–3.75; P < 0.0001) for women and 1.40 (95% CI 1.16–1.67; P = 0.0003) for men, adjusting for age, gender, race, hypertension, diabetes, and dyslipidemia. A limitation of this database is that it contains incomplete data on smoking. Smoking could not be included in the overall regression model, and some of the increased risk may be accounted for by differences in smoking rates.
AMI rates and cardiovascular risk factors were increased in HIV compared with non-HIV patients, particularly among women. Cardiac risk modification strategies are important for the long-term care of HIV patients.
To investigate whether elevated C-reactive protein (CRP) levels and HIV infection are independently associated with acute myocardial infarction (AMI) among patients receiving care in a large US health care system.
Analyses included patients receiving care in the Partners HealthCare System between January 1997 and December 2006, with a most recent CRP less than 3 years and more than 1 week before AMI. Over this period, 70,357 (487 HIV and 69,870 non-HIV) patients met these criteria, from the background population of 1,648,687 patients followed in the system. We included both CRP and high-sensitivity CRP and defined elevated CRP based on the normal range of the assay used. We used multivariate logistic regression analysis to test the association of elevated CRP and HIV with AMI after adjustment for demographic and other cardiovascular covariates, including hypertension, diabetes, and dyslipidemia.
In univariate analyses, elevated CRP and HIV were each significantly associated with AMI [odds ratio (OR) 2.51; 95% confidence interval (CI) 2.27 to 2.78; P < 0.0001 for elevated CRP and OR 2.07; 95% CI 1.31 to 3.10; P = 0.001 for HIV]. In a combined model including CRP category and HIV status, elevated CRP (OR 2.50; 95% CI 2.26 to 2.77; P < 0.0001) and HIV (OR 1.74; 95% CI 1.10 to 2.61; P = 0.01) were both independently associated with AMI. In a fully adjusted model controlling for age, sex, race, hypertension, diabetes, and dyslipidemia, both elevated CRP (OR 2.13; 95% CI 1.92 to 2.37; P < 0.0001) and HIV (OR 1.93; 95% CI 1.21 to 2.93; P = 0.004) remained independently associated with AMI. Compared with patients with normal CRP and without HIV, the OR for AMI was increased more than 4-fold among patients with HIV and elevated CRP.
Elevated CRP and HIV are independently associated with increased AMI risk, and patients with HIV with increased CRP have a markedly increased relative risk of AMI. Measurement of CRP may be useful in the cardiovascular risk assessment of patients with HIV.
C-reactive protein; coronary disease; HIV; myocardial infarction; risk factors
HIV-infected patients are at increased risk of coronary artery disease (CAD). We evaluated the cost-effectiveness of cardiac screenings for HIV-positive men at intermediate or greater CAD risk.
We developed a lifetime microsimulation model of CAD incidence and progression in HIV-infected men.
Input parameters were derived from two HIV cohort studies and the literature. We compared no CAD screening with stress testing and coronary computed tomography angiography (CCTA)-based strategies. Patients with test results indicating 3-vessel/left main CAD underwent invasive coronary angiography (ICA) and received coronary artery bypass graft surgery. In the “Stress-testing+Medication”/“CCTA+Medication” strategies, patients with 1-/2-vessel CAD results received lifetime medical treatment without further diagnostics whereas in the “Stress-testing+Intervention”/“CCTA+Intervention” strategies, patients with these results underwent ICA and received percutaneous coronary intervention.
Compared to no screening, the “Stress-testing+Medication”, “Stress-testing+Intervention”, “CCTA+Medication” and “CCTA+Intervention” strategies resulted in 14, 11, 19, and 14 quality-adjusted life days per patient and incremental cost effectiveness ratios of 49,261, 57,817, 34,887 and 56,518 € per quality-adjusted life year (QALY), respectively. Screening only at higher CAD risk thresholds was more cost-effective. Repeated screening was clinically beneficial compared to one-time screening but only “Stress-testing+Medication” every five years remained cost-effective. At a willingness-to-pay threshold of 83,000 €/QALY (~100,000 US$/QALY), implementing any CAD screening was cost-effective with a probability of 75-95%.
Screening HIV-positive men for CAD would be clinically beneficial and comes at a cost-effectiveness ratio comparable to other accepted interventions in HIV care.
HIV; coronary heart disease; prevention; cost-effectiveness; Markov model
miRNAs are important regulators of biological processes in many tissues, including the differentiation and function of brown and white adipocytes. The endoribonuclease dicer is a major component of the miRNA-processing pathway, and in adipose tissue, levels of dicer have been shown to decrease with age, increase with caloric restriction, and influence stress resistance. Here, we demonstrated that mice with a fat-specific KO of dicer develop a form of lipodystrophy that is characterized by loss of intra-abdominal and subcutaneous white fat, severe insulin resistance, and enlargement and “whitening” of interscapular brown fat. Additionally, KO of dicer in cultured brown preadipocytes promoted a white adipocyte–like phenotype and reduced expression of several miRNAs. Brown preadipocyte whitening was partially reversed by expression of miR-365, a miRNA known to promote brown fat differentiation; however, introduction of other miRNAs, including miR-346 and miR-362, also contributed to reversal of the loss of the dicer phenotype. Interestingly, fat samples from patients with HIV-related lipodystrophy exhibited a substantial downregulation of dicer mRNA expression. Together, these findings indicate the importance of miRNA processing in white and brown adipose tissue determination and provide a potential link between this process and HIV-related lipodystrophy.
HIV; atherosclerosis; myocardial infarction; plaque; cardiovascular disease
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.
branched-chain amino acids; insulin resistance; pediatric obesity; metabolomics; type 2 diabetes
HIV-1 elite controllers (EC) spontaneously maintain suppressed levels of viremia, but exhibit significant immune activation. We investigated coronary atherosclerosis by coronary CT angiography (CTA) in: 1) EC, 2) non EC, chronically HIV-1 infected, ART-treated patients with undetectable viral load (“chronic HIV”), and 3) HIV-negative controls. Prevalence of atherosclerosis (78% vs. 42%, P<0.05) and markers of immune activation were increased in EC compared to HIV-negative controls. sCD163, a monocyte activation marker, was increased in EC compared to chronic HIV-1 (P<0.05) and compared to HIV-negative controls (P< 0.05). These data suggest a significant degree of coronary atherosclerosis and monocyte activation among EC.
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.
atherosclerosis; receptor activator of nuclear factor kappa β ligand; osteoprotegerin; coronary artery disease; HIV
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.
sCD163; monocyte/macrophage activation; insulin resistance
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.
HIV; stroke; cerebrovascular; cardiovascular; vascular risk factors
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.
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.
tesamorelin; GHRH; HIV; intra-abdominal fat; adiponectin; tissue plasminogen activator; plasminogen activator inhibitor 1