Jeffrey Wei

Soluble CD163, a Novel Marker of Activated Macrophages, Is Elevated and Associated With Noncalcified Coronary Plaque in HIV-Infected Patients

BACKGROUND Pro-inflammatory monocytes/macrophages may contribute to increased atherosclerosis in human immunodeficiency virus (HIV)-infected patients. We investigate--to our knowledge, for the first time--sCD163 and other markers of monocyte activation in relationship to atherosclerotic plaque in HIV-infected patients. METHODS One hundred two HIV-infected and 41 HIV-seronegative men with equivalent cardiovascular risk factors and without history of coronary artery disease were prospectively recruited and underwent computed tomography coronary angiography. RESULTS sCD163 levels and presence of plaque were significantly higher among antiretroviral-treated subjects with undetectable HIV RNA levels, compared with seronegative controls (1172 ± 646 vs. 883 ± 561 ng/mL [P = .02] for sCD163 and 61% vs. 39% [P = .03] for presence of plaque). After adjusting for age, race, lipids, blood pressure, glucose, smoking, sCD14, and HIV infection, sCD163 remained independently associated with noncalcified plaque (P = .008). Among HIV-infected patients, sCD163 was associated with coronary segments with noncalcified plaque (r = 0.21; P = .04), but not with calcium score. In contrast, markers of generalized inflammation, including C-reactive protein level, and D-dimer were not associated with sCD163 or plaque among HIV-infected patients. CONCLUSIONS sCD163, a monocyte/macrophage activation marker, is increased in association with noncalcified coronary plaque in men with chronic HIV infection and low or undetectable viremia. These data suggest a potentially important role of chronic monocyte/macrophage activation in the development of noncalcified vulnerable plaque. CLINICAL TRIAL REGISTRATION NCT00455793.

Arterial inflammation in patients with HIV

CONTEXT Cardiovascular disease is increased in patients with human immunodeficiency virus (HIV), but the specific mechanisms are unknown. OBJECTIVE To assess arterial wall inflammation in HIV, using 18fluorine-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET), in relationship to traditional and nontraditional risk markers, including soluble CD163 (sCD163), a marker of monocyte and macrophage activation. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study of 81 participants investigated between November 2009 and July 2011 at the Massachusetts General Hospital. Twenty-seven participants with HIV without known cardiac disease underwent cardiac 18F-FDG-PET for assessment of arterial wall inflammation and coronary computed tomography scanning for coronary artery calcium. The HIV group was compared with 2 separate non-HIV control groups. One control group (n = 27) was matched to the HIV group for age, sex, and Framingham risk score (FRS) and had no known atherosclerotic disease (non-HIV FRS-matched controls). The second control group (n = 27) was matched on sex and selected based on the presence of known atherosclerotic disease (non-HIV atherosclerotic controls). MAIN OUTCOME MEASURE Arterial inflammation was prospectively determined as the ratio of FDG uptake in the arterial wall of the ascending aorta to venous background as the target-to-background ratio (TBR). RESULTS Participants with HIV demonstrated well-controlled HIV disease (mean [SD] CD4 cell count, 641 [288] cells/μL; median [interquartile range] HIV-RNA level, <48 [<48 to <48] copies/mL). All were receiving antiretroviral therapy (mean [SD] duration, 12.3 [4.3] years). The mean FRS was low in both HIV and non-HIV FRS-matched control participants (6.4; 95% CI, 4.8-8.0 vs 6.6; 95% CI, 4.9-8.2; P = .87). Arterial inflammation in the aorta (aortic TBR) was higher in the HIV group vs the non-HIV FRS-matched control group (2.23; 95% CI, 2.07-2.40 vs 1.89; 95% CI, 1.80-1.97; P < .001), but was similar compared with the non-HIV atherosclerotic control group (2.23; 95% CI, 2.07-2.40 vs 2.13; 95% CI, 2.03-2.23; P = .29). Aortic TBR remained significantly higher in the HIV group vs the non-HIV FRS-matched control group after adjusting for traditional cardiovascular risk factors (P = .002) and in stratified analyses among participants with undetectable viral load, zero calcium, FRS of less than 10, a low-density lipoprotein cholesterol level of less than 100 mg/dL (<2.59 mmol/L), no statin use, and no smoking (all P ≤ .01). Aortic TBR was associated with sCD163 level (P = .04) but not with C-reactive protein (P = .65) or D-dimer (P = .08) among patients with HIV. CONCLUSION Participants infected with HIV vs noninfected control participants with similar cardiac risk factors had signs of increased arterial inflammation, which was associated with a circulating marker of monocyte and macrophage activation.

Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men.

Objective: 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. Results: 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. Conclusion: 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.

Increased coronary atherosclerosis and immune activation in HIV-1 elite controllers.

HIV-1 elite controllers spontaneously maintain suppressed levels of viremia, but exhibit significant immune activation. We investigated coronary atherosclerosis by coronary computed tomography angiography (CTA) in elite controllers, nonelite controller, chronically HIV-1 infected, antiretroviral therapy (ART)-treated patients with undetectable viral load (‘chronic HIV’), and HIV-negative controls. Prevalence of atherosclerosis (78 vs. 42%, P < 0.05) and markers of immune activation were increased in elite controllers compared with HIV-negative controls. sCD163, a monocyte activation marker, was increased in elite controllers compared with chronic HIV-1 (P < 0.05) and compared with HIV-negative controls (P < 0.05). These data suggest a significant degree of coronary atherosclerosis and monocyte activation among elite controllers.

Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial.

BACKGROUND HIV-infected patients have a high risk of myocardial infarction. We aimed to assess the ability of statin treatment to reduce arterial inflammation and achieve regression of coronary atherosclerosis in this population. METHODS In a randomised, double-blind, placebo-controlled trial, 40 HIV-infected participants with subclinical coronary atherosclerosis, evidence of arterial inflammation in the aorta by fluorodeoxyglucose (FDG)-PET, and LDL-cholesterol concentration of less than 3.37 mmol/L (130 mg/dL) were randomly assigned (1:1) to 1 year of treatment with atorvastatin or placebo. Randomisation was by the Massachusetts General Hospital (MGH) Clinical Research Pharmacy with a permuted-block algorithm, stratified by sex with a fixed block size of four. Study codes were available only to the MGH Research Pharmacy and not to study investigators or participants. The prespecified primary endpoint was arterial inflammation as assessed by FDG-PET of the aorta. Additional prespecified endpoints were non-calcified and calcified plaque measures and high risk plaque features assessed with coronary CT angiography and biochemical measures. Analysis was done by intention to treat with all available data and without imputation for missing data. The trial is registered with ClinicalTrials.gov, number NCT00965185. FINDINGS The study was done from Nov 13, 2009, to Jan 13, 2014. 19 patients were assigned to atorvastatin and 21 to placebo. 37 (93%) of 40 participants completed the study, with equivalent discontinuation rates in both groups. Baseline characteristics were similar between groups. After 12 months, change in FDG-PET uptake of the most diseased segment of the aorta was not different between atorvastatin and placebo, but technically adequate results comparing longitudinal changes in identical regions could be assessed in only 21 patients (atorvastatin Δ -0.03, 95% CI -0.17 to 0.12, vs placebo Δ -0.06, -0.25 to 0.13; p=0.77). Change in plaque could be assessed in all 37 people completing the study. Atorvastatin reduced non-calcified coronary plaque volume relative to placebo: median change -19.4% (IQR -39.2 to 9.3) versus 20.4% (-7.1 to 94.4; p=0.009, n=37). The number of high-risk plaques was significantly reduced in the atorvastatin group compared with the placebo group: change in number of low attenuation plaques -0.2 (95% CI -0.6 to 0.2) versus 0.4 (0.0, 0.7; p=0.03; n=37); and change in number of positively remodelled plaques -0.2 (-0.4 to 0.1) versus 0.4 (-0.1 to 0.8; p=0.04; n=37). Direct LDL-cholesterol (-1.00 mmol/L, 95% CI -1.38 to 0.61 vs 0.30 mmol/L, 0.04 to 0.55, p<0.0001) and lipoprotein-associated phospholipase A2 (-52.2 ng/mL, 95% CI -70.4 to -34.0, vs -13.3 ng/mL, -32.8 to 6.2; p=0.005; n=37) decreased significantly with atorvastatin relative to placebo. Statin therapy was well tolerated, with a low incidence of clinical adverse events. INTERPRETATION No significant effects of statin therapy on arterial inflammation of the aorta were seen as measured by FDG-PET. However, statin therapy reduced non-calcified plaque volume and high-risk coronary plaque features in HIV-infected patients. Further studies should assess whether reduction in high-risk coronary artery disease translates into effective prevention of cardiovascular events in this at-risk population. FUNDING National Institutes of Health, Harvard Clinical and Translational Science Center, National Center for Research Resources.

Increased coronary artery calcium score and noncalcified plaque among HIV-infected men: relationship to metabolic syndrome and cardiac risk parameters.

Objective:In this study, the effects of traditional cardiac risk factors on coronary artery calcium (CAC) score and presence of plaque, including noncalcified plaque, measured by computed tomography coronary angiography, were compared among HIV-infected and non-HIV-infected subjects, with respect to the presence of the metabolic syndrome (MS). Design and Methods:HIV-infected men recruited for the presence of the MS (HIV + MS, n = 27) were compared with 2 control groups, HIV-infected men recruited without regard to metabolic criteria (HIV, n = 87), and HIV-negative control men (C, n = 40), also recruited without regard to any metabolic criterion. Results:All 3 groups were similar in age, demographic parameters, and smoking. MS was seen in 100% of the HIV + MS group, compared with 28% in the HIV-infected control group and 11% in the HIV-negative controls. HIV + MS subjects had higher mean CAC score than HIV-infected controls (72 ± 25 vs. 30 ± 8, P = 0.04, HIV + MS vs. HIV) and HIV-negative controls (72 ± 25 vs. 18 ± 7; P = 0.02, HIV + MS vs. C). With respect to CAC, only the HIV + MS group had increased CAC compared with non-HIV. In contrast, both HIV groups demonstrated an increased prevalence of plaque [63% vs. 38%, P = 0.04 (HIV + MS vs. C) and 59% vs. 38%, P = 0.02, (HIV vs. C)] and increased number of noncalcified plaque segments compared with the HIV-negative group [1.26 ± 0.31 vs. 0.45 ± 0.16, P = 0.01 (HIV + MS vs. C); 1.02 ± 0.18 vs. 0.45 ± 0.16, P = 0.04 (HIV vs. C)]. Plaque and noncalcified plaque did not differ significantly between the HIV groups. Conclusions:Metabolic abnormalities in HIV patients are specifically associated with increased coronary artery calcification, whereas HIV itself or other factors may be associated with the development of noncalcified lesions.

Reduced Growth Hormone Secretion Is Associated with Increased Carotid Intima-Media Thickness in Obesity

CONTEXT Obesity is associated with reduced GH. OBJECTIVE The aim of the study was to determine whether reduced GH is associated with increased carotid intima-media thickness (cIMT) in obesity. DESIGN A total of 102 normal-weight and obese men and women without known hypopituitarism were studied. Subjects underwent GH stimulation testing with GHRH-arginine. Lipid profile, inflammatory markers, oral glucose tolerance test, abdominal computed tomography, dual-energy x-ray absorptiometry, and cIMT were measured. Relative GH deficiency was defined as peak GH of 4.2 microg/liter or less. Subjects were separated based on BMI and GH testing into three groups: normal weight, obese GH sufficient (GHS), and obese relative GH deficient (GHD). Age, gender, and race were similar between the groups. BMI, percentage body fat, and visceral adiposity did not differ between obese GHS and relative GHD. RESULTS Peak GH was associated with cIMT, IGF-I, high-density lipoprotein, low-density lipoprotein, triglycerides, adiponectin, C-reactive protein, and TNF-alpha (all P < 0.05). Obese GHS subjects had similar cIMT compared to normal-weight subjects (P = not significant), whereas obese GHD subjects had higher cIMT compared to normal-weight subjects (P < 0.05) (normal weight, 0.645 +/- 0.023, vs. obese GHS, 0.719 +/- 0.021, vs. obese GHD, 0.795 +/- 0.063 mm; P = 0.01 by ANOVA). Similar results were seen in sensitivity analyses with less stringent cutoffs (< 5, < or = 8, < 9 microg/liter) to define GHD. In multivariate modeling, peak GH remained significantly associated with cIMT after controlling for age, gender, race, tobacco, blood pressure, cholesterol, and fasting glucose (R(2) for model, 0.35; P < 0.0001). CONCLUSIONS These results suggest that reduced GH secretion is associated with a more abnormal metabolic phenotype in obesity, characterized by increased cIMT, dyslipidemia, insulin resistance, and inflammation.

Increased epicardial adipose tissue volume in HIV-infected men and relationships to body composition and metabolic parameters

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-infected patients than that in controls (P = 0.04). In HIV patients, epicardial fat volume was strongly associated with visceral adipose tissue area (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, visceral adipose tissue and antiretroviral therapy. Epicardial fat may be an important fat depot in HIV-infected patients.

Receptor activator of nuclear factor-κB ligand (RANKL) and its relationship to coronary atherosclerosis in HIV patients.

Abstract:HIV-infected individuals have an increased prevalence of coronary artery disease. Receptor activator of nuclear factor-&kgr;B ligand (RANKL) and osteoprotegerin have been postulated as mediators of vascular calcification. 78 HIV-infected men and 32 healthy controls without history of coronary artery disease were prospectively recruited to undergo cardiac computed tomography and computed tomography angiography to assess coronary artery calcium and plaque burden. Soluble receptor activator of nuclear factor-&kgr;B ligand 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]. Soluble receptor activator of nuclear factor-&kgr;B ligand was negatively associated with the number of coronary segments with plaque (Spearman &rgr; = −0.41, P < 0.001) and Agatston calcium score (&rgr; = −0.30, P < 0.01) in HIV-infected individuals even after adjusting for traditional cardiovascular risk factors.

Retinol-binding protein levels are increased in association with gonadotropin levels in healthy women

Recent studies have demonstrated an association between retinol-binding protein (RBP4) and insulin resistance. Retinol-binding protein is decreased in women and elevated in polycystic ovary syndrome. However, prior studies have not investigated the relationship between RBP4, gonadal steroids, and gonadotropins in healthy women. The aim of this study was to determine the RBP4 levels in a cohort of healthy women with a range of body mass indices and glucose tolerances to investigate the relationship between RBP4, gonadotropin levels, and menopausal status. Serum RBP4 levels were measured by enzyme-linked immunosorbent assay and quantitative Western blot in 88 healthy women (aged 24-59 years) from the general community in a cross-sectional study. Retinol-binding protein was higher in postmenopausal compared with premenopausal women (26.1 +/- 2.1 vs 19.3 +/- 0.5 mug/mL, P = .001). In univariate analysis, RBP4 was associated with follicle-stimulating hormone (r = 0.37, P = .0004), luteinizing hormone (r = 0.3, P = .005), and sex hormone-binding globulin (r = -0.24, P = .03) and trended to significance with estradiol (P = .09) but not with free testosterone or dehydroepiandrosterone sulfate. Retinol-binding protein was also associated with insulin at 2 hours during an oral glucose tolerance test (r = 0.24, P = .03) and the area under the curve for insulin during the oral glucose tolerance test (r = 0.26, P = .02). In multivariate regression modeling, both follicle-stimulating hormone (P = .03) and luteinizing hormone (P = .04) remained significantly associated with RBP4 after controlling for estradiol, sex hormone-binding globulin, insulin area under the curve, cholesterol, triglycerides, waist-to-hip ratio, and tumor necrosis factor alpha. Retinol-binding protein was not associated with inflammatory markers or with carotid intima-media thickness. Therefore, RBP4 is higher in postmenopausal women and is associated with gonadotropin concentrations in healthy women.