Subclinical myocyte injury, fibrosis and strain in relationship to coronary plaque in asymptomatic HIV-infected individuals.

BACKGROUND: Cardiovascular disease (CVD) rates are increased in HIV. The degree to which myocyte injury, strain, and fibrosis occur prior to clinical disease and relate to coronary plaque in HIV is unknown. OBJECTIVE: To investigate newer cardiac biomarkers of subclinical myocyte injury [high-sensitivity troponin T (hs-cTnT)], strain (amino terminal proB-type natriutretic peptide), fibrosis (soluble ST2, Galectin-3), and vascular inflammation (oxidized LDL, lipoprotein-associated phospholipase A2) in HIV-infected individuals and non-HIV controls and relate these to coronary plaque by cardiac computed tomography angiography. DESIGN: Observational. METHODS: Markers were investigated in 155 HIV-infected and 70 non-HIV-infected participants without known CVD and with low traditional CVD risk and related to cardiac computed tomography angiography data. RESULTS: Age, sex, and race did not differ between the groups. Hs-cTnT [3.1 (3.0, 6.4) vs. 3.0 (3.0, 4.0) ng/l, P = 0.03], Galectin-3 [13.5 (10.6, 18.1) vs. 11.6 (9.9, 14.5) ng/ml, P = 0.002], and soluble ST2 [31.5 (24.5, 41.5) vs. 28.3 (20.2, 33.5) ng/ml, P = 0.01] were significantly higher in HIV-infected participants vs. CONTROLS: Detectable hs-cTnT (seen in 50% of HIV participants) related to the overall presence of plaque [odds ratio (OR) 2.3, P = 0.01] and particularly to coronary calcium (OR for Agatston calcium score > 0, 3.3, P = 0.0008 and OR for calcified plaque 7.4, P = 0.01) in HIV, but not in non-HIV. CONCLUSION: Subclinical myocyte injury is observed among young, asymptomatic HIV-infected individuals with low traditional cardiac risk factors. In the setting of HIV infection, the presence of detectable cardiac troponin is strongly associated with coronary plaque, particularly calcified plaque among an asymptomatic group. Future studies are needed to assess if early subclinical injury marked by hs-cTnT predicts plaque progression and cardiac events in HIV.

Dysfunctional Subcutaneous Fat With Reduced Dicer and Brown Adipose Tissue Gene Expression in HIV-Infected Patients.

CONTEXT: HIV patients are at an increased risk for cardiometabolic disease secondary to depot-specific alterations in adipose function, but mechanisms remain poorly understood. OBJECTIVE: The endoribonuclease Dicer has been linked to the modulation of brown and white adipocyte differentiation. We previously demonstrated that Dicer knockout mice undergo transformation of brown adipose tissue to white adipose tissue and develop a lipodystrophic phenotype. We hypothesized reduced Dicer and brown adipose tissue gene expression from nonlipomatous sc fat among HIV patients with a lipodystrophic phenotype. DESIGN: Eighteen HIV (nine with and without lipodystrophic changes in fat distribution, characterized by excess dorsocervical adipose tissue [DCAT]) and nine non-HIV subjects underwent punch biopsy of abdominal sc fat to determine expression of Dicer and other adipose-related genes. RESULTS: HIV subjects with long-duration antiretroviral use demonstrated excess DCAT vs non-HIV subjects (9.8 ± 1.0 vs 6.6 ± 0.8 cm(2), P = .02) with similar body mass index. Dicer expression was decreased in abdominal sc fat of HIV vs non-HIV (4.88 [1.91, 11.93] vs 17.69 [10.72, 47.91], P = .01), as were PPARα, ZIC1, PRDM16, DIO2, and HSP60 (all P ≤ .03). Moreover, the expression of Dicer (2.49 [0.02, 4.88] vs 11.20 [4.83, 21.45], P = .006), brown fat (PPARα [P = .002], ZIC1 [P = .004], LHX8 [P = .03], PRDM16 [P = .0008], PAT2 [P = .008], P2RX5 [P = .02]), beige fat (TMEM26 [P = .004], CD137 [P = .008]), and other genes (DIO2 [P = .002], leptin [P = .003], HSP60 [P = .0004]) was further decreased in abdominal sc fat comparing HIV subjects with vs without excess DCAT. Down-regulation of Dicer in the abdominal sc fat correlated with the down-regulation of all brown and beige fat genes (all P ≤ .01). CONCLUSION: Our results demonstrate dysfunctional sc adipose tissue marked by reduced Dicer in relationship to the down-regulation of brown and beige fat-related genes in lipodystrophic HIV patients and may provide a novel mechanism for metabolic dysregulation. A strategy to increase browning of white adipose tissue may improve cardiometabolic health in HIV.

Effects of lifestyle modification and metformin on irisin and FGF21 among HIV-infected subjects with the metabolic syndrome.

OBJECTIVE: Few studies have investigated irisin and FGF21 to elucidate the role of these hormones to regulate 'beiging' in HIV-infected patients. DESIGN: Fifty HIV-infected subjects with the metabolic syndrome were previously recruited and randomized to receive lifestyle modification (LSM) and/or metformin over 12 months. In the current study, we assessed FGF21 and irisin at baseline and after intervention. In addition, we assessed circulating FGF21 and irisin in relationship to brown adipose tissue (BAT) gene expression in dorsocervical subcutaneous fat biopsies from 13 HIV-infected subjects. RESULTS: At baseline, prior to intervention, HIV-infected subjects demonstrated increased log FGF21 (2·13 ± 0·06 vs 1·98 ± 0·05 pg/ml, P = 0·05) and log irisin (0·33 ± 0·02 vs 0·17 ± 0·04 µg/ml, P = 0·003) compared with healthy controls well matched based on waist circumference. After 12 months, HIV-infected subjects randomized to LSM demonstrated a relative reduction in FGF21 compared with those not randomized to LSM (-10 [-35,22] vs 40 [0,94] %change, P = 0·01). Changes in FGF21 were inversely associated with improved parameters of energy homoeostasis, including increased REE (ρ = -0·34, P = 0·046) and max VO2 (ρ = -0·38, P = 0·02), and reduced RQ (ρ = 0·40, P = 0·02) among all HIV-infected subjects. Increased UCP-1 (r = 0·75, P = 0·003), DIO2 (r = 0·58, P = 0·04) and CideA (r = 0·73, P = 0·01) gene expression in dorsocervical fat was significantly associated with FGF21 in HIV-infected subjects. CONCLUSION: HIV-infected subjects with metabolic complications demonstrate increases in FGF21 in relationship to BAT gene expression. Relative reductions in FGF21 in those receiving long-term LSM relate to overall improvements in energy expenditure parameters. In contrast, irisin levels are elevated in HIV-infected subjects, but are not influenced by LSM nor associated with BAT gene expression.

Soluble CD163 is associated with shortened telomere length in HIV-infected patients.

Telomere length (TL) and immune activation markers were measured in a cohort of HIV-infected (n = 102) and age-matched non-HIV-infected (n = 41) men. TL was significantly shorter in HIV-infected compared with non-HIV-infected subjects (P = 0.04). Univariate analysis revealed a strong inverse relationship of TL to sCD163, and thus, monocyte/macrophage activation, among the HIV group (ρ = -0.30, P = 0.003). In multivariate modeling among the whole group, HIV-positive serostatus (P = 0.06) and sCD163 (P = 0.05) remained predictors of TL controlling for age and smoking status. Our data demonstrate that increased immune activation relates to shorter TL in HIV.