Suman Srinivasa

Noncalcified Coronary Atherosclerotic Plaque and Immune Activation in HIV-Infected Women

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.

Plaque burden in HIV-infected patients is associated with serum intestinal microbiota-generated trimethylamine

Objective:Some intestinal microbiota-generated metabolites of phosphatidylcholine are recognized to be proatherogenic. As the HIV population is vulnerable to cardiovascular disease and can develop intestinal dysbiosis associated with systemic inflammation, we investigated the novel relationship between microbiota-derived metabolites of phosphatidylcholine and coronary atherosclerosis in HIV. Design/Methods:One hundred and fifty-five HIV-infected and 67 non-HIV-infected individuals without known history of cardiovascular disease were previously recruited to assess coronary plaque by computed tomography angiography. In the current study, we evaluate whether serum choline, trimethylamine (TMA), or trimethylamine-N-oxide (TMAO) levels are associated with plaque features. Results:Young, asymptomatic HIV-infected patients (age 47 ± 7 years) demonstrated significantly higher prevalence of plaque (53 vs. 35%, P = 0.01) and number of total plaque segments (1.8 ± 2.5 vs. 1.2 ± 2.2, P = 0.03) when compared with well matched noninfected individuals with similar comorbidities. TMA was significantly associated with calcium score (r = 0.22, P = 0.006), number of total (r = 0.20, P = 0.02) and calcified (r = 0.18, P = 0.03) plaque segments, and calcium plaque volume (r = 0.19, P = 0.02) and mass (r = 0.22, P = 0.009) in the HIV cohort only. In multivariate modeling among HIV-infected patients, TMA remained significantly associated with calcium score (P = 0.008), number of total (P = 0.005) and calcified (P = 0.02) plaque segments, and calcium plaque volume (P = 0.01) and mass (P = 0.007), independent of Framingham risk score. In contrast, there was no association of TMAO to coronary plaque features in either cohort. Conclusion:A link between TMA and atherosclerosis has not previously been established. The current study suggests that TMA may be a nontraditional risk factor related to the number of plaque segments and severity of calcified plaque burden in HIV.

RAAS Activation Is Associated With Visceral Adiposity and Insulin Resistance Among HIV-infected Patients

CONTEXT Little is known about renin-angiotensin-aldosterone system (RAAS) activation in relationship to visceral adipose tissue (VAT) accumulation in HIV-infected patients, a population at significant risk for insulin resistance and other metabolic disease. DESIGN Twenty HIV and 10 non-HIV-infected subjects consumed a standardized low sodium or liberal sodium diet to stimulate or suppress the RAAS, respectively. RAAS parameters were evaluated in response to each diet and a graded angiotensin II infusion. Further analyses were performed after groups were substratified by median VAT measured by magnetic resonance imaging. RESULTS Aldosterone concentrations during the low-sodium diet were higher in HIV than non-HIV-infected subjects [13.8 (9.7, 30.9) vs 9.2 (7.6, 13.6) ng/dL, P = .03] and increased across groups stratified by visceral adipose tissue (VAT) [8.5 (7.1, 12.8), 9.2 (8.1, 21.5), 11.4 (9.4, 13.8), and 27.2 (13.0, 36.9) ng/dL in non-HIV-infected without increased VAT, non-HIV-infected with increased VAT, HIV-infected without increased VAT, HIV-infected with increased VAT, respectively, overall trend P = .02]. Under this condition, plasma renin activity [3.50 (2.58, 4.65) vs 1.45 (0.58, 2.33) ng/mL · h, P = .002] was higher among the HIV-infected subjects with vs without increased VAT. Differences in the suppressibility of plasma renin activity by graded angiotensin infusion were seen stratifying by VAT among the HIV-infected group (P < .02 at each dose). In addition, aldosterone (P = .007) was an independent predictor of insulin resistance in multivariate modeling, controlling for VAT and adiponectin. CONCLUSION These data suggest excess RAAS activation in relationship to visceral adiposity in HIV-infected patients that may independently contribute to insulin resistance. Mineralocorticoid blockade may have therapeutic potential to reduce metabolic complications in HIV-infected patients with increased visceral adiposity.

MECHANISMS IN ENDOCRINOLOGY: Metabolic and body composition effects of newer antiretrovirals in HIV-infected patients

In the absence of a cure, HIV-infected patients are being successfully treated with antiretroviral therapies (ART) and living longer. Indeed, an increasing number of HIV-infected patients are living beyond the age of 50 years, and in that regard, the use of ART has transformed HIV into a chronic medical condition. As more HIV-infected patients are virologically controlled and living longer, the trajectory of disease morbidity has shifted, however, primarily from opportunistic infections and immune dysfunction to metabolic complications. Evidence suggests that HIV-infected patients acquire significant metabolic risks, including lipodystrophic changes, subclinical atherosclerosis, and insulin resistance. The etiology of these metabolic complications specifically in HIV-infected patients is not entirely clear but may be related to a complex interaction between long-term consequences of infection and HIV itself, chronic use of antiretrovirals, and underlying inflammatory processes. Previous classes of ART, such as protease inhibitors (PIs) and reverse transcriptase inhibitors, have been implicated in altering fat redistribution and lipid and glucose homeostasis. Advances in drug development have introduced newer ART with strategies to target novel mechanisms of action and improve patient adherence with multi-class drug combinations. In this review, we will focus on these newer classes of ART, including selected entry inhibitors, integrase inhibitors, and multi-class drug combinations, and two newer PIs, and the potential of these newer agents to cause metabolic complications in HIV-infected patients. Taken together, further reduction of morbidity in HIV-infected patients will require increasing awareness of the deleterious metabolic complications of ART with subsequent management to mitigate these risks.

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

Few studies have investigated irisin and FGF21 to elucidate the role of these hormones to regulate ‘beiging’ in HIV‐infected patients.

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

Abstract: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 (&rgr; = −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.

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.

Reduced ovarian reserve relates to monocyte activation and subclinical coronary atherosclerotic plaque in women with HIV

Objective:To investigate differences in subclinical coronary atherosclerotic plaque and markers of immune activation among HIV-infected and non-HIV-infected women categorized by degree of ovarian reserve and menopause status. Design:Cross-sectional evaluation. Methods:Seventy-four women (49 HIV-infected, 25 non-HIV-infected) without known cardiovascular disease (CVD) were classified as premenopausal, premenopausal with reduced ovarian reserve, or postmenopausal based on menstrual history and anti-Müllerian hormone (AMH) levels. Participants underwent contrast-enhanced coronary computed tomography angiography and immune phenotyping. Comparisons in coronary atherosclerotic plaque burden and immune markers were made between the HIV-infected and non-HIV-infected women overall and within the HIV-infected and non-HIV-infected women by reproductive classification group. Results:Among the overall group of HIV-infected women, the women with reduced ovarian reserve (undetectable AMH) had a higher prevalence of coronary atherosclerotic plaque (52 versus 6%, P = 0.0007) and noncalcified plaque (48 versus 6%, P = 0.002), as well as higher levels of log sCD163 (P = 0.0004) and log MCP-1 (P = 0.006), compared with the premenopausal women with measurable AMH. Furthermore, reduced ovarian reserve in the HIV-infected group related to noncalcified plaque, controlling for traditional CVD risk factors (P = 0.04) and sCD163 (P = 0.03). Conclusion:HIV-infected women with reduced ovarian reserve have increased subclinical coronary atherosclerotic plaque compared with premenopausal women in whom AMH is measurable. This relationship holds when controlling for CVD risk factors (including age) and immune activation. Our findings demonstrate that reduced ovarian reserve may contribute to CVD burden in HIV-infected women and support a comprehensive assessment of CVD risk prior to completion of menopause in this population.

Acute hyperinsulinemia effects on systemic markers of immune activation in HIV

&NA; The well treated HIV population remains at risk for insulin resistance and chronic immune activation. We tested the effects of acute hyperinsulinemia on inflammation in HIV. Twenty HIV-infected and 10 non-HIV-infected individuals well matched for BMI underwent oral glucose tolerance testing to stimulate insulin secretion and assess for changes in circulating soluble CD163, soluble CD14, and monocyte chemoattract protein 1. Soluble CD14 decreased significantly after stimulation of hyperinsulinemia and no significant changes in soluble CD163 or monocyte chemoattract protein 1 were demonstrated in HIV-infected and non-HIV-infected groups.