Persistent immune activation is thought to contribute to heightened atherosclerotic cardiovascular disease (ASCVD) risk among people with human immunodeficiency virus (PWH).
Participants (≥18 years) ...with or without human immunodeficiency virus (HIV) and without history of clinical ASCVD were enrolled. We hypothesized that increased macrophage-specific arterial infiltration would relate to plaque composition and systemic immune activation among PWH. We applied a novel targeted molecular imaging approach (technetium-99m 99mTc-tilmanocept single photon emission computed tomography SPECT/CT) and comprehensive immune phenotyping.
Aortic 99mTc-tilmanocept uptake was significantly higher among PWH (n = 20) than participants without HIV (n = 10) with similar 10-year ASCVD risk (P = .02). Among PWH, but not among participants without HIV, noncalcified aortic plaque volume related directly to aortic 99mTc-tilmanocept uptake at different uptake thresholds. An interaction (P = .001) was seen between HIV status and noncalcified plaque volume, but not calcified plaque (P = .83). Systemic levels of caspase-1 (P = .004), CD14-CD16+ (nonclassical/patrolling/homing) monocytes (P = .0004) and CD8+ T cells (P = .005) related positively and CD4+/CD8+ T-cell ratio (P = .02) inversely to aortic 99mTc-tilmanocept uptake volume.
Macrophage-specific arterial infiltration was higher among PWH and related to noncalcified aortic plaque volume only among PWH. Key systemic markers of immune activation relating to macrophage-specific arterial infiltration may contribute to heightened ASCVD risk among PWH.
NCT02542371.
Objective Basal (unstimulated) LH levels and leuprolide stimulation tests are used to define pubertal status of children presenting with signs of early puberty. The primary aims of this study were to ...(i) confirm utility of detectable basal LH levels in precluding the need for leuprolide stimulation testing, and, (ii) determine whether duration of testing could be abbreviated from usual 3 h test without compromising sensitivity. Methods We reviewed morning basal and leuprolide-stimulated LH levels in 105 children, aged 1-9 years (mean 6.9 years, SD 1.8) who were seen for concerns of precocious puberty and received a leuprolide stimulation test between June 2006 and March 2017. Results A pubertal basal LH level had high specificity and poor sensitivity for the following outcome measures: (1) peak stimulated LH≥5 mIU/mL (2) treatment with GnRHa; and (3) a composite outcome of (1) and/or (2). Following leuprolide stimulation, LH response was highest at 180 min in most children (n=78, 74.3%). Using a single cutoff of LH≥5 mIU/mL at any timepoint, 25% of children would have been misdiagnosed with an abbreviated 60 min test. A single sample at 180 min would have correctly identified 97% of patients. Conclusions A pubertal basal LH level is sufficient to distinguish children with precocious puberty without stimulation testing. However, prepubertal basal LH had relatively poor negative predictive value to refute CPP, necessitating clinical follow-up and/or a leuprolide stimulation test. For a cutoff of LH≥5 mIU/mL at any timepoint, test duration of 180 min maximizes sensitivity.
Obesity is increasing at an alarming rate. The effectiveness of currently available strategies for the treatment of obesity (including pharmacologic, surgical, and behavioral interventions) is ...limited. Understanding the neurobiology of appetite and the important drivers of energy intake (EI) can lead to the development of more effective strategies for the prevention and treatment of obesity. Appetite regulation is complex and is influenced by genetic, social, and environmental factors. It is intricately regulated by a complex interplay of endocrine, gastrointestinal, and neural systems. Hormonal and neural signals generated in response to the energy state of the organism and the quality of food eaten are communicated by paracrine, endocrine, and gastrointestinal signals to the nervous system. The central nervous system integrates homeostatic and hedonic signals to regulate appetite. Although there has been an enormous amount of research over many decades regarding the regulation of EI and body weight, research is only now yielding potentially effective treatment strategies for obesity. The purpose of this article is to summarize the key findings presented in June 2022 at the 23rd annual Harvard Nutrition Obesity Symposium entitled “The Neurobiology of Eating Behavior in Obesity: Mechanisms and Therapeutic Targets.” Findings presented at the symposium, sponsored by NIH P30 Nutrition Obesity Research Center at Harvard, enhance our current understanding of appetite biology, including innovative techniques used to assess and systematically manipulate critical hedonic processes, which will shape future research and the development of therapeutics for obesity prevention and treatment.
Women with HIV (WHIV) on anti-retroviral therapy (ART) are living longer but facing heightened vulnerability to heart failure.
We investigated metabolic/hormonal/immune parameters relating to ...diastolic dysfunction-a precursor to heart failure-among WHIV without known cardiovascular disease (CVD).
Nineteen ART-treated WHIV and 11 non-HIV-infected women without known CVD enrolled and successfully completed relevant study procedures cardiac magnetic resonance spectroscopy (MRS) and cardiac MRI. Groups were matched on age and body mass index. Primary outcome measures included intramyocardial triglyceride content (cardiac MRS) and diastolic function (cardiac MRI). Relationships between intramyocardial triglyceride content and clinical parameters were also assessed.
Among WHIV (vs non-HIV-infected women), intramyocardial triglyceride content was threefold higher 1.2 (0.4, 3.1) vs 0.4 (0.1, 0.5)%, P = 0.01, and diastolic function was reduced (left atrial passive ejection fraction: 27.2 ± 9.6 vs 35.9 ± 6.4%, P = 0.007). There was a strong inverse relationship between intramyocardial triglyceride content and diastolic function (ρ = -0.62, P = 0.004). Among the whole group, intramyocardial triglyceride content did not relate to chronologic age but did increase across the reproductive aging spectrum (P = 0.02). HIV status and reproductive aging status remained independent predictors of intramyocardial triglyceride content after adjusting for relevant cardiometabolic parameters (overall model R2 = 0.56, P = 0.003; HIV status P = 0.01, reproductive aging status P = 0.02).
For asymptomatic WHIV, increased intramyocardial triglyceride content is associated with diastolic dysfunction. Moreover, relationships between intramyocardial triglyceride accumulation and women's reproductive aging are noted.
Women with HIV (WWH) have heightened heart failure risk. Plasma OPN (osteopontin) is a powerful predictor of heart failure outcomes in the general population. Limited data exist on relationships ...between plasma OPN and surrogates of HIV-associated heart failure risk.
Prospective, cross-sectional.
We analyzed relationships between plasma OPN and cardiac structure/function (assessed using cardiovascular magnetic resonance imaging) and immune activation (biomarkers and flow cytometry) among 20 WWH and 14 women without HIV (WWOH).
Plasma OPN did not differ between groups. Among WWH, plasma OPN related directly to the markers of cardiac fibrosis, growth differentiation factor-15 (ρ = 0.51, P = 0.02) and soluble interleukin 1 receptor-like 1 (ρ = 0.45, P = 0.0459). Among WWH (but not among WWOH or the whole group), plasma OPN related directly to both myocardial fibrosis (ρ = 0.49, P = 0.03) and myocardial steatosis (ρ = 0.46, P = 0.0487). Among the whole group and WWH (and not among WWOH), plasma OPN related directly to the surface expression of C-X3-C motif chemokine receptor 1 (CX3CR1) on nonclassical (CD14-CD16+) monocytes (whole group: ρ = 0.36, P = 0.04; WWH: ρ = 0.46, P = 0.04). Further, among WWH and WWOH (and not among the whole group), plasma OPN related directly to the surface expression of CC motif chemokine receptor 2 (CCR2) on inflammatory (CD14+CD16+) monocytes (WWH: ρ = 0.54, P = 0.01; WWOH: ρ = 0.60, P = 0.03), and in WWH, this held even after controlling for HIV-specific parameters.
Among WWH, plasma OPN, a powerful predictor of heart failure outcomes, related to myocardial fibrosis and steatosis and the expression of CCR2 and CX3CR1 on select monocyte subpopulations. OPN may play a role in heart failure pathogenesis among WWH.
NCT02874703.
Abstract
Background
People with human immunodeficiency virus (PWH) demonstrate increased atherosclerotic cardiovascular disease (ASCVD). Statins are being studied to prevent ASCVD in human ...immunodeficiency virus (HIV), but little is known regarding the effects of statins on a broad range of inflammatory and cardiovascular proteins in this population.
Methods
We used a highly specific discovery proteomic approach (Protein Extension Assay), to determine statin effects on over 350 plasma proteins in relevant ASCVD pathways among HIV and non-HIV groups. Responses to pitavastatin calcium were assessed in 89 PWH in the INTREPID trial and 46 non-HIV participants with features of central adiposity and insulin resistance. History of cardiovascular disease was exclusionary for both studies.
Results
Among participants with HIV, PCOLCE (enzymatic cleavage of type I procollagen) significantly increased after pitavastatin therapy and PLA2G7 (systemic marker of arterial inflammation) decreased. Among participants without HIV, integrin subunit alpha M (integrin adhesive function) and defensin alpha-1 (neutrophil function) increased after pitavastatin therapy and PLA2G7 decreased. At baseline, comparing participants with and without HIV, differentially expressed proteins included proteins involved in platelet and endothelial function and immune activation.
Conclusions
Pitavastatin affected proteins important to platelet and endothelial function and immune activation, and effects differed to a degree within PWH and participants without HIV.
We assessed the effects of pitavastatin on a broad array of proteins using a highly specific proximity extension assay (PEA) in HIV and metabolic syndrome non-HIV patients. Our results highlight effects on key inflammatory, collagen, neutrophil, and integrin functions.
BACKGROUND:HIV-negative individuals with in utero HIV exposure represent an emerging population, exceeding 18 million people worldwide. Long-term clinical outcomes among HIV-exposed uninfected (HEU) ...individuals into adolescence and young adulthood remain unknown.
SETTING:US academic health system.
METHODS:In this observational cohort study, we leveraged a patient data registry to identify 50 HEU adolescents and young adults. We also identified 141 HIV-unexposed controls that were matched to HEU subjects up to 3:1 on age of last encounter (±2 years), birthdate (±5 years), sex, race/ethnicity, and zip code. All subjects were born since January 1, 1990, with medical records available into adolescence and young adulthood. Primary outcomes were most recent body mass index (BMI) z-score and presence of reactive airway disease (RAD). Records were manually reviewed to extract health information.
RESULTS:Fifty HEU adolescents and young adults (18 ± 3 years, 54% men) and 141 matched controls (19 ± 3 years, 54% men) were compared. HEU individuals had a higher BMI z-score (1.12 ± 1.08 vs. 0.73 ± 1.09, P = 0.03) and an increased prevalence of obesity (42% vs. 22%, P = 0.009) compared with controls. HEU subjects also had a higher prevalence of RAD vs. controls (40% vs. 23%, P = 0.03). These differences persisted on adjusting for demographic, socioeconomic, maternal, and birth-related factors. Maternal prenatal CD4 T-cell count was inversely associated with BMI z-score among HEU adolescents (r = −0.47, P = 0.01).
CONCLUSIONS:HEU adolescents and young adults exhibited a heightened prevalence of obesity and RAD compared with HIV-unexposed controls. Additional studies are needed to optimize care for the expanding population of HEU individuals transitioning to adulthood.
Abstract
Background
The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis modulates critical metabolic pathways; however, little is known regarding effects of augmenting pulsatile GH ...secretion on immune function in humans. This study used proteomics and gene set enrichment analysis to assess effects of a GH releasing hormone (GHRH) analog, tesamorelin, on circulating immune markers and liver tissue in people with human immunodeficiency virus (HIV) (PWH) and nonalcoholic fatty liver disease (NAFLD).
Methods
92 biomarkers associated with immunity, chemotaxis, and metabolism were measured in plasma samples from 61 PWH with NAFLD who participated in a double-blind, randomized trial of tesamorelin versus placebo for 12 months. Gene set enrichment analysis was performed on serial liver biopsies targeted to immune pathways.
Results
Tesamorelin, compared to placebo, decreased interconnected proteins related to cytotoxic T-cell and monocyte activation. Circulating concentrations of 13 proteins were significantly decreased, and no proteins increased, by tesamorelin. These included 4 chemokines (CCL3, CCL4, CCL13 MCP4, IL8 CXCL8), 2 cytokines (IL-10 and CSF-1), and 4 T-cell associated molecules (CD8A, CRTAM, GZMA, ADGRG1), as well as ARG1, Gal-9, and HGF. Network analysis indicated close interaction among the gene pathways responsible for these proteins, with imputational analyses suggesting down-regulation of a closely related cluster of immune pathways. Targeted transcriptomics using liver tissue confirmed a significant end-organ signal of down-regulated immune activation pathways.
Conclusions
Long-term treatment with a GHRH analog reduced markers of T-cell and monocyte/macrophage activity, suggesting that augmentation of the GH axis may ameliorate immune activation in an HIV population with metabolic dysregulation, systemic and end organ inflammation.
Clinical Trials Registration. NCT02196831.
Treatment with a growth hormone releasing hormone analog in people with human immunodeficiency virus and nonalcoholic fatty liver disease decreased circulating proteins associated with immune activation pathways. Gene set enrichment analysis of RNA-seq in liver confirmed down-regulation of end-organ immune activation pathways.
Abstract
Context
HIV-infected individuals demonstrate increased renin-angiotensin-aldosterone system activation in association with visceral adiposity, insulin resistance, and inflammation. A ...physiologically based treatment approach targeting mineralocorticoid receptor (MR) blockade may improve metabolic and inflammatory indices in HIV.
Objective
To investigate effects of eplerenone on insulin sensitivity, inflammatory indices, and other metabolic parameters in HIV.
Design
Six-month, double-blind, randomized, placebo-controlled trial.
Setting
Academic clinical research center.
Participants
HIV-infected individuals with increased waist circumference and abnormal glucose homeostasis.
Intervention
Eplerenone 50 mg or placebo daily.
Outcome
The primary end point was change in insulin sensitivity measured by the euglycemic-hyperinsulinemic clamp technique. Secondary end points included change in body composition and inflammatory markers.
Results
Forty-six individuals were randomized to eplerenone (n = 25) vs placebo (n = 21). Eplerenone did not improve insulin sensitivity 0.48 (−1.28 to 1.48) vs 0.43 (−1.95 to 2.55) mg/min/μIU/mL insulin; P = 0.71, eplerenone vs placebo when measured by the gold standard euglycemic-hyperinsulinemic clamp technique. Intramyocellular lipids (P = 0.04), monocyte chemoattractant protein-1 (P = 0.04), and high-density lipoprotein (P = 0.04) improved among those randomized to eplerenone vs placebo. Trends toward decreases in interleukin-6 (P = 0.10) and high-sensitivity C-reactive protein (P = 0.10) were also seen with eplerenone vs placebo. Plasma renin activity and aldosterone levels increased in the eplerenone vs placebo-treated group, demonstrating expected physiology. MR antagonism with eplerenone was well tolerated among the HIV population, with no considerable changes in blood pressure or potassium.
Conclusion
MR blockade may improve selected metabolic and inflammatory indices in HIV-infected individuals. Further studies are necessary to understand the clinical potential of MR antagonism in HIV.
Six months of eplerenone vs placebo has neutral effects on insulin sensitivity and improves metabolic (intramyocellular lipids and HDL) and inflammatory (MCP-1) indices among HIV-infected individuals.
HIV-exposed uninfected (HEU) individuals are predisposed to adverse health outcomes, which in part may stem from the influence of an altered intrauterine milieu on fetal programming. The placenta ...serves as a readout for the effects of the maternal environment on the developing fetus and may itself contribute to the pathogenesis of disease.
US academic health system.
We leveraged a previously established registry-based cohort of HEU adolescents and young adults to identify 26 subjects for whom placental histopathology was available. We further obtained placental tissue from 29 HIV-unexposed pregnancies for comparison. We examined differences in placental histopathology between the groups and related villous vascularity in the HEU group to prenatal maternal characteristics and long-term health outcomes.
Placentas from HEU pregnancies demonstrated a higher blood vessel count per villus as compared with controls (5.9 ± 1.0 vs. 5.4 ± 0.8; P = 0.05), which was independent of maternal prenatal age, race, body mass index, smoking status, hemoglobin, and gestational age. Furthermore, within the HEU group, lower CD4+ T-cell count during pregnancy was associated with greater placental vascularity (r = -0.44; P = 0.03). No significant relationships were observed between placental blood vessel count per villus and body mass index z-score or reactive airway disease among HEU individuals later in life.
Placentas from HEU pregnancies demonstrated increased villous vascularity compared with HIV-unexposed controls in proportion to the severity of maternal immune dysfunction. Further studies are needed to examine intrauterine exposure to hypoxia as a potential mechanism of fetal programming in HIV.
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