CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

774

Endothelial Microvesicles: Circulating Biomarker and Mediator of Vascular Dysfunction With HIV-1 Emily I Ostrander 1 , Vinicius P. Garcia 1 , Hannah K. Fandl 1 , Auburn R. Berry 1 , Hannah L. Cardenas 1 , Jared J. Greiner 1 , Brian L. Stauffer 1 , Elizabeth Connick 2 , Christopher DeSouza 1 1 University of Colorado Boulder, Boulder, CO, USA, 2 University of Arizona, Tucson, AZ, USA Background: We have previously reported that circulating endothelial cell derived extracellular microvesicles (EMVs) are elevated in adults living with HIV (ALWH) receiving antiretroviral therapy (ART) contributing to endothelial vasodilator dysfunction by negatively affecting endothelial nitric oxide synthase (eNOS) and, in turn, impairing NO production. However, whether elevations in circulating EMVs and their pathologic effects on endothelial NO production was a direct effect of HIV-1 or a consequence of ART is unknown. The experimental aims of this study were to determine: 1) whether circulating EMVs are elevated in treatment-naïve ALWH and associated with HIV-1-related endothelial vasodilator dysfunction; and 2) the effects of EMVs isolated from treatment naïve ALWH on endothelial cell NO production, in vitro. Methods: Twenty-four sedentary, adults were studied: 12 healthy (10M/2F; age 35±2 yr) and 12 treatment naïve ALWH (10M/2F; 35±2 yr; viral load: 7342 copies/mL). All subjects were non-obese, normotensive, normolipidemic and free of overt cardiometabolic disease. Circulating EMV (CD144-PE) number was determined by flow cytometry. Forearm blood flow (FBF: via plethysmography) was assessed by intra-arterial infusion of acetylcholine and sodium nitroprusside. Human coronary artery endothelial cells were cultured and treated with EMVs (CD144-PE) isolated from the healthy and treatment naïve ALWH. Results: Circulating EMVs were ~75% higher (P<0.05) in the treatment naïve ALWH (234±20 EMV/μL) vs healthy (135±13 EMV/μL) adults. FBF responses to acetylcholine were significantly lower (~20%) in the treatment naïve ALWH adults (from 5.6±0.3 to 12.6±1.1 mL/100 mL tissue/min vs 4.9±0.2 to 15.8±1.1 mL/100 mL tissue/min). There were no significant differences between the groups in FBF response to sodium nitroprusside. EMVs were strongly and inversely associated with the vasodilator response to acetylcholine (r=-0.49; P=0.01). Moreover, expression of phosphorylated eNOS (78.5±6.1 vs 102.9±7.9 AU) and NO production (6.0±0.4 vs 7.3±0.4 μmol/L) was significantly lower in cells treated with EMVs from treatment naïve ALWH vs healthy adults. Conclusion: HIV-1 is associated with elevated circulating EMVs. Moreover, circulating EMVs are not only a systemic biomarker, but appear to be a mechanistic factor underlying endothelial dysfunction with HIV-1. Circulating EMVs represent a novel causative factor underlying vascular abnormalities and the increased CVD risk associated with HIV-1. Transcriptional Signatures Underlying Cardiovascular Disease in Persons Living With HIV Laventa Obare 1 , Heather Beasley 1 , Xiuqi Zhang 1 , Andrea G. Marshall 1 , Rama D. Gangula 1 , Yan Ru Su 1 , Tarek Absi 1 , Sara Gianella 2 , Melanie R. McReynolds 3 , Antentor O. Hinton 1 , Celestine Wanjalla 1 1 Vanderbilt University, Nashville, TN, USA, 2 University of California San Diego, La Jolla, CA, USA, 3 Pennsylvania State University, University Park, PA, USA Background: While statins for primary prevention reduce cardiovascular events, persons with HIV (PWH) have increased risk of cardiovascular disease, likely linked to persistent inflammation. Studies on immune drivers of atherosclerosis among PWH are needed to define additional therapeutic targets. Methods: We obtained thoracic aorta from diseased PWH (n=3) and without HIV (n=14). Autopsies were performed within 25 hours of death. The donors with HIV included 1 female (Caucasian) and 2 males (Caucasian and Hispanic) ages 52, 65 and 72. Exclusion criteria included known autoimmune disease. We used droplet digital polymerase chain reaction (ddPCR), western blot and immunohistochemistry to detect and quantify HIV. We used spatial transcriptomics (Visium) and metabolomics to define differences in aorta by HIV status (n=4 per group). Differentially expressed genes were identified using the Loupe Browser 6 software, based on their statistical significance and fold change computed using the negative binomial test. Genes with adjusted p-values, FDR < 0.05, were considered significantly different. Global metabolomic profiling of aorta was performed using ultrasensitive Hydrophilic Interaction Liquid Chromatography-Mass Spectrometry (HILIC-MS). We detected over 320 metabolites in both (+) and (-) ionization modes. Analysis was performed using MetaboAnalyst 5.0.

773

Relating Pitavastatin Effects on Inflammatory Biomarkers to Plaque Changes in REPRIEVE Steven Grinspoon 1 , Michael T. Lu 1 , Sara McCallum 1 , Markella Zanni 1 , Borek Foldyna 1 , Kayla Paradis 1 , Carl J. Fichtenbaum 2 , Judith A. Aberg 3 , Gerald S. Bloomfield 4 , Carlos D. Malvestutto 5 , Judith S. Currier 6 , Thomas Mayrhofer 1 , Julia Karady 1 , Heather J. Ribaudo 7 , Pamela S. Douglas 8 1 Massachusetts General Hospital, Boston, MA, USA, 2 University of Cincinnati, Cincinnati, OH, USA, 3 Icahn School of Medicine at Mt Sinai, New York, NY, USA, 4 Duke University, Durham, NC, USA, 5 The Ohio State University, Columbus, OH, USA, 6 University of California Los Angeles, Los Angeles, CA, USA, 7 Harvard TH Chan School of Public Health, Boston, MA, USA, 8 Duke University School of Medicine, Durham, NC, USA Background: The REPRIEVE trial demonstrated that pitavastatin reduced the risk of major adverse cardiovascular events (MACE) by 35% and LDL by 30% compared to placebo over median 5.1 years of follow up. The REPRIEVE mechanistic study further demonstrated pitavastatin was associated with a significant reduction in progression of noncalcified coronary plaque volume compared to placebo as well as changes in oxLDL and LpPLA2. This analysis further interrogates these findings to examine whether pitavastatin effects on lipids and these inflammatory biomarkers relate to changes in plaque. Methods: Coronary plaque volume was assessed at baseline and 24 months by CT angiography, using a threshold of <350 HU to define noncalcified plaque. Biomarker changes were analyzed on the log2 scale. Pearson correlation was used to assess associations between changes in LDL, biomarkers, and plaque (0 to 24 months). For this mechanistic assessment, analyses were restricted to participants who remained on randomized treatment for 24 months with biomarkers assessed. Results: The 604 participants (304 pitavastatin, 300 placebo) included in the analysis were representative of the substudy population (mean age 51 years, sex 17% female, CVD risk median 4.6%). Over 24 months, pitavastatin was associated with a 19% [95% CI 8, 29] reduction in oxLDL and a 10% [-6, 14] reduction in LpPLA2 compared to neutral changes or increases in the placebo group. Corresponding mean fold changes in each group were 0.81 [0.71, 0.92] vs. 1.00 [0.89, 1.13] for oxLDL and 0.90 [0.87, 0.94] vs. 1.17 [1.13, 1.21] for LpPLA2, pitavastatin vs. placebo, respectively. No associations between changes in LDL, oxLDL, or LpPLA2, and either non-calcified or total plaque volume were apparent (|rho| < 0.15, Figure). Adjustment for changes in the biomarkers did not impact the effect of pitavastatin to reduce noncalcified plaque. Similar results were seen in the entire substudy population and the subset with plaque at baseline. Conclusion: Pitavastatin significantly reduced LDL and key biomarkers of lipid oxidation and arterial inflammation in REPRIEVE, but these changes were not associated with changes in noncalcified or total plaque volumes. Further studies will assess effects of these pathways on MACE and also the effects of pitavastatin on other mechanistic pathways which might link statin effects to improvements in coronary artery disease indices and MACE in PWH.

Poster Abstracts

775

CROI 2024 232