Statin-dependent and -independent pathways are associated with major adverse cardiovascular events in people with HIV

BACKGROUNDStatin therapy lowers the risk of major adverse cardiovascular events (MACE) among people with HIV (PWH). Residual risk pathways contributing to excess MACE beyond LDL-cholesterol (LDL-C) are not well understood. Our objective was to evaluate the association of statin-responsive and other inflammatory and metabolic pathways with MACE in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE).METHODSCox proportional hazards models were used to assess the relationship between MACE and proteomics measurements at study entry and year 2, adjusting for time-updated statin use and the baseline 10-year atherosclerotic cardiovascular disease risk score. We built a machine-learning (ML) model to predict MACE using baseline protein values with significant associations.RESULTSFor 765 individuals (age: 50.8 ± 5.9 years, 82% men, 18% women), among 7 proteins changing with statin versus placebo, angiopoietin-related protein 3 (ANGPTL3) related most strongly to MACE (adjusted HR [aHR]: 2.31 per 2-fold-higher levels; 95% CI: 1.11-4.80; P = 0.03), such that lower levels of ANGPTL3 achieved with statin therapy were associated with lower MACE risk. Among 248 proteins that did not change in response to statin therapy, 26 were associated with MACE at a FDR below 0.05. These proteins represented a predominantly humoral immune response, leukocyte chemotaxis, and cytokine pathways. Our proteomics ML model achieved a 10-fold cross-validated concordance index (C-index) of 0.74 ± 0.11 to predict MACE, improving on models using traditional risk prediction scores only (C-index: 0.61 ± 0.18).CONCLUSIONSANGPTL3, as well as key inflammatory pathways, may contribute to a residual risk of MACE among PWH, beyond LDL-C.TRIAL REGISTRATIONClinicalTrials.gov: NCT02344290.FUNDINGNIH, Kowa Pharmaceuticals America, Gilead Sciences, ViiV Healthcare.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-09-09
DOI
https://doi.org/10.1172/jci196021
Citations
3
Primary Topic
HIV-related health complications and treatments
Type
article
Field-Weighted Citation Impact
6.76

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article

Statin-dependent and -independent pathways are associated with major adverse cardiovascular events in people with HIV

Márton Kolossváry, Markella V. Zanni, Heather J. Ribaudo, Carl J. Fichtenbaum et al.
3 citations
Journal of Clinical Investigation
HIV-related health complications and treatments
6.76
article

Statin-dependent and -independent pathways are associated with major adverse cardiovascular events in people with HIV

Márton Kolossváry, Markella V. Zanni, Heather J. Ribaudo, Carl J. Fichtenbaum, Sarah M Chu, Craig A. Sponseller, Amy Shirong Lu, Borek Foldyna, Pamela S. Douglas, Steven Grinspoon, Michael T. Lu, Christopher R. deFilippi, Carlos Malvestutto, Gerald S. Bloomfield, Marissa R Diggs, Judith S. Currier, Sara McCallum, Judith A. Aberg, Irini Sereti
article en
3 citations

Abstract

BACKGROUNDStatin therapy lowers the risk of major adverse cardiovascular events (MACE) among people with HIV (PWH). Residual risk pathways contributing to excess MACE beyond LDL-cholesterol (LDL-C) are not well understood. Our objective was to evaluate the association of statin-responsive and other inflammatory and metabolic pathways with MACE in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE).METHODSCox proportional hazards models were used to assess the relationship between MACE and proteomics measurements at study entry and year 2, adjusting for time-updated statin use and the baseline 10-year atherosclerotic cardiovascular disease risk score. We built a machine-learning (ML) model to predict MACE using baseline protein values with significant associations.RESULTSFor 765 individuals (age: 50.8 ± 5.9 years, 82% men, 18% women), among 7 proteins changing with statin versus placebo, angiopoietin-related protein 3 (ANGPTL3) related most strongly to MACE (adjusted HR [aHR]: 2.31 per 2-fold-higher levels; 95% CI: 1.11-4.80; P = 0.03), such that lower levels of ANGPTL3 achieved with statin therapy were associated with lower MACE risk. Among 248 proteins that did not change in response to statin therapy, 26 were associated with MACE at a FDR below 0.05. These proteins represented a predominantly humoral immune response, leukocyte chemotaxis, and cytokine pathways. Our proteomics ML model achieved a 10-fold cross-validated concordance index (C-index) of 0.74 ± 0.11 to predict MACE, improving on models using traditional risk prediction scores only (C-index: 0.61 ± 0.18).CONCLUSIONSANGPTL3, as well as key inflammatory pathways, may contribute to a residual risk of MACE among PWH, beyond LDL-C.TRIAL REGISTRATIONClinicalTrials.gov: NCT02344290.FUNDINGNIH, Kowa Pharmaceuticals America, Gilead Sciences, ViiV Healthcare.

Journal of Clinical InvestigationVol. 135(22)
Boston University (US), Harvard University (US), Alabama State University (US), University of California, Los Angeles (US), Duke University (US), Montgomery Botanical Center (US), The Ohio State University Wexner Medical Center (US), Gordon Center for Medical Imaging (US), Massachusetts General Hospital (US), Clinical Research Institute (US), Cancer Research And Biostatistics (US), Duke Institute for Health Innovation (US), National Institute of Allergy and Infectious Diseases (US), Alaska Heart and Vascular Institute (US), The Ohio State University (US), University of Cincinnati Medical Center (US), Icahn School of Medicine at Mount Sinai (US)
American Heart Association, Amgen, Eli Lilly and Company, Pfizer, AstraZeneca, Massachusetts General Hospital, Gilead Sciences, Regeneron Pharmaceuticals, ViiV Healthcare, ACT Government, Kowa Company, MacroGenics, Siemens Healthineers, National Institutes of Health, Abbott Diagnostics, Nutrition Obesity Research Center at Harvard, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases
Openalex Percentile: Top 3%
HIV-related health complications and treatments
6.76
DOIOpen Access PDFOpenAlex
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