Statin-dependent and -independent pathways are associated with major adverse cardiovascular events in people with HIV
Márton Kolossváry, Irini Sereti, Markella V. Zanni, Carl J. Fichtenbaum, Judith A. Aberg, Gerald S. Bloomfield, Carlos D. Malvestutto, Judith S. Currier, Sarah M. Chu, Marissa R. Diggs, Alex B. Lu, Christopher deFilippi, Borek Foldyna, Sara McCallum, Craig A. Sponseller, Michael T. Lu, Pamela S. Douglas, Heather J. Ribaudo, Steven K. Grinspoon
Márton Kolossváry, Irini Sereti, Markella V. Zanni, Carl J. Fichtenbaum, Judith A. Aberg, Gerald S. Bloomfield, Carlos D. Malvestutto, Judith S. Currier, Sarah M. Chu, Marissa R. Diggs, Alex B. Lu, Christopher deFilippi, Borek Foldyna, Sara McCallum, Craig A. Sponseller, Michael T. Lu, Pamela S. Douglas, Heather J. Ribaudo, Steven K. Grinspoon
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Clinical Research and Public Health AIDS/HIV Cardiology Inflammation

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

Abstract

BACKGROUND Statin 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).METHODS Cox 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.RESULTS For 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).CONCLUSIONS ANGPTL3, as well as key inflammatory pathways, may contribute to a residual risk of MACE among PWH, beyond LDL-C.TRIAL REGISTRATION ClinicalTrials.gov: NCT02344290.FUNDING NIH, Kowa Pharmaceuticals America, Gilead Sciences, ViiV Healthcare.

Authors

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

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Figure 2

Association between proteomics markers and MACE or hard MACE.

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Association between proteomics markers and MACE or hard MACE. (A) Volcan...
(A) Volcano plot of HRs and P values for given proteins and MACE. HRs were estimated from Cox proportional hazards models using both potential proteomics measurements including statin use as a time-dependent covariate and 10-year baseline ASCVD risk score. HRs are per protein doubling. Red proteins indicate associations at an FDR below 0.05 level. The x axis is on a log2 scale. Dotted line indicates a nominal P value of 0.05. Dashed line indicates a HR of 1. (B) Volcano plot of HRs and P values for given proteins and hard MACE. Hard MACE is defined as cardiovascular death, myocardial infarction, or stroke. HRs were estimated from Cox proportional hazards models using both potential proteomics measurements including statin use as a time-dependent covariate and baseline 10-year ASCVD risk score. HRs are per protein doubling. Red proteins indicate associations at an FDR below 0.05. The x axis is on a log2 scale. Dotted line indicates a nominal P value of 0.05. Dashed line indicates a HR of 1. ANGPT2, angiopoietin-2; CD70, CD70 antigen; CD83, CD83 antigen; CSF1, processed macrophage colony-stimulating factor 1; CXCL13, C-X-C motif chemokine 13; FABP4, fatty acid–binding protein, adipocyte; GAL9, galectin-9; GRN, paragranulin; HGF, hepatocyte growth factor α chain; MCP2, C-C motif chemokine 8; MCP3, C-C motif chemokine 7; NOS3, nitric oxide synthase, endothelial; NT-PROBNP, NT-proBNP; OPN, osteopontin; PDCD1, programmed cell death protein 1; SHPS1, tyrosine-protein phosphatase non-receptor-type substrate 1; TCN2, transcobalamin-2; TNFRSF9, TNF receptor superfamily member 9; TNFSF13B, TNF ligand superfamily member 13b, membrane form; VEGFA, vascular endothelial growth factor A.