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Pitavastatin, Procollagen Pathways, and Plaque Stabilization in Patients With HIV: A Secondary Analysis of the
Márton Kolossváry1, Samuel R Schnittman1,2, Markella V Zanni1
1Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, Boston.
Importance:
In a mechanistic substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) randomized clinical trial, pitavastatin reduced noncalcified plaque (NCP) volume, but specific protein and gene pathways contributing to changes in coronary plaque remain unknown.
Objective:
To use targeted discovery proteomics and transcriptomics approaches to interrogate biological pathways beyond low-density lipoprotein cholesterol (LDL-C), relating statin outcomes to reduce NCP volume and promote plaque stabilization among people with HIV (PWH).
Design, Setting, And Participants:
This was a post hoc analysis of the double-blind, placebo-controlled, REPRIEVE randomized clinical trial. Participants underwent coronary computed tomography angiography (CTA), plasma protein analysis, and transcriptomic analysis at baseline and 2-year follow-up. The trial enrolled PWH from April 2015 to February 2018 at 31 US research sites. PWH without known cardiovascular diseases taking antiretroviral therapy and with low to moderate 10-year cardiovascular risk were eligible. Data analyses were conducted from October 2023 to February 2024.
Intervention:
Oral pitavastatin calcium, 4 mg per day.
Main Outcomes And Measures:
Relative change in plasma proteomics, transcriptomics, and noncalcified plaque volume among those receiving treatment vs placebo.
Results:
Among 558 individuals (mean [SD] age, 51 [6] years; 455 male [82%]) included in the proteomics assessment, 272 (48.7%) received pitavastatin and 286 (51.3%) received placebo. After adjusting for false discovery rates, pitavastatin increased abundance of procollagen C-endopeptidase enhancer 1 (PCOLCE), neuropilin 1 (NRP-1), major histocompatibility complex class I polypeptide-related sequence A (MIC-A) and B (MIC-B), and decreased abundance of tissue factor pathway inhibitor (TFPI), tumor necrosis factor ligand superfamily member 10 (TRAIL), angiopoietin-related protein 3 (ANGPTL3), and mannose-binding protein C (MBL2). Among these proteins, the association of pitavastatin with PCOLCE (a rate-limiting enzyme of collagen deposition) was greatest, with an effect size of 24.3% (95% CI, 18.0%-30.8%; P < .001). In a transcriptomic analysis, individual collagen genes and collagen gene sets showed increased expression. Among the 195 individuals with plaque at baseline (88 [45.1%] taking pitavastatin, 107 [54.9%] taking placebo), changes in NCP volume were most strongly associated with changes in PCOLCE (%change NCP volume/log2-fold change = -31.9%; 95% CI, -42.9% to -18.7%; P < .001), independent of changes in LDL-C level. Increases in PCOLCE related most strongly to change in the fibro-fatty (<130 Hounsfield units) component of NCP (%change fibro-fatty volume/log2-fold change = -38.5%; 95% CI, -58.1% to -9.7%; P = .01) with a directionally opposite, although nonsignificant, increase in calcified plaque (%change calcified volume/log2-fold change = 34.4%; 95% CI, -7.9% to 96.2%; P = .12).
Conclusions And Relevance:
Results of this secondary analysis of the REPRIEVE randomized clinical trial suggest that PCOLCE may be associated with the atherosclerotic plaque stabilization effects of statins by promoting collagen deposition in the extracellular matrix transforming vulnerable plaque phenotypes to more stable coronary lesions.
Trial Registration:
ClinicalTrials.gov Identifier: NCT02344290.
Insights
Pitavastatin treatment in people with HIV (PWH) increased procollagen C-endopeptidase enhancer 1 (PCOLCE) and collagen gene expression, promoting plaque stabilization. This suggests PCOLCE mediates statin
Area of Science:
- Cardiovascular Medicine
- HIV Research
- Proteomics and Transcriptomics
Background:
- The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) demonstrated pitavastatin reduces coronary noncalcified plaque (NCP) volume in people with HIV (PWH).
- However, the specific molecular pathways underlying these plaque changes remain largely unknown, particularly beyond lipid-lowering effects.
Purpose of the Study:
- To investigate the proteomic and transcriptomic changes associated with pitavastatin treatment in PWH.
- To identify biological pathways involved in NCP reduction and plaque stabilization, independent of LDL-cholesterol (LDL-C) levels.
Main Methods:
- A post hoc analysis of the REPRIEVE trial utilized proteomics and transcriptomics on plasma samples from participants at baseline and 2-year follow-up.
- Coronary computed tomography angiography (CTA) was used to assess changes in NCP volume.
- Statistical analyses were performed to correlate proteomic/transcriptomic changes with plaque volume modifications.
Main Results:
- Pitavastatin significantly altered the abundance of several plasma proteins, notably increasing procollagen C-endopeptidase enhancer 1 (PCOLCE), a key enzyme in collagen deposition.
- Transcriptomic analysis revealed increased expression of collagen genes.
- Changes in NCP volume were strongly associated with changes in PCOLCE abundance, independent of LDL-C reduction, particularly affecting the fibro-fatty plaque component.
Conclusions:
- Pitavastatin's plaque-stabilizing effects in PWH may be mediated by increased PCOLCE and collagen synthesis, promoting a shift from vulnerable to stable plaque phenotypes.
- These findings highlight novel molecular mechanisms of statin action in cardiovascular risk reduction for PWH.
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