Pitavastatin, Procollagen Pathways, and Plaque Stabilization in Patients With HIV: A Secondary Analysis of the REPRIEVE Randomized Clinical Trial.

Background

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).

利用靶向发现蛋白质组学和转录组学方法，探究与低密度脂蛋白胆固醇(LDL-C)无关的生物学通路，将他汀类药物的疗效与减少非钙化斑块(NCP)体积和促进斑块稳定化相关联，针对HIV感染者(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.

设计、设置和参与者：这是对双盲、安慰剂对照的REPRIEVE随机临床试验的事后分析。参与者在基线和2年随访时接受了冠状动脉计算机断层扫描血管造影（CTA）、血浆蛋白分析和转录组分析。

The trial enrolled PWH from April 2015 to February 2018 at 31 US research sites.

该试验从2015年4月到2018年2月在美国的31个研究地点招募了PWH（血友病患者）。

PWH without known cardiovascular diseases taking antiretroviral therapy and with low to moderate 10-year cardiovascular risk were eligible.

没有已知心血管疾病的PWH（接受抗逆转录病毒治疗）且10年心血管风险低至中等者符合入选条件。

Data analyses were conducted from October 2023 to February 2024.

数据分析从2023年10月进行至2024年2月。

intervention

Oral pitavastatin calcium, 4 mg per day.

口服皮托伐他汀钙，每天4毫克。

main_outcomes_and_measures

Relative change in plasma proteomics, transcriptomics, and noncalcified plaque volume among those receiving treatment vs placebo.

接受治疗组与安慰剂组相比，血浆蛋白质组学、转录组学和非钙化斑块体积的相对变化。

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.

在纳入蛋白质组学评估的558名个体中（平均[标准差]年龄，51[6]岁；455名为男性[82%]），272名（48.7%）接受了皮托伐他汀治疗，286名（51.3%）接受了安慰剂。

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).

在校正假发现率后，皮托伐他汀增加了前胶原C末端肽酶增强剂1（PCOLCE）、神经突触蛋白1（NRP-1）、主要组织相容性复合体I类多肽相关序列A（MIC-A）和B（MIC-B）的丰度，并降低了组织因子通路抑制剂（TFPI）、肿瘤坏死因子配体超家族成员10（TRAIL）、血管生成素相关蛋白3（ANGPTL3）和甘露糖结合蛋白C（MBL2）的丰度。

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).

在这些蛋白质中，匹伐他汀与PCOLCE（胶原沉积的限速酶）的关联最大，效应大小为24.3%（95%置信区间，18.0%-30.8%；P < .001）。

In a transcriptomic analysis, individual collagen genes and collagen gene sets showed increased expression.

在转录组分析中，个体胶原蛋白基因和胶原蛋白基因集显示出表达增加。

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.

在基线时有195名斑块患者（88名[45.1%]服用匹伐他汀，107名[54.9%]服用安慰剂），非钙化斑块体积的变化与PCOLCE的变化最为密切相关（非钙化斑块体积变化百分比/对数2倍变化 = -31.9%；95%置信区间，-42.9%至-18.7%；P < .001），与LDL-C水平的变化无关。

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).

PCOLCE的增加与非钙化斑块的纤维脂肪成分（<130 Hounsfield单位）的变化最为密切相关（纤维脂肪体积变化百分比/对数2倍变化 = -38.5%；95%置信区间，-58.1%至-9.7%；P = .01），而钙化斑块则呈现方向相反但不显著的增加（钙化体积变化百分比/对数2倍变化 = 34.4%；95%置信区间，-7.9%至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.

REPRIEVE随机临床试验的次要分析结果表明，PCOLCE可能通过促进细胞外基质中胶原蛋白的沉积，与他汀类药物的动脉粥样硬化斑块稳定化效果相关，将易损斑块表型转变为更稳定的冠状动脉病变。

trial_registration

ClinicalTrials.gov Identifier: NCT02344290.

临床试验注册号：NCT02344290。