Kolossváry Márton, Schnittman Samuel R, Zanni Markella V, Fitch Kathleen V, Fichtenbaum Carl J, Aberg Judith A, Bloomfield Gerald S, Malvestutto Carlos D, Currier Judith, Diggs Marissa R, deFilippi Christopher, Eckard Allison Ross, Curran Adrian, Centinbas Murat, Sadreyev Ruslan, Foldyna Borek, Mayrhofer Thomas, Karady Julia, Taron Jana, McCallum Sara, Lu Michael T, Ribaudo Heather J, Douglas Pamela S, Grinspoon Steven K
Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, Boston.
Division of Infectious Diseases, Massachusetts General Hospital, Boston.
JAMA Cardiol. 2025 Mar 1;10(3):254-264. doi: 10.1001/jamacardio.2024.4115.
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.
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.
Oral pitavastatin calcium, 4 mg per day.
Relative change in plasma proteomics, transcriptomics, and noncalcified plaque volume among those receiving treatment vs placebo.
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).
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.
ClinicalTrials.gov Identifier: NCT02344290.
在预防HIV患者血管事件随机试验（REPRIEVE）的一项机制亚研究中，匹伐他汀可降低非钙化斑块（NCP）体积，但导致冠状动脉斑块变化的特定蛋白质和基因途径仍不清楚。
使用靶向发现蛋白质组学和转录组学方法，探究低密度脂蛋白胆固醇（LDL-C）之外的生物途径，将他汀类药物降低NCP体积和促进HIV感染者（PWH）斑块稳定的结果与之关联起来。
设计、地点和参与者：这是对双盲、安慰剂对照的REPRIEVE随机临床试验的一项事后分析。参与者在基线和2年随访时接受冠状动脉计算机断层扫描血管造影（CTA）、血浆蛋白质分析和转录组分析。该试验于2015年4月至2018年2月在美国31个研究地点招募PWH。符合条件的PWH为未患已知心血管疾病、正在接受抗逆转录病毒治疗且10年心血管风险低至中度者。数据分析于2023年10月至2024年2月进行。
口服匹伐他汀钙，每日4毫克。
接受治疗者与接受安慰剂者相比，血浆蛋白质组学、转录组学和非钙化斑块体积的相对变化。
在纳入蛋白质组学评估的558名个体（平均[标准差]年龄，51[6]岁；455名男性[82%]）中，272名（48.7%）接受匹伐他汀治疗，286名（51.3%）接受安慰剂治疗。在调整错误发现率后，匹伐他汀增加了前胶原C端肽酶增强子1（PCOLCE）、神经纤毛蛋白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，并降低了组织因子途径抑制剂（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。在这些蛋白质中，匹伐他汀与PCOLCE（胶原沉积的限速酶）的关联最为显著，效应大小为24.3%（95%CI，18.0%-30.8%；P<0.001）。在转录组分析中，单个胶原基因和胶原基因集显示表达增加。在基线时有斑块的195名个体中（88名[45.1%]服用匹伐他汀，107名[54.9%]服用安慰剂），NCP体积的变化与PCOLCE的变化最为密切相关（NCP体积变化百分比/log2倍变化=-31.9%；95%CI，-42.9%至-18.7%；P<0.001），与LDL-C水平变化无关。PCOLCE的增加与NCP的纤维脂肪（<130亨氏单位）成分变化最为密切相关（纤维脂肪体积变化百分比/log2倍变化=-38.5%；95%CI，-58.1%至-9.7%；P=0.01），而钙化斑块有方向相反但不显著的增加（钙化体积变化百分比/log2倍变化=34.4%；95%CI，-7.9%至96.2%；P=0.12）。
REPRIEVE随机临床试验的这项二次分析结果表明，PCOLCE可能通过促进细胞外基质中的胶原沉积，将易损斑块表型转变为更稳定的冠状动脉病变，从而与他汀类药物的动脉粥样硬化斑块稳定作用相关。
ClinicalTrials.gov标识符：NCT02344290。
