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PubMed2026

Polygenic Risk Based Detection and Treatment of Subclinical Coronary Atherosclerosis in the PROACT Clinical Trials.

BACKGROUND: Coronary artery disease (CAD) polygenic risk scores (PRS) may identify individuals at elevated genetic risk "flying under the radar" in contemporary practice. The aims of the PROACT (Polygenic Risk Based Detection and Treatment of Subclinical Coronary Atherosclerosis) trials are to prospectively identify these individuals, quantify subclinical coronary plaque, and slow its progression with pharmacologic interventions. OBJECTIVES: The aim of this study is to report interim feasibility and implementation findings from PROACT, a genotype-first, biobank-enabled trial, characterizing eligibility yield, callback engagement, and subclinical coronary atherosclerosis on coronary computed tomographic angiography among individuals with high CAD PRS. METHODS: Within a hospital-based biobank, adults 40 to 75 years of age with high CAD PRS, without cardiovascular disease, and not on lipid-lowering therapy were invited. The authors characterize 2,495 eligible individuals with high CAD PRS, report on the feasibility and early operational outcomes of a genotype-first callback strategy for a clinical trial in the first 1,314 invited, and describe plaque prevalence by age and sex in the first 204 participants using coronary computed tomographic angiography. RESULTS: Among 64,092 genotyped participants, 2,495 (3.9%) were eligible and had high CAD PRS despite low clinical risk (median 10-year pooled cohort equations risk for atherosclerotic cardiovascular disease 3%; Q1-Q3: 1%-8%). Recruitment showed high engagement: among 1,314 invited individuals, 283 (21.5%) opted in, and 204 (15.5%) completed baseline imaging. Compared with participants who did not opt in, those who opted in had higher specialty care engagement and lived closer to the study site. Analysis of the first 204 participants enrolled by January 31, 2025 (mean age 56.3 ± 8.5 years, 69% women), showed that despite the low clinical risk and favorable cardiovascular health (mean Life's Essential 8 score 73.3 ± 11.5 vs the U.S. average of ∼65), one-half the participants (102 of 204) had subclinical plaque. Subclinical plaque prevalence was 76.2% in men and 38.3% in women and was high across age groups. CONCLUSIONS: These exploratory findings highlight the feasibility of implementing genotype-first recruitment for prevention trials and reveal a large proportion of "silent" high-genetic risk individuals with subclinical plaque for whom pharmacotherapy could be beneficial but who remain undetected by standard clinical assessments. (Polygenic Risk Based Detection of Subclinical Coronary Atherosclerosis and Change in Cardiovascular Health [PROACT 1], NCT05819814; Polygenic Risk Based Detection of Subclinical Coronary Atherosclerosis and Intervention With Statin and Colchicine [PROACT 2], NCT05850091).

Adult↗

PubMed2025

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

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.

Humans↗