Highly Selective PPARα (Peroxisome Proliferator‐Activated Receptor α) Agonist Pemafibrate Inhibits Stent Inflammation and Restenosis Assessed by Multimodality Molecular‐Microstructural Imaging

Abstract

BACKGROUND New pharmacological approaches are needed to prevent stent restenosis. This study tested the hypothesis that pemafibrate, a novel clinical selective PPARα (peroxisome proliferator‐activated receptor α) agonist, suppresses coronary stent‐induced arterial inflammation and neointimal hyperplasia. METHODS AND RESULTS Yorkshire pigs randomly received either oral pemafibrate (30 mg/day; n=6) or control vehicle (n=7) for 7 days, followed by coronary arterial implantation of 3.5 × 12 mm bare metal stents (2–4 per animal; 44 stents total). On day 7, intracoronary molecular‐structural near‐infrared fluorescence and optical coherence tomography imaging was performed to assess the arterial inflammatory response, demonstrating that pemafibrate reduced stent‐induced inflammatory protease activity (near‐infrared fluorescence target‐to‐background ratio: pemafibrate, median [25th‐75th percentile]: 2.8 [2.5–3.3] versus control, 4.1 [3.3–4.3], P =0.02). At day 28, animals underwent repeat near‐infrared fluorescence–optical coherence tomography imaging and were euthanized, and coronary stent tissue molecular and histological analyses. Day 28 optical coherence tomography imaging showed that pemafibrate significantly reduced stent neointima volume (pemafibrate, 43.1 [33.7–54.1] mm 3 versus control, 54.2 [41.2–81.1] mm 3 ; P =0.03). In addition, pemafibrate suppressed day 28 stent‐induced cellular inflammation and neointima expression of the inflammatory mediators TNF‐α (tumor necrosis factor‐α) and MMP‐9 (matrix metalloproteinase 9) and enhanced the smooth muscle differentiation markers calponin and smoothelin. In vitro assays indicated that the STAT3 (signal transducer and activator of transcription 3)–myocardin axes mediated the inhibitory effects of pemafibrate on smooth muscle cell proliferation. CONCLUSIONS Pemafibrate reduces preclinical coronary stent inflammation and neointimal hyperplasia following bare metal stent deployment. These results motivate further trials evaluating pemafibrate as a new strategy to prevent clinical stent restenosis.