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

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  Figure 1. Study scheme and analysis protocol. Pemafibrate administration (30 mg/animal/day) was initiated at day −7 and continued until animals were harvested at day 28 (total 35‐day protocol). On day 0, BMSs (3.5 × 12 mm) were deployed into the pig RCA and LAD coronary arteries. Arterial injury was induced by stent balloon overinflation under IVUS guidance. Intravascular imaging using IVUS and NIRF‐OCT was performed on day 7 at 24 hours after intravenous injection of ProSense VM110, a NIRF molecular imaging reporter of cathepsin protease activity. Tissues were harvested at day 28 for analysis. BMS indicates bare metal stent; IVUS, intravascular ultrasound; LAD, left anterior descending coronary artery; NIRF, near‐infrared fluorescence; OCT, optical coherence tomography; qPCR, quantitative polymerase chain reaction; and RCA, right coronary artery.

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  Figure 2. The effects of pemafibrate on in vivo arterial inflammatory cathepsin activity 7 days after stent implantation. A, NIRF signals in the RCA and LAD of a representative control and pemafibrate‐treated animal. The day 7 NIRF signal intensity, reflecting inflammatory cathepsin protease activity, was lower in stents of pigs treated with pemafibrate compared with controls. The NIRF signal in nonstented areas was used as the background/reference measurement. A total of 4 representative stents are shown (left, control; right, pemafibrate [all 2‐dimensional NIRF maps equally windowed]). B, The NIRF inflammation signal measured as the TBR was significantly lower in pemafibrate‐treated animals (9 stents, 3 animals in each group). Each dot indicates 1 stent. Horizontal lines and error bars indicate medians and 25th to 75th percentiles, respectively. LAD indicates left anterior descending coronary artery; NIRF, near‐infrared fluorescence; RCA, right coronary artery; and TBR, target‐to‐background ratio. *P<0.05.

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  Figure 3. Assessment of pemafibrate on in‐stent neointima formation. Representative figures of OCT imaging (day 28), histology, and 3‐dimensional representation (day 28) in the control and pemafibrate groups, respectively. A, OCT showed that pemafibrate attenuated in‐stent neointima formation. (Scale bars=1 mm.) Movat’s pentachrome demonstrated more fibrous, less mucinous (proteoglycan), and lower cell accumulation around stent struts as well as in the adventitia in the pemafibrate‐treated animals. (Scale bars=100 µm.) Representative images of 3‐dimensional neointima reconstructions in the control and pemafibrate groups. *Neointima. B, Neointima volume per stent assessed at day 28 was suppressed by pemafibrate treatment (n=20 stents, 6 animals in the control group; n=24 stents, 7 animals in the pemafibrate group). C, Longitudinal analysis OCT images showed a lower percent luminal stenosis in the pemafibrate‐treated pigs (P<0.001), particularly toward the distal stent edge. D, Longitudinal analysis of histological images showed similar findings as did the OCT analysis, with lower neointima area across the stent in the pemafibrate group; however, this trend was not statistically significant…

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  Figure 4. The effects of pemafibrate on peri‐stent strut cell accumulation and proliferation. A, Hematoxylin‐eosin and immunofluorescence staining of tissues around stent struts on day 28. Cell accumulation and the number of Ki‐67+ cells were lower in the pemafibrate group than the control group, whereas SMα‐actin expression was higher. B, Nuclear count around stent struts per 0.01 mm2 (100 × 100 µm) was significantly lower in the pemafibrate group on a per‐strut basis (left, N=504 control, N=432 pemafibrate; P=0.016 [box plots indicate medians and 25th–75th percentiles]) as well as on a per‐animal basis (right, N=7 control, N=6 pemafibrate, 72 stent struts analyzed per animal; P=0.008 [horizontal line and error bars indicate medians and 25th–75th percentiles, respectively]). C–E, Histological analysis at day 28 (n=84 sections in the control group, n=72 sections in the pemafibrate group [box plots indicate medianss and 25th–75th percentiles]) revealed lower peri‐strut inflammation, granulomatous inflammation percentage, and vascular injury scores in the pemafibrate group. (Scale bar=100 µm.) Ad indicates adventitia; I, intima; M, media; Pema., pemafibrate; S, stent; and SMα, smooth muscle…