Abstract
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Objectives: The aim of this study is applying non-invasive multimodality imaging to investigate the potential therapeutic effects of MCC950, a novel selective NLRP3 inflammasome inhibitor, during both the acute and the chronic phases following Myocardial Infarction (MI).
Methods: C57BL/6 mice were subjected to the MI or Sham model. Positron emission tomography /X-ray computed tomography (PET/CT) imaging with 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) was undertaken in order to monitor any post-MI inflammation changes on 1, 3, 5 and 7 days. 18F-FDG PET/CT and echocardiography were both used to quantitate any alterations of infarct size and cardiac function on 7 and 28 days post-MI. TUNEL staining and Western Blotting were performed to assess myocardial apoptosis.
Results: Dynamic 18F-FDG PET/CT revealed that MI+MCC950 group had a lower accumulation of 18F-FDG at infarct region as early as day one, and remained lower until day seven post-MI when compared to the MI group (infarct region/skeletal muscle ratio based on SUVmean: Day one, 2.37±0.11 vs 2.83±0.13, P < 0.05; Day three, 3.10±0.28 vs 3.93±0.29, P < 0.05; Day five, 2.74±0.43 vs 3.69±0.32, P < 0.05; Day seven, 1.89±0.26 vs 2.51±0.27, P < 0.05.). What’s more, MCC950 inhibited infarct size expanding on day 7 (31.90±1.60% vs 36.30±3.31%, P < 0.05 vs MI group), meanwhile with a non-significant further increase on day 28 (33.05±2.18% vs 31.90±1.60%, P > 0.05 vs MI+MCC950 group on day 7). The use of echocardiography suggested that MCC950 treatment increased ejection fraction (EF) and fraction shortening (FS), (EF: 48.72±3.86% vs 39.64±2.85%, P < 0.05; FS: 22.93±2.58% vs 17.54±1.91%, P < 0.05), meanwhile decreased end-diastolic volume (EDV) and end-systolic volume (ESV) when compared with that in the MI group on day 28 (EDV: 70.91±3.31 vs 82.40±5.30 ul, P < 0.05; ESV: 38.95±4.38 vs 50.29±3.76 ul, P < 0.05). In addition, attenuated myocardium apoptosis was also observed in MI+MCC950 group (11.85±2.43% vs 22.47±3.62%, P < 0.05 vs MI group). Conclusions: MCC950 has the potential to reduce inflammatory response, infarct size and to preserve cardiac function post-MI. Dynamic multimodality imaging including 18F-FDG PET/CT (imaging inflammatory response), 18F-FDG PET/CT (imaging myocardium) and echocardiograph may be a potential method for basic research and clinical translation in the use of anti-inflammation therapy for myocardial infarction. Research Support.: International Cooperation Program of Xijing Hospital (Grant No. XJZT15G01), Shaanxi Science & Technology Co-ordination & Innovation Project (Grant No. 2016KTCQ03-09) and Shaanxi Innovation capability support plan (Grant No.2018PT-08).