The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: A multicenter FDG- PET trial Hamed Emami a, 1 , Esad Vucic a, 1 , Sharath Subramanian a , Amr Abdelbaky a , Zahi A. Fayad c , Shuyan Du d , Eli Roth e , Christie M. Ballantyne f , Emile R. Mohler g , Michael E. Farkouh h , Joonyoung Kim d , Matthew Farmer d , Li Li d , Alexander Ehlgen d , Thomas H. Langenickel d , Linda Velasquez d , Wendy Hayes d , Ahmed Tawakol a, b, * a Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA b Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA c Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA d Exploratory Clinical & Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA e Division of Cardiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA f Division of Atherosclerosis and Vascular Medicine, Baylor College of Medicine and Houston Methdodist DeBakey Heart and Vascular Center, Houston, TX, USA g Hospital of the University of Pennsylvania, Philadelphia, PA, USA h Peter Munk Cardiac Centre and the Heart and Stroke Richard Lewar Centre of Excellence, The University of Toronto, ON, Canada article info Article history: Received 26 November 2014 Received in revised form 16 March 2015 Accepted 25 March 2015 Available online 28 March 2015 Keywords: FDG Inflammation Atherosclerosis MAPK Imaging abstract Objectives: This study evaluated the effect of p38 mitogen-activated protein kinase (p38MAPK) inhibitor, BMS-582949, on atherosclerotic plaque inflammation, using 18 FDG-PET imaging. p38MAPK is an important element of inflammatory pathways in atherothrombosis and its inhibition may lead to reduced inflammation within atherosclerotic plaques. Methods: Subjects with documented atherosclerosis (n ¼ 72) on stable low-dose statin therapy and having at least one lesion with active atherosclerotic plaque inflammation in either aorta or carotid arteries were randomized to BMS-582949 (100 mg once daily), placebo, or atorvastatin (80 mg once daily), for 12 weeks. Arterial inflammation was assessed using 18 FDG-PET/CT imaging of the carotid ar- teries and aorta. Uptake of arterial 18 FDG was assessed as target-to-background ratio (TBR): 1) as a mean of all slices of the index vessel, and 2) within active slices of all vessels (AS: which includes only slices with significant inflammation (TBR  1.6) at the baseline). Results: Treatment with BMS-582949 did not reduce arterial inflammation relative to placebo, (DTBR index: 0.10 [95% CI: 0.11, 0.30], p ¼ 0.34; DTBR AS : 0.01 [0.31, 0.28], p ¼ 0.93) or hs-CRP (median %DCRP [IQR]: 33.83% [153.91] vs. 16.71% [133.45], p ¼ 0.61). In contrast, relative to placebo, statin intensification was associated with significant reduction of hs-CRP (%DCRP [IQR]: 17.44% [54.68] vs.16.71% [133.45], p ¼ 0.04) and arterial inflammation in active slices (DTBR AS ¼0.24 [95% CI: 0.46, 0.01], p ¼ 0.04). Conclusions: The findings of this study demonstrates that in stable atherosclerosis, 12 weeks of treat- ment with BMS-582949 did not reduce arterial inflammation or hs-CRP compared to placebo, whereas intensification of statin therapy significantly decreased arterial inflammation. © 2015 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Cardiovascular disease (CVD) is the leading cause of mortality worldwide [1]. Atherothrombosis is the primary cause of ischemic CVD and is caused by the accumulation of inflammatory cells, which culminates in the development of complex athero- sclerotic plaques, precursors of acute coronary syndromes [2]. Abbreviations: 18 FDG, 18 F-fluorodeoxyglucose; hs-CRP, high sensitivity C-reac- tive peptide; MAPK, mitogen-activated protein kinase; PET, positron emission to- mography; ROI, region of interest; SUV, standardized uptake value; TBR, target-to- background ratio. * Corresponding author. Cardiac MR PET CT Program and Cardiology Division, Massachusetts General Hospital, 165 Cambridge Street, Suite 400, Boston, MA, 02114, USA. E-mail address: atawakol@partners.org (A. Tawakol). 1 Contributed equally to this work. Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis http://dx.doi.org/10.1016/j.atherosclerosis.2015.03.039 0021-9150/© 2015 Elsevier Ireland Ltd. All rights reserved. Atherosclerosis 240 (2015) 490e496