The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: A multicenter FDG-PET trial. Issue 2 (June 2015)

• Record Type: Journal Article
• Authors: Emami, Hamed; Vucic, Esad; Subramanian, Sharath; Abdelbaky, Amr; Fayad, Zahi A.; Du, Shuyan; Roth, Eli; Ballantyne, Christie M.; Mohler, Emile R.; Farkouh, Michael E.; Kim, Joonyoung; Farmer, Matthew; Li, Li; Ehlgen, Alexander; Langenickel, Thomas H.; Velasquez, Linda; Hayes, Wendy; Tawakol, Ahmed
• Is Part Of: Atherosclerosis. Volume 240:Issue 2(2015)
• Page Start: 490
• Page End: 496
• Publication Date: 2015-06
• Subjects: FDG -- Inflammation -- Atherosclerosis -- MAPK -- Imaging; 18FDG 18F-fluorodeoxyglucose -- hs-CRP high sensitivity C-reactive peptide -- MAPK mitogen-activated protein kinase -- PET positron emission tomography -- ROI region of interest -- SUV standardized uptake value -- TBR target-to-background ratio; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2015.03.039
• Languages: English
• ISSNs: 0021-9150

Abstract

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 = 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 arteries 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, (ΔTBRindex: 0.10 [95% CI: −0.11, 0.30], p = 0.34; ΔTBRAS : −0.01 [−0.31, 0.28], p = 0.93) or hs-CRP (median %ΔCRP [IQR]: 33.83% [153.91] vs. 16.71% [133.45], p = 0.61). In contrast, relative to placebo, statin intensification was associated with significant reduction of hs-CRP (%ΔCRP [IQR]: −17.44% [54.68] vs. 16.71% [133.45], p = 0.04) and arterial inflammation in active slices (ΔTBRAS = −0.24 [95% CI: −0.46, −0.01], p = 0.04). Conclusions: The findings of this study demonstrates that in stable atherosclerosis, 12 weeks of treatment with BMS-582949 did not reduce arterial inflammation or hs-CRP compared to placebo, whereas intensification of statin therapy significantly decreased arterial inflammation. Highlights: We evaluated the effect of p38MAPK inhibitor, BMS-582949, on arterial inflammation. Subjects with known ASCVD were randomized to BMS-582949, placebo, or atorvastatin. We demonstrate that treatment with BMS-582949 did not reduce arterial inflammation. Intensification of statin therapy (positive control) reduced arterial inflammation.