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Atherosclerosis. 2015 Jun;240(2):490-6. doi: 10.1016/j.atherosclerosis.2015.03.039. Epub 2015 Mar 28.

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

Author information

1
Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
2
Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3
Exploratory Clinical & Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
4
Division of Cardiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
5
Division of Atherosclerosis and Vascular Medicine, Baylor College of Medicine and Houston Methdodist DeBakey Heart and Vascular Center, Houston, TX, USA.
6
Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
7
Peter Munk Cardiac Centre and the Heart and Stroke Richard Lewar Centre of Excellence, The University of Toronto, ON, Canada.
8
Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: atawakol@partners.org.

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, (ΔTBR index: 0.10 [95% CI: -0.11, 0.30], p = 0.34; ΔTBR AS: -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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00570752.

KEYWORDS:

Atherosclerosis; FDG; Imaging; Inflammation; MAPK

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