Effects of p38 Mitogen-Activated Protein Kinase Inhibition on Vascular and Systemic Inflammation in Patients With Atherosclerosis

被引：140

作者：

Elkhawad, Maysoon ^{[2
,3
]}

Rudd, James H. F. ^{[3
]}

Sarov-Blat, Lea ^{[1
]}

Cai, Gengqian ^{[1
]}

Wells, Richard ^{[2
]}

Davies, L. Ceri ^{[4
]}

Collier, David J. ^{[4
]}

Marber, Michael S. ^{[5
]}

Choudhury, Robin P. ^{[6
]}

Fayad, Zahi A. ^{[7
]}

Tawakol, Ahmed ^{[8
,9
]}

Gleeson, Fergus V. ^{[6
]}

Lepore, John J. ^{[1
]}

Davis, Bill ^{[10
]}

Willette, Robert N. ^{[1
]}

Wilkinson, Ian B. ^{[2
]}

Sprecher, Dennis L. ^{[1
]}

Cheriyan, Joseph ^{[2
,10
,11
]}

机构：

[1] GlaxoSmithKline, Metab Pathways & Cardiovasc Therapy Area Unit, King Of Prussia, PA 19406 USA

[2] Univ Cambridge, Clin Pharmacol Unit, Cambridge, England

[3] Univ Cambridge, Div Cardiovasc Med, Cambridge, England

[4] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Ctr Clin Pharmacol, London, England

[5] Kings Coll London, London WC2R 2LS, England

[6] Univ Oxford, Oxford, England

[7] Mt Sinai Med Ctr, New York, NY 10029 USA

[8] Massachusetts Gen Hosp, Boston, MA 02114 USA

[9] Harvard Univ, Sch Med, Boston, MA USA

[10] GlaxoSmithKline Clin Unit, Cambridge, England

[11] Natl Hlth Serv Fdn Trust, Cambridge Univ Hosp, Cambridge, England

来源：

JACC-CARDIOVASCULAR IMAGING | 2012年 / 5卷 / 09期

关键词：

atherosclerosis; biomarkers; imaging; inflammation; p38 mitogen-activated protein kinase inhibition; randomized controlled trial; POSITRON-EMISSION-TOMOGRAPHY; C-REACTIVE PROTEIN; PLAQUE INFLAMMATION; CARDIOVASCULAR-DISEASE; REDUCES INFLAMMATION; DENSITY-LIPOPROTEIN; GLUCOSE-TRANSPORT; F-18-FDG PET; MACROPHAGES; CELLS;

D O I：

10.1016/j.jcmg.2012.02.016

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

OBJECTIVES This study sought to determine the effects of a p38 mitogen-activated protein kinase inhibitor, losmapimod, on vascular inflammation, by F-18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography imaging. BACKGROUND The p38 mitogen-activated protein kinase cascade plays an important role in the initiation and progression of inflammatory diseases, including atherosclerosis. METHODS Patients with atherosclerosis on stable statin therapy (n = 99) were randomized to receive losmapimod 7.5 mg once daily (lower dose [LD]), twice daily (higher dose [HD]) or placebo for 84 days. Vascular inflammation was assessed by FDG positron emission tomography/computed tomography imaging of the carotid arteries and aorta; analyses focused on the index vessel (the artery with the highest average maximum tissue-to-background ratio [TBR] at baseline). Serum inflammatory biomarkers and FDG uptake in visceral and subcutaneous fat were also measured. RESULTS The primary endpoint, change from baseline in average TBR across all segments in the index vessel, was not significantly different between HD and placebo (Delta TBR: -0.04 [95% confidence interval [CI]: -0.14 to +0.06], p = 0.452) or LD and placebo (Delta TBR: -0.02 [95% CI: -0.11 to +0.06], p = 0.579). However, there was a statistically significant reduction in average TBR in active segments (TBR >= 1.6) (HD vs. placebo:Delta TBR: -0.10 [95% CI: -0.19 to -0.02], p = 0.0125; LD vs. placebo:Delta TBR: -0.10 [95% CI: -0.18 to -0.02], p = 0.0194). The probability of a segment being active was also significantly reduced for HD when compared with placebo (OR: 0.57 [95% CI: 0.41 to 0.81], p = 0.002). Within the HD group, reductions were observed in placebo-corrected inflammatory biomarkers including high-sensitivity C-reactive protein (% reduction: -28% [95% CI: -46 to -5], p = 0.023) as well as FDG uptake in visceral fat (Delta SUV: -0.05 [95% CI: -0.09 to -0.01], p = 0.018), but not subcutaneous fat. CONCLUSIONS Despite nonsignificant changes for the primary endpoint of average vessel TBR, HD losmapimod reduced vascular inflammation in the most inflamed regions, concurrent with a reduction in inflammatory biomarkers and FDG uptake in visceral fat. These results suggest a systemic anti-inflammatory effect. (A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging; NCT00633022) (J Am Coll Cardiol Img 2012;5:911-22) (C) 2012 by the American College of Cardiology Foundation

引用

页码：911 / 922

页数：12

共 35 条

[1]

Inhibition of p38 Mitogen-Activated Protein Kinase Improves Nitric Oxide-Mediated Vasodilatation and Reduces Inflammation in Hypercholesterolemia [J].