Abstract 16936: Inhibition of p38 Mitogen-Activated Protein Kinase Attenuates Vascular and Systemic Inflammation in Patients with Atherosclerosis as Assessed by 18-F Fluorodeoxyglucose PET-CT
Macrophage infiltration and associated cytokines, growth factors and metalloproteinases feature prominently in inflamed atherosclerotic plaque, accompanied by activation of p38 mitogen-activated protein kinase (p38MAPK). We hypothesized that plaque-associated macrophage glucose utilization would be lowered by a selective p38MAPK inhibitor, losmapimod, in patients with atherosclerosis on statins.
Methods: A total of 99 patients with active arterial inflammation using 18-F FDG PET-CT imaging (maximum tissue to Background ratio, TBR≥1.6 in the aorta/carotids) were randomized to losmapimod 7.5mgBD, 7.5mgOD or placebo (PBO) for 84 days (CT.gov NCT00633022). Images from the “qualifying vessel” (vessel with highest baseline TBR) were analysed. The most active segments (contiguous slices with TBR≥1.6) were identified for pre-dose and Day 84 scans, and analyzed using a mixed effect model. Inflammatory biomarkers, including hsCRP, were also measured.
Results: Treatment with 84 days of losmapimod reduced vascular inflammation on FDG PET-CT from baseline in the active segments of the qualifying vessels (7.5mgBD [ΔTBR=-0.14; 95%CI -0.20,-0.08; p<0.0001]; 7.5mgOD [ΔTBR=-0.14; 95%CI -0.20,-0.07; p<0.0001]) whilst placebo did not (ΔTBR=-0.04; 95%CI -0.09,0.02; p=0.1773). When corrected for PBO, treatment effects persisted: 7.5mgBD, p=0.0125; 7.5mgOD, p=0.0194. Losmapimod 7.5mgBD also significantly reduced inflammatory biomarkers vs PBO: IL8 -27% (95%CI -43,-6; p=0.015), MMP9NGAL dimer -34% (95%CI -53,-6; p=0.02) and MCP1 -19% (95%CI -30,-5; p=0.007), but not sICAM or IL6. There was a non-significant trend in these biomarkers with 7.5mgOD but no change with PBO. Baseline hsCRP was 1.17 ± 2.01, falling by 28% (95%CI -46,-5; p=0.023) with 7.5mgBD vs PBO; a non-significant trend was observed with 7.5mgOD (-20%, 95%CI -40,6; p=0.12). hsCRP reduction progressively attenuated in losmapimod groups. Overall, losmapimod was well tolerated.
Conclusion: Losmapimod decreased FDG PET-CT defined vascular inflammation beyond standard therapies in an atherosclerotic population. It reduced inflammatory biomarkers including hsCRP, suggesting a systemic effect. This study supports p38MAPK inhibition as a therapeutic target in atherosclerosis.
- © 2010 by American Heart Association, Inc.