Abstract 266: Darapladib, A Selective Inhibitor Of Lp-PLA2, Reduces Coronary Atherosclerosis In Diabetic, Hypercholesterolemic Swine
Background: Although epidemiologic studies have demonstrated an association between elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) levels and risk of cardiac events, it is not known whether Lp-PLA2 is causally involved in the development of atherosclerosis. The purpose of this study was to determine the effect of selective inhibition of Lp-PLA2 on coronary atherosclerosis in diabetic (DM)/ hypercholesterolemic (HC) swine.
Methods: Male Yorkshire pigs with streptozocin-induced DM and HC induced with dietary cholesterol feeding were randomized, 1 month later, into treatment (darapladib [SB-480848] 10 mg/kg/day; n=20) or control groups (n=17). Animals were sacrificed 28 weeks after induction and morphometry of the left anterior descending coronary artery was performed. Other coronary arteries were used for gene expression studies (TaqMan) and vascular Lp-PLA2 levels were measured in aortae.
Results: Mean glucose and cholesterol levels did not differ between treated and control animals. At completion of the study, darapladib reduced elevated plasma and vascular Lp-PLA2 activity by 89% (p<0.001) and 84% (p<0.001), respectively, compared with controls. Analysis of coronary gene expression demonstrated that darapladib significantly reduced expression of 24 out of 90 genes associated with human atherosclerosis; many were related to leukocyte activity (e.g. CD68, Lp-PLA2, and chemokine receptor/ligand mRNAs). This effect on atherosclerotic gene expression was associated with significantly decreased plaque area from 0.636 ± 0.874 mm2 in controls to 0.179 ± 0.208 mm2 in treated animals (p<0.05). Moreover, treatment was associated with decreased incidence of necrotic cores (10% vs 41%, p=0.05) and significant preservation of coronary media (p=0.004).
Conclusions: In DM/HC swine, selective inhibition of Lp-PLA2 with darapladib reduced coronary inflammatory gene expression, an effect which was associated with smaller, less complex, coronary lesions. This is the first demonstration of a reduction in coronary atherosclerosis by selective inhibition of Lp-PLA2 in an animal model of complex atherosclerotic disease and suggests that darapladib may stabilize atherosclerotic plaque by reducing vascular inflammation.