Abstract 594: Selective Inhibition Of Lipoprotein-associated Phospholipase A2 Attenuates Markers Of Plaque Vulnerability In Humans
Background: Lp-PLA2, an emerging marker of CV risk, generates products of oxidized LDL that may contribute to inflammation and apoptosis. Although Lp-PLA2 is highly expressed in thin-cap fibroatheroma and ruptured plaques, its role in mediating lesion vulnerability remains unknown.
Material and Methods: Patients were randomized to receive placebo or the selective Lp-PLA2 inhibitor, darapladib, (40 or 80 mg po) for 14 days prior to carotid endartherectomy. In the post hoc analysis, caspase activities were measured in carotid plaques (colorimetric assays: AU/mg of protein) and correlated with inhibition of Lp-PLA2 activity in plasma (radiometric assay) using Spearman’s rank method.
Results: Caspase-8 (initiator) and -3 (effector) activities were measured as the index of apoptosis in carotid atheroma specimens. In the validation study, carotid atheroma (n=10) exhibited augmented levels of caspase activities compared to non-diseased vessels (n=8) (caspase-8: 4.74±0.3 vs 2.59±0.2; caspase-3: 10.2±0.9 vs 4.15±0.4 p<0.001). Next, caspase-8 (n=39) and -3 (n=59) were measured in plaque samples derived from the dose-ranging study with darapladib. In patients treated with darapladib, caspase-8 activity within the plaques was significantly reduced [placebo: 4.66±0.48; 40 mg: 3.4±0.4, NS; 80 mg: 3.0±0.52, p=0.042 versus placebo (ANOVA with Bonferroni adjustment)]. Similarly, downstream caspase-3 was also decreased in the high dose group (placebo: 11.8±0.84; 40 mg: 10.4±0.88, NS; 80 mg: 6.5±1.0 p=0.0004 versus placebo). To further explore the relationship between Lp-PLA2 activity and markers of apoptosis, plaque caspase activity was correlated with Lp-PLA2 inhibition in plasma. Plaque caspase-8 and -3 correlated with inhibition of Lp-PLA2 activity in plasma (caspase-8: r=-0.34, p=0.039; caspase-3: r=−0.51, p<0.0001).
Conclusions: Inhibition of Lp-PLA2 reduced activity of proapoptotic caspases in human atheroma. The results suggest that Lp-PLA2 inhibition may attenuate noxious effects of oxidized LDL and promote lesion stabilization in high risk patients.