Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that is produced by inflammatory cells in atherosclerotic lesions. It has previously been shown to be present at higher levels in the core of ruptured atherosclerotic plaques, although it was unclear whether this was merely an association or whether the enzyme played a key role in plaque vulnerability.
Wilensky et al. selectively inhibited Lp-PLA2 in a swine model of atherosclerosis by the administration of darapladib, and found levels of Lp-PLA2 in the both plasma and atherosclerotic plaque were lowered. Furthermore, a significant decrease in plaque area was noted, and in particular a decrease in necrotic core area and reduced medial destruction. In addition, coronary gene expression analysis demonstrated that darapladib had a general anti-inflammatory action, reducing the expression of genes associated with macrophage and T-lymphocyte functioning.
This is the first paper to prove the pathological role of Lp-PLA2 in unstable plaque formation. Studies of darapladib in humans are currently underway; early data has already shown the ability of the drug to reduce inflammatory biomarkers in patients already on statin therapy, the effect this will have on patient outcomes is awaited.
- Wilensky RL, Shi Y, Mohler ER et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med 2008;14:1059-1066