Atherosclerosis and its clinical manifestations are widely prevalent throughout the world. Atherogenesis is highly complex and is modulated by numerous genetic and environmental risk factors. A large body of basic scientific and clinical research supports the conclusion that inflammation plays a significant role in atherogenesis along the entire continuum of its progression. Inflammation adversely impacts intravascular lipid handling and metabolism, resulting in the development of macrophage foam cells, fatty streaks and atheromatous plaque formation. Given the enormous human and economic cost of myocardial infarction, ischemic stroke, peripheral arterial disease and amputation, and premature death and disability, considerable effort is being committed to refining our ability to correctly identify patients at heightened risk for atherosclerotic vascular disease and acute cardiovascular events so that they can be treated earlier and more aggressively. Serum markers of inflammation have emerged as an important component of risk factor burden. Serum lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) potentiates intravascular inflammation and atherosclerosis. A variety of epidemiologic studies support the utility of Lp-PLA(2) measurements for estimating and further refining cardiovascular disease risk. Drug therapies to inhibit Lp-PLA(2) are in development and show considerable promise. In addition to substantially inhibiting Lp-PLA(2), darapladib reduces the progression of the necrotic core volume of coronary artery atheromatous plaque.
        
Title: Darapladib and atherosclerotic plaque: should lipoprotein-associated phospholipase A2 be a therapeutic target? McCullough PA Ref: Curr Atheroscler Rep, 11:334, 2009 : PubMed
There is great interest in developing a reliable measure of atherosclerotic disease activity that can serve as an index of response to antiatherosclerotic therapies. The epidemiologic relationship between lipid measures, most notably low-density lipoprotein cholesterol (LDL-C), and binary cardiovascular events has been confirmed in treatment trials reliably demonstrating a reduction in LDL-C translating into improved cardiovascular outcomes. Lipoprotein-associated phospholipase A2 (LpPLA2) is part of a family of lipases involved in the modification of lipids within the atheroma and may be a complimentary therapeutic target to the reduction of LDL-C in patients with advanced atherosclerosis. Darapladib is an orally available, specific inhibitor of LpPLA2 activity and has been shown to reduce lysophosphatidylcholine content and expression of multiple genes associated with macrophage and T-lymphocyte functioning, with considerable decrease in plaque and necrotic core area. Thus, this agent holds the hope of being a bona fide antiatherosclerotic therapy that can be gauged through blood measurement of LpPLA2 activity.