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The Spin Stops Here: Inhibition of Lipoprotein-Associated Phospholipase A2— A Promising Target but a Negative Initial Trial?

¹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; ² Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN.

^aAddress correspondence to this author at: Department of Laboratory Medicine and Pathology, Mayo Clinic, Hilton 310-B, 200 First ST SW, Rochester, MN 55905. Fax 507-266-2888; e-mail jaffe.allan@mayo.edu.

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Current treatment strategies have resulted in significant reductions in morbidity and mortality associated with cardiovascular disease; however, significant residual risk remains. As an example, in the PROVE IT–TIMI 22 trial (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22), 22.4% of patients experienced an adverse event despite achieving a median LDL cholesterol concentration of 62 mg/dL (1.6 mmol/L) (1). These and similar findings have led to the search for novel therapeutic modalities. A logical place to start is control of inflammation. Darapladib (GlaxoSmithKline) is a novel oral therapeutic agent with potential antiinflammatory properties that inhibits lipoprotein-associated phospholipase A2 (Lp-PLA2).¹

Lp-PLA2 is produced by macrophages and circulates bound to LDL. In experimental models, it appears to be central in the atherosclerotic process. Lp-PLA2 acts on oxidized phospholipids to produce free oxidized fatty acids and lysophosphatidylcholine, a proatherogenic inflammatory mediator that increases expression of adhesion molecules and cytokines, is a chemoattractant for macrophages, and induces vascular smooth muscle migration (2)(3). Immunohistochemical studies have shown that Lp-PLA2 is present in atherosclerotic lesions, and is particularly intense in "rupture-prone lipid laden" lesions with thin-cap fibroatheromas, (4). Unlike many other inflammatory mediators, Lp-PLA2 is not an acute-phase reactant (5); thus issues associated with acute-phase reactants are averted. For these reasons, Lp-PLA2 has emerged recently as an independent marker of cardiovascular risk and events.

Although not all prospective studies have demonstrated an association between high plasma Lp-PLA2 concentrations and poor cardiovascular outcomes, the majority of studies reported are strongly positive. In a recent metaanalysis (6) including more than 20 000 patients from 14 epidemiologic studies, high Lp-PLA2 concentration was an independent risk factor for cardiovascular events. This is especially true in regard to the associations with stroke, which seem particularly strong (. . . [Full Text of this Article]

Inhibition of Lp-PLA2

Publication Bias

IVUS

Darapladib Inhibition

Where Do We Go From Here?