Background-Inflammatory mediators that originate in vascular and extravascular tissues promote coronary lesion formation. Adipose tissue may function as an endocrine organ that contributes to an inflammatory burden in patients at risk of cardiovascular complications. In this study, we sought to compare expression of inflammatory mediators in epicardial and subcutaneous adipose stores in patients with critical CAD. Methods and Results-Paired samples of epicardial and subcutaneous adipose tissues were harvested at the outset of elective CABG surgery (nϭ42; age 65Ϯ10 years).

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This study demonstrates translocation of adventitial fibroblasts to neointima, their phenotypic modulation to myofibroblasts, and distinct characteristics of myofibroblasts within neointima after severe endoluminal coronary injury. These findings suggest the significance of vascular fibroblasts in the process of arterial repair.

Increased lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA 2 is a causative agent. Here we show that selective inhibition of Lp-PLA 2 with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA 2 activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA 2 inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke.Atherosclerosis, the most common cause of myocardial infarction, stroke and cardiovascular death, is an inflammatory-immunomodulatory disease 1,2 . A key early step in its development is the accumulation and subsequent oxidation of low-density lipoproteins COMPETING INTERESTS STATEMENTThe authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturemedicine/. Lp-PLA 2 , also known as platelet-activating factor acetylhydrolase or type VIIA PLA 2 , is a calcium-independent phospholipase A 2 . In humans, Lp-PLA 2 is secreted by leukocytes and is associated with circulating LDL and macrophages in atherosclerotic plaques. Although some have hypothesized that Lp-PLA 2 has a protective role in atherosclerotic lesion development 9,10 , the preponderance of recent data suggests that Lp-PLA 2 has an active role in atherosclerotic development and progression [11][12][13] . Elevated circulating Lp-PLA 2 activity predicts increased cardiovascular risk 14 . A proatherogenic role for Lp-PLA 2 has been postulated on the basis of its ability to generate two key proinflammatory mediators, lysophosphatidylcholine (LPC) and oxidized nonesterified fatty acids (oxNEFAs), through the cleavage of oxidized or polar phospholipids generated during LDL oxidation 15,16 . Evidence exists for a regulatory role of these proinflammatory lipids, particularly of LPC 12,13,17 , in promoting atherosclerotic plaque development that can ultimately lead to the formation of a necrotic core. These steps include recruitment and activation of leukocytes 12,18 , induction of apoptosis 12,19 and impaired removal of dead cells 20,21 . The demonstration that Lp-PLA 2 is highly upregulated in macrophages undergoing apoptosis within the necrotic core and fibrous cap of vulnerable and ruptured plaques, ...