Objective-We recently demonstrated that inducible cyclooxygenase/PGE synthase-1 (COX-2/mPGES-1) are overexpressed in symptomatic plaques in association with PGE 2 -dependent metalloproteinase (matrix metalloproteinase [MMP]) biosynthesis and plaque rupture. However, it is not known which of the 4 PGE 2 receptors (EP1-4) mediates macrophage metalloproteinase generation. The aim of this study was to characterize EP1-4 expression in plaques from symptomatic and asymptomatic patients undergoing carotid endarterectomy and correlate it with the extent of inflammatory infiltration, COX-2/mPGES-1 and MMP expression and clinical features of patients' presentation. Methods and Results-Plaques were analyzed for COX-2, mPGES-1, EP1-4, MMP-2, and MMP-9 by immunohistochemistry, reverse-transcription polymerase chain reaction and Western blot; zymography was used to detect MMP activity. We observed strong EP4 immunoreactivity, only very weak staining for EP2, and no expression of EP1 and EP3 in atherosclerotic plaques. EP4 was more abundant in MMP-rich symptomatic lesions, whereas EP2 was no different between symptomatic and asymptomatic plaques. Lesional macrophages synthesize matrix metalloproteinases (MMPs), proteolytic enzymes capable of degrading plaque constituents. 3 Interestingly, it has been shown that secretion of 72-kDa (MMP-2) and 92-kDa gelatinase (MMP-9) by macrophages in human atherosclerotic plaques occurs through a prostaglandin (PG) PGE 2 -dependent mechanism. 4 PGE 2 signaling involves the modulation of inducible cyclooxygenase-2 (COX-2) and type 1 microsomal PGE synthase (mPGES-1). 5 Consistent with the hypothesis of COX-2 and mPGES-1 contributing to the clinical instability of atherosclerotic plaques, we recently reported enhanced MMP-2 and MMP-9 production by macrophages in symptomatic plaques caused by the enhancement in PGE 2 synthesis as a result of the induction of the functionally coupled COX-2/mPGES-1. 4 However, the specific cellular receptor(s) by which PGE 2 may influence MMP generation in plaque macrophages is still unknown. PGE 2 can act through at least 4 different receptors (EPs), termed EP1-4. Recently, 2 major studies have suggested that EP4 could be the main receptor involved in the pathophysiology of inflammatory human diseases. In fact, Takayama et al 6 identified EP4 receptor as the predominant PGE 2 receptor isoform present in human macrophages and demonstrated EP4 receptor involvement in the inhibition of macrophagederived chemokine production in vitro. In contrast, McCoy et al 7 using mice selectively lacking each of the 4 known EP receptors showed that only the EP4 Ϫ/Ϫ mice have a high resistance to development of experimental rheumatoid arthritis, and that bone samples isolated from arthritis-resistant EP4 Ϫ/Ϫ mice expressed significantly less MMP-2 than did EP4 ϩ/ϩ cells after PGE 2 treatment. 8 Thus, the possibility that the overexpression of 1 specific receptor for PGE 2 might influence the mechanism of PGE 2 -

Our results support the feasibility and safety of Impella-assisted percutaneous coronary intervention in high-risk patients. Prospective randomized trials are needed to test the clinical impact of such an innovative approach.

We conclude that increased sCD40L is associated with late restenosis after PTCA. This may provide an important biochemical link between restenosis and aspirin-insensitive platelet activation. These results provide a rationale for studies with new antiplatelet treatments in patients who underwent PTCA.

BackgroundPlatelet activation is involved in acute coronary syndromes (ACS). Incomplete suppression by low‐dose aspirin treatment of thromboxane (TX) metabolite excretion (urinary 11‐dehydro‐TXB2) is predictive of vascular events in high‐risk patients. Myeloid‐related protein (MRP)‐8/14 is a heterodimer secreted on activation of platelets, monocytes, and neutrophils, regulating inflammation and predicting cardiovascular events. Among platelet transcripts, MRP‐14 has emerged as a powerful predictor of ACS.Methods and ResultsWe enrolled 68 stable ischemic heart disease (IHD) and 63 ACS patients, undergoing coronary angiography, to evaluate whether MRP‐8/14 release in the circulation is related to TX‐dependent platelet activation in ACS and IHD patients and to residual TX biosynthesis in low‐dose aspirin–treated ACS patients. In ACS patients, plasma MRP‐8/14 and urinary 11‐dehydro‐TXB2 levels were linearly correlated (r=0.651, P<0.001) but significantly higher than those in IHD patients (P=0.012, P=0.044) only among subjects not receiving aspirin. In aspirin‐treated ACS patients, MRP‐8/14 and 11‐dehydro‐TXB2 were lower versus those not receiving aspirin (P<0.001) and still significantly correlated (r=0.528, P<0.001). Higher 11‐dehydro‐TXB2 significantly predicted higher MRP‐8/14 in both all ACS patients and ACS receiving aspirin (P<0.001, adj R2=0.463 and adj R2=0.497) after multivariable adjustment. Conversely, plasma MRP‐8/14 (P<0.001) and higher urinary 8‐iso‐prostaglandin F2α (P=0.050) levels were significant predictors of residual, on‐aspirin, TX biosynthesis in ACS (adjusted R2=0.384).ConclusionsCirculating MRP‐8/14 is associated with TX‐dependent platelet activation in ACS, even during low‐dose aspirin treatment, suggesting a contribution of residual TX to MRP‐8/14 shedding, which may further amplify platelet activation. Circulating MRP‐8/14 may be a target to test different antiplatelet strategies in ACS.