Expression of ATP binding cassette transporter A1 (ABCA1), a major regulator of high density lipoprotein (HDL) biogenesis, is known to be up-regulated by the transcription factor liver X receptor (LXR) α, and expression is further enhanced by activation of the peroxisome proliferator activated receptors (PPARs). We investigated this complex regulatory network using specific PPAR agonists: four fibrates (fenofibrate, bezafibrate, gemfibrozil and LY518674), a PPAR δ agonist (GW501516) and a PPAR γ agonist (pioglitazone). All of these compounds increased the expression of LXRs, PPARs and ABCA1 mRNAs, and associated apoA-I-mediated lipid release in THP-1 macrophage, WI38 fibroblast and mouse fibroblast. When mouse fibroblasts lacking expression of PPAR α were examined, the effects of fenofibrate and LY518674 were markedly diminished while induction by other ligands were retained. The PPAR α promoter was activated by all of these compounds in an LXR α-dependent manner, and partially in a PPAR α-dependent manner, in mouse fibroblast. The LXR responsive element (LXRE)-luciferase activity was enhanced by all the compounds in an LXR α-dependent manner in mouse fibroblast. This activation was exclusively PPAR α-dependent by fenofibrate and LY518674, but nonexclusively by the others. We conclude that PPARs and LXRs are involved in the regulation of ABCA1 expression and HDL biogenesis in a cooperative signal transduction pathway.

Background-Statins exert antiinflammatory and antiproliferative actions independent of cholesterol lowering. To determine whether these actions might affect neointimal formation, we investigated the effect of simvastatin on the response to experimental angioplasty in LDL receptor-deficient (LDLR Ϫ/Ϫ ) mice, a model of hypercholesterolemia in which changes in plasma lipids are not observed in response to simvastatin. Methods and Results-Carotid artery dilation (2.5 atm) and complete endothelial denudation were performed in male C57BL/6J LDLR Ϫ/Ϫ mice treated with low-dose (2 mg/kg) or high-dose (20 mg/kg) simvastatin or vehicle subcutaneously 72 hours before and then daily after injury. After 7 and 28 days, intimal and medial sizes were measured and the intima to media area ratio (I:M) was calculated. Total plasma cholesterol and triglyceride levels were similar in simvastatin-and vehicle-treated mice. Intimal thickening and I:M were reduced significantly by low-and high-dose simvastatin compared with vehicle alone. Simvastatin treatment was associated with reduced cellular proliferation (BrdU), leukocyte accumulation (CD45), and platelet-derived growth factor-induced phosphorylation of the survival factor Akt and increased apoptosis after injury. Conclusions-Simvastatin

hile coronary perforation is an uncommon complication following percutaneous coronary intervention (PCI), [1][2][3][4][5][6][7][8] it is one that may lead to cardiac tamponade, 6-9 emergency coronary artery bypass surgery (CABG), or pseudoaneurysm formation, 10 with the potential for late coronary rupture. New coronary devices that resect (eg, directional or transluminal extraction atherectomy), ablate (eg, rotational atherectomy or excimer laser angioplasty), or score (eg, the cutting balloon) atherosclerotic plaque may increase the risk of coronary perforation, and a number of angiographic risk factors for its occurrence have been described previously. [11][12][13][14] The use of newer higher-weight and hydrophilic coronary guidewires may also increase the risk of coronary perforation, particularly during the treatment of chronic coronary occlusions. Clinical algorithms for the treatment of coronary perforation based on angiographic and clinical criteria have been Circulation Journal Vol.66, April 2002 less well studied. Moreover, descriptions of the long-term sequelae after coronary perforation, and delineation of the potential risk for late pseudoaneurysm formation and coronary rupture, have been lacking.The present study examines the frequency of coronary perforation during PCI, evaluates the management strategies used to treat the perforation, and describes the long-term prognosis in patients who have developed coronary perforation during PCI. To address these issues, we reviewed our experience with coronary perforation in a consecutive series of 7,443 patients undergoing PCI at a single, highvolume clinical center. Methods Patient PopulationBetween January 1992 and December 1996, 7,443 coronary interventional procedures were performed in the Cardiac Catheterization Laboratory at National Toyohashi Higashi Hospital. These procedures included conventional balloon angioplasty (n=4,895; 65.8%), cutting balloon angioplasty (n=1,274; 17.1%), coronary artery stenting (n=810; 10.9%), directional coronary atherectomy (DCA) (n=440; 5.9%), and transluminal extraction catheter atherectomy (n=24, 0.32%). Coronary perforation is a rare but serious complication that occurs during percutaneous coronary intervention (PCI). This study examines the frequency of coronary perforation during PCI, evaluates the management strategies used to treat perforations, and describes the long-term prognosis of patients who have developed coronary perforation during PCI. Coronary perforations were found in 69 (0.93%) of 7,443 consecutive PCI procedures, occurring more often after use of a new device (0.86%) than after use of balloon angioplasty (0.41%) (p<0.05).Coronary perforation was attributable solely to the coronary guidewire in 27 (0.36%) cases. Coronary perforations were divided into 2 types: (1) Those with epicardial staining without a jet of contrast extravasation (type I, n=51), and (2) those with a jet of contrast extravasation (type II, n=18). Patients with type I and type II perforations were managed by observation only (3...

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uidewire crossing is the most important component of a successful percutaneous coronary intervention (PCI) for chronic total occlusions (CTO). Several special guidewires, such as the Magnum wire, [1][2][3] Laser wire 4-6 and hydrophilic wire, 7 have been developed and favorable results have been reported. Other than these guidewires, some Japanese products, such as the Athlete, Miracle, and Conquest wires (Asahi Intecc, Seto, Japan), 8 are used in some countries and constitute a range of stiff products. In particular, the Conquest wire is a tapered spring coil wire with a very stiff tip (9 g) that gives good torque control and penetrating ability even in hard fibrous plaque. This type of guidewire may be the last choice for uncrossable, very old CTOs. 8 Although the Athlete wires will advance into a false lumen at the end of the procedure in unsuccessful cases, we can also use them to penetrate the flap to re-enter the true lumen as a second step.Coronary angiography is limited as a guide for guidewire crossing in PCI for CTOs. On the other hand, by showing the cross-sectional anatomy of the coronary vessels, intravascular ultrasound (IVUS) can provide information on the plaque morphology and distribution, 9 and the exact location of the guidewires within a coronary artery, discriminating a false lumen from the true lumen before guidewire crossing. We report here a novel application of IVUS for very old and hard CTOs (abrupt occlusion with a side branch in case 1 and bending occlusion with severe calcification in case 2) in which the use of very stiff guidewires caused dissections, decreasing the collateral flow. Case Reports Case 1: Side Branch MethodA 68-year-old Japanese man had experienced chest oppression on effort since May 2000. He visited hospital in July 2000, and coronary angiography revealed a CTO in the proximal segment of the large left circumflex coronary artery (LCX). There was no significant stenosis in the left anterior descending coronary artery (LAD) or the right coronary artery (RCA). His coronary arteries were left dominant. He had not had any episodes suggestive of acute myocardial infarction. Cardiac catheterization revealed left ventricular dysfunction and moderate mitral regurgitation. PCI for the CTO was unsuccessful at that time. He was treated medically and his condition improved. However, he complained of chest oppression on effort again in October 2001. We attempted to re-open the CTO of the LCX. The age of this CTO was unknown, but was thought to be more than 18 months, based on the angiographic record. We obtained the consent of the patient after fully explaining the efficacy and risks associated with our new technique using IVUS before the PCI.The occlusion was severely calcified and flush with the orifice of the vessel, tapering nicely into a large obtuse marginal artery (Fig 1a). A 10Fr JCL 4.0 with a side hole (Bright Chip, Cordis, Miami, FL, USA) was used in order to prepare for the possible use of a rotablator with a 2.5-mm burr. A 2.9Fr IVUS catheter (Ultracross, Boston Sci...

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The risk of cardiovascular diseases in diabetic patients and even in those with IGT are associated with insulin resistance, two-to threefold higher than that in control subjects [1]. The United Kingdom Prospective Diabetes Study (UKPDS) and other similar studies indicated that intensive control of blood glucose in diabetic patients prevents and slows the progression of microvascular complications, but has little effect on the prevention of macrovascular complications i. e. acute myocardial infarction (AMI) [2]. Excessive macrovascular diseases in diabetes have thus been considered to be due to insulin resistance and/or hyperinsulinaemia.A recent study has shown that vascular inflammation with atherosclerosis is responsible for the onset of AMI [3]. Adhesion of leukocytes to the endothelium, which is regulated by several endothelial adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), E-selectin and P-selectin, is the first and crucial step in both atherosclerosis and vascular inflammation. Whereas endothelial dysfunction induced by insulin resistance and/or hyperinsulin- AbstractAims/hypothesis. The association of insulin resistance and compensatory hyperinsulinaemia with increased coronary events in diabetic patients is poorly understood. There are few publications about the direct atherogenic actions of insulin on the endothelium compared with those on vascular smooth muscle cells. The aim of this study was to elucidate whether high insulin directly affects neutrophil-endothelial cell adhesion and surface expression of endothelial adhesion molecules. We also examined what intracellular mechanisms are involved in these events. Methods. Studies of adhesion between neutrophils from healthy volunteers and human umbilical vein endothelial cells incubated in insulin-rich medium were carried out. Adhered neutrophils were quantified by measuring their myeloperoxidase activities and surface expression of endothelial adhesion molecules was examined using an enzyme immunoassay. Results. High insulin enhanced neutrophil-endothelial cell adhesion with an increase in the expression of intercellular adhesion molecule-1 but not E-selectin or P-selectin. Both phenomena were attenuated by pretreatment with protein kinase C inhibitors and a mitogen activated protein kinase inhibitor. Conclusions/interpretation. These results suggest that hyperinsulinaemia causes vascular injury by directly exacerbating neutrophil-endothelial cell adhesion through increasing endothelial expression of intercellular adhesion molecule-1 via activation of protein kinase and mitogen activated protein kinase pathways. [Diabetologia (2002) 45:556±559]