Background-Inhibition of cholesteryl ester transfer protein (CETP) is an efficient way to increase high-density lipoprotein (HDL) levels in humans. We investigated the effects of the inhibition of CETP activity by a CETP inhibitor, JTT-705, on the function and composition of HDL particles. Methods and Results-Japanese white rabbits were fed either normal rabbit chow LRC-4 (nϭ10) or a food admixture of LRC-4 and 0.75% JTT-705 (nϭ10) for 7 months. JTT-705 significantly inhibited CETP activities, increased HDL cholesterol (HDL-C) levels and the ratio of HDL 2 -C/HDL 3 -C, and decreased the fractional esterification rate of cholesterol in HDL, indicating preferentially increased large HDL particles. Treatment with JTT-705 increased all of the 3 charge-based HDL subfractions as determined by capillary isotachophoresis: fast-migrating, intermediate-migrating, and slow-migrating HDL. The percentage of slow HDL, ie, apolipoprotein E (apoE)-containing HDL and levels of apoE in HDL fraction, was also increased. JTT-705 treatment increased serum paraoxonase activity and HDL-associated platelet-activating factor acetylhydrolase activity, but decreased the plasma lysophosphatidylcholine concentration. Key Words: cholesteryl ester transfer protein inhibition Ⅲ apolipoprotein E-containing high-density lipoprotein Ⅲ capillary isotachophoresis Ⅲ paraoxonase (PON1) Ⅲ platelet-activating factor acetylhydrolase Ⅲ lysophosphatidylcholine Ⅲ rabbits I ncreased levels of low-density lipoprotein cholesterol (LDL-C) and reduced levels of high-density lipoprotein cholesterol (HDL-C) are known risk factors for coronary heart disease (CHD). The balance between HDL-C and LDL-C is known to be important in predicting the risk of CHD. 1 Although statin drugs potently lower LDL-C levels, their ability to raise HDL levels is limited. HDL helps to protect against atherosclerosis mainly because of its role in the reverse cholesterol transport process and its anti-oxidative and anti-inflammatory properties. Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl ester (CE) from HDL to apolipoprotein B (apoB)-containing lipoproteins and of triglyceride from triglyceride-rich remnants to HDL and LDL. 2 The HDL level has been shown to be influenced by CETP based on the fact that patients with genetic CETP deficiency have extremely high levels of HDL. 3 Although whether CETP is anti-atherogenic or proatherogenic depends on the metabolic background, and the exact role that CETP plays in atherosclerosis is still controversial, inhibition of CETP activity by small molecular CETP inhibitors, including JTT-705 and torcetrapib, has been shown to be an efficient way to raise HDL levels in subjects with normal 4,5 and low HDL-C levels. 6 HDL consists of heterogeneous particles that differ in density and size. Inhibition of CETP activity by torcetrapib in subjects with low HDL-C levels caused a much greater percentage increase in HDL 2 -C levels than in HDL 3 -C levels, and increased large HDL particles as determined by nuclear magnetic ...

Objective: The aim of this study was to evaluate the role of glycoxidation in the calcification of the internal thoracic artery (ITA) in diabetes mellitus (DM). Methods: ITA samples were obtained from 17 patients with type 2 DM (age 62.9 ± 10.5 years) and 12 age-matched, nondiabetic patients (age 62.5 ± 10.2 years) who underwent coronary artery bypass grafting. These samples were analyzed histopathologically and assessed for calcification by von Kossa staining and for glycoxidation by immunohistochemistry using anti-N^Ε-(carboxymethyl)lysine (CML) antibody. Morphometric evaluation of calcification of the medial layer, intimal thickness and intima-to-media ratio was performed using NIH image software. To evaluate the mechanism of the interaction between calcification and glycoxidation, we developed an in vitro model of calcification of collagen that was chemically modified by glucose, glutaraldehyde or epoxy compound. The calcium-binding activity of these collagens was determined in hydrolysates using atomic absorption spectrophotometry. Results: ITAs of both diabetic and nondiabetic patients were free of atherosclerosis, and no differences were found between the two groups with regard to intimal thickness and intima-to-media ratio. Areas of calcification were noticed in both groups in the tunica media, but not in the tunica intima. Calcium deposits were localized within the extracellular matrix, which was immunohistochemically positive for CML. The extent of medial layer calcification was significantly greater in diabetic patients than nondiabetic subjects, but was independent of known risk factors such as hypertension, hyperlipidemia, obesity and history of old myocardial infarction. The binding activity of collagen was time-dependently increased with in vitro incubation of glucose. A significant increase in the calcium-binding ability was observed in glucose- and glutaraldehyde-modified collagens, but not in epoxy compound-modified collagen. Conclusion: Our results suggest that glycoxidative modification of the extracellular matrix, in particular collagen, of the vascular wall may enhance the development of ITA calcification in diabetic patients.

Background: Coronary artery bypass grafting (CABG) for hemodialysis patients is high risk compared with other patient groups. The aim of this study was t o analyze the potential benefits of off-pump CABG for hemodialysis patients. Methods: From April 1994 through December 2000, 26 hemodialysis patients underwent CABG. The off-pump group consisted of 15 patients operated on without a pump and t h e on-pump group consisted of 11 patients operated on with a pump. Results: There was n o difference between the t w o groups with regard t o mean age, mean number of diseased vessels and mean number of anastomoses per patient. No patient died in either group during hospitalization. The postoperative complication rate was l o w in both groups. The postoperative ventilation time was

ERAH can be performed safely, and the early results are satisfactory. Endoscopic vessel harvesting is therefore recommended as the technique of choice for RA harvesting.

Small artery elasticity index (SAEI) as determined by a new non-invasive pulse-wave contour analysis has been used to identify abnormalities of the arterial wall associated with aging, hypertension (HT), endothelial dysfunction, and coronary artery disease (CAD). The present study examined the influence and interaction of CAD risk factors on the association between SAEI in risk-associated patients with CAD (case subjects, n = 178) and without CAD (control subjects, n = 202). Case subjects had a lower SAEI than control subjects, and age was consistently and negatively correlated with SAEI. The HT was related to reduced SAEI in female subjects overall and in male case subjects. In male patients with hypertension, the association between SAEI and CAD was significant (P < .05) after considering conventional risk factors of CAD. In conclusion, age and HT should be considered when using SAEI in the early diagnosis of CAD, and lower SAEI could be of greatest diagnostic value in male patients with HT.