No abstract

To investigate the clinical significance of circulating matrix metalloproteinases (MMPs) and their tissue inhibitos (TIMPs) in patients with premature coronary atheroscrelosis, we studied 53 consecutive male patients with angiographically defined premature (<65 years) and stable coronary artery disease. Plasma levels of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 were determined in peripheral blood by a sandwich enzyme immunoassay, and the results were compared with those from 133 age-matched control males. There were significant differences in all the MMPs and TIMPs (p<0.001) between patients and controls. In the patient group, the levels of MMP-9 (mean +/- SD (ng/ml) 27.2 +/- 15.2/21.8 +/- 15.2) and TIMP-1 (130.4 +/- 55.7/94.5 +/- 26.3) were significantly higher, and the levels of MMP-2 (632.5 +/- 191.6/727.6 +/- 171.4), MMP-3 (53.1 +/- 31.2/79.6 +/- 29.9), and TIMP-2 (24.7 +/- 15.2/35.4 +/- 16.4) were significantly lower than those of controls. We found significant positive correlation between plasma MMP-9 levels and low-density lipoprotein (LDL)-cholesterol levels (Rs = 0.168, p = 0.022), and significant negative correlation between plasma MMP-9 levels and high-density lipoprotein (HDL)-cholesterol levels (Rs = -0.164, p = 0.026) by Spearman rank correlation test. In contrast, plasma MMP-2 (Rs = 0.181, p = 0.014) and MMP-3 (Rs = 0.260, p = 0.0004) levels were positively correlated with HDL-cholesterol levels. TIMP-2 levels were negatively correlated with total cholesterol (Rs = -0.197, p = 0.007) and LDL-cholesterol (Rs = -0.168, p=0.022) levels. These results suggest that the circulating levels of MMPs and TIMPs are altered in patients with premature coronary atherosclerosis and that plasma lipoprotein cholesterol levels correlate with these, possibly as a result of the lipoprotein-vessel wall interactions.

The mechanisms responsible for interindividual variation in response to statin therapy remain uncertain. It has been shown that hepatic cholesterol synthesis is associated with ATP binding cassette transporter G5 and G8 (ABCG5/8) activities. To test the hypothesis that genetic variation in ABCG5/8 might influence the plasma lipid response to statin therapy, we examined five nonsynonymous polymorphisms at the ABCG5/8 loci (Q604E, D19H, Y54C, T400K, and A632V) in 338 hypercholesterolemic patients treated with 10 mg atorvastatin. In carriers of the D19H variant, means of posttreatment values and adjusted percent reductions in LDL cholesterol (LDLC) were significantly lower ( P ϭ 0.028) and greater ( P ϭ 0.036) (112 mg/ dl, 39.7%) than those of noncarriers (119 mg/dl, 36.2%), respectively, while no significant difference was observed in percent reductions in total cholesterol. Stepwise multiple regression analysis revealed significant and independent associations with absolute or percent reduction between D19H genotype and posttreatment LDL cholesterol levels. The other polymorphisms were not significantly associated with treatment effects. These results suggest that, in patients with hypercholesterolemia, the ABCG8 D19H variant is associated with greater LDLC-lowering response to atorvastatin therapy. -Kajinami, K., M. E. Brousseau, C. Nartsupha, J. M. Ordovas, and E. J. Schaefer. ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin. In hepatocytes, the reduction in cholesterol content, in turn, causes a decrease in the secretion of apolipoprotein B (apoB)-containing lipoproteins and an upregulation of LDL receptor activity, both of which contribute to the reduction in plasma LDL cholesterol (LDLC) levels observed with statin therapy. ATP binding cassette transporters G5 and G8 (ABCG5/8) are unique proteins located in the plasma membrane, as well as in the intracellular membranes of enterocytes and hepatocytes. Mutations in the genes encoding for ABCG5/8 have been identified as the cause of sitosterolemia (9-11), a rare inborn error of metabolism characterized by elevated plasma levels of plant sterols due to hyperabsorption and decreased biliary sterol secretion. Impairment of these pathways results in a decrease of cholesterol biosynthesis in hepatocytes (12, 13), raising the possibility that interindividual variation in plasma cholesterol concentrations (14,15), and possibly the response to statin treatment, is, in part, due to variation in the ABCG5/8 genes.We, and others, have previously shown that apoE genotype is associated with the plasma lipid response to statin therapy (16,17). The present study was undertaken to test the hypothesis that polymorphisms at the ABCG5/8 gene loci are associated with plasma lipid response to statin treatment. SUBJECTS AND METHODSStudy subjects were the same patient group, in which we found the gender-specific effects of apoE genotype on plasma

The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, has been shown to reduce major cardiovascular events in both primary and secondary prevention, and statins became one of the most widely prescribed classes of drugs throughout the world. Previously, statins have been well tolerated and have shown favorable safety profiles. However, the voluntary withdrawal of cerivastatin from the market because of a disproportionate number of reports of rhabdomyolysis-associated deaths drew attention to the pharmacokinetic profile of statins, which may possibly have been related to serious drug-drug interactions.Pitavastatin (NK-104, previously called itavastatin or nisvastatin, Kowa Company Ltd., Tokyo) is a novel, fully synthetic statin, which has a potent cholesterol-lowering action. The short-term and long-term lipid-modifying effects of pitavastatin have already been investigated in subjects with primary hypercholesterolemia, heterozygous familial hypercholesterolemia, hypertriglyceridemia, and type-2 diabetes mellitus accompanied by hyperlipidemia. Within the range of daily doses from 1 to 4 mg, the efficacy of pitavastatin as a lipid-lowering drug seems to be similar, or potentially superior, to that of atorvastatin.According to the results of pharmacokinetic studies, pitavastatin showed favorable and promising safety profile; it was only slightly metabolized by the cytochrome P450 (CYP) system, its lactone form had no inhibitory effects on the CYP3A4-mediated metabolism of concomitantly administered drugs; P-glycoprotein-mediated transport did not play a major role in its disposition, and pitavastatin did not inhibit P-glycoprotein activity.It could be concluded that pitavastatin could provide a new and potentially better therapeutic choice for lipid-modifying therapy than do the currently available statins. The efficacy and safety of higher dose treatment, as well as its long-term effects in the prevention of coronary artery disease, should be further investigated.

No abstract

Our purpose was to compare HDL subpopulations, as determined by nondenaturing two-dimensional gel electrophoresis followed by immunoblotting for apolipoprotein A-I (apoA-I), apoA-II, apoA-IV, apoCs, and apoE in heterozygous, compound heterozygous, and homozygous subjects for cholesteryl ester transfer protein (CETP) deficiency and controls. Heterozygotes, compound heterozygotes, and homozygotes had CETP masses that were 30, 63, and more than 90% lower and HDL-cholesterol values that were 64, 168, and 203% higher than those in controls, respectively. Heterozygotes had ‫ف‬ 50% lower pre ␤ -1 and more than 2-fold higher levels of ␣ -1 and pre ␣ -1 particles than controls. Three of the five heterozygotes' ␣ -1 particles also contained apoA-II, which was not seen in controls. Compound heterozygotes and homozygotes had very large particles not observed in controls and heterozygotes. These particles contained apoA-I, apoA-II, apoCs, and apoE. However, these subjects did not have decreased pre ␤ -1 levels. Our data indicate that CETP deficiency results in the formation of very large HDL particles containing all of the major HDL apolipoproteins except for apoA-IV. We hypothesize that the HDL subpopulation profile of heterozygous CETP-deficient patients, especially those with high levels of ␣ -1 containing apoA-I but no apoA-II, represent an improved antiatherogenic state, although this might not be the case for compound heterozygotes and homozygotes with very large, undifferentiated HDL particles. -Asztalos, B. F., K. V. Horvath, K. Kajinami, C. Nartsupha, C. E. Cox, M. Batista, E. J. (1, 2). The major role of CETP is a net transfer of CE from HDL to TG-rich lipoprotein (TRL) and of LDL and TG from TRL to LDL and HDL. CETP mRNA is expressed in several tissues, but the majority of circulating CETP originates from the liver (3).CETP plays a key role in HDL metabolism (4). It regulates total plasma HDL-cholesterol (HDL-C) level and also facilitates the remodeling of HDL particles (5). A high CETP concentration correlates with a low HDL-C level, a strong risk factor for coronary artery disease (6). On the other hand, Asian subjects with CETP deficiency have markedly increased HDL-C (3-to 6-fold) and apoA-I concentrations (7-9). CETP deficiency-induced increase in HDL-C level is mainly found in the large HDL2 subclass. Moreover, the average HDL size of CETP-deficient subjects is significantly increased and enriched in cholesterol (10). These large HDL particles have been reported to be less effective in promoting cholesterol efflux from lipidloaded macrophages than HDL particles of control subjects (11).Several mutations of the CETP gene have been identified as causes of CETP deficiency and increased HDL-C levels. These include a G-to-A substitution within intron 14 at the donor splice site (Int14A), a mutation that is present in up to 2% of the total Japanese population and in as many as 27% of people in the Omagari area of Japan, as well as a missense mutation in exon 15 (D422G) present in up to 7% of the Japanese...

No abstract

An elevated level of low-density lipoprotein (LDL)-cholesterol has been recognised as the most important risk factor for coronary artery disease (CAD). Development of the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) ('statins'), a rate-limiting key enzyme of cholesterol synthesis pathway, has revolutionised the cholesterol-lowering therapy. In the last decade, effective primary and secondary preventive measures have been established in several statin trials to prevent future events of CAD by lowering LDL-cholesterol levels. These results supported the 'lower is better' hypothesis in the relationship between LDL-cholesterol levels and CAD. NK-104 (pitavastatin, previously named as itavastatin or nisvastatin, Kowa Company Ltd., Tokyo) has recently been developed as a new chemically synthesised and powerful statin. On the basis of reported data, the potency of NK-104 is dose-dependent and appears to be equivalent to that of atorvastatin. This new statin is safe and well-tolerated in the treatment of patients with hypercholesterolaemia. The cytochrome P450 system only slightly modifies NK-104, which suggests the clinical advantage of this agent, because the prevalence of clinically significant interactions with a number of other commonly used drugs can be considered to be extremely low. NK-104 can provide a new and potentially superior therapeutic agent when compared with currently available other statins. Randomised controlled clinical trials to assess the long-term effects of this new statin on CAD would be required.