More western hypercholesterolemic patients achieve Japanese atherosclerosis society LDL-C targets with rosuvastatin therapy than with atorvastatin therapy

212

St&l

40 &day with coadministration). The primary endpoint was proportion of patients achieving target LDL-C G2.6 mmol/L at Week 14. Results: Addition of ezetimibe to atorvastatin 10 mg/day followed by response-based titration of atorvastatin significantly increased proportion of patients reaching target LDL-C to 22% (67/305) versus titration of atorvastatin alone of 7% (23/316; piO.01). Ezetimibe+atorvastatin 10 mg significantly reduced LDL-C versus atorvastatin 20 mg at Week 4 (22.8% versus 8.6%; p
I675 REVERSE 0. Stein’, ‘Hadassah

CHOLESTEROL

Y. Stein2. IHadassah-Hebrew

TRANSPORT

Uniuersify University Hospital, Jerusalem, Israel

IN VIVO

School

ofMedicine,

We have developed a mouse model that permits quantification of cholesterol efflux in viva under various experimental conditions and mimics to some extent cholesterol removal from an atheroma. It is based on the creation of a lipoprotein cholesterol depot by injection of cationized LDL into the rectus femoris muscle, which induces a sterile infiltrate of mononuclear cells. The rate of clearance of the injected cholesterol is a measure of reverse cholesterol transport (RCT). Currently we used this methodology in mice expressing simian cholesteryl ester transfer protein (CETP). High levels of plasma CETP did not significantly change RCT, but permitted evaluation of putative role of CETP in transfer of esterified cholesterol from the injected site to the liver. We also compared the rate of cholesterol clearance in mice C57BL/6 (susceptible) and C3WHe.I (resistant) to diet induced atherosclerosis, using male and female mice fed chow or an atherogenic diet. The loss of exogenous cholesterol mass from the muscle injected with cationized LDL was faster in chow fed C3H than in C57BU6 mice. This difference was much more pronounced when the mice were fed the atherogenic diet. Comparison of cholesterol efflux from macrophages, mediated by ABCAl, to free apoA1, with or without CAMP, LXR and RXR ligands, revealed a higher efflux from cells of C3H than C57BU6 mice. The more rapid rate of cholesterol efflux from the injected muscle, together with a higher response to apoA1 in the macrophages of C3H mice, could contribute to their resistance to atherosclerosis.

I676 ALTERATION

IN ANTIOXIDANT CAPACITY IN CHRONIC RENAL FAILURE AND HEMODIALYSIS PATIENTS: A POSSIBLE EXPLANATION FOR THE INCREASED CARDIOVASCULAR RISK IN THESE PATIENTS

Z.G. Stoikova’ , S.A. Dzhekova-Stojkova2, G.L. Bosilkova2, M.A. Krstevska2. ‘Medical Faculty, Department ofMedical and Experimental Physiology: ‘Medical Faculty, Department ofMedical and Experimental Biochemistry, Skopje, Republic ofMacedonia

Excessive penetration of reactive oxygen species is one of the incriminated mechanisms in the pathogenesis of progressive renal injury. The high incidence of cardiovascular disease in chronic renal failure and hemodialyzed (HD) patients is now well established and the involement of oxidative stress has been hypothesized in these phenomena. The aim of our study was to evaluate the level of oxidative stress in patients with chronic renal failure receiving hemodialysis, before and after the dialysis session, carried out on a high biocompatible polyacrylonitrile membrane. The concetration of serum total antioxidant status (TAS) and activity of the enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD) were determined spectrophotometrically in 26 patients with chronic renal failure before and after hemodyalisis and compared with the results of the apparently healthy agematched control group (N=105). While the concentration of TAS was higher in the patients with chronic renal failure before HD and lower after HD, then the SOD and GPx activities were lower before and higher after HD compared to the controls. The coefficient of correlation between TAS and GPx was significantly increased after HD (r=O.52 vs. 0.15). Our study demonstrates that profound disturbances in the redox system occur during the course of chronic renal failure and hemodialysis, and may provide an explanation for the cardiovascular complications in these patients.

LIPASE RELEASES FFA FROM HDL I677 ENDOTHELIAL DERIVED PHOSPHOLIPIDS AND MEDIATES THEIR UPTAKE

INTO HEPG2

CELLS

J.G. Strauss2, M. Hayn2, R. Zechne?, S. Frank’. ‘Institute ofMedical Biochemistry and Medical Molecular Biology, ‘Institute of Molecular Biology, Biochemistry and Microbiology, Karl-Franzens-Uniuersify Graz, Austria

Endothelial lipase (EL) is a new member of the triglyceride lipase gene family. EL is a phospholipase with very little triglyceride lipase activity. Our recent studies demonstrated that EL can increase HDL binding and holo particle uptake as well as the selective uptake of HDL derived CE (cholesteryl ester). To investigate the effects of EL on cellular metabolism of FFA released from HDL associated phospholipids HepG2 cells, infected with EL-expressing adenovims (EL-Ad) or LacZ-Ad (control), were incubated with 14C-(dipalmithoyl)-phosphatidylcholine labeled HDL (14C- PC-HDL) for lh or 5h, respectivly. 14C-PL, -TG and -FFA, were measured in the medium and the cell lysates of HepG2 cells upon incubation by thin layer chromatography. In the cell lysates of EL-Ad infected cells the amounts of both 14C-PC and 14C-TG were increased 4-fold compared to LacZ-Ad infected cells whereas 14C-FFA were not detected in the lysates. In the media of EL-Ad infected cells 14C- FFA were elevated 2-fold compared to control LacZ-Ad infected cells. The expression of MUT-EL lacking the phospholipase activity led to only slightly increased accumulation of 14C-PC in the cell lysates compared to LacZ-Ad infected cells. The Ql-MS analysis of the EL-Ad infected cells incubated with HDL in LPDS or with 10% FCS, respectively, revealed profound accumulation of phosphatidylcholine in the cell lysate. Thus we conclude that the active enzyme can release FFA from the HDL-phospholipids and in turn this FFA are partially liberated to the medium and partially taken up by the cells and used for the synthesis of TG and PL. I678 SUPERFICIAL MARKER

FEMORAL ARTERY OF INFLAMMATION

G. Strubel, K. Kroeger,

of Essen, Germany

G. Rudofsky.

OCCLUSION

Department

AND

ofAngiology, Uniuersify

Background:

Atherosclerosis is induced by a large variety of risk factors. It is in discussion if inflammatory processes may have also an direct or indirect influence. The age of manifestation and the location of peripheral arterial occlusive disease (PAOD) is not strictly correlated to the number of classical rik factors. There is only less information how far inflammation might be a reason for early manifestation of PAOD. Thus we analysed age dependent changes of blood sedimentation rates (BSR), fibrinogen and c-reactive protein (CRP) in patients with isolated superficial femoral artery occlusions (SFA). Patients and Methods: In 97 consecutive patients (67 men and 30 women) with a mean age of 68&9 years (range: 4486 years)suffering from an isolated SFA occlusion BSR, fibrinoggen and CRP were determined. 21 patients with PAOD stage IV according to Fontaine were excluded because of the existence of local infections. Results: After excluding the PAOD IV patients CRP-values were 2.4&3.3 mg/dl (range: O.l-17.1), fibrinogen values 419&151.5 mg/ dl (range: 204-1000) and BSR-values 22&18 mm according to Westergreen (range: 2_78).Analysing three different age-groups younger patients showed higher CRP and fibrinogen levels (patients 50-59 years: CRP 2.74&4.09 mg/dl, fibrinogen 471&216.1 mg/dl) then patients in the sixties (60-69 years: CRP 2.69&3.11 mg/dl, fibrinogen 432&137.3 mg/dl) and patients between 70-79 years (CRP 1.75&2.02 mg/dl, fibrinogen 387&103.9 mg/dl). The BSR-values did not vary with age. Conclusion: The results show that inflammation might play a more important role in younger patients with SFA occlusions. I679 MORE

WESTERN HYPERCHOLESTEROLEMIC PATIENTS ACHIEVE JAPANESE ATHEROSCLEROSIS SOClETY LDL-C TARGETS WITH ROSUVASTATIN THERAPY THAN WITH ATORVASTATIN THERAPY

K. Stmtt’, R. Caplan2, H. Hutchinson2. ‘AstraZeneca, MaccZesJieZd, Cheshire, UK: ‘AstraZeneca Lt Wilmington, DE, USA Background:

Rosuvastatin (RSY Crestor) reduced LDL-C dosedependently and to a similar magnitude in Western and Japanese hypercholesterolemic patients in dose-ranging studies. Data from comparative

73rd EAS Congress

suprun

trials of RSV and atorvastatin (ATV) (prospectively designed for pooling) in which drugs were administered at a tied dose to Western hypercholesterolemic patients were analyzed to assess achievement of Japanese Atherosclerosis Society (JAS) LDL-C targets. Methods: JAS LDL-C goals by risk categories are: A (lowest-risk, hypercholesterolemia without other risk factors) 1140 mg/dL; B (medium-risk, hypercholesterolemia plus other risk factors) 1120 mg/dL; and C (highestrisk, coronary artery disorders) ~100 mg/dL. Achievement of JAS targets was determined from 3 trials in Western patients with LDL-C 3160 and 1250 mg/dL comparing RSV 5 mg and RSV 10 mg vs. ATV 10 mg for 12 weeks. Results: The vast majority of patients fall into medium- or high-risk groups. Proportions of patients achieving treatment goals with RSV 5 mg, RSV 10 mg, and ATV 10 mg were as follows (number of patients in risk group, which were comparable across treatment groups): Total: 59%*** (390), 73%*** (389), and 44% (393). High-risk (509): 36%***, 61%***, and 17%. Medium-risk (641): 75%**, 83%***, and 63%. Low-risk (22): 89%, 88%, and 100% (**at least PiO.01 for RSV vs. ATV; ***at least PiO.001 for RSV vs. ATV). Conclusion: RSV 5 mg and 10 mg help significantly more patients to achieve JAS LDL-C targets compared with ATV 10 mg overall and particularly in the high-risk groups. I680 INHIBITION

ABSORPTION

OF INTESTINAL BY EZETIMIBE

CHOLESTEROL IN HUMANS

T. Sudhop’, D. Lutjohann’, A. Kodal’, D. Tribble’, S. Shah’, I. Perevozskaya’, K. van Bergmann’. ‘Uniuersify ofBonn, Germany, ‘Merck Research Laboratories, Rahway, NJ, USA Background:

Ezetimibe has been shown to inhibit cholesterol absorption in a variety of animal models. Methods: The effect of ezetimibe (10 mg/day) on cholesterol absorption and synthesis was investigated in a randomized, double-blind, placebocontrolled, crossover study in 18 adult males with mild to moderate hypercholesterolemia. Treatment periods lasted 2 weeks with an intervening 2-week washout period. Fractional cholesterol absorption was measured by the continuous dual-isotope feeding method using deuterium-labeled markers. Cholesterol synthesis was examined by the fecal balance method. Lathosterol was measured using GLC. All parameters were calculated as geometric means&SD. The effect of treatment for ezetimibe versus placebo was assessed as a ratio of geometric means (ezetimibe/placebo). Results: Fractional cholesterol absorption was 49.8&13.8% on placebo and 22.7&25.8% on ezetimibe, indicating a reduction of 54% (piO.001). Cholesterol synthesis increased by 89% from 931&1027 to 1763&1098 mg/day (p
PROTEIN LEVEL A USEFUL MARKER OF SEVERITY AND INFARCT SIZE IN PATIENTS WITH ACUTE ST ELEVATION MYOCARDIAL INFARCTION?

M. Suleiman’ , Y. Levy’, A. Roguin’ , D. Aronson’ , M. Halabi’ , A. Goldberg’, A. Kerner’ , M. Kapeliovich’ , H. Hammerman’. ‘Zntensiue Coronary Care Unit, ‘Internal Medicine D, Rambam Medical Centq Bruce Rapapport Faculty ofMedicine, Haifa. Israel Background

and Objectives: Elevated C-reactive protein (CRP), a marker of chronic inflammation and acute phase reactant, has recently been shown to be predictive of recurrent coronary events. Our aim was to assess the value of CRP level as a marker of severity in prospective series of consecutive patients with acute ST-segment elevation myocardial infarction (STEMI) and its correlation to clinical and echocardiographic parameters. Methods and Results: CRP levels were measured within 24 hours of symptoms onset by highly-sensitive assay in 126 consecutive patients (mean age 62&13, 68% men) with first acute STEMI. Infarct size and

213

LV systolic function were assessed by peak creatine kinase (CK) levels and two-dimensional echocardiographic examination performed on day 2 or 3. The patients were divided into 2 groups according to their CRP levels (CRPi3.4 mg/dL, n=95 and CRP>3.4 mg/dL, n=31). Both groups were comparable in most variables. Patients with elevated CRP levels had more anterior infarcts (65% vs 44%, PiO.OOl), larger infarct size (peak CK 3152&491 vs. 1792&214, P=O.O04), worse LV systolic function (21% had severely reduced LV function vs. 4%, P=O.OOS), higher wall motion score index (1.78&0.3 vs. 1.51&0.3, PiO.OOl), and higher incidence ofKillip 34 classification (45% vs. 4%, PiO.001). Additionally, patients with elevated CRP levels had significantly higher in-hospital mortality rate (16% vs. l%, PiO.001). Conclusion: CRP level on admission is a useful marker of severity in patients with acute STEMI. Elevated levels are associated with increased in-hospital mortality, larger infarct size and worse Killip classification. 16821 THE Kl2lQ

POLYMORPHISM IN THE PLASMA CELL MEMBRANE GLYCOPROTEIN 1 (PC-l) GENE PREDISPOSES TO EARLY MYOCARDIAL INFARCTION

R. Sunder-Plassmann' , G. Endler’ , H. Sunder-Plassmann’ , M. Exner’ , M. Schillinge?, A. Klimesch’ , S. Kapiotis’ , S. Meier’ , F. Kunz’ , K. Hube?, C. Mannhalter’, 0. Wagner’. ‘Department ofMedical and Chemical Laboratory Diagnostics, 2Department ofInternal Medicine IZ, Division ofCardiology, Uniuersify ofVienna Medical School, Austria Elevated plasma cell membrane glycoprotein 1 (PC-l) expression and the frequent PC-l Kl2lQ polymorphism have recently been associated with insulin resistance. Since insulin resistance represents an important risk factor for atherosclerotic vascular disease and myocardial infarction, we investigated the involvement of the PC-l Kl2lQ polymorphism in the development of myocardial infarction. In the present study, we analyzed 234 patients (mean age 56.0&l 1.7 years, 181 male, 53 female) at a defined end point of atherosclerotic vascular disease ~ i.e. patients who had suffered myocardial infarction according to WHO criteria ~ for the PC-l Kl2lQ mutation by a newly developed mutagenic separated PCR assay. The presence of the Q allele was significantly associated with younger age at the time of first myocardial infarction suggesting a more rapid progression of endothelial dysfunction. In a multivariate analysis carriers of the 12lQ allele exhibited a 2.6 fold increased odds (95% CI: 1.14.4) for suffering myocardial infarction within the first and second tertile of age (160 years). Our data indicate that the PC-l 12lQ allele might predispose independently of other well established risk factors for early myocardial infarction and that genotyping for the PC-l Kl2lQ polymorphism, if confirmed in an independent collective, might be considered worth screening in patients with a family history of atherosclerotic vascular disease and myocardial infarction. I683 LDL -INDUCED

INTERCELLULAR LIPID ACCUMULATION CAUSES OVEREXPRESSION OF PROINFLAMMATORY CYTOKINES

1.V Suprun’, E.R. Andreeva’, L.A. Medvedeva’, T.A. Scalbe’, S.M. Baida' ,A.N. Orekhov’. ‘Institute ofEqwimental Cardiology, ‘Institute forAtherosclerosis Research, Moscow, Russia In spite of substantial evidence for association of inflammation and atherosclerosis progression, still no suggestions exist to point out the correlation between lipid deposition in vascular wall and local inflammatory process. We have studied the effect of intracellular lipid accumulation on proinflammatory cytokines expression in cultured human intimal cells, namely, TNF-c( and IL-l. HLA-DR expression was also studied. All of them are believed to stimulate migration and activation of hematogenic cells. After incubation of cultured cells with native or modified LDL, intracellular cholesterol level was measured, as well as TNF-IX, IL-l and HLA-DR expression. It was demonstrated that native LDL did not induce any changes in intracellular cholesterol content or cytokines and HLADR expression. On the opposite, naturally occurring modified LDL caused significant intracellular cholesterol accumulation that was accompanied by overexpression of TNF-IX, IL-l and HLA-DR. The significant (piO.05) positive correlation between these parameters (r=O.986, 0.968 and 0.934 for TNF-IX, IL-l and HLA-DR, respectively). Similar results were obtained using cultured human macrophages. We can assume that LDL-induced intracellular lipid accumulation stimulates the expression of proinflammatory cytokines and HLA-DR, thus playing a significant role in the development

73rd EAS Congress