Improved peripheral endothelial function in postmenopausal women with coronary artery disease after acute oral intake of 17 β-estradiol valerate

Thursday, 27 May 1999 Poster session: Lipid lowering drugs 50 yrs., and 20 men, aging 24-70 yrs., mean 49 yrs.). Twelve patients received 40 rag/day and twenty patients received 80 rag/day for six weeks. Blood samples were taken after an overnight fast before and 6 weeks after simvastatin treatment. Total plasma cholesterol was measured enzymatically, 24S-OH-Chol and 27-OH-Chol with a high sensitive isotope dilution method using gas-chromatography mass spectrometry. During treatment with 40 rag/day total plasma cholesterol decreased significantly from 282+41 mg/dl (mean+-SD) to 184+34 mg/dl (-35%; p = 0.003). Plasma 24S-OH-Chol and 27-OH-Chol decreased also significantly from 95+-24 ng/ml to 685= 19 ng/ml (-28%; p < 0.001) and from 205±51 ng/ml to 148+28 ng/ml (26%; p = 0.007), respectively. However, the ratio 24S-OH-Chol/cholesterol and 27-OH-Chol/cholesterol increased significantly. Administration of 80 rag/day resulted in a reduction of plasma cholesterol from 359+-77 mg/dl to 231+- 47 mg/dl (-35%; p < 0.001). Plasma concentrations of 24S-OH-Chol decreased from I11+-36 ng/ml to 62-1-22 ng/ml (-43%; p < 0.001) and 27OH-Chol from 254+-61 ng/ml to 157+-46 ng/ml (-37%; p < 0.001). Percent reduction of cholesterol was not different for 40 and 80 mg of simvastatin, whereas the high dose reduced 24S-OH-Chol to a significant greater extend than cholesterol (-43% versus -35%, p = 0.05). Thus, the ratio of 24S-OHChol to cholesterol decreased significantly (p = 0.002), in contrast to the ratio 27-OH-Chol to cholesterol. The results could indicate that high doses of simvastatin influence cholesterol metabolism in the brain. The study was supported by a grant from the Bundesministerium fiir Bildung, Wissenschaft, Forschung und Technologie (01 EC9402). CHOLESTEROL REDUCTION IMPROVES MYOCARDIAL PERFUSION ABNORMALITIES IN NORMOLIPIDEMIC PATIENTS WITH CORONARY ARTERY DISEASE (CAD) J.M. Mostaza, M.V. Gomez, E Gallardo, M.L. Salazar, R. Martin-Jadraque, L. Plaza-Celemin, I. Gonzalez-Maqueda, L. Martin-Jadraque. From the

dtherosclerosis Unit, Nuclear Medicine and CardioloKv Seruices of the C.I.C. Instituto de Salttd Carlos II1 and the Coronao, Unit qf Ho,wital "La Pa:", Spain Objective: To evaluate if pravastatin treatment increases myocardial perfusion, as assessed by Thallium-201 Single Photon Emission Computed Tomography (SPECTI dipyridamole testing, in normolipidemic patients with CAD. Methods: Randomized, placebo controlled study with a crossover design. Twenty normnlipidemic CAD patients were randomly assigned to receive 20 mg ofpravastatin in a single nocturnal dose or placebo for 16 weeks and then crossed over to the opposite medication for a further 16 weeks. Lipid and lipoprotein analysis and dipyridamole Thallium-201 SPECT were performed at the end of each period. SPECT images were I I visually analysed in 8 myocardial segments using a 4 points scoring system by two independent observers. A summed stress score and a summed rest score were obtained for each patient. Quantitative evaluation was performed by the Cedars Sinai method. The magnitude of the defect was expressed as a percentage of global myocardial perfusion. Results: Total and LDL cholesterol during placebo were 214+28 mg/dl and 149+24 mg/dl. Values on pravastatin were 170+-22 mg/dl and 103+-23 mg/dl. Summed stress score and summed rest score were lower on pravastatin than on placebo (7.5 vs 6, p = 0.023 and 3 vs 2, p = 0.059 respectively). Quantitative analysis showed a smaller perfusion defect with pravastatin (29.2%) compared with placebo (33.8%), p = 0.019 during dipyridamole stress. No differences were found at rest. Conclusion: Reduction of cholesterol levels with pravastatin in normolipidemic subjects with CAD improves myocardial perfusion during dipyridamole stress Thallium-201 SPECT. SIMVASTATIN AND LIPOSTABIL INDUCE BENEFICIAL CHANGES IN HIGH DENSITY LIPOPROTEINS PHOSPHOLIPID COMPOSITION I.N. Ozerova, I.V. Paramonova, N.M. Akhmedzhanov, N.V. Perova. National

Research Center for Preoentive Medicine, Moscow, Russia It was shown that the decrease of total cholesterol level under simvastatin administration is accompanied by the increase of high density lipoprotein cholesterol (HDL C) concentration. One of the reasons explaining this HDL C elevation might be changes in their phospholipid composition, because it is known that phospholipids are involved into HDL-mediated cholesterol acception. The aim was to study HDL phospholipid composition under the hyperlipidemias treatment by HMG-CoA reductase inhibitor - simvastatin (Zocor, MSD) in comparison with lipostabil (Rhone Poulenc Rorer), the

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essential phospholipids, mainly consisting of phosphatydilcholine. Twenty patients (aged 40-59) with low density lipoprotein cholesterol (LDL C) greater, than 130 mg/dl received either simvastatin (n = 10) or lipostabil in = 10) during 2 months. There were no differences between two groups in baseline levels of total C, triglycerides, LDL C and HDL C. While simvastatin therapy was accompanied by significant decrease in total C and LDL C, and by HDL C increase (47+2.7 vs 44-1-2.5 mg/dl; P < 0.02), lipostabil resulted only in slight HDL C elevation (42+0.9 vs 40+1.2 mg/dl; P < 0.05). Surprisingly, that simvastatin induced HDL phospholipid composition changes: the increase of phosphathydilcholine (from 69.1+2.32 to 76.4+1.47%; P < 0.001) and phosphathydilethanolamine (from 1.4+ 0+28 to 2.6+0.27%; P < 0.001) portion, and the decrease of lysophosphathydilcholine (from 13.2+0.94 to 8.3+0.62%; P < 0.001) and sphingomyelin (from 13.0+1.68 to 9.3+ 1.15%; P < 0.01 ) portion. These changes were similar to those found in patients receiving lipostabil. Thus, the beneficial effect of simvastatin was related not only to its ability to reduce LDL C and elevate HDL C but also realized in specific changes in HDL phospholipid composition, which determine the HDL surface layer fluidity improving HDL functional properties. Simvastatin probably exerts influence via pleiotropic effects on the lipoprotein components synthesis in the liver. IMPROVED PERIPHERAL ENDOTHELIAL FUNCTION IN POSTMENOPAUSAL WOMEN WITH CORONARY ARTERY DISEASE AFTER ACUTE ORAL INTAKE OF 17 li-ESTRADIOL VALERATE

M.D. Enderle, R. Sayer, B. Balletshofer, C. Meisner1, A.O. Mueck 2, R. Haasis 3, H.U. Haerin~. M. Pfohl. Dept. of Endocrinology, Metabolism. and Pathobiochemist~: "Dept. ObGyn. Section of Clinical Pharmacology: ! Inst. for Medical Information Processing." j Dept. of Cardiology, University of Tuebingen. German), Objectives: We studied the acute effect of a single dose of orally administered 17 [:~-estradiol valerate (E2) on the peripheral endothelial dependent and independent vasodilation in postmenopausal women with coronary artery disease (CAD). Background: Chronic estrogen supplementation is known to improve endothelium dependent vasodilatation in postmenopausal women. Methods: 20 postmenopausal women (age: 64.9 (7.2) y, heightt: 1.61 (0.04) m, weight: 68.6 (10.6) kg) with angiographically confirmed CAD were randomly examined for flow-associated vasodilatation (= FAD%, a marker for endothelial dependent vasodilatation) and for glyceryltrinitrate (400 I-tg, p.o.) induced vasodilatation (= GTN~o, representing endothelial independent vasodilatation) two hours after placebo controlled, randomized crossover intake of 4 mg E2 p.o.. Results: FAD% after placebo intake was clearly impaired (3.5 (1.7)%). After the oral intake of 4 mg E2, FAD% improved by 42% to 5.0 (2.8)% (P = 0.02). GTN% was not significantly influenced by the oral E2 (E2:12.6 (5.7) v placebo: I 1.2 (6.9)%, P = 0.14). Conclusions: Peripheral endothelial dependent vasodilatafion can partially be restored by a single oral dose of 4 mg E2. This indicates a vasoprotective effect of hormone replacement therapy beyond its genomic and lipid modifying actions and might lead to a potential role of estrogen in the acute treatment of coronary artery disease. PREDICTIVE FACTORS O F THE EFFICACY OF ATORVASTATIN IN MIXED DYSLIPIDEMIA (ZAR STUDY). A MULTIVARIATE ANALYSIS J.M a. Sol 1, C. Diaz 1, R. Aristegui t , C. Pueyo 1, G. Hernfindez1. For the

ZAR study group," I R&D Department, Parke-Dauis, Spain OBjetives: Mixed dyslipidemia (MD) display a variety of risk factors that may influence the effect of lipid-lowering drugs. Methodology: A 12-week, noncomparative study evaluated the efficacy and safety of atorvastatin 10 mg/d in 12.000 dyslipidemic patients, 31% of which had MD. A multivariate analysis of the influence of demographic and baseline lipid data on the efficacy of atorvastatin in reaching LDL-c and TG goals in MD has been addressed. Results: As an average, atorvastatin 10 mg/d reached LDL-c target in 76%, TG in 55% and both LDL-c and TG in 43% o f patients. Patients were stratified according to the number of risk factors (RF) in moderate (I-2 RF) (MR) (n = 698), high risk (_>2 RF) (HR) (n = 817), and coronary artery disease (CAD) (n = 209). Multiple logistic function analysis confirmed that baseline TG and LDL-c, smoking, diabetes, and hypertension were

71st EAS Congress and Satellite Symposia