Simvastatin, transdermal patch and oral estrogen-progestin preparation in hypercholesterolemic postmenopausal women: A randomized, placebo-controlled clinical trial

Wednesday June 28, 2000: Poster Abstracts P: W24 Hormones and Cardiovascular Disease

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WeP65:W23 J Genetic hypercholestecolemia is associated with inflammation T. Sampietro, R. Licitra, E Bigazzi, S. Fusaro, A. Ciardi, A. Buratti, M. Taddei, M. Tuoni, A. Bionda. Institute of Clinical Physiology, CNR, Pisa;

Department of Internal Medicine, University of Pisa, Italy Hypercholesterolemia is associated with all the pathologic features of the atherosclerotic process. The link between hypereholesterolemia and the inflammatory aspects of atherosclerosis is not yet clear. We wanted to verify wether hypercholesterolemia is associated with higher values of inflanunation markers, particularly those molecules with the potential role of reflecting the arterial wall status, in subjects with primary (PH), compared to a group of controls, their relationship with Lipid profiles. Therefore we measured C3, C4, C reactive protein, adhesion molecules in 36 patients with primary hypercholesterolemia in comparison to a group of 48 normal controls. All patients did not present intereurrent disease or other conditions likely to be associated with an acute phase response, as further confirmed by undetectable values of IL-6. Results: Hypereholesterolemics, compared to controls, showed higher mean values of C3 (157.1 -4- 43.5 vs 101.4 4- 17.9 mg/dl; p < 0.0001), C4 (41.1 =k 15.7 vs 21.2 -I- 6.5 p < 0.0001), median C reactive protein values (0.333, range: 0.300-1.460, vs 0.300, range: 0.300-1.300 mg/dl; p < 0.0001), mean sICAM1 values (254.8 4- 84.9 vs 110.7 4- 30.3 p < 0.0001). Conclusions: Elevation of circulating inflammation molecules in primary hypereholesterolemia would suggest a direct role of high plasma cholesterol in inducing vascular inflammation. I

Hyperiipidemia, bone marrow stem cells and IWeP66:W23 [ atherosclerosis E.L. Soboleva, R.S. Akchurin, V.N. Smimov, LE. Chazov. Cardiology

Research Center, Moscow, Russia The effects of hyperlipidemia (HLP) on vascular wall atherogenesis is likely to be mediated via bone marrow stem cells (colony-forming units, or CFU) for hemopoiefic and stromal differentiation lineages. This conclusion is based on analysis of bone marrow biopsy specimens, culturing of human intimal vascular cells and the study of blood mononuclear fraction of patients with HLP in semisolid and liquid test-systems using hystochemical, immunochemical and electron microscopy techniques. The following effects of HLP on bone marrow and on CFU were observed: 1) aplasia of mieloid tissue and development of mielofibrosis; 2) presence of stromal CFU for fibroblasts (CFU-f) in blood and the elevation of stromal/hemopoietic CFU's ratio depending on the severity of HLP; 3) appearance in blood of HLP patients of megakariocytes with high proliferative potential and also CFU for blast colonies and osteoclast colonies; 4) presence of bone marrow hemopoietic and stromai CFU in loci of lipid intimal infiltration. The presence of these hemopoietic and stromal CFU in vascular intima and their circulation in peripheral blood suggest the possibility of local hemopoiesis in vascular wall. Penetrating vascular intima, stromal CFU may provide necessary microsurrounding for local hemopoesis. Intimal hemopoietic loci may serve as the source of various growth factors and may predetermine future location of clinically manifested plaques.

Methods and Results: Plasma leptin levels were measured in 64 male patients who underwent coronary angiography between November 1994 and July 1997. These patients were not on insulin treatment and coronary angiography showed severe stenosis (>75% diameter). The number of CCVs per one diseased vessel was counted in each patient. When these patients were categorized into two groups based on the grade of CCVs development, high plasma leptin concentrations were present in patients with good collateral circulation (1.51 4- 0.77 ng/ml, mean 4- SD) but not in those with no or poor collateral circulation (1.12 -4- 0.58 ng/ml, P < 0.05). Conclusions: We conclude that circulating leptin levels might promote the development of CCVs in humans patients with coronary artery stenosis. WeP2:W24 ] Simvastatin, transdermal patch and oral estrogen-progestin preparation in hypereholesterolemic postmenopausal women: A randomized, placebo-controlled clinical trial G.B. Vigna 1, P. Donegal1, R. Zanca 1, G. Santoro I , A. Passaro J , F. Pansini 2, G. Mollica 2, R. Fel/in I . t Dept. Int. Medicine 2; 2Dept. Obstetrics and

Gynecology, Univ. of Ferrara, Ferrara, Italy

Objective: Hormonal Replacement Therapy (HRT) seem to favorably influence the plasma lipid profile. Only few investigations compared the effects of HRT with HMG-CoA inhibitors in post-menopausal women. We performed a randomized, placebo-controlled trial in women with recent-onset spontaneous menopause, aiming at comparing the relative effects of different hypolipidemic strategies. Methods: Fifty-four consecutive healthy women aged >45 years, with amenorrhea by 6-60 months, serum FSH > 40 U/L and slight to moderate hypercholesterolemia (LDL-chol. 160-250 mg/dl, HDL-cbol. < 75 mg/dl and triglycerides < 200 mg/dl) were enrolled and randomized to dietetic advice [placebo group, P], Simvastatin 10 mg [S], 0.625 mg of coniugated equine estrogens [CEE] or 50/zg estrogen transdermai patch [TDE]. In the latter 2 cases the progestative nomegestrol was added to estrogens (days 17-28 of the cicle). Lipoprotein parameters were evaluated after separating VLDLs by ultracentrifugation. Results: Total and LDL-chol. significantly decrased in S, CEE and TDE (but not P) groups compared to baseline (-18.9% + 17.1 [p < 0.001], - 1 2 . 6 % 4- 8.7, [p < 0.01] -10.0% 4- 10.9 [p < 0.05], and -29.2% 420.8 [p < 0.001], -18.3% 4- 8.8. [p < 0.001], - 1 1 . 5 % 4- 14.4 [p < 0.05], respectively) but only Simvastatin showed an effect significantly superior to diet alone (p < 0.01). A p t B was decreased by all drugs (marginally in the TDE group), and Simvastatin was more effective than either P or TDE groups. Triglyceride concentration and VLDL-chol. did not vary during treatments. HDL-chol. and A p t A-1 increased significantly in the S group (+18.9% + 19.3 and +11.6%15.5, p < 0.0 1); lipoprotein(a) was decreased by both HRTs (-31.5% and -21.7% for CCE and TDE respectively, p < 0.05). Conclusions: HRT, particularly CCE, seems rather effective and well tolerated in post-menopausal hypereholesterolemic women, but low-dosage Simvastatin is superior in LDL-lowering.

WeP3:W24 ] LCAT catalyzes the esteriflcation of estradioi (E2) in HDL particles 1 A. Htckerstedt , M. Jauhiainen2, M.J. Tikkanen 3. l'3Department of Internal i

Medicine; 2National Public Health Institute, Helsinki, Finland

P:W24

HORMONES AND CARDIOVASCULAR DISEASE

WeP1 :W24 [ High plasma ieptin concentrations enhance the development of coronary collateral vessel network in patients with coronary artery stenosis J

T. Yasumasul, K. Takahara l, R. Kouzuma2, H. Tasaki 2, Y. Nakashima2.

Department of Medical Technology 1; I School of Health Sciences; 2The Second Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan

Objective: Although myocardial ischemia significantly correlate with the development of coronary collateral vessels (CCVs), there is considerable variation in the number of CCVs in patients with ischemic heart disease. The underlying mechanisms of this variability are not well understood. Leptin is a peptide hormone involved in the regulation of body fat as well as promotion of angiogenesis via activation of endothelial cells. The aim of this study was to investigate the effect of leptin on the formation of CCVs.

Objective: To investigate the possibility that lecithin: cholesterol acyltransferase (LCAT) could esterify not only cholesterol but also estrogens. Previous results have provided indirect evidence for this indicating that the LCAT inhibitor, 5,5-dithiobis-2-nitrobenzoic acid, reduced the conversion of estrogens to fatty acid esters. Esterified estrogens could according to some studies act as antioxidants in lipoprotein particles in viva. Methods and Results: High density lipoprotein (HDL) was isolated from fresh, male plasma and gel filtrated removin~ molecules not attached to HDL. HDL was incubated with labeled estradiol (H-E2) with and without purified LCAT at 37°C for 24 hours. Samples were again gel filtered and the radioactivity and protein concentrations were measured from the eluted fractions. Most of the radioactivity obtained coincided with the protein peak in all samples, suggesting that 3H-E2 was attached to HDL. HDL-containing fractions were extracted and subjected to bydrophobic gel chromatography to separate esters from unesterified 3 H-E2. The amount of attached 3 H-E2 esters was doubled following the addition of highly purified plasma LCAT. The ester fraction was further analyzed by thin layer chromatography (TLC) demonstrating that the radioactivity comigrated with the E2-17-stearate standard. Saponification

Xllth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000