Effect of hormone therapy, tibolone and raloxifene on circulating vascular endothelial growth factor in Greek postmenopausal women

OBJECTIVE: To evaluate the effect of continuous combined hormone therapy (HT), tibolone and raloxifene on circulating vascular endothelial growth factor (VEGF) in postmenopausal women. DESIGN: One-year prospective intervention study. METHODS: One hundred and forty-six postmenopausal women with a mean age of 51.8+/-4.1 (s.d.) years received 0.625 mg conjugated equine estrogen (CEE) plus 5 mg medroxyprogesterone acetate (MPA) (CEE/MPA, n=34), 2.5 mg tibolone (n=37), 60 mg raloxifene (n=40) or no active treatment (control group, n=35). Plasma VEGF was estimated at baseline and at 6 and 12 months. RESULTS: In both the CEE/MPA-treated and the tibolone-treated groups plasma VEGF increased significantly at month 6 and remained elevated at month 12 (CEE/MPA baseline: 268.1+/-187.8 pg/ml, month 6: 320.0+/-175.3 pg/ml, month 12: 321.1+/-181.8 pg/ml, P=0.01; tibolone baseline: 240.6+/-165.8 pg/ml, month 6: 271.4+/-172.7 pg/ml, month 12: 274.8+/-183.1 pg/ml, P=0.03). These changes were significantly different from the respective changes in the control group after adjusting for T-score in bone densitometry (CEE/MPA: P=0.02, tibolone: P=0.04). The effect of HT or tibolone on plasma VEGF was mainly evident in women with low baseline VEGF levels (<243.2 pg/ml, median for whole sample). On the contrary, VEGF levels in the raloxifene-treated or the control group did not change throughout the study. CONCLUSION: Both continuous combined HT and tibolone increased circulating VEGF in postmenopausal women, while raloxifene had no effect. Further research is needed to clarify the clinical relevance of these findings with respect to cardiovascular risk in postmenopausal women.     

Serum lipids and apolipoproteins in Greek postmenopausal women: association with estrogen,estrogen-progestin,tibolone and raloxifene therapy

The aim of this study was to assess lipid and apolipoprotein levels in postmenopausal women taking various regimens of replacement therapy or no therapy. Seven hundred forty-eight postmenopausal women followed in the Menopause Clinic of the 2nd Department of Obstetrics and Gynecology, University of Athens, Aretaieion Hospital, were studied in a cross-sectional design. Women were either non-users of replacement therapy (no. = 511) or users of one of the following regimens: conjugated equine estrogen 0.625 mg (CEE, no. = 34), CEE 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA, no. = 60), 17beta-estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA, no. = 44), tibolone 2.5 mg (no. = 84), raloxifene HCI 60 mg (no. = 51). Total cholesterol (TC), LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C), triglycerides (TG), apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) levels were assessed. Women were grouped according to replacement regimen and mean levels of lipid and apolipoproteins were compared between groups. Women in the raloxifene group were older and longer menopaused. After adjustment for age and duration of menopause, TG levels were significantly lower in the tibolone and E2/NETA groups (75 and 89.9 mg/dl, respectively) compared to non-users. TC was lower in all therapy groups, but the difference acquired significance only in the E2/NETA (207.8 mg/dl), compared to non-users (231.5 mg/dl). LDL-C levels were significantly lower in the CEE (133.8 mg/dl), CEE/MPA (130.4 mg/dl) and raloxifene group (129.9 mg/dl) compared to non-users (151.9 mg/dl). There was no difference in HDL-C levels between users and non-users (58.9 mg/dl) except for the tibolone group where HDL-C was significantly lower (48.6 mg/dl). ApoA1 levels were significantly higher in the CEE/MPA group (194.4 mg/dl) and significantly lower in the tibolone group (141.6 mg/dl) compared to non-users (170.4 mg/dl). No difference was detected between groups concerning ApoB levels. In conclusion, tibolone therapy is associated with lower TG levels as well as lower HDL and ApoA1 levels. ERT, continuous combined estrogen-progestin therapy (HRT) and raloxifene are associated with lower LDL-C levels. Among continuous combined HRT users, CEE/MPA is associated with higher ApoA1 levels, while E2/NETA with lower TG levels. Large prospective randomized studies are required to validate these results.     

Raloxifene,conjugated oestrogen and endothelial function in postmenopausal women

OBJECTIVES: To study the long-term effects of raloxifene, a potential designer oestrogen, and oestrogen monotherapy on endothelial function in healthy postmenopausal women. DESIGN: A 2-year double-blind, randomized and placebo-controlled study in an Academic Medical Center. Fifty-six hysterectomized but otherwise healthy postmenopausal women randomly received raloxifene hydrochloride 60 mg day-1 (n = 15) or 150 mg day-1 (n = 13), conjugated equine oestrogen (CEE) 0.625 mg day-1 (n = 15), or placebo (n = 13). MAIN OUTCOME MEASURES: Endothelial function as estimated from brachial artery flow-mediated, endothelium-dependent vasodilation and nitroglycerine-induced endothelium-independent vasodilation, and plasma levels of the endothelium-derived regulatory proteins, von Willebrand factor (vWF) and endothelin (ET). RESULTS: Raloxifene 60 mg did not significantly affect endothelial function. As compared with placebo, at 6 months of therapy, raloxifene 150 mg and CEE were associated with a mean increase in vWF of 25.5% point (95% CI 3.6-47.3) and 26.6% point (95% CI 6.9-46.3), respectively. At 24 months of therapy, raloxifene 150 mg was associated with a mean decrease in ET of 0.96 pg mL-1 (95% CI -1.57 to -0.36). Raloxifene nor CEE significantly affected endothelium-dependent and/or -independent vasodilation. CONCLUSIONS: Our results suggest that long-term therapy with raloxifene or oral CEE does not affect endothelium-dependent vasodilation in healthy postmenopausal women. Raloxifene 150 mg day-1 might have both positive and negative effects on endothelium. The clinical significance of these findings remains to be investigated.     

Effect of hormone replacement therapy on nitric oxide bioactivity and monocyte chemoattractant protein-1 levels.

BACKGROUND: Vascular inflammation plays an important role in the pathogenesis of atherosclerosis. We investigated the effect of hormone replacement therapy (HRT) on vasomotor function and monocyte chemoattractant protein (MCP)-1 levels, an important serological marker of inflammation. METHODS: We administered micronized progesterone (MP) 200 mg for 10 days with conjugated equine estrogen (CEE) 0.625 mg for 25 days and remaining 5 days off cyclically during 2 months to 20 healthy postmenopausal women (PMW). We measured NO bioactivity and plasma levels of MCP-1 before and after HRT in 20 PMW. And we measured plasma levels of MCP-1 in each 20 subjects of premenopausal women, men <50, and men >50 years, respectively. RESULTS: MP combined with CEE significantly improved the percent flow-mediated dilator response to hyperemia relative to baseline measurements (P<0.001). PMW receiving HRT had lower levels of MCP-1 than those not receiving HRT (121+/-38 versus 146+/-44 pg/ml, P<0.001). In all comparisons, subjects with high estrogen status had significantly lower MCP-1 levels than subjects with low estrogen status (P<0.001 by ANOVA). Premenopausal women had lower levels of MCP-1 than men of a similar age (106+/-14 versus 164+/-40 pg/ml, P<0.001). PMW not receiving HRT had similar levels of MCP-1 compared with men of a similar age (146+/-44 versus 143+/-29 pg/ml, P=0.816). Premenopausal women had markedly lower levels of MCP-1 than PMW not receiving HRT (106+/-14 versus 146+/-44 pg/ml, P=0.001). PMW receiving HRT had similar levels of MCP-1 compared with premenopausal women (121+/-38 versus 106+/-14 pg/ml, P=0.323). CONCLUSION: These findings might provide at least a partial explanation for the protection against cardiovascular disease experienced by premenopausal women, and the loss of that protection following menopause.     

Clinical and neurohumoral consequences of diuretic withdrawal in patients with chronic, stabilized heart failure and systolic dysfunction

BACKGROUND: Loop diuretics are beneficial in heart failure in the short term because they eliminate fluid retention, but in the long-term, they could adversely influence prognosis due to activation of neurohumoral mechanisms. AIMS: To explore the changes induced by diuretic withdrawal in chronic nonadvanced heart failure. METHODS: Diuretics were withdrawn in 26 stabilized heart failure patients with systolic dysfunction (ejection fraction [EF]<45%). Clinical status was evaluated by physical exam, exercise capacity (corridor test) and New York Heart Association (NYHA) class. Biochemical and neurohumoral determinations were performed at baseline and at 3 months. RESULTS: At 3 months, 17 out of 26 patients (65%) were able to tolerate diuretic interruption without a deterioration in exercise capacity or New York Heart Association functional class. Renal function parameters improved (baseline urea 46.2+/-10.8 to 39.2+/-10.1 mg/dl at 3 months, p=0.014; creatinine 1.1+/-0.23 to 0.98+/-0.2 mg/dl, p=0.013). Glucose metabolism also improved (fasting glucose 151+/-91 to 122+/-14 mg/dl, p=0.035). Heart rate and systolic blood pressure did not significantly change, while diastolic blood pressure increased (from 80+/-10 to 87+/-13 mm Hg, p=0.006). Neurohumoral determinations showed a decrease in plasma renin activity (4.19+/-5.96 to 2.88+/-4.98 ng/ml, p=0.026), with no changes in aldosterone, arginine-vasopressin, endothelin-1 and norepinephrine. In contrast, atrial natriuretic peptide significantly increased (115+/-87 to 168+/-155 pg/ml, p=0.004). CONCLUSION: Diuretic withdrawal in stabilized heart failure with systolic dysfunction is associated with an improvement in renal function parameters, glucose metabolism and some neurohumoral parameters, such as plasma renin activity; however, atrial natriuretic peptide levels increased.     

Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormone replacement therapy on plasma no concentrations, endothelin-1 levels, and endothelium-dependent vasodilation in postmenopausal women

The endothelium is thought to play an important role in the genesis of atherosclerosis, and several lines of evidence suggest that the effect of an intervention on endothelial function might predict its involvement in coronary disease progression and in the rate of cardiovascular events. Estrogen has direct effects on the blood vessel wall, indicating that vascular endothelium may play a key role in the cardiovascular protective effects of hormone replacement therapy (HRT). Raloxifene relaxes coronary arteries in vitro by an estrogen receptor-dependent and NO-dependent mechanism, thus suggesting that this selective estrogen receptor modulator could also have beneficial effects on endothelial function. This study compared the effects of HRT and raloxifene on NO products, endothelin-1 plasma levels, and endothelium-dependent vasodilatation in postmenopausal women. Healthy postmenopausal women (n=90) were enrolled in a double-blind, randomized, placebo-controlled, 6-month trial. Women were randomly assigned to receive continuous HRT (1 mg 17beta-estradiol combined with 0.5 mg norethisterone acetate), raloxifene (60 mg/d), or placebo for 6 months. Flow-mediated endothelium-dependent vasodilation of the brachial artery, plasma NO concentrations, and endothelin levels were measured at baseline and after 6 months of therapy. The mean baseline level of NO breakdown products was 26.5+/-10.7 micromol/L and increased to 36.3+/-11.4 micromol/L after 6 months of treatment with raloxifene. The mean baseline plasma endothelin level was 17.3+/-8.9 pg/mL and decreased to 11.5+/-2.1 pg/mL after 6 months of treatment with the selective estrogen receptor modulator. The mean baseline ratio of NO (breakdown products) to endothelin was also significantly increased at the end of treatment with raloxifene. Postmenopausal women treated with HRT had similar changes in plasma nitrites/nitrates and endothelin levels as well as in the ratio of NO to endothelin. In contrast, these markers of endothelial function did not change in the placebo-treated women. Flow-mediated endothelium-dependent vasodilation of the brachial artery was 8.3+/-2.1% at baseline and increased to 12.3+/-2.1% after 6 months of treatment with raloxifene. HRT also caused a significant and similar increase in flow-mediated endothelium-dependent vasodilation. No change in flow-mediated vasodilation was observed in the participants treated with placebo. We conclude that raloxifene therapy and HRT influence endothelial function and improve flow-mediated endothelium-dependent vasodilation to a comparable extent in healthy postmenopausal women at least after a 6-month treatment period. However, further investigation is warranted to enhance our understanding of the mechanisms of the effect of raloxifene on vascular function and to determine whether its effect on endothelial function may contribute to the reduction in cardiovascular-related morbidity and mortality.     

Effects of raloxifene on gonadotrophins, sex hormones, bone turnover and lipids in healthy elderly men

OBJECTIVE: To explore effects on serum lipids, pituitary-gonadal axis, prostate and bone turnover of the administration of the mixed oestrogen agonist/antagonist raloxifene in healthy elderly men. PARTICIPANTS: Thirty healthy men aged 60-70 years randomly received raloxifene 120 mg/day (n=15) or placebo (n=15) for 3 months. MEASUREMENTS: In this double-blind, placebo-controlled study, serum gonadotrophins, sex hormones, prostate specific antigen (PSA), a marker of bone turnover, urinary hydroxyproline (OHPro) and cholesterol were measured at baseline and after 3 months. RESULTS: Raloxifene significantly increased serum concentrations of LH and FSH (by 29% and 21%), total testosterone (20%), free testosterone (16%) and bioavailable testosterone (not bound to sex hormone-binding globulin (SHBG; 20%). In parallel with testosterone, 17 beta-oestradiol also increased by 21%. SHBG increased by 7%. Total cholesterol (TChol) decreased significantly, from 5.7 to 5.5 mmol/l (P=0.03). Low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) showed a trend to decrease. Overall, there was no change in urinary OHPro/creatinine ratio as a marker for bone resorption. However, the raloxifene-induced increases in both serum testosterone and 17 beta-oestradiol were significantly related to a lower OHPro/creatinine ratio. Total PSA increased by 17% without significant changes in free PSA or free/total PSA ratio. Participants reported no side effects and raloxifene was well tolerated. CONCLUSION: In healthy elderly man, raloxifene 120 mg/day for 3 months increased LH, FSH and sex steroid hormones. Potentially beneficial effects were the small but significant decrease in TChol and the trend towards a decrease in LDL-c. Negative effects were the trend towards a decrease in HDL-c and the significant increase in serum PSA. A decrease in markers of bone resorption during raloxifene treatment was found only in men with relatively high increases in serum testosterone and 17 beta-oestradiol. Overall, there were no clear beneficial effects of administration of raloxifene to ageing men in this preliminary investigation.     

A comparison of the short-term effects of oral conjugated equine estrogens versus transdermal estradiol on C-reactive protein, other serum markers of inflammation, and other hepatic proteins in naturally menopausal women

OBJECTIVE: Our objective was to compare the effects of oral vs. transdermal estrogen therapy on C-reactive protein (CRP), IL-6, E- and P-selectin, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule-1, serum amyloid A, transferrin, prealbumin, IGF-I, SHBG, thyroxine-binding globulin (TBG), and cortisol-binding globulin (CBG) in naturally menopausal women. DESIGN: This was a randomized, open-label crossover clinical trial. A 6-wk withdrawal from prior hormone therapy (baseline) was followed in randomized order by 12-wk oral conjugated equine estrogens (CEEs) (0.625 mg/d) and 12-wk transdermal estradiol (E2) (0.05 mg/d), with oral micronized progesterone (100 mg/d) given continuously during both regimens. RESULTS: A total of 27 women enrolled, and 25 completed both treatment periods. Nine parameters changed significantly during oral CEE (median percent change from baseline; P value): CRP (192%; P <0.001); E-selectin (-16.3%; P = 0.003); P-selectin (-15.3%; P = 0.012); ICAM-1 (-5%; P = 0.015); transferrin (5.3%; P = 0.024); IGF-I (-30.5%; P < 0.001); SHBG (113%; P < 0.001); TBG (38%; P < 0.001); and CBG (20%; P < 0.001). With transdermal E2, only three parameters changed significantly and to a lesser degree: ICAM-1 (-2.1%; P = 0.04); IGF-I (-12.5%; P < 0.001); and SHBG (2.6%; P = 0.042). During oral CEE the intrasubject changes in CRP correlated strongly with the changes in serum amyloid A (r = 0.805; P < 0.001), and were only weakly associated with the changes in SHBG (r = 0.248; nonsignificant), TBG (0.430; P = 0.031), and CBG (r = 0.072; nonsignificant). The log-log relationship between CRP and IL-6 observed at baseline showed a parallel shift during oral CEE, suggesting an amplified hepatic response or a greater sensitivity to IL-6 stimulation. CONCLUSION: Compared with oral CEE, transdermal E2 exerts minimal effects on CRP and the other inflammation and hepatic parameters.     

Beta adrenergic receptors and experimental left ventricular hypertrophy]

The effects of sinoaortic denervation (SAD) on the development of left ventricular hypertrophy (R: heart weight/total body weight; LVT : left ventricular thickness), myocardial beta-adrenergic receptivity ([125I]CYP binding; adenylate cyclase activity) and plasma catecholamine levels (HPLC) were investigated in both normotensive (group 1) and hypertensive dogs evaluated (group 2) 1 and 18 months (group 3) after SAD. Noradrenaline (NA) and adrenaline (A) plasma levels were 461 +/- 54 and 85 +/- 45 pg/ml in controls, 861 +/- 185 and 191 +/- 23 pg/ml in group 2 (P < 0.05) and were normal in group 3 (426 +/- 132 and 110 +/- 16 pg/ml). R and LVT values were higher (p < 0.05) in SAD dogs (R = 7.7 +/- 0.1 and 7.8 +/- 0.2; LVT = 13.6 +/- 1.3 and 14.2 +/- 0.9 mm in groups 2 and 3 respectively) than in group 1 (R = 6.7 +/- 0.1, LVT = 9.3 +/- 0.8 mm). In group 1, the total number of beta-adrenoceptors (beta-AR) was 37 +/- 11 and 29 +/- 6 fmol/mg prot in left ventricule (LV) and right auricle (RA) respectively. Bmax was significantly lower in group 2 (LV: 10 +/- 3; RA: 13 +/- 2 fmol/mg prot, p < 0.05) than in group 1 but was normal in group 3 (LV: 37 +/- 3 and RA: 31 +/- 3 fmol/mg prot).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of conjugated oestrogen and droloxifene on the renin-angiotensin system, blood pressure and renal blood flow in postmenopausal women

OBJECTIVE: The aim of this study was to evaluate the effect of conjugated equine oestrogen (CEE), and droloxifene, a selective oestrogen receptor modulator (SERM) on individual components of renin-angiotensin-aldosterone (RAAS) and blood pressure (BP) in postmenopausal women. DESIGN AND PATIENTS: Twenty-one normotensive (NT) and 10 hypertensive (HT) postmenopausal women received either CEE (0.625 mg/day) or droloxifene (60 mg/day) for 6 weeks and, after a 4-week washout, were restudied on the alternate medication. MEASUREMENTS: Hormones of the RAAS and supine BP were measured prior to and at the end of each drug treatment in all subjects. In a subgroup of the NT (n = 10), 24 h ambulatory BP was performed and renal blood flow was determined by PAH clearance both basally and in response to 45-min angiotensin II (Ang II) infusion (3 ng/kg/min). RESULTS: CEE significantly increased angiotensinogen, decreased active renin and angiotensin-converting enzyme (ACE), and maintained plasma immunoreactive (ir) angiotensin I (Ang I) levels compared to baseline. With droloxifene, angiotensinogen, active renin and Ang I remained unchanged. Both CEE and droloxifene significantly increased plasma ir-Ang II levels (pmol/l) in NT (baseline: 25.7 +/- 2.5, CEE: 36.6 +/- 3.4, droloxifene: 33.3 +/- 3.1, P < 0.002) and HT women (baseline: 17.9 +/- 2.3, CEE: 27.9 +/- 3.2, droloxifene: 25.9 +/- 4.9, P < 0.005). Renal blood flow was lower on CEE (P = 0.02) compared with baseline. Systemic BP (supine and 24-h ambulatory) was unchanged during both treatments. CONCLUSION: This study demonstrates higher circulating levels of ir-Ang II with CEE and droloxifene.     

Effect of raloxifene on activated protein C (APC) resistance in postmenopausal women and on APC resistance and homocysteine levels in elderly men: two randomized placebo-controlled studies.

Raloxifene, a selective estrogen receptor modulator, like hormonal replacement therapy increases the risk of venous thromboembolism in postmenopausal women. A possible explanation for the increased thrombotic risk could be an increase in acquired resistance to activated protein C (APC). In two randomized, placebo-controlled, double-blind studies we determined the effect of raloxifene on the normalized APC sensitivity ratios (nAPCsr). The nAPCsr were determined with the thrombin generation-based APC resistance test. In the first study 83 postmenopausal women (age, 51.1 +/- 2.7 years) randomly received daily 0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate (n=17), 60 mg raloxifene (n=23), 150 mg raloxifene (n=20) or placebo (n=23) for 24 months. At baseline and after 6, 12 and 24 months the nAPCsr were measured. In the second study 30 elderly men (age, 64.4 +/- 2.4 years) randomly received 120 mg raloxifene (n=15) or placebo (n=15) for 3 months. At baseline and after 3 months the nAPCsr and fasting homocysteine levels were measured. In postmenopausal women conjugated equine estrogen/medroxyprogesterone acetate significantly increased the nAPCsr from 1.26 +/- 0.82 to 2.87 +/- 0.86 at 24 months (P <0.0005 compared with placebo). Raloxifene had no significant effect on nAPCsr compared with placebo in both women and men. The results did not change after excluding carriers of factor V Leiden. Also fasting homocysteine levels were not affected by raloxifene in the aging men. It is concluded that raloxifene, in contrast to combined hormonal replacement therapy, does not increase APC resistance.     

Effects of long-term treatment with prostacyclin on plasma adrenomedullin in patients with primary pulmonary hypertension]

OBJECTIVES: This study investigated whether plasma levels of adrenomedullin, a potent vasodilating endogenous neurohumoral mediator, are useful for assessing the severity of primary pulmonary hypertension. METHODS: Seventeen pediatric patients with primary pulmonary hypertension (eight girls, nine boys, mean age 12 +/- 4 years) were enrolled in this study. Thirteen patients in New York Heart Association (NYHA) classes III and IV had been treated with long-term continuous intravenous prostacyclin (PGI2) infusion therapy, and four patients in classes I and II had received beraprost sodium, an oral PGI2 analogue. Blood samples were taken from all patients at the first visit. Plasma levels of atrial and brain natriuretic peptide (ANP, BNP) and endothelin-1, and mature-type adrenomedullin were measured. The relationships were investigated between neurohumoral mediator levels and NYHA class, pulmonary hemodynamics, and exercise capacity assessed by 6-minute walk test. The changes in neurohumoral mediator levels at 1 month, 3 months, and 6 to 12 months were also evaluated in 11 survivors with long-term PGI2 treatment. RESULTS: All neurohumoral mediator levels were positively correlated with severity of NYHA class. Patients in class IV demonstrated significantly elevated neurohumoral mediator levels, except endothelin-1, in comparison with patients in classes I-III. Neurohumoral mediator levels had a significant negative correlation with exercise capacity. Stepwise regression analysis revealed that the BNP to ANP ratio (BNP/ANP) was the most powerful independent factor for total pulmonary resistance (r = 0.85, p = 0.0071) and cardiac index (r = 0.84, p = 0.009). Adrenomedullin was significantly correlated with BNP (r = 0.53, p = 0.03), endothelin-1 (r = 0.66, p = 0.006), and BNP/ANP (r = 0.73, p = 0.0009). ANP and BNP decreased from 196 +/- 213 and 494 +/- 361 pg/ml at baseline to 74 +/- 47 and 153 +/- 133 pg/ml at 1 month, respectively. There was an apparent re-increase in both ANP (187 +/- 194 pg/ml) and BNP (466 +/- 621 pg/ml) at 3 months, regardless of improvement in NYHA class and exercise capacity after long-term PGI2 treatment. In contrast, adrenomedullin decreased from 3.0 +/- 2.2 (baseline) to 1.7 +/- 0.7 fmol/ml at 1 month and 1.6 +/- 0.5 fmol/ml at 3 months. Adrenomedullin was slightly increased at 6-12 months (2.1 +/- 0.9 fmol/ml) without statistical significance. There was a significant relationship between the changes in adrenomedullin at 3 months compared to values at initiation of PGI2 therapy and the changes in mean pulmonary arterial pressure (r = 0.97, p = 0.0041). CONCLUSIONS: Plasma levels of neurohumoral mediators are useful for assessing the severity of primary pulmonary hypertension. In particular, adrenomedullin was valuable for evaluating both cardiac performance and pulmonary hemodynamics after long-term treatment with PGI2 in patients with primary pulmonary hypertension.     

The Ca2+-sensitizer levosimendan improves oxidative damage, BNP and pro-inflammatory cytokine levels in patients with advanced decompensated heart failure in comparison to dobutamine

AIM: To investigate the effect of a new inotropic drug, levosimendan compared with dobutamine on levels of brain natriuretic peptide (BNP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and malondialdehyde (MDA) in patients with severe decompensated heart failure. METHODS AND RESULTS: Twenty-nine consecutive patients (22 males and 7 females), mean age 70.5+/-9.9 years, with decompensated heart failure on standard medical therapy, were randomised to receive either a 24 h infusion of levosimendan (n=15) or dobutamine (n=14). Blood samples were drawn at baseline, 48 h and 5 days post infusion. Levosimendan produced a significant reduction in BNP compared to baseline, at both 48 h (744.1+/-100 vs 1136.3+/-93.7 pg/ml, p=0.04) and 5 days (446+/-119.3 vs 1136.3+/-93.7 pg/ml, p=0.03), while IL-6 values decreased after 5 days (4.8+/-1.3 vs 8.6+/-1.5 pg/ml, p=0.01). MDA levels were significantly lower 5 days after levosimendan compared to baseline (2.3+/-0.2 vs 3+/-0.3 microM, p=0.01). TNF-alpha levels did not differ between the groups. The comparison of percentage alteration compared to baseline showed that BNP (-44.5+/-7.6% vs 4.8+/-18.7%, p=0.025), MDA (-21.8+/-5.1% vs 14.9+/-8.5%, p=0.001) and IL-6 (-38.8+/-12.5% vs 70.2+/-24%, p=0.001) levels were significantly lower in the levosimendan group 5 days after treatment compared to the dobutamine group. CONCLUSIONS: Treatment with levosimendan in advanced decompensated heart failure exerts a beneficial hemodynamic, anti-inflammatory and antioxidant effect. These findings may give an insight into the favourable impact on mortality that levosimendan appears to have in published multicenter trials.     

Determinants of left ventricular hypertrophy and its progression in high-flux haemodialysis

AIM: To identify factors contributing to the development and progression of left ventricular hypertrophy (LVH) in patients on high-flux haemodialysis. METHOD: Fifty patients without clinical cardiac disease underwent baseline echocardiography, related measurements and follow-up studies 6-12 months later. RESULTS: Residual urea clearance was lower (0.7 +/- 1.1 vs. 2.2 +/- 2.4 ml/min; p = 0.034) while systolic blood pressure (162 +/- 21 vs. 147 +/- 11 mm Hg; p = 0.003), duration of dialysis dependence (38 +/- 37 vs. 17 +/- 13 months; p = 0.004) and interdialytic weight gain (1.98 + 0.84 vs. 1.32 + 1.08 kg; p = 0.026) were higher in those with LVH. Parathyroid hormone changed less in those whose LVH regressed (186 +/- 89 vs. 303 +/- 280 pg/ml; p = 0.032). Regression did not occur when parathyroid hormone was >300 pg/ml. ACE gene polymorphism did not affect LVH development or progression. CONCLUSION: Systolic hypertension, duration of dialysis dependence and high interdialytic weight gains promote LVH. Hyperparathyroidism retards LVH regression.     

Effects of long-lasting raloxifene treatment on serum prolactin and gonadotropin levels in postmenopausal women

OBJECTIVE: To evaluate the effects of a 6 month administration of raloxifene hydrochloride, a selective estrogen receptor modulator which was recently approved for the prevention of osteoporosis, on serum gonadotropin and prolactin (PRL) levels and on TRH-stimulated PRL responsiveness in postmenopausal women who have not undergone estrogen replacement therapy. DESIGN AND METHODS: Sixteen healthy postmenopausal women were divided into two groups on the basis of their bone status, evaluated by dual energy X-ray absorptiometry at the lumbar level. Eight women (chronological age 52.4+/-4.1 (s.d.) years, menopausal age 42.4+/-3.9 years), in whom T-score L2-L4 was less than -2.5 s.d., were treated with raloxifene (60 mg p.o.) administered daily for 6 months (group 1), while the other eight women (chronological age 52.6+/-2.5 years, menopausal age 42.1+/-3.6 years), in whom the T-score L2-L4 ranged between -1 and -2.5 s.d., were used as a control group (group 2). Serum PRL, FSH, LH and 17beta-estradiol (E2) levels were evaluated at baseline and after 3 and 6 months of treatment. In all subjects, PRL responsiveness to TRH (200 microg i.v.) administration was evaluated at baseline and at the end of the study. RESULTS: At baseline, mean PRL, LH and FSH levels were not significantly different in the two groups (PRL 133.6+/-21.7 vs 136.7+/-28.1 mIU/l (NS), LH 25.1+/-6.8 vs 24.4+/-6.7 mIU/ml (NS), FSH 74.4+/-25.0 vs 71.1+/-24.1 mIU/ml (NS), in group 1 and group 2 respectively). No significant variations in serum FSH and LH values, in either group, or in serum PRL levels in group 2, were observed at the 3 and 6 month examinations. On the contrary, serum PRL values decreased significantly in group 1 after 3 months (100.1+/-47.7 mIU/l, P<0.05) and 6 months (81.5+/-30.2 mIU/l, P<0.001). At baseline, no significant differences were observed in the TRH-stimulated serum PRL peak between the groups (1015.4+/-30.5 vs 1030.2+/-25.7 mIU/l in group 1 and in group 2 respectively), while it decreased significantly at the 6 month examination in group 1 (770.5+/-47.4 mIU/l, P<0.001) and it was significantly lower than in group 2 (1068.1+/-301.8 mIU/l, P=0.02). Serum E2 was not detected at baseline and at each examination, in all patients. CONCLUSIONS: The decrease of PRL values induced by long-term raloxifene administration in postmenopausal women could be explained by a direct antiestrogenic effect of raloxifene on lactotrope cells or by the recently suggested increase of opiatergic tone on the hypothalamic-pituitary region.     

Impact of right atrial-left ventricular dual-chamber permanent pacing in patients with severely symptomatic hypertrophic obstructive cardiomyopathy.

BACKGROUND: Effective alternatives to surgical myectomy for patients with symptomatic hypertrophic obstructive cardiomyopathy (HOCM) remain unestablished. Dual-chamber (DDD) pacing was evaluated in these patients using right atrial (RA) and epicardial left ventricular (LV) leads. METHODS AND RESULTS: In 6 patients with HOCM refractory to medical therapy and conventional RA-right ventricular (RV) DDD pacing, we implanted DDD pacemakers using RA and epicardial LV leads. The baseline intraventricular pressure gradient before pacemaker implantation was 103+/-44 mmHg. The pressure gradient decreased significantly to 8+/-16 mmHg by temporary RA-LV DDD pacing (p=0.006), while it decreased only to 68+/-25 mmHg by temporary RA-RV pacing (NS). It was nearly eliminated to 1+/-2 mmHg (p=0.027) 3 months after RA-LV DDD pacemaker implantation. LV end-diastolic pressure, cardiac index and systolic aortic pressure did not change significantly. New York Heart Association class improved in all patients (p=0.023). Brain and atrial natriuretic peptide concentrations, respectively 516+/-286 and 143+/-34 pg/ml at baseline, decreased significantly to 230+/-151 and 93+/-44 pg/ml 3 months after implantation (p=0.027 and 0.028). CONCLUSION: RA-LV DDD pacemaker implantation is a useful option for patients with symptomatic HOCM.     

Transient myocardial ischemia stimulates atrial natriuretic factor release.

Atrial natriuretic factor release during transient myocardial ischemia was investigated in 29 patients with coronary artery disease and symptoms of angina (Canadian Cardiovascular Association classes II-III). Eleven patients (group I) underwent single-vessel percutaneous transluminal coronary angioplasty. Repeat determinations of mean pulmonary artery wedge pressure and blood sampling from pulmonary artery for atrial natriuretic factor measurements were performed at baseline, and at 2, 5, and 15 minutes after percutaneous transluminal coronary angioplasty was begun. Baseline atrial natriuretic factor levels (34.6 +/- 4.5 pg/ml) rose to 56.3 +/- 7.3 pg/ml (p = 0.02) and decreased at 5 minutes (43.7 +/- 5.7 pg/ml, not significant) and 15 minutes (35.3 +/- 4.4 pg/ml, not significant). Changes in atrial natriuretic factor concentrations were significantly correlated with those in mean pulmonary artery wedge pressure (2 minutes: r = 0.69, p = 0.02; 5 minutes: r = 0.90, p less than 0.001). In group II (n = 10) the increase in atrial natriuretic factor after dye load occurred later (baseline: 25.8 +/- 2.1; 60 minutes: 40.6 +/- 2.6 pg/ml; p = 0.005) than that observed in group I after percutaneous transluminal coronary angioplasty. In group III, atrial natriuretic factor during angina rose as early (baseline 11.3 +/- 1.3; 5 minutes: 20 +/- 2.3 pg/ml; p = 0.006) as after percutaneous transluminal coronary angioplasty. Results indicate that transient myocardial ischemia stimulates atrial natriuretic factor release, probably through changes in cardiac function.     

Total estradiol, free estradiol, sex hormone-binding globulin, and the fraction of estradiol bound to sex hormone-binding globulin in human follicular fluid

Sex hormone-binding globulin (SHBG), percent free estradiol (E2), the fraction of E2 bound to SHBG, and total E2 were measured in the serum and follicular fluid of 12 women (25 follicles) who had received gonadotropin stimulation in an in vitro fertilization program. The women were classified as high or low responders based on peak serum E2 levels (high responders: peak E2, greater than 1500 pg/ml; low responders: peak E2, less than 1000 pg/ml). During treatment, serum levels of SHBG increased in high responders from 55 +/- 8.8 (+/- SEM) to 96 +/- 16 nM (P less than 0.01), but did not change in low responders. SHBG was more concentrated in follicular fluids from high responders (142 +/- 12.5 nM) than in those from low responders (44.4 +/- 5.8 nM). A positive correlation was found between serum and follicular fluid levels of SHBG (r = 0.873; P less than 0.01). In follicular fluid, total E2 levels, which varied from 100-2650 ng/ml, correlated (r = 0.790; P less than 0.01) closely with SHBG levels. The percent free E2 averaged 5.9% (range, 4-10.6%) in follicular fluid compared to 1.8% (range, 1.5-2.1%) in serum. An inverse correlation (r = -0.661; P less than 0.01) was found between total E2 concentrations and percent free E2 in follicular fluid. The relationship between serum and follicular fluid levels of SHBG suggests that SHBG in follicles arises from the circulation. Although SHBG is present in follicular fluid in amounts similar to those in serum, the large quantities of E2 in preovulatory follicules exceed the binding capacity for SHBG, and the majority of E2 appears to be bound to albumin. Hence, it seems unlikely that SHBG in follicular fluid regulates estrogen action in ovarian target cells.     

Effects of hyaluronate on CD44 expression of infiltrating cells in exudate of rat air pouch, induced by sensitization with lipopolysaccharide.

OBJECTIVE: To investigate the effects of hyaluronate (HA) on CD44 expression of infiltrating cells in vivo. METHODS: Intra-air pouch injection of 10 microg lipopolysaccharide (LPS) with 0.4, 4.0, or 40 mg HA, 40 mg carboxymethylcellulose (CMC), or saline was performed on rats immunized with LPS. The percentage of CD44+ cells in the exudate of the air pouch was measured by flow cytometry, and the concentrations of interleukin 1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in the air pouch exudate were measured by ELISA. IL-1beta and TNF-alpha in the air pouch lining layer were stained by immunohistochemistry. RESULTS: The percentage of CD44+ cells in air pouch exudate was greater in the presence of HA, with a dose dependent increase (0.4 mg, 9.4+/-2.6%, n = 4; 4.0 mg, 13.8+/-2.9%, n = 4; 40 mg, 24.9+/-6.3%, n = 3; p < 0.05), while it was 4.9+/-1.2% (n = 4) in the presence of 40 mg CMC. The concentration of IL-1beta was lower in the presence of 40 mg HA (251.0+/-61.4 pg/ml, n = 4) or 40 mg CMC (168.2+/-43.5 pg/ml, n = 4; p < 0.05) than in saline (403.0+/-60.5 pg/ml, n = 4). The concentration of TNF-alpha was lower in the presence of 40 mg HA (14.0+/-6.7 pg/ml, n = 4) or 40 mg CMC (7.04+/-7.0 pg/ml, n = 4) than in saline (38.2+/-12.2 pg/ml, n = 4). Extensively stained lining cells in superficial layer of the air pouch with IL-1beta and TNF-alpha were observed in rats inoculated with 0.4 mg HA. CONCLUSION: These findings suggest that HA might affect the inflammatory process through modifying CD44 expression on infiltrating cells in air pouch exudate.     

Tibolone improves myocardial perfusion in postmenopausal women with ischemic heart disease: an open-label exploratory pilot study.

OBJECTIVES: We sought to determine the effect of tibolone on myocardial perfusion in postmenopausal women with ischemic heart disease. BACKGROUND: Tibolone is a steroid that relieves climacteric symptoms and prevents osteoporosis. Recent studies have suggested a cardioprotective effect of this compound. However, its role on myocardial perfusion remains uncertain. METHODS: Single-photon emission computed tomography myocardial perfusion imaging was performed in 26 postmenopausal women. Patients were randomly assigned to tibolone for six months (treatment group) or to usual care (control group). All women underwent cardiac imaging at baseline and at six months. RESULTS: Mean stress perfusion defect (summed stress score) was moderate and did not differ between the two groups (8 +/- 3 vs. 9 +/- 4; p = NS). Summed difference score also was similar for both groups (7 +/- 3 vs. 8 +/- 3; p = NS). The six-month study revealed that summed stress and summed difference scores significantly improved in the treatment group (to 3 +/- 3 and to 2 +/- 2; p < 0.001) whereas it remained unchanged for control patients (to 10 +/- 4 and to 8 +/- 2; p = NS). CONCLUSIONS: In postmenopausal women with ischemic heart disease, six months of therapy with tibolone significantly improved stress myocardial perfusion and the "amount of ischemia."