Dimitra Kotsopoulos

Postmenopausal Hormone Replacement Therapy Increases Coagulation Activity and Fibrinolysis

Hormone replacement therapy (HRT) appears to be cardioprotective in postmenopausal women; however, concerns exist over its thrombogenic effects. To address the effects of combined HRT on coagulation and fibrinolysis, we have measured circulating markers of these processes in a double-blind placebo-controlled trial. Forty-two healthy postmenopausal women aged 50 to 75 years received continuous combined HRT with 2 mg estradiol+1 mg norethisterone or placebo for 6 weeks. Hormone profiles were measured at baseline, and lipid and hemostatic parameters were measured at baseline and after 6 weeks of therapy. Baseline characteristics were similar in the 2 groups. With change from baseline the main outcome measure, HRT increased the markers of coagulation (prothrombin fragments 1+2, 0.20+/-0.06 versus 0.06+/-0.04 nmol/L, P=0.0005; soluble fibrin, 2.3+/-0.4 versus 0.25+/-0.3 microgram/mL, P=0.0004), reduced plasma fibrinolytic inhibitory activity (plasminogen activator inhibitor-1, -0.67+/-0.16 versus 0.24+/-0.21 U/mL, P=0.002), and increased fibrinolysis (D-dimer, 24+/-12 versus -6+/-8 ng/mL, P=0.04) compared with placebo. Increases in soluble fibrin and D-dimer were positively correlated (r=0.59, P=0.02), but changes in plasminogen activator inhibitor-1 and D-dimer were unrelated. Although baseline hemostatic and lipid parameters were correlated, there were no associations between changes in hemostatic markers and lipids after treatment. Short-term oral combined continuous HRT (estradiol and norethisterone) increased thrombin and fibrin generation, reduced plasma fibrinolytic inhibitory activity, and increased fibrinolysis. Enhanced fibrinolysis was related to increased fibrin generation but not reduced plasma fibrinolytic inhibitory activity. Coagulation activation may partly explain the increases in venous thrombosis and cardiovascular events reported with the use of combined HRT.

Effects of Blood Pressure, Smoking, and Their Interaction on Carotid Artery Structure and Function

In the present study, we examined the relationships among carotid blood pressure, arterial geometry, and wall stress and determined the impact of hypertension, smoking status, and their interaction on these relationships. The study involved 679 subjects aged 49 to 82 years: 372 smokers (190 men and 182 women) and 307 nonsmokers (110 men and 197 women). Blood samples were taken to determine total cholesterol levels. Central pulse pressure was derived from measured brachial artery pressure with a linear regression equation from data obtained in a subgroup of 276 subjects that related brachial and carotid pulse pressures; the latter was measured with applanation tonometry. Carotid intima-media thickness (IMT), lumen diameter (D), and stiffness index (SI) were determined with high-resolution B-mode ultrasound. Mean and pulsatile circumferential stress (&sfgr;C) was calculated according to the Laplace relationship. Indexes of arterial geometry and function were adjusted for age, height, and heart rate. Hypertension (treated and/or screening blood pressure of >140/90 mm Hg) was present in 71 nonsmokers and 186 smokers. Nonsmokers and smokers did not differ in blood pressure and cholesterol levels. Hypertension and smoking individually and interactively significantly increased adjusted IMT, D, and SI. The radius-to–wall thickness ratio (R/IMT) (where R=D/2) and &sfgr;C were increased in hypertensives. SI was correlated with IMT (r =0.56, P <0.001); radius-to–wall thickness ratio was inversely correlated with central pulse pressure (r =−0.38, P <0.001). Smoking did not influence these relationships. In conclusion, carotid artery wall remodeling appears to follow Laplace’s law but is insufficient to prevent an increase in circumferential stress in hypertensive subjects. Unlike hypertension, smoking does not influence the lumen-to-wall ratio but has a significant effect on wall stiffness.

The effects of soy protein containing phytoestrogens on menopausal symptoms in postmenopausal women.

Objective To analyze the impact of soy protein dietary supplements containing phytoestrogens on menopausal symptoms in healthy postmenopausal women. Methods A double-blind, placebo-controlled trial was conducted in 94 healthy postmenopausal women aged 50–75 years, with 44 randomized to soy supplements containing 118 mg of isoflavones (daidzein, genistein, glycitein and their respective glycosides), and 50 to an identically presented casein placebo. A validated questionnaire on menopausal symptoms was administered at baseline and at 3 months of treatment. Compliance was assessed by high-performance liquid chromatography assay of urinary phytoestrogens. Statistical analysis was completed using non-parametric statistical methods and multivariate analysis. Results At baseline 80% of women recruited were experiencing menopausal symptoms, although symptom severity was mild. Those consuming phytoestrogen supplements had 13- and 17-fold increases in urinary excretion of genistein and daidzein, respectively, with no change in the placebo group. Active soy supplements did not significantly alter either individual symptoms or specific symptom category scores when compared to placebo. Within-group comparisons revealed that the active group reported a significant improvement in vaginal dryness (p = 0.01), libido (p =0.009), facial hair (p = 0.04) and dry skin (p =0.027). However, similarly, those on placebo reported an improvement in libido (p =0.015), facial hair (p = 0.014) and dry skin (p = 0.011) but not vaginal dryness. Conclusions In this group of 94 older postmenopausal women with a high frequency of mild menopausal symptoms, 3 months of soy supplements containing phytoestrogens did not provide symptomatic relief compared with placebo.

The effects of soy protein containing isoflavones on lipids and indices of bone resorption in postmenopausal women.

objective To assess the effect of a dietary soy protein supplement containing isoflavones on lipids and indices of bone resorption in postmenopausal women.

Impact Of Physical And Physiological Factors On Arterial Function

1. Arterial function measurements are increasingly used as surrogate markers of cardiovascular disease and it is important to define which non‐pathological factors may influence these measurements.

Vascular dysfunction and autonomic neuropathy in Type 2 diabetes

Aimsu2003 To test the hypothesis that arterial dysfunction in Type 2 diabetes is related to autonomic neuropathy.

A placebo‐controlled trial of long‐term oral combined continuous hormone replacement therapy in postmenopausal women: effects on arterial compliance and endothelial function

OBJECTIVE To study the effects of long‐term combined continuous oral hormone replacement therapy (HRT) on vascular function in healthy postmenopausal women.

Relationship of waist and hip circumference with coagulation and fibrinolysis in postmenopausal women

The contribution of obesity to the occurrence of cardiovascular events may not be wholly related to its influence on traditional risk factors. Coagulation and fibrinolysis may also influence cardiovascular risk, but the relationship of adiposity with these processes is unclear. The aim of the present study was to investigate the relationships of BMI (body mass index), waist circumference, hip circumference and WHR (waist-to-hip ratio) with VIIc (factor VII activity), plasma markers of thrombin generation [F1+2 (prothrombin fragment 1+2)], fibrin formation [SF (soluble fibrin)] and fibrin turnover (D-dimer), and PAI-1 (plasminogen activator inhibitor-1; a marker of fibrinolytic inhibitory capacity). The study cohort was 80 healthy postmenopausal women who were not diabetic, current smokers or taking hormone therapy and who had a fasting sample of blood collected. VIIc, F1+2, SF and PAI-1 were all positively correlated with BMI, waist circumference and WHR, whereas D-dimer was positively correlated with waist circumference and WHR, but not BMI. WHR was the strongest correlate of all the markers except for PAI-1, which was most closely related to BMI. Hip circumference became a negative correlate of F1+2 and D-dimer after adjusting for waist circumference. The relationships of WHR with F1+2 and SF, but not with VIIc and D-dimer, were independent of traditional risk factors. The positive association between waist circumference and markers of thrombin generation, fibrin production and fibrin turnover suggests that abdominal adiposity may contribute to atherothrombosis by activating intravascular coagulation. In contrast, a larger hip circumference appears to have a protective affect against coagulation activation.

The Melbourne Atherosclerosis Vitamin E Trial (MAVET): A study of high dose vitamin E in smokers

Objective Our aim was to evaluate whether vitamin E (500IU) slowed the progression of carotid atherosclerosis in a population of chronic smokers over 4 years as measured by ultrasound determination of carotid intima-media thickness (IMT) and systemic arterial compliance (SAC). Methods The Melbourne Atherosclerosis Vitamin E Trial (MAVET) was a randomized, double-blind, placebo-controlled trial in which 409 male and female smokers aged 55 years and over were randomized to receive 500IU per day of natural vitamin E or placebo. The primary endpoint was progression of carotid atherosclerosis determined by intima-media thickness of the right common carotid artery. Secondary outcomes were change in systemic arterial compliance and low-density lipoprotein (LDL) oxidative susceptibility over time. Results The mean increase in intima-media thickness over time in the vitamin E group was 0.0041 mm/year faster than placebo (95% confidence interval −0.0021 to 0.0102 mm/year, P=0.20). Similarly, a non-significant difference between vitamin E and placebo was found for rate of change in systemic arterial compliance (P=0.11). Vitamin E supplementation did, however, significantly reduce LDL oxidative susceptibility (P>0.001). Conclusion Vitamin E supplementation is ineffective in reducing the progression of carotid atherosclerosis as measured by intima-media thickness in chronic smokers. This finding extends our knowledge of lack of effectiveness of vitamin E supplementation in populations with high oxidant stress. Eur J Cardiovasc Prev Rehabil 13:341-347

Effects of combined oral hormone replacement therapy on tissue factor pathway inhibitor and factor VII.

Oral combined hormone replacement therapy (HRT) with oestradiol and norethisterone increases plasma levels of prothrombin fragment 1+2 (F1+2), indicating an increase in thrombin generation, but the mechanisms underlying this increase are uncertain. The aim of this randomized, placebo-controlled study was to determine whether an increase in factor VII, a factor that combines with tissue factor to activate the extrinsic pathway, or a decrease in tissue factor pathway inhibitor (TFPI), an inhibitor of extrinsic pathway activation, may contribute to increases in thrombin generation occurring with HRT. Healthy postmenopausal women aged 50-75 years received placebo (n=19) or oral combined HRT (n=18) and had blood collected for measurement of factor VII coagulation activity (VIIc), activated factor VII (VIIa) and TFPI at baseline and at 6 weeks. Baseline characteristics were similar in the two groups, including age, body mass index and cholesterol levels. As reported previously, HRT increased the F1+2 concentration by 20%. Placebo had no effect on VIIc, VIIa or TFPI, but 6 weeks of combined HRT decreased VIIc [from 1.11+/-0.06 (mean+/-S.E.M.) to 1.03+/-0.06 i.u./ml; P<0.03], VIIa [from 43.9; 10.8-198.3 (median; range) to 35.0; 6.3-66.8 m-units/ml; P<0.03] and TFPI [from 81.3+/-6.5 to 60.4+/-5.5 ng/ml; P<0.0001]. The decrease in TPFI with HRT was not correlated with the elevation in F1+2 levels. In conclusion, the increase in thrombin generation seen with HRT is not due to an effect on factor VII; in addition, while a contribution from the decrease in TFPI is possible, increased thrombin generation is not directly related to the decrease in TFPI.