Irena Keber

The effect of various menopausal hormone therapies on markers of inflammation, coagulation, fibrinolysis, lipids, and lipoproteins in healthy postmenopausal women

Objective: Androgenic progestins such as norethisterone acetate (NETA) may influence the effect of estradiol (E2) therapy. We compared the influence of oral E2, with and without NETA, and transdermal E2 on markers of coagulation, fibrinolysis, and inflammation and on lipids and lipoproteins in healthy postmenopausal women. Design: A total of 112 healthy postmenopausal women were randomized to receive treatment with either oral E2, with or without NETA, transdermal E2, or placebo. At baseline and after 28 weeks, levels of serum lipids and lipoproteins and markers of coagulation, fibrinolysis, and inflammation were determined. Results: Of the fibrinolytic parameters, oral E2 (P < 0.05) and E2 with NETA (P < 0.01) shortened euglobulin clot lysis time. Oral E2 decreased plasminogen activator inhibitor-1 activity (P < 0.05). Oral E2 with NETA reduced plasminogen activator inhibitor-1 antigen levels (P < 0.01) and increased D-dimer antigen levels (P < 0.001). All three modes of menopausal hormone therapy reduced tissue type plasminogen activator antigen. Of the coagulation parameters, both routes of E2 therapy decreased fibrinogen levels (P = 0.002 for oral and P = 0.007 for transdermal E2), whereas E2 with NETA showed no effect. The decrease of fibrinogen was larger after oral E2 (P = 0.02). Oral E2 with NETA reduced antithrombin III (P < 0.001) and protein C (P < 0.001) activity. Oral E2 (P = 0.04) and E2 with NETA (P < 0.01) increased C-reactive protein (CRP). Transdermal E2 showed no influence on CRP. The addition of NETA influenced the change in CRP, as the increase in CRP was more pronounced after E2 without NETA (P = 0.005). The levels of serum amyloid A, interleukin-6, and tumor necrosis factor-&agr; did not change significantly after any of the modes of hormone therapy. Of the lipids and lipoproteins, oral E2 decreased low-density lipoprotein cholesterol (P < 0.01), lipoprotein (a) (P < 0.05), and increased high-density lipoprotein cholesterol (P < 0.05). Transdermal E2 decreased triglycerides (P < 0.02) and increased high-density lipoprotein cholesterol (P < 0.03). Oral E2 with NETA decreased total cholesterol (P < 0.01) and high-density lipoprotein cholesterol (P < 0.005). Conclusions: Oral E2, with or without NETA, produced no net activation of coagulation but improved fibrinolysis. Both modes of oral menopausal hormone therapy have a greater impact on markers of inflammation, coagulation, fibrinolysis, lipids, and lipoproteins than transdermal E2. NETA attenuates some E2 effects. Further studies are needed to elucidate the impact of these effects on clinical endpoints.

Double blind, randomized study of estradiol replacement therapy on markers of inflammation, coagulation and fibrinolysis

Estrogen replacement therapy (ERT) has been found to be associated with increased cardiovascular risk in the first year after initiation of ERT. We compared the effects of oral and transdermal estradiol (E2) replacement therapy on markers of inflammation, coagulation and fibrinolysis in a randomized double-blind trial. Forty-three healthy women were randomized 6 weeks after surgically induced menopause to receive treatment with either oral or transdermal E2 over a period of 28 weeks. At baseline and after 28 weeks, levels of serum lipids and lipoproteins, and markers of coagulation, fibrinolysis and inflammation were determined. Among fibrinolytic parameters, oral E2 shortened euglobulin clot lysis time (P<0.05) and reduced tissue type plasminogen activator antigen (P=0.01) and plasminogen activator inhibitor activity (P<0.05). Among coagulation parameters, both routes of E2 replacement decreased fibrinogen levels (P=0.002 for oral and P=0.007 for transdermal E2). Oral E2 resulted in an increase in C-reactive protein (CRP) from 2.15 (0.71-4.05) to 3.41 (1.12-5.92) mg/l (P=0.04), while transdermal E2 showed no effect. Levels of serum amyloid A (SAA), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) did not change significantly after oral and transdermal E2. Oral E2 significantly improved the lipid profile, while transdermal E2 had a less pronounced effect. Both oral and transdermal E2 significantly reduced fasting glucose. Oral E2 was associated with a pro-inflammatory response, but at the same time improved fibrinolytic capacity, showed no pro-coagulatory effects, and acted beneficially on lipids and lipoproteins. There was no influence of transdermal E2 on markers of coagulation activation, fibrinolysis and inflammation, but it decreased fibrinogen levels significantly. Further studies are needed to explore the clinical relevance of these observations.

Improvement of endothelial function with metformin and rosiglitazone treatment in women with polycystic ovary syndrome

OBJECTIVE There is evidence of preclinical cardiovascular disease even in young women with polycystic ovary syndrome (PCOS). The aim of our study was to assess and compare the effects of metformin (MET) and rosiglitazone (ROSI) on endothelial function in PCOS patients. METHODS For 6 months, 26 women with PCOS received either MET or ROSI. Blood samples for assessment of androgens, lipids, and high-sensitive C-reactive protein were taken at baseline and at endpoint. Endothelium-dependent flow-mediated dilation (FMD) and glyceryl trinitrate-induced endothelium-independent dilation of brachial artery were studied before and after treatment. Homeostasis model assessment (HOMA(IR)) calculation was applied as a measure of insulin resistance (IR). RESULTS With treatment, FMD of brachial artery improved significantly from 4.2+/-6.6 to 10.2+/-5.9% in MET group (P=0.036) and from 2.9+/-3.2 to 7.6+/-4.9% in ROSI group (P=0.026), MET being as effective as ROSI (P=0.70). The endothelium-independent dilation did not change. Additionally, administration of MET was associated with a significant decrease in HOMA(IR) (P=0.003), serum total and serum-free testosterone (P=0.045 and P=0.008 respectively) and significantly higher frequencies of menstrual bleeding (P=0.006). CONCLUSIONS A 6-month therapy with insulin sensitizers, MET and ROSI, resulted in marked improvement of endothelial function in young PCOS patients without clinically evident atherosclerosis who were not severely insulin resistant. Neither drug was superior to the other. We conclude that therapeutic intervention with either insulin sensitizer may reverse the atherosclerotic process in PCOS patients at its early stage.

Interleukin-6 is a stronger prognostic predictor than high-sensitive C-reactive protein in patients with chronic stable heart failure.

Heart failure is characterized by activation of the immune system which is strongly associated with disease severity and outcome. We sought to compare the prognostic impact of two established inflammatory markers — interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) — in patients with chronic heart failure. In stable, optimally managed outpatients with chronic heart failure, baseline levels of hsCRP and IL-6 were determined. Clinical follow-up was obtained and the rate of events (heart failure related deaths or hospitalizations) were recorded. We included 201 patients (32.7% female, NYHA class II [66.2%] or III [33.8%], mean age 70 years). During a median follow up of 614 (367−761) days, 64 (30.9%) patients experienced an event; those with an event had higher levels of hsCRP (median 2.93 [interquartile range 2.36−8.92] vs 2.23 [1.32−5.77] mmol/l) and IL-6 (7.8 [4.7−10.3] vs 4.3 [2.6−7.9] pg/ml). However, on Cox multivariate analysis, IL-6 but not hsCRP emerged as an independent predictor of prognosis (hazard ratio HRadjusted 2.74, 95% confidence interval 1.17−6.43; P = 0.020). Our findings suggest that IL-6 is a better prognostic predictor than hsCRP in patients with chronic stable heart failure.

Statin and fibrate treatment of combined hyperlipidemia: the effects on some novel risk factors.

The effects of cerivastatin and fenofibrate on proteins involved in haemostasis and on markers of inflammation were investigated in otherwise healthy middle-aged males with combined hyperlipidemia. Besides classical risk factors, other so-called novel risk factors for coronary artery disease are seen to be playing an increasingly important role in the development and progression of atherosclerosis. Thirty-eight males, aged 49 +/-5 years were randomised to 12 weeks treatment either with cerivastatin at a daily dose of 0.2 mg to 0.4 mg to achieve the LDL cholesterol goal of <3.0 mM, or with fenofibrate 250 mg daily. Fasting serum lipids, homocysteine, total and free tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor (PAI-1) and tissue plasminogen activator (t-PA) antigen and activity, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured. No change in homocysteine level was observed in the cerivastatin group, while after fenofibrate administration it increased (p <0.0001). Total TFPI decreased significantly after cerivastatin (p = 0.002), but not after fenofibrate. Free TFPI did not decrease after either drug. Neither drug affected (t-PA) antigen and activity, while fenofibrate increased PAI-1 antigen (p <0.05) and activity (p <0.05). Cerivastatin decreased serum CRP values by 49.5% (p = 0.001), and fenofibrate by 29.8% (p = 0.03). The decreases of CRP in the two groups differed significantly (p = 0.04). IL-6 levels decreased significantly in the fenofibrate group (39%; p <0.0001), but not in the cerivastatin group (15%; p = 0.24) No significant decreases were observed for TNF-alpha. Cerivastatin had neutral effects on fibrinolysis, homocysteine or coagulation. On the other hand, fenofibrate increased PAI-1 antigen and activity and homocysteine, and did not affect coagulation. Both cerivastatin and fenofibrate reduced CRP levels, the decrease being significantly greater after cerivastatin. Fenofibrate also significantly decreased IL-6.

Increased Plasminogen Activator Inhibitor Activity in Survivors of Myocardial Infarction Is Associated with Metabolic Risk Factors of Atherosclerosis

To assess the relationship between the fibrinolytic system and coronary risk factors, several fibrinolytic parameters were measured in 72 male survivors of myocardial infarction and in 53 age-matched healthy controls. The coronary patients had significantly higher plasminogen activator inhibitor (PAI) activity than the control subjects, while t-PA antigen did not differ between the groups. After stratifying the coronary patients in 14 diabetic and 58 nondiabetic patients, the elevated PAI activity remained limited to the diabetic group. PAI activity correlated significantly with systolic blood pressure, blood glucose, body mass index and LDL cholesterol. In multivariate regression analysis, significant associations persisted between PAI and diabetes, body mass index and LDL cholesterol. Coronary disease had no impact on the regression model. Our results suggest that the increased PAI-1 in selected groups of coronary patients is not a consequence of coronary disease itself, but is rather related to the metabolic risk factors of atherosclerosis, especially diabetes.

Interleukin-6 Correlates with Endothelial Dysfunction in Young Post-Myocardial Infarction Patients

Background: The estimation of coronary risk based on consideration of classical risk factors is insufficient in young patients with myocardial infarction who have low expressions of classical risk factors. Endothelial dysfunction (ED) and markers of vascular inflammation may be more appropriate for risk estimation. The relations among ED and inflammation markers in such patients have not yet been explored. Patients and Methods: Twenty-one patients (on average 44 years old) in the stable phase after myocardial infarction, with low expressions of risk factors, were included in the study. The control group consisted of 25 healthy age-matched males. ED was estimated by ultrasound measurement of the endothelium-dependent dilatation of the brachial artery. The following inflammation markers were measured: hsCRP, interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), ICAM-1, VCAM-1, selectin-P and selectin-E. Results: Patients had a significantly reduced level of endothelium-dependent vasodilatation (5.6 ± 3.5 vs. 8.8 ± 6.5%, p < 0.05), and an increased level of IL-6 (3.2 [1.5–8.4] vs. 1.4 [0.9–2.3] ng/ml; p < 0.01). All other inflammation markers were comparable to controls. We found a significant negative correlation between ED and the levels of IL-6 (r = –0.54, p = 0.012). Conclusion: It appears that IL-6 is the most valuable circulating marker of ED, and consequently a useful marker of coronary risk.

Validation of self assessment patient knowledge questionnaire for heart failure patients.

Background: Several studies showed insufficient knowledge and poor compliance to non-pharmacological management in heart failure patients. Only a limited number of validated tools are available to assess their knowledge. The aim of the study was to test our 10-item Patient knowledge questionnaire. Methods: The Patient knowledge questionnaire was administered to 42 heart failure patients from Heart failure clinic and to 40 heart failure patients receiving usual care. Construct validity (Pearson correlation coefficient), internal consistency (Cronbach α), reproducibility (Wilcoxon signed rank test), and reliability (chi-square test and Students t-test for independent samples) were assessed. Results: Overall score of the Patient knowledge questionnaire had the strongest correlation to the question about regular weighing (r = 0.69) and the weakest to the question about presence of heart disease (r = 0.33). There was a strong correlation between question about fluid retention and questions assessing regular weighing, (r = 0.86), weight of one litre of water (r = 0.86), and salt restriction (r = 0.57). The Cronbach α was 0.74 and could be improved by exclusion of questions about clear explanation (Chronbach α 0.75), importance of fruit, soup, and vegetables (Chronbach α 0.75), and self adjustment of diuretic (Chronbach α 0.81). During reproducibility testing 91% to 98% of questions were answered equally. Patients from Heart failure clinic scored significantly better than patients receiving usual care (7.9 (1.3) vs. 5.7 (2.2), p < 0.001). Conclusions: Patient knowledge questionnaire is a valid and reliable tool to measure knowledge of heart failure patients.

Both cerivastatin and fenofibrate improve arterial vasoreactivity in patients with combined hyperlipidaemia

Abstract. Šebeštjen M, Žegura B, Keber I (Department of Angiology, Hospital of Internal Medicine, University Clinical Centre, Ljubljana, Slovenia). Both cerivastatin and fenofibrate improve arterial vasoreactivity in patients with combined hyperlipidaemia. J Intern Med 2002; 251: 77–85.

Patients' knowledge and beta blocker treatment improve prognosis of patients from a heart failure clinic

Several studies have shown improvement of prognosis in patients managed in heart failure (HF) clinics. However, the value of the individual management components is not well established.