Haplotype of the Lipoprotein(a) Gene Variants rs10455872 and rs3798220 Is Associated with Parameters of Coagulation, Fibrinolysis, and Inflammation in Patients after Myocardial Infarction and Highly Elevated Lipoprotein(a) Values.

Lipoprotein(a) (Lp(a)) is an independent risk factor for future coronary events. Variants rs10455872 and rs3798220 in the gene encoding Lp(a) are associated with an increased Lp(a) concentration and risk of coronary artery disease. We aimed to determine whether in high-risk coronary artery disease patients these two genetic variants and the kringle IV type 2 (KIV-2) repeats are associated with impairment of inflammatory and hemostatic parameters. Patients after myocardial infarction with elevated Lp(a) levels were included. Blood samples underwent biochemical and genetic analyses. In carriers of the AC haplotype, the concentrations of tumor necrosis factor (TNF)-α (4.46 vs. 3.91 ng/L, p = 0.046) and plasminogen activator inhibitor-1 (PAI-1) (p = 0.026) were significantly higher compared to non-carriers. The number of KIV-2 repeats was significantly associated with the concentration of high-sensitivity C-reactive protein (ρ = 0.251, p = 0.038) and overall fibrinolytic potential (r = -0.253, p = 0.038). In our patients, a direct association between the AC haplotype and both TNF-α and PAI-1 levels was observed. Our study shows that the number of KIV-2 repeats not only affects proatherosclerotic and proinflammatory effects of Lp(a) but is also associated with its antifibrinolytic properties.

Smoking and Diabetes Attenuate Number of CD34+ Haematopoietic Stem Cells in Peripheral Blood of Patients with Advanced Peripheral Artery Disease.

Peripheral artery disease (PAD) is a globally prevalent problem with limited treatment options, leaving up to a fifth of patients remediless. The emergence of new studies on cell therapy in recent years offers a new promising option for their treatment. Our aim was to explore how the number of CD34+ hematopoietic cells in the peripheral blood of PAD patients is associated with patients' functional as well as atherogenic factors. We selected 30 patients with advanced PAD, recorded their performance in a walking test in standard conditions and sampled their blood for further analysis with an emphasis on CD34+ cell selection and counting. No correlation of the CD34+ cell number was confirmed with any of the observed laboratory parameters. There was an association between the claudication distance and the number of CD34+ cells (r = -0.403, p = 0.046). The number of CD34+ cells differed between patients with and without type II diabetes (p = 0.071) and between active smokers, past smokers, and non-smokers (p = 0.035; p = 0.068, p = 0.051, respectively), with both smoking and presence of diabetes type II having a negative effect on the number of CD34+ cells. Our study demonstrated a dependence of the CD34+ cell number on the patient's characteristics.

Predictors of functional and morphological arterial wall properties in coronary artery disease patients with increased lipoprotein (a) levels before and after treatment with proprotein convertase subtilisin-kexin type 9 inhibitors.

BACKGROUND: In addition to proatherogenic properties, lipoprotein (a) (Lp(a)) has also pro-inflammatory, antifibrinolytic and prothrombogenic features. The aim of the current study was to identify the predictors of functional and morphological properties of the arterial wall in patients after myocardial infarction and increased Lp(a) levels at the beginning and after treatment with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors. METHODS: Seventy-six post-myocardial infarction patients with high Lp(a) levels were included in the study. Ultrasound measurements of flow-mediated dilation of brachial artery (FMD), carotid intima-media thickness (c-IMT) and pulse wave velocity (PWV) were performed initially and after 6 months of treatment. At the same time points lipids, Lp(a), inflammatory and hemostasis markers were measured in blood samples. RESULTS: In linear regression model FMD significantly correlated with age at first myocardial infarction (ß = 0.689; p = 0.022), high-sensitivity C-reactive protein (ß = -1.200; p = 0.009), vascular cell adhesion protein 1 (VCAM-1) (ß = -0.992; p = 0.006), overall coagulation potential (ß = 1.428; p = 0.014) and overall hemostasis potential (ß = -1.473; p = 0.008). c-IMT significantly correlated with age at first myocardial infarction (ß = 0.574; p = 0.033) and Lp(a) (ß = 0.524; p = 0.040). PWV significantly correlated with systolic blood pressure (ß = 0.332; p = 0.002), tumor necrosis factor alpha (ß = 0.406; p = 0.002), interleukin-8 (ß = -0.315; p = 0.015) and plasminogen activator inhibitor 1 (ß = 0.229; p = 0.031). After treatment FMD reached statistical significance only in univariant analysis with systolic blood pressure (r = -0.286; p = 0.004) and VCAM-1 (r = -0.229; p = 0.024). PWV and c-IMT correlated with age (r = 0.334; p = 0.001 and r = 0.486; p < 0.0001, respectively) and systolic blood pressure (r = 0.556; p < 0.0001 and r = 0.233; p = 0.021, respectively). CONCLUSIONS: Our results suggest that age, systolic blood pressure, Lp(a) levels and other biochemical markers associated with Lp(a) are predictors of functional and morphological properties of the arterial vessel wall in post-myocardial patients with high Lp(a) levels initially. However, after 6 months of treatment with PCSK9 inhibitors only age and systolic blood pressure seem to be predictors of these properties. TRIAL REGISTRATION: The protocol for this study was registered with clinicaltrials.gov on November, 3 2020 under registration number NCT04613167.

The Influence of Treatment with PCSK9 Inhibitors and Variants in the CRP (rs1800947), TNFA (rs1800629), and IL6 (rs1800795) Genes on the Corresponding Inflammatory Markers in Patients with Very High Lipoprotein(a) Levels.

Chronic inflammation contributes significantly to the development and progression of atherosclerosis. However, the factors that lead to an inflammatory imbalance towards a proinflammatory state are not yet fully understood. The CRP rs1800947, TNFA rs1800629, and IL6 rs1800795 polymorphisms may play a role in the pathogenesis of atherosclerosis and were therefore selected to investigate the influence of genetic variability on the corresponding plasma levels after treatment with a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. A group of 69 patients with stable coronary artery disease after myocardial infarction before the age of 50 years and very high lipoprotein(a) levels were enrolled in the study. All patients received a PCSK9 inhibitor (evolocumab or alirocumab). Genotyping was performed using TaqMan assays (CRP rs1800947, TNFA rs1800629, and IL6 rs1800795). Consistent with previous studies, no significant change in levels of inflammatory biomarkers was observed after 6 months of treatment with PCSK9 inhibitors. We also did not detect any significant association between single nucleotide polymorphisms CRP rs1800947, TNFA rs1800629, and IL6 rs1800795 and plasma levels of high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-α (TNF-α), or interleukin 6 (IL6), respectively, at enrollment. However, the difference in IL6 levels after treatment with PCSK9 inhibitors was statistically significant (p = 0.050) in patients with IL6-74CC genotype, indicating the possible role of the IL6 rs1800795 polymorphism in modulating inflammation.

Smoking and diabetes attenuate beneficial effects of PSCK9 inhibitors on arterial wall properties in patients with very high lipoprotein (a) levels.

Background and aims: Elevated lipoprotein (a) (Lp(a)) and low-density lipoprotein cholesterol levels (LDL-C) are significant residual risk factors for cardiovascular events. Treatment with protein convertase subtilisin kexin type 9 (PCSK9) inhibitors reduces the levels of both. Less is known about effects of PCSK9 inhibitors on functional and morphological properties of the arterial wall. The aim of the present study was to determine whether other factors besides decreased LDL-C and Lp(a) are associated with functional (flow-mediated dilation [FMD]) and morphological (carotid intima-media thickness [c-IMT], pulse-wave velocity [PWV]) changes of the arterial wall properties in patients with coronary artery disease (CAD) treated with alirocumab and evolocumab. Methods: One hundred patients with CAD after myocardial infarction before 55 years and with high Lp(a) were randomised to lipid-lowering therapies without PCSK9 inhibitors (control; N = 31), or with alirocumab 150 mg SC (N = 35) or evolocumab 140 mg SC (N = 34), every 2 weeks. All patients underwent blood sampling for biochemical analyses and ultrasound measurements for FMD, c-IMT and PWV. Results: There were no significant changes in FMD for the control (10.7% ± 6.6%-11.1% ± 4.4%, p = 0.716) and alirocumab (10.7% ± 5.9%-11.2% ± 5.3%, p = 0.547) groups, while evolocumab promoted significant increase (11.2% ± 6.8%-14.1% ± 6.6%, p < 0.0001). Only in non-smokers and non-diabetics significant improvements in FMD (p < 0.0001) after treatment with PCSK9 inhibitors were observed. Conclusion: These data show that for patients with CAD and high Lp(a) levels, beneficial effects of PCSK9 inhibitors on the arterial wall properties can be attenuated by specific risk factors, such as smoking and diabetes.

Lipoprotein(a)-The Crossroads of Atherosclerosis, Atherothrombosis and Inflammation.

Increased lipoprotein(a) (Lp(a)) levels are an independent predictor of coronary artery disease (CAD), degenerative aortic stenosis (DAS), and heart failure independent of CAD and DAS. Lp(a) levels are genetically determinated in an autosomal dominant mode, with great intra- and inter-ethnic diversity. Most variations in Lp(a) levels arise from genetic variations of the gene that encodes the apolipoprotein(a) component of Lp(a), the LPA gene. LPA is located on the long arm of chromosome 6, within region 6q2.6-2.7. Lp(a) levels increase cardiovascular risk through several unrelated mechanisms. Lp(a) quantitatively carries all of the atherogenic risk of low-density lipoprotein cholesterol, although it is even more prone to oxidation and penetration through endothelia to promote the production of foam cells. The thrombogenic properties of Lp(a) result from the homology between apolipoprotein(a) and plasminogen, which compete for the same binding sites on endothelial cells to inhibit fibrinolysis and promote intravascular thrombosis. LPA has up to 70% homology with the human plasminogen gene. Oxidized phospholipids promote differentiation of pro-inflammatory macrophages that secrete pro-inflammatory cytokines (e. g., interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor-α). The aim of this review is to define which of these mechanisms of Lp(a) is predominant in different groups of patients.

Pulmonary hypertension in patients with advanced heart failure is associated with increased levels of interleukin-6.

CONTEXT: Inflammatory, endothelial and neurohormonal biomarkers are involved in heart failure (HF) and pulmonary hypertension (PH) pathogenesis. OBJECTIVE: To study these biomarkers in PH due to advanced HF. MATERIALS AND METHODS: Thirty adults with HF were included. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hsCRP), endothelin-1 and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were measured in peripheral vein and pulmonary artery during right heart catheterisation. RESULTS: IL-6, TNF-α, hsCRP and NT-proBNP correlated with pulmonary pressures independent of ventricular function, HF etiology and vascular bed. IL-6 was independent predictor of systolic pulmonary artery pressure (sPAP). DISCUSSION AND CONCLUSION: Inflammatory biomarkers correlate to PH severity. IL-6 predicts sPAP in advanced HF.

Influence of spironolactone treatment on endothelial function in non-obese women with polycystic ovary syndrome.

OBJECTIVE: Accumulating evidence connects polycystic ovary syndrome (PCOS) with increased risk of cardiovascular disease. Endothelial dysfunction is present in PCOS and represents an early, reversible marker of cardiovascular damage. As androgens and renin-angiotensin-aldosterone system are implicated in the atherogenesis process of PCOS, we tested the hypothesis that treatment with spironolactone, an androgen and mineralocorticoid receptor blocking drug, might reverse endothelial dysfunction in PCOS. PATIENTS: A total of 30 non-obese PCOS patients, compared with 20 body mass index matched control subjects, were evaluated. PCOS patients were given spironolactone 100 mg daily in 21-day long intervals followed by a 7-day pause, for 6 months. MEASUREMENTS: Flow-mediated dilatation (FMD), glyceryl trinitrate-induced dilatation, free testosterone, androstenedione, DHEA-sulfate, total, low-density lipoprotein (LDL)-, high-density lipoprotein-cholesterol, and triglycerides were determined at baseline and after 6 months. RESULTS: Results are expressed as median (25-75th percentile). At baseline, FMD was significantly lower in PCOS patients than in controls: 6.0 (0.0-11.7) vs 10.2 (6.8-15.9) %, P=0.018. This difference disappeared after 6 months of spironolactone treatment, as FMD in PCOS patients significantly increased to 8.3 (5.7-10.3) %, P=0.034, and was no longer different from controls. In PCOS patients, serum androgen levels did not change during treatment, while total and LDL-cholesterol decreased significantly from 4.8 (4.1-5.1) mmol/l to 4.4 (3.9-4.8) mmol/l and from 2.5 (2.1-3.1) to 2.2. (2.1-2.5) mmol/l, P<0.05 and P<0.05 respectively. CONCLUSION: Treatment with spironolactone normalized endothelial function and improved cholesterol levels in non-obese PCOS patients.

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 HR(adjusted) 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.

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 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-alpha (TNF-alpha), 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.

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 (E(2)) therapy. We compared the influence of oral E(2), with and without NETA, and transdermal E(2) 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 E(2), with or without NETA, transdermal E(2), 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 E(2) (P < 0.05) and E(2) with NETA (P < 0.01) shortened euglobulin clot lysis time. Oral E(2) decreased plasminogen activator inhibitor-1 activity (P < 0.05). Oral E(2) 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 E(2) therapy decreased fibrinogen levels (P = 0.002 for oral and P = 0.007 for transdermal E(2)), whereas E(2) with NETA showed no effect. The decrease of fibrinogen was larger after oral E(2) (P = 0.02). Oral E(2) with NETA reduced antithrombin III (P < 0.001) and protein C (P < 0.001) activity. Oral E(2) (P = 0.04) and E(2) with NETA (P < 0.01) increased C-reactive protein (CRP). Transdermal E(2) showed no influence on CRP. The addition of NETA influenced the change in CRP, as the increase in CRP was more pronounced after E(2) without NETA (P = 0.005). The levels of serum amyloid A, interleukin-6, and tumor necrosis factor-alpha 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 E(2) decreased triglycerides (P < 0.02) and increased high-density lipoprotein cholesterol (P < 0.03). Oral E(2) with NETA decreased total cholesterol (P < 0.01) and high-density lipoprotein cholesterol (P < 0.005). CONCLUSIONS: Oral E(2), 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 E(2). NETA attenuates some E(2) effects. Further studies are needed to elucidate the impact of these effects on clinical endpoints.

Inflammation markers in young post-myocardial patients exhibiting various expressions of classic coronary risk factors.

OBJECTIVE: We investigated inflammation markers in young post-myocardial infarction patients exhibiting various expressions of classical risk factors. METHODS: Forty-one male patients with high (n=20) and low (n=21) expression of classical risk factors (risk of coronary events calculated by the prospective cardiovascular Munster study program high or low, respectively), on average 44 years old, who were in the stable phase after myocardial infarction (on average 20.5 months after myocardial infarction) were included in the study. The control group consisted of 25 healthy, age-matched men. The following inflammation markers were measured: leukocyte count, high-sensitive C-reactive protein, interleukin-6, tumor necrosis factor-alpha, intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, selectin-P and selectin-E. RESULTS: No differences in the levels of leukocytes, high-sensitive C-reactive protein, tumor necrosis factor-alpha, intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, selectin-P and selectin-E were found between the group of patients and the controls. In contrast, interleukin-6 was significantly (P<0.01) elevated in the group of patients with high [2.5 (1.9-5.3) ng/ml] and low [3.2 (1.5-8.4) ng/ml] expression of risk factors compared with the controls [1.4 (0.9-2.3) ng/ml]. Significantly, there was no difference in interleukin-6 between the two groups of patients. CONCLUSIONS: We did not find differences in inflammation markers between young post-myocardial infarction patients with or without classical risk factors. Thus, it seems that the presence of (treated) risk factors or their absence does not affect the levels of inflammation markers in the stable period after myocardial infarction. Importantly, we found similarly elevated interleukin-6 in both groups of patients, most probably indicating slight local vascular inflammation. Interleukin-6 appears to be the most suitable marker of vascular inflammation in post-myocardial infarction patients who are aggressively treated pharmacologically.

Determinants of endothelial dysfunction and carotid intima-media thickness in combined hyperlipidemia.

BACKGROUND: Early functional and morphological changes in the course of the atherosclerotic process are manifested as endothelial dysfunction and increased intima-media thickness (IMT) of the arterial wall. These are both associated with various atherosclerotic risk factors. We investigated whether the same factors are associated with functional and morphological changes of the arterial wall in men with combined hyperlipidemia. METHODS: Flow-mediated dilatation (FMD) of the brachial artery and carotid IMT were measured in 72 male patients aged 46+/-5 years with combined hyperlipidemia. Serum lipoproteins, fibrinolytic and coagulation parameters, blood glucose, proinflammatory cytokines and C-reactive protein were also measured. RESULTS: Tumor necrosis factor-alpha, interleukin 6 and apolipoprotein (apo) B were found to be independent predictors of FMD, explaining 87% of FMD variability in multivariate analysis. On the other hand, total tissue factor pathway inhibitor and apo B were independent predictors of increased carotid IMT, explaining 82% of the variation in carotid IMT. CONCLUSIONS: Apo B, which is a marker for the presence of the atherogenic lipoproteins, is associated with both functional and morphological changes of the artery wall. In addition, in asymptomatic overweight middle-aged men with combined hyperlipidemia, functional changes are associated with proinflammatory cytokines, while morphological changes are associated with coagulation parameters.

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.

Orally and transdermally replaced estradiol improves endothelial function equally in middle-aged women after surgical menopause.

OBJECTIVE: Improvement in endothelial function may be an important mechanism by which estrogen replacement therapy protects postmenopausal women against coronary artery disease. We determined whether the vascular effects of estradiol depend on the route of administration. STUDY DESIGN: Six weeks after surgically induced menopause, 43 healthy women were assigned randomly to 28 weeks of treatment by either orally or transdermally replaced estradiol. Endothelium-dependent and endothelium-independent dilation were calculated with the use of the diameters of the brachial artery that were measured at rest by high resolution ultrasound scanning after reactive hyperemia and after sublingual glyceryl trinitrate. RESULTS: Endothelium-dependent dilation increased after oral estradiol replacement from 6% +/- 3.9% to 13.2% +/- 4.4% (P <.0001) and after transdermal estradiol replacement from 7% +/- 4.9% to 14.9% +/- 5.6%(P <.0001). Endothelium-independent dilation did not change significantly in either group. The improvements in endothelium-dependent dilation after estrogen substitution were independent of the changes in blood lipids and lipoproteins. CONCLUSION: Both oral and transdermal long-term replacement of estradiol lead to improved endothelial function in healthy middle-aged women after surgically induced menopause.

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.