Extended-release niacin/laropiprant improves endothelial function in patients after myocardial infarction.

Raising high-density lipoprotein cholesterol (HDL-C) is an important strategy for reducing residual cardiovascular risk. In the present study, we sought to assess the effect of extended-release niacin/laropiprant on endothelial function in patients after a myocardial infarction with target low-density lipoprotein cholesterol (LDL-C). In this double-blind, placebo-controlled trial, 63 men (35-60 years of age) after a myocardial infarction were randomized to either niacin/laropiprant (1000/20 mg daily for 4 weeks and 2000/40 mg daily thereafter) or placebo. Flow-mediated dilation (FMD) and nitroglycerin-induced (GTN) dilation of the brachial artery, total cholesterol (TC), LDL-C, HDL-C, triglycerides (TG), lipoprotein(a) [Lp(a)], and apolipoprotein (Apo) A1/B were measured at baseline and after 12 weeks of intervention. FMD significantly increased (from 3.9 ± 5.1 to 9.8 ± 4.4%, p < 0.001) in the niacin/laropiprant group, but not in the placebo group (4.6 ± 4.4 to 6.1 ± 4.4%, p = 0.16) (p = 0.02 for comparison of interventions). GTN dilation also increased in the niacin/laropiprant group (from 12.5 ± 6.1 to 16.7 ± 4.8%, p = 0.02), but not in the placebo group (13.4 ± 5.0 to 15.1 ± 5.2%, p = 0.18), (p = 0.60 for comparison of interventions). Niacin/laropiprant reduced TC and LDL-C (p = 0.05 for both) and increased HDL-C (p < 0.001) without influencing TG, with no changes in the placebo group. Lp(a) (p = 0.026) and ApoB (p = 0.014) were significantly lower in the niacin/laropiprant group, with no difference in the placebo group. ApoA1 did not change in either of the groups (p = 0.13; p = 0.26). FMD and GTN dilation improvements did not correlate with changes in the lipid profile. Niacin/laropiprant improves endothelium-dependent and endothelium-independent dilation of the brachial artery. This improvement does not correlate with changes in lipid parameters.

Prognostic impact of haemostatic derangements in chronic heart failure.

Heart failure is characterised by activation of haemostasis. We sought to explore the prognostic impact of deranged haemostasis in chronic heart failure. In stable, optimally managed outpatients with chronic heart failure, baseline levels of prothrombin fragment F1+2, D-dimer, and tPA and PAI-1 antigens were determined. Clinical follow-up was obtained and the rate of events (heart failure related deaths or hospitalisations) was recorded. We included 195 patients [32.3% female, NYHA class II (66.2%) or III (33.8%), mean age 71 years]. During a median follow up of 693 (interquartile range [IQR] 574-788) days, 63 (30.9%) patients experienced an event; those with an event had higher levels of tPA antigen (median 11.8 [IQR 8.7-14.0] vs. 9.4 [7.9-12.1] microg/l; p = 0.033) and D-dimer (938 [485-1269] vs. 620 [37-1076] microg/l; p = 0.018). However, on Cox multivariate analysis, only tPA levels above optimal cut-off value of 10.2 microg/l (but not D-dimer) emerged as an independent predictor of prognosis (HR(adjusted) 2.695, 95% confidence interval 1.233-5.363; p = 0.017). Our findings suggest that elevated tPA antigen levels are an independent prognostic predictor in patients with chronic stable heart failure.

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.

Nonpharmacologic measures and drug compliance in patients with heart failure: data from the EuroHeart Failure Survey.

Advice on lifestyle, diet, vaccination, and therapy are part of the standard management of heart failure (HF). However, there is little information on whether patients with HF recall receiving such recommendations and, if so, whether they report following them. We obtained information on the recall of and adherence to nonpharmacologic advice from patients enrolled in the EuroHeart Failure Survey. This article focuses on 2,331 patients who had a clinical diagnosis of HF during the index admission and attended an interview 12 weeks after discharge. Their mean age was 67 +/- 12 years and 38% were women. Patients recalled receiving 4.1 +/- 2.7 items of advice with higher rates in Central Europe and the Mediterranean region. Recall of dietary advice (cholesterol or fat intake, 63%; dietary salt, 60%) was higher than for some other interventions (influenza vaccination, 36%; avoidance of nonsteroidal anti-inflammatory drugs, 17%). Among those who recalled the advice, a substantial proportion indicated that they did not follow advice completely (cholesterol and fat intake, 61%; dietary salt, 63%; influenza vaccination, 75%; avoidance of nonsteroidal anti-inflammatory drugs, 80%), although few patients indicated they ignored the advice completely. Patients who recalled >4 items versus < or =4 items of advice were younger and more often received angiotensin-converting enzyme inhibitors (71% vs 62%), beta-blockers (51% vs 38%), and spironolactone (25% vs 21%). In conclusion, after hospitalization for HF, many patients do not recall nonpharmacologic advice. In addition, a substantial proportion of those who recall the advice follow it incompletely. Younger age and prescription of appropriate pharmacologic treatment are associated with higher rates of recall and implementation.

Recall of lifestyle advice in patients recently hospitalised with heart failure: a EuroHeart Failure Survey analysis.

BACKGROUND: There are limited data on recall and implementation of lifestyle advice in patients with heart failure (HF). AIM: To investigate what advice patients with HF recall being given, and whether they report following the advice they remember. METHODS AND RESULTS: 3261 patients with suspected HF participating in the EuroHeart Failure Survey were interviewed by a health professional 12 weeks after hospital discharge. Patients recalled receiving 46% of pre-specified items of advice and 67% reported that they followed these completely. Both recall (53%) and implementation (71%) was best in patients with left ventricular systolic dysfunction (LVSD). In multivariate analysis, younger age, male sex, patient awareness of the condition and patients reporting that they received a clear explanation of the diagnosis by a health professional, all factors associated with having LVSD, were the strongest predictors of recall. CONCLUSIONS: Recall of and adherence to advice by patients with HF in this large European cross-sectional survey was disappointing. Responsibility for patient education lies with health professionals who should ensure that patients receive and understand advice, and are able to recall and follow it. A greater awareness of the issues surrounding lifestyle advice and more evidence supporting its value could improve patient care.

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.

Time Trends in Lifestyle, Risk Factor Control, and Use of Evidence-Based Medications in Patients With Coronary Heart Disease in Europe: Results From 3 EUROASPIRE Surveys, 1999-2013.

BACKGROUND: The EUROASPIRE (European Action on Secondary and Primary Prevention by Intervention to Reduce Events) cross-sectional surveys describe time trends in lifestyle and risk factor control among coronary patients between 1999 and 2013 in Belgium, Czech Republic, Finland, France, Ireland, the Netherlands, Poland, Slovenia, and the United Kingdom as part of the EuroObservational Research Programme under the auspices of European Society of Cardiology. OBJECTIVES: This study sought to describe time trends in lifestyle, risk factor control, and the use of evidence-based medication in coronary patients across Europe. METHODS: The EUROASPIRE II (1999 to 2000), III (2006 to 2007), and IV (2012 to 13) surveys were conducted in the same geographical areas and selected hospitals in each country. Consecutive patients (≤70 years) after coronary artery bypass graft, percutaneous coronary intervention, or an acute coronary syndrome identified from hospital records were interviewed and examined ≥6 months later with standardized methods. RESULTS: Of 12,775 identified coronary patients, 8,456 (66.2%) were interviewed. Proportion of current smokers was similar across the 3 surveys. Prevalence of obesity increased by 7%. The prevalence of raised blood pressure (≥140/90 mm Hg or ≥140/80 mm Hg with diabetes) dropped by 8% from EUROASPIRE III to IV, and therapeutic control of blood pressure improved with 55% of patients below target in IV. The prevalence of low-density lipoprotein cholesterol ≥2.5 mmol/l decreased by 44%. In EUROASPIRE IV, 75% were above the target low-density lipoprotein cholesterol <1.8 mmol/l. The prevalence of self-reported diabetes increased by 9%. The use of evidence-based medications increased between the EUROASPIRE II and III surveys, but did not change between the III and IV surveys. CONCLUSIONS: Lifestyle habits have deteriorated over time with increases in obesity, central obesity, and diabetes and stagnating rates of persistent smoking. Although blood pressure and lipid management improved, they are still not optimally controlled and the use of evidence-based medications appears to have stalled apart from the increased use of high-intensity statins. These results underline the importance of offering coronary patients access to modern preventive cardiology programs.

Clopidogrel is associated with a lesser increase in NT-proBNP when compared to aspirin in patients with ischemic heart failure.

BACKGROUND: Aspirin has been associated with adverse heart failure outcomes, probably because of a blunting interaction with angiotensin-converting enzyme (ACE) inhibitors. Therefore, we hypothesized that clopidogrel when compared with aspirin would be associated with a slower progression of heart failure as determined by levels of amino-terminal pro-brain natriuretic peptide (NT-proBNP). METHODS AND RESULTS: In an open-label, randomized, 2-treatment, 2-period crossover study, 18 patients with ischemic heart failure (14 post-myocardial infarction, left ventricular ejection fraction 0.32 +/- 0.08), median age 73, New York Heart Association class II (11 patients) or III (7 patients), all taking ACE inhibitors were included. Patients were randomized to 8 weeks of aspirin 100 mg/day followed by 8 weeks of clopidogrel 75 mg/day, or the reversed sequence. Blood levels of NT-proBNP were measured using sandwich immunoassay. Patients on aspirin experienced an 8-times greater increase in log-transformed values of NT-proBNP compared with patients on clopidogrel (average change 4.757% versus 0.597%; P = .0395 for intervention, P = .4453 for period, P = .4046 for sequence). We observed no change in functional class, 6-minute walking test, creatinine levels, or electrolytes. CONCLUSION: Aspirin is associated with a greater increase in natriuretic peptides (log-transformed NT-proBNP levels), implying that aspirin therapy is associated with a more progressive course of heart failure.

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.

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

BACKGROUND: 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. AIM: To assess the prognostic value of pharmacological treatment and patient's knowledge in patients receiving care in a HF clinic. METHODS AND RESULTS: In our prospective cohort study we followed 115 patients (50 from an HF clinic and 65 receiving usual care) for at least 12 months. Knowledge was assessed using a Patient Knowledge Questionnaire (PKQ). During a median follow-up of 561 days, fewer patients from the HF clinic died or were rehospitalized due to HF than those receiving usual care (42% vs. 65%, p = 0.016). The prescription rates of ACE inhibitors (94% to 98%) and beta blockers (40% to 94%) increased in the patients from the HF clinic. In these patients the PKQ score also increased from 4.8 (1.5) to 7.9 (1.3), p<0.001. In the Cox proportional hazard model, treatment with beta blockers at > or = 50% of the target daily dose (Hazard Ratio [HR] 0.3, 95% Confidence Interval [CI] 0.10-0.95) and a PKQ score <7 (HR 3.92, 95% CI 1.39-11.03) predicted prognosis in the patients from the HF clinic. CONCLUSIONS: Patient management in the HF clinic reduced the incidence of death or of HF rehospitalization. Poor prognosis of patients receiving care in the HF clinic was predicted by poor patient knowledge and underdosing with beta blockers.

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.

Body composition changes in patients with systolic heart failure treated with beta blockers: a pilot study.

BACKGROUND: Cachexia is an independent risk factor for mortality in chronic heart failure (CHF). Beta blockers can reduce body energy expenditure and improve efficiency of substrate utilization. AIM: To assess the changes in body composition in non-cachectic patients with CHF treated with beta blockers. METHODS: We prospectively followed 41 non-cachectic ambulatory CHF patients (mean age 67 +/- 10 years, ejection fraction 37 +/- 4%) treated with beta blockers for at least 6 months. Body composition was measured by bioimpedance. RESULTS: At baseline 16/41 patients were treated with beta blockers while at the end of follow-up all patients received beta blockers (31/41 at full recommended dose). During follow up of 263 +/- 106 days body weight (83.1 +/- 16.7 vs. 83.0 +/- 16.9 kg), body mass index (29.3 +/- 5.5 vs. 29.3 +/- 5.6) and total body water did not change (51.2 +/- 6.4% vs. 51.0 +/- 6.4%), while total body fat mass (27.4 +/- 9.6 to 28.3 +/- 10.2 kg, median change +0.89 kg, p = 0.01) and percent of total body fat increased (32.3 +/- 7.4% to 33.4 +/- 7.5%, median change +0.7%, p < 0.001). New York Heart Association class and Minnesota Living with Heart Failure Questionnaire improved from 2.9 +/- 0.4 and 48 +/- 15 to 2.3 +/- 0.6 and 32 +/- 16, respectively (p < 0.001 for both). CONCLUSION: In patients with CHF, treatment with beta blockers can increase total body fat mass and total body fat content.

Heart failure clinic in a community hospital improves outcome in heart failure patients.

PRINCIPLES: Heart failure is associated with a grim prognosis. Disease management programmes can improve prognosis in heart failure patients but the applicability to the general population remains limited. We aimed to compare the outcome, pharmacological therapy, and quality of life in unselected heart failure patients from a community hospital area who were managed either in the heart failure clinic or who received the usual care. METHODS AND RESULTS: We followed 115 patients receiving care in the heart failure clinic (n = 50) or the usual care (n = 65) for at least twelve months. During the follow-up of 561 (463, 701) days significantly less patients from the heart failure clinic were rehospitalized due to heart failure or died (42% vs 65%). Assignment to the heart failure clinic (Hazard ratio [HR] 0.39, 95% Confidence interval [CI] 0.20-0.75), New York Heart Association class (HR 2.32, 95% CI 1.22-4.41), and systolic blood pressure (HR 0.98, 95% CI 0.96-0.99) independently predicted occurrence of heart failure rehospitalisations or death. At the end of the follow-up patients from the heart failure clinic received more optimal pharmacological therapy and reported better quality of life. CONCLUSIONS: Patient management in the community hospital heart failure clinic reduced the incidence of heart failure rehospitalisation or death with further benefits in terms of pharmacological therapy and quality of life.

Rosuvastatin versus atorvastatin in achieving lipid goals in patients at high risk for cardiovascular disease in clinical practice: A randomized, open-label, parallel-group, multicenter study (DISCOVERY Alpha study).

BACKGROUND: The majority of clinical trials investigating the clinical benefits of lipid-lowering therapies (LLTs) have focused on North American or western and nothern European populations. Therefore, it is timely to confirm the efficacy of these agents in other patient populations in routine clinical practice. OBJECTIVE: The aim of the Direct Statin COmparison of low-density lipoprotein cholesterol (LDL-C) Values: an Evaluation of Rosuvastatin therapY (DISCOVERY) Alpha study was to compare the effects of rosuvastatin 10 mg with those of atorvastatin 10 mg in achieving LDL-C goals in the Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice guidelines. METHODS: This randomized, open-label, parallel-group study was conducted at 93 centers in eastern Europe (Estonia, Latvia, Romania, Russia, Slovenia), Central and South America (Chile, Dominican Republic, El Salvador, Guatemala, Honduras, Nicaragua, Panama), and the Middle East (Israel, Kuwait, Saudi Arabia, United Arab Emirates). Male and female patients aged ≥18 years with primary hypercholesterolemia (LDL-C level, >135 mg/dL if LLT-naive or ≥120 mg/dL if switching statins; triglyceride [TG] level, <400 mg/dL) and a 10-year coronary heart disease (CHD) risk >20% or a history of CHD or other established atherosclerotic disease were eligible for inclusion in the study. Patients were randomly assigned to receive rosuvastatin 10-mg or atorvastatin 10-mg tablets QD for 12 weeks. No formal statistical analyses or comparisons were performed on lipid changes between switched and LLT-naive patients because of the different lipid inclusion criteria for these patients. The primary end point was the proportion of patients achieving 1998 European LDL-C goals after 12 weeks of treatment. A subanalysis was performed to assess the effects of statins in patients who had received previous statin treatment versus those who were LLT-naive. Tolerability was assessed using laboratory analysis and direct questioning of the patients. RESULTS: A total of 1506 patients (52.1% women, 47.9% men; mean [SD] age, 58.2 [10.8] years) participated in the study (rosuvastatin, 1002 patients; atorvastatin, 504 patients; previous LLT, 567 patients). A significantly higher proportion of patients achieved 1998 European LDL-C goals after 12 weeks with rosuvastatin 10 mg than with atorvastatin 10 mg (72.5% vs 56.6%; P < 0.001). Similarly, more patients achieved the 2003 European LDL-C goals with rosuvastatin 10 mg compared with atorvastatin 10 mg (57.5% vs 39.2%). Rosuvastatin 10 mg was associated with a significantly greater change in LDL-C levels compared with atorvastatin 10 mg, in patients who were LLT-naive (LDL-C: -44.7% vs -33.9%; P < 0.001) and in patients who had received previous LLT (LDL-C: -32.0% vs -26.5%; P = 0.006). TG levels were also decreased with rosuvastatin 10 mg and atorvastatin 10 mg, although there was no significant difference between treatments. Similarly, there was no significant difference in the increase in high-density lipoprotein cholesterol levels between treatments. The most common adverse events overall were headache 16/1497 (1.1%), myalgia 10/1497 (0.7%), and nausea 10/1497 (0.7%). CONCLUSIONS: In this study in patients with primary hypercholesterolemia in clinical practice, greater reductions in LDL-C levels were achieved with a starting dose (10 mg) of rosuvastatin compared with atorvastatin 10 mg, with more patients achieving European LDL-C goals. Both treatments were well tolerated.

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.

Deletion/insertion polymorphism in the angiotension - converting enzyme gene as a risk factor in the Slovenian patients with coronary heart disease.

The angiotensin-converting enzyme (ACE) plays by degradation of angiotensin I and bradykinin, an important role in modulations of smooth muscle proliferation and vascular tone. Typical plasma levels of ACE accompany the I/D polymorphism; however, a controversy exists as to whether the DD genotype of the ACE polymorphism affects the risk for the development of coronary heart disease (CHD). We compared the I/D polymorphism in 171 Slovenian CHD patients that were younger man 55 years with 134 healthy control individuals. The DD genotype is associated with a 2.3 - fold increase in the risk for CHD.

Improvement of early functional atherosclerotic changes in males with hypercholesterolemia after vitamin E supplementation.

Vitamin E as an antioxidant vitamin reduces the susceptibility of low-density lipoprotein (LDL) cholesterol to oxidation and may have antiatherosclerotic effects. We tested the hypothesis that six months of 400 mg vitamin E supplementation favourably affects early functional changes in atherosclerotic process in subjects with hypercholesterolemia. The diameter of the brachial artery at rest, after reactive hyperemia (representing endothelium -dependent vasodilatation) and after sublingual glyceryl -trinitrate (representing endothelium - independent vasodilatation), were determined by ultrasonographic method (B mode) before and after the intervention period. After the intervention period the brachial endothelium - dependent vasodilatation increased significantly in the vitamin E group while it did not change in the placebo group. In conclusion, six months of oral vitamin E supplementation results in improvement of the endothelium - dependent vasodilatation in men with hypercholesterolemia.

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.

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.

A randomized, placebo-controlled trial of the effects of continuous combined hormone replacement therapy on coagulation and fibrinolytic systems in healthy postmenopausal women.

OBJECTIVE: To investigate the effects of combined hormone replacement therapy (HRT) on various parameters of coagulation and fibrinolysis that may contribute to increased risk for venous thromboembolic events. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Academic hospital. PATIENT(S): Sixty-one healthy postmenopausal women with intact uterus. INTERVENTION(S): Patients were randomized to receive continuous combined HRT (estradiol, 2 mg/d, and norethisterone acetate, 1 mg/d) or placebo for 6 months. MAIN OUTCOME MEASURE(S): Markers of coagulation and fibrinolysis were measured before therapy and after 3 and 6 months of therapy. RESULT(S): The groups did not differ significantly in levels of prothrombin fragments 1 and 2 and thrombin-antithrombin III complex after 3 and 6 months of therapy. After 6 months of HRT, significant decreases in activity of antithrombin III and protein C and levels of plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator antigen, and euglobulin clot lysis time and a significant increase in D-dimer level were found compared with placebo. CONCLUSION(S): Continuous combined HRT for several months produced no net activation of coagulation but improved fibrinolysis in healthy postmenopausal women with no risk factors for venous thromboembolic events.