Ingebjørg Seljeflot

Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease

INTRODUCTION The purpose of the present study was to study the concept of aspirin resistance or non-responsiveness by investigating the response to long-term aspirin therapy in patients with a former acute myocardial infarction (AMI). MATERIALS AND METHODS Patients with an AMI (n=202) randomly assigned to aspirin 160 mg/day (n=71), aspirin 75 mg/day and warfarin (INR 2.0-2.5) (n=58) or warfarin (INR 2.8-4.2) (n=73) were evaluated by the PFA-100(R), biochemical variables and clinical events after a mean treatment period of 4 years. RESULTS The limit for being an aspirin non-responder was defined as the 95th percentile value in the warfarin alone group (196 s) with the epinephrine cartridge. In patients on aspirin alone 25/71 (35%) were non-responders and on the combination 23/58 (40%). With the adenosine diphosphate (ADP) cartridge only minor differences were found. The levels of thromboxane B(2) in both aspirin groups, in responders as well as in non-responders, were extremely low compared to the warfarin alone group. Evaluating both aspirin groups together (n=129), the levels of soluble P-selectin were significantly higher in non-responders as compared to responders (p=0.012). During the observation period of 4 years with limited number of events, there was a tendency for higher event rates in non-responders as compared to responders (36% vs. 24%, p=0.28). CONCLUSIONS In our evaluation of the PFA-100(R) a considerable number of post-AMI patients seemed to be non-responders to long-term aspirin therapy in doses of 75 and 160 mg/day. Circulating levels of P-selectin were higher in the non-responders. A tendency to higher incidence of clinical events among non-responders was observed.

Increased insulin sensitivity and fibrinolytic capacity after dietary intervention in obese women with polycystic ovary syndrome

In overweight women with polycystic ovary syndrome (PCOS), increased insulin resistance has been observed. Since abdominal obesity is associated with impaired fibrinolytic capacity and elevated levels of plasminogen activator inhibitor (PAI-1) and since PAI-1 seems to be related to insulin resistance, we investigated the possible effects of dietary intervention on lipids, fibrinolysis, coagulation, and insulin sensitivity in obese PCOS women. Nine women aged 22 to 39 years (median weight, 97 kg) ate a protein-rich very—low-calorie diet (VLCD) (Nutrilett, Nycomed Pharma, Oslo, Norway; 421 kcal/d) for 4 weeks (part 1). After significant reductions of body fat (13%, P < .01), two of nine women achieved regular menstruation and became pregnant. Six of the remaining women continued on a conventional low-calorie diet (1,000 to 1,500 kcal/d) for the next 20 weeks (part 2), during which time they were generally able to preserve the body fat loss obtained in part 1 of the study. During part 1, significant reductions of total serum cholesterol (29%, P = .001) and fasting triglyceride ([TG] 31%, P < .05) levels were observed, as well as significant reductions of fasting glucose (6%, P < .05) and insulin (20%, P < .05). Insulin sensitivity (glucose disposal rate [GDR]) was increased by 93% (P < .05). After finishing part 2, insulin sensitivity was still significantly increased (86%, P < .05) and PAI-1 activity was significantly reduced (54%, P < .05). Moreover, overall fibrinolytic activity was significantly improved (serum d-dimer concentration increased by 75%, P < .05). In conclusion, through intensive dietary intervention with adequate loss of weight it is possible to change an unfavorable atherothrombogenic risk profile in overweight (PCOS) women. Most convincingly, significantly increased insulin sensitivity and fibrinolytic capacity were observed.

n-3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study ☆

Abstract OBJECTIVES The aim of the study was to investigate whether omega-3 fatty acids (n-3 FA) reduce the occurrence of restenosis after percutaneous transluminal coronary angioplasty. BACKGROUND Meta-analyses have shown significant reduction of restenosis after coronary angioplasty upon supplementation with n-3 FA. METHODS In a prospective, placebo-controlled, double-blind study, 500 patients were randomly allocated to treatment with n-3 FA (Omacor™, Pronova AS, Oslo, Norway) 5.1 g/day or corn oil (placebo) starting at least two weeks prior to elective coronary angioplasty. The treatment was continued until restenosis evaluation by quantitative coronary angiography after six months. Stenosis was defined as a minimal luminal diameter (MLD) 50% or an increase in stenosis of ≥0.7 mm. Three-hundred ninety-two patients fulfilled the criteria for initial stenosis and successful coronary angioplasty, and, except four patients who died, none were lost for follow-up. RESULTS Restenosis occurred in 108/266 (40.6%) of the treated stenoses in the Omacor group and in 93/263 (35.4%) in the placebo group (odds ratio [OR] 1.25, 95% confidence interval [CI] [0.87–1.80] p = 0.21). In the Omacor group one or more restenoses occurred in 90/196 (45.9%) patients as compared with 86/192 (44.8%) in the placebo group (OR 1.05, 95% CI [0.69–1.59] p = 0.82). CONCLUSIONS Supplementation with 5.1 g n-3 FA/day for six months, initiated at least two weeks prior to coronary angioplasty did not reduce the incidence of restenosis.

Dairy products and metabolic effects in overweight men and women: results from a 6-mo intervention study

BACKGROUND Some epidemiologic studies have suggested inverse relations between intake of dairy products and components of the metabolic syndrome. OBJECTIVE The objective was to investigate the effects of an increased intake of dairy products in persons with a habitually low intake on body composition and factors related to the metabolic syndrome. DESIGN Middle-aged overweight subjects (n = 121) with traits of the metabolic syndrome were recruited in Finland, Norway, and Sweden and randomly assigned into milk or control groups. The milk group was instructed to consume 3-5 portions of dairy products daily. The control group maintained their habitual diet. Clinical investigations were conducted on admission and after 6 mo. RESULTS There were no significant differences between changes in body weight or body composition, blood pressure, markers of inflammation, endothelial function, adiponectin, or oxidative stress in the milk and the control groups. There was a modest unfavorable increase in serum cholesterol concentrations in the milk group (P = 0.043). Among participants with a low calcium intake at baseline (<700 mg/d), there was a significant treatment effect for waist circumference (P = 0.003) and sagittal abdominal diameter (P = 0.034). When the sexes were analyzed separately, leptin increased (P = 0.045) and vascular cell adhesion molecule-1 decreased (P = 0.001) in women in the milk group. CONCLUSIONS This study gives no clear support to the hypothesis that a moderately increased intake of dairy products beneficially affects aspects of the metabolic syndrome. The apparently positive effects on waist circumference and sagittal abdominal diameter in subjects with a low calcium intake suggest a possible threshold in relation to effects on body composition.

Increased levels of asymmetric dimethylarginine in populations at risk for atherosclerotic disease. Effects of pravastatin.

The aim of the present study was to investigate plasma levels of asymmetric dimethylarginine (ADMA), an important endogenous inhibitor of nitric oxide synthase, in populations at high risk for atherosclerosis as compared to healthy controls, and furthermore to evaluate the effect of cholesterol lowering therapy in individuals with hypercholesterolemia. The present study consisted of 32 men with untreated hypercholesterolemia (HC group), 38 individuals with well-controlled insulin-dependent diabetes mellitus (DM group) and 20 healthy individuals (controls). The HC subjects were randomly allocated into a double blinded, placebo-controlled cross-over designed study with 8 weeks treatment with pravastatin (40 mg/day) or matching placebo. ADMA levels were statistically significantly higher in DM and HC individuals as compared to controls (P<0.001 for both), and the L-arginine/ADMA ratios were significantly lower in both groups (P<0.001 and P<0.005, respectively). Significant reductions in total cholesterol (TC) and LDL-C levels on pravastatin were obtained (P<0.001 for both), whereas no changes were observed in the levels of ADMA or the L-arginine/ADMA ratios. Statistically significant correlations between ADMA and TC and LDL-C were found (r=0.41, P<0.001 for both). In conclusion, significantly elevated ADMA levels and reduced L-arginine/ADMA ratios were found in individuals with diabetes type-1 as well as in hypercholesterolemia. Treatment with pravastatin 40 mg/day for 8 weeks had no effect on the levels of ADMA in hypercholesterolemic men.

Reduced expression of endothelial cell markers after 1 year treatment with simvastatin and atorvastatin in patients with coronary heart disease.

The study was aimed at investigating the effects, after treatment for 1 year, of two different statins on the levels of circulating biochemical markers of endothelial function in patients with established coronary heart disease, with the hypothesis that statins might reduce these levels. Twenty-eight patients were randomized to treatment with atorvastatin and 30 to simvastatin for 1 year. The starting dose in both groups was 20 mg/day. Soluble forms of P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were determined to assess inflammatory activity of the endothelium, and tissue plasminogen activator antigen (tPAag), von Willebrand factor and thrombomodulin for evaluation of the haemostatic function. In the total study population there were significantly reduced levels after 1 year treatment in ICAM-1 (P<0.001), E-selectin (P=0.022) and P-selectin (P<0.001), whereas a significant increase was observed in VCAM-1 (P=0.003). Almost the same pattern was seen within both groups although the increase in VCAM-1 was only seen in the simvastatin group (P=0.017). An overall reduction in tPAag was further observed (P=0.048). The reduction in proinflammatory and to some extent haemostatic markers of endothelial function after 1 year treatment with either simvastatin or atorvastatin may be indicative of a less activated state of the endothelium which possibly may contribute to modulation of the progression of atherosclerosis.

A comparison of the effects of cheese and butter on serum lipids, haemostatic variables and homocysteine.

Milk fat contains considerable amounts of saturated fatty acids, known to increase serum cholesterol. Little is known, however, about the relative effect of different milk products on risk factors for CHD. The aim of the present study was to compare the effects of Jarlsberg cheese (a Norwegian variety of Swiss cheese) with butter on serum lipoproteins, haemostatic variables and homocysteine. A controlled dietary study was performed with twenty-two test individuals (nine men and thirteen women) aged 23-54 years. The subjects consumed three isoenergetic test diets, with equal amounts of fat and protein, and containing either cheese (CH diet), butter + calcium caseinate (BC diet) or butter + egg-white protein (BE diet). The study was a randomised cross-over study and the subjects consumed each diet for 3 weeks, with 1 week when they consumed their habitual diet in between. Fasting blood samples were drawn at baseline and at the end of each period. Serum was analysed for lipids and plasma for haemostatic variables and homocysteine. Total cholesterol was significantly lower after the CH diet than after the BC diet (-0.27 mmol/l; P=0.03), while the difference in LDL-cholesterol was found to be below significance level (-0.22 mmol/l; P=0.06). There were no significant differences in HDL-cholesterol, triacylglycerols, apo A-I, apo B or lipoprotein (a), haemostatic variables and homocysteine between the diets. The results indicate that, at equal fat content, cheese may be less cholesterol increasing than butter.

The role of interleukin-18 in the metabolic syndrome

The metabolic syndrome is thought to be associated with a chronic low-grade inflammation, and a growing body of evidence suggests that interleukin-18 (IL-18) might be closely related to the metabolic syndrome and its consequences. Circulating levels of IL-18 have been reported to be elevated in subjects with the metabolic syndrome, to be closely associated with the components of the syndrome, to predict cardiovascular events and mortality in populations with the metabolic syndrome and to precede the development of type 2 diabetes. IL-18 is found in the unstable atherosclerotic plaque, in adipose tissue and in muscle tissue, and is subject to several regulatory steps including cleavage by caspase-1, inactivation by IL-18 binding protein and the influence of other cytokines in modulating its interaction with the IL-18 receptor. The purpose of this review is to outline the role of IL-18 in the metabolic syndrome, with particular emphasis on cardiovascular risk and the potential effect of life style interventions.

Increased activation of coagulation and formation of late deep venous thrombosis following discontinuation of thromboprophylaxis after hip replacement surgery

Hip replacement surgery (HRS) is associated with a high frequency of deep vein thrombosis (DVT). At the same time there is a substantial systemic and local activation of coagulation. This study indicates that discontinuation of thromboprophylaxis one week after surgery may allow a second wave of coagulation and fibrinolysis activation to occur. An almost parallel increase in plasma TAT and D-dimer levels between the 6th and the 35th postoperative day may indicate late DVT formation. Repeated bilateral ascending venography is though to be necessary to evaluate the suitability of using selected activation markers of the coagulation and fibrinolytic systems as indices of DVT formation.

Frequency of Left Ventricular Thrombus in Patients With Anterior Wall Acute Myocardial Infarction Treated With Percutaneous Coronary Intervention and Dual Antiplatelet Therapy

The aim of the present study was to investigate the prevalence of left ventricular (LV) thrombus formation and important determinants in patients with acute ST elevation myocardial infarction localized to the anterior wall treated with percutaneous coronary intervention (PCI) and dual-antiplatelet therapy. One hundred selected patients with ST elevation myocardial infarctions revascularized with PCI in the left anterior descending coronary artery were included. The patients participated in the Autologous Stem Cell Transplantation in Acute Myocardial Infarction (ASTAMI) trial. All were treated with aspirin 75 mg/day and clopidogrel 75 mg/day and underwent serial echocardiography and magnetic resonance imaging during the first 3 months after PCI. After 4 to 5 days, the ejection fraction and infarct size in percentage of the left anterior descending coronary artery area were assessed using single photon-emission computed tomography in addition to the ejection fraction by echocardiography. LV thrombi were detected in 15 patients during the first 3 months, 2/3 of them within the first week. No differences in baseline characteristics between the groups with and without LV thrombi were shown. However, in the thrombus group, significantly higher peak creatine kinase levels (6,128 vs 2,197 U/L, p <0.01), larger infarct sizes (82.5% vs 63.8%, p <0.01), and lower ejection fractions on single photon-emission computed tomography (35.5% vs 40.0%, p = 0.03) and on echocardiography (43.0% vs 46.0%, p = 0.03) were found compared to patients without LV thrombi. In conclusion, LV thrombus formation is a frequent finding in patients with anterior wall ST elevation myocardial infarction treated acutely with PCI and dual-antiplatelet therapy and should be assessed by echocardiography within the first week.