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Aims With improvement in survival of chronic heart failure (HF), the clinical importance of co-morbidity is increasing. The aim of this study was to assess the incidence and risk of cancer and all-cause mortality in a large Danish HF cohort. Methods and results A total of 9307 outpatients with verified HF without a prior diagnosis of cancer (27% female, mean age 68 years, 89% with LVEF

Aims The optimal duration of a public heart failure (HF) clinic programme is unknown. This substudy of the NT-proBNP stratified follow-up in outpatient heart failure clinics (NorthStar) trial was designed to evaluate the effect of extended follow-up in an outpatient HF clinic on long-term adherence to guideline-based therapy. Methods and results Patients with HF with reduced EF on optimal medical therapy (n = 921) were randomized to either extended follow-up in the HF clinic (n = 461) or discharge to primary care (n = 460) and followed for a median of 4.1 years (range: 13 months to 6.1 years). The effect of the HF clinic intervention on treatment adherence (time to at least a 90 day break in treatment) was estimated by drug dispensing from pharmacies of an ACE inhibitor/ARB, beta-blocker (BB), or mineralocorticoid receptor antagonist (MRA). Median age was 69 years, 25% were females, LVEF was 30%, and 90% were in NYHA class II–III. The HF clinic intervention did not reduce time to a 90 day break in treatment with either an ACE inhibitor/ARB [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.34–1.97, P = 0.650], a BB (HR 1.09, 95% CI 0.53–2.66, P = 0.820), or an MRA (HR 1.30, 95% CI 0.85–2.00, P = 0.238). Conclusions Extended follow-up in an outpatient HF clinic did not improve long-term adherence to guideline-based therapy, and adherence did not deteriorate when follow-up was shifted from the HF clinic to primary care.

Aims Undertreatment with evidence-based pharmacotherapy for heart failure (HF) is an important problem, and it has been suggested that specialized HF clinics (HFCs) can improve treatment initiation and correct dosing. The objective of this study was to examine long-term adherence to and dosages of evidence-based pharmacotherapy during and after participation in specialized HFCs. Methods and results Initiation, dosages, and adherence were studied in patients with systolic HF attending HFCs in Denmark from 2002 to 2009. Information was obtained from an electronic patient file and research database used in the HFCs combined with prescription data from the Danish Registry of Medicinal Product Statistics. A total of 8792 patients were included in the study. The mean age was 68 years; with a mean LVEF of 30%, and 72% were males. Long-term adherence to treatment was high for the patients who initiated renin–angiotensin system (RAS) inhibitors and beta-blockers. Adherence after 1 year was 93% for RAS inhibitors, 92% for beta-blockers, and 86% for spironolactone. After 3 years, it was 90% for RAS inhibitors, 88% for beta-blockers, and 74% for spironolactone. For patients referred back to their general practitioner (GP), adherence 1 year after they left the HFC was 89% for RAS inhibitors, 89% for beta-blockers, and 72% for spironolactone. Conclusion In specialized outpatient HFCs, long-term adherence to RAS inhibitors and beta-blockers is close to optimal. Importantly, adherence was maintained after patients were referred back to their GP for continued management. This is likely to provide long-term benefits for the patients.

SUMMARY Intravenous iron preparations have shown benefit in patients with chronic heart failure (CHF) and iron deficiency. Iron isomaltoside 1000 (Monofer) is a novel intravenous iron compound with low immunological activity of the isomaltoside and low free-iron-related toxicity. The primary objective of this open-label, non-comparative, multicenter pilot study was to test the safety of iron isomaltoside 1000 in patients with CHF and anemia. In addition, its effect on markers of iron deficiency, anemia and on quality of life was assessed. Twenty patients with CHF and iron deficiency anemia attended six visits during the 8-week study period. Iron isomaltoside 1000 was infused at baseline (mean dose 868 mg, range 650–1000 mg). No treatment-related adverse reactions, no acute anaphylactic or delayed allergic reactions and no clinically significant changes in routine clinical laboratory safety tests or vital signs were observed. Markers of iron deficiency, anemia and quality of life improved from baseline with increase in mean value of 49% at 4 weeks in overall quality of life. Iron isomaltoside 1000 administered as a fast single infusion without a test dose to patients with CHF improved quality-of-life assessments and was well tolerated in this pilot safety study.

Eugen-Olsen J, Andersen O, Linneberg A, Ladelund S, Hansen TW, Langkilde A, Petersen J, Pielak T, Moller LN, Jeppesen J, Lyngbaek S, Fenger M, Olsen MH, Hildebrandt PR, Borch-Johnsen K, Jorgensen T, Haugaard SB (Copenhagen University, Hvidovre Hospital, Hvidovre; Copenhagen University Hospital, Glostrup; Copenhagen University Hospital, Copenhagen; Copenhagen University Hospital, Glostrup; Copenhagen University, Hvidovre Hospital, Hvidovre; Steno Diabetes Center, Gentofte; University of Aarhus, Aarhus; University of Copenhagen, Copenhagen; Copenhagen University, Hvidovre Hospital, Hvidovre, Denmark). Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population. J Intern Med 2010; 268: 296–308. Background. Low-grade inflammation is thought to contribute to the development of cardiovascular disease (CVD), type-2 diabetes mellitus (T2D), cancer and mortality. Biomarkers of inflammation may aid in risk prediction and enable early intervention and prevention of disease. Objective. The aim of this study was to investigate whether plasma levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) are predictive of disease and mortality in the general population. Design. This was an observational prospective cohort study. Cohort participants were included from June 1993 to December 1994 and followed until the end of 2006. Setting. General adult Caucasian population. Participants. The MONICA10 study, a population-based cohort recruited from Copenhagen, Denmark, included 2602 individuals aged 41, 51, 61 or 71 years. Measurements. Blood samples were analysed for suPAR levels using a commercially available enzyme-linked immunosorbent assay. Risk of cancer (n = 308), CVD (n = 301), T2D (n = 59) and mortality (n = 411) was assessed with a multivariate proportional hazards model using Cox regression. Results. Elevated baseline suPAR level was associated with an increased risk of cancer, CVD, T2D and mortality during follow-up. suPAR was more strongly associated with cancer, CVD and mortality in men than in women, and in younger compared with older individuals. suPAR remained significantly associated with the risk of negative outcome after adjustment for a number of relevant risk factors including C-reactive protein levels. Limitation. Further validation in ethnic populations other than Caucasians is needed. Conclusion. The stable plasma protein suPAR may be a promising biomarker because of its independent association with incident cancer, CVD, T2D and mortality in the general population.

Semisynthetic human insulin (Novo) was compared with porcine insulin with regard to absorption from subcutaneous depots, blood glucose control and plasma insulin concentrations in patients, and the binding to insulin receptors of porcine and human origin. The binding affinities of semisynthetic human insulin and porcine insulin were identical with human erythrocyte receptors and receptors on porcine hepatocytes. The subcutaneous absorption of semisynthetic human and porcine 125I-labelled insulin both of soluble and lente type was identical. The metabolic control study was performed as a double-blind crossover study in eight type I diabetics. They received semisynthetic human insulin and porcine insulin (of soluble as well as lente type) for 10 days each, the last 7 days in each period being the observation period. Blood glucose concentration was measured 9 times per 24 hours. No statistically significant differences were found between mean blood glucose levels at the 9 samplings or in the overall mean blood glucose concentration. Further, the blood glucose control was evaluated as a function of time by a computerized method for time series analysis of a complex dynamic system. This method described adequately each blood glucose value as a linear function of the immediately preceding blood glucose value and that measured 24 hours before. No difference was found between human and porcine insulin when the blood glucose control was assessed by this method. Plasma concentrations of total insulin (IRI) and free IRI before and 3 hours after the morning insulin injection were identical in the two treatment periods. It is concluded that human and porcine insulin can be interchanged in the treatment of diabetics without changing the dose.

Background: Biomarkers of endothelial dysfunction, such as soluble E-selectin, and von Willebrand factor (vWf) are elevated in patients with chronic heart failure (CHF). The impact of diabetes mellitus (DM) on these biomarkers, and their relation to prognosis remains unknown. Aims: to investigate the impact of DM on plasma levels and the prognostic value of E-selectin and vWf in patients with CHF. Methods and results: Plasma levels of E-selectin and vWf were measured in 195 CHF patients with (n = 48, 24.5%), and without DM, and in 116 age-matched healthy controls. Compared with controls, median plasma E-selectin levels were higher in CHF patients with DM (P = 0.012), but not in CHF patients without DM (P = 0.45); vWf levels were also higher in CHF patients with DM (P < 0.001), but not without DM (P = 0.108). E-selectin was associated with risk of recurrent ischaemic cardiovascular events among CHF patients with DM (HR 2.60; P = 0.009), but not among patients without DM (HR 1.09; P = 0.60) per 1 SD increment in log transformed variable. vWf was not related with outcome in CHF patients with or without DM. Conclusions: Plasma levels of E-selectin and vWf are elevated in CHF patients with DM but not in those without DM. High E-selectin levels may be associated with ischaemic events in patients with DM.

Introduction: Atrial fibrillation (AF) is common in patients with heart failure (HF) due to left ventricular systolic dysfunction (LVSD), with conflicting prognostic data. The aim of our study was to assess the prevalence and incidence of AF in patients with HF and to determine the prognostic impact of baseline AF and the development of new onset AF. Methods and results: We included 1019 outpatients with HF due to LVSD; follow-up time ranged from 3 to 64months. At baseline 26.4% of patients had AF. Of the 284 patients with a follow-up ECG and baseline SR, 18.7% developed new onset AF. Patients with AF were older (p

Background: The usefulness of brain-natriuretic-peptide (BNP) and N-terminal-pro-brain-natriuretic-peptide (NT-proBNP) for monitoring of chronic heart failure (CHF) patients has been questioned because of high levels of unexplained variation. Aims: Week-to-week total variance (CVT), unexplained variation (CVI), reference change values (RCV), index of individualities (IOI) and number of samples (N) with week-to-week intervals needed to estimate the underlying homeostatic set point (15%) for BNP and NT-proBNP were calculated in pre-specified stable CHF patients. Methods and results: We measured plasma concentrations of BNP and NT-proBNP, clinical and laboratory variables in 20 CHF patients with a 7-days interval. Only patients considered to be in steady state were included. The CVI was 15% (BNP) and 8% (NT-proBNP). CVT was 16% (BNP) and 8% (NT-proBNP) and RCV was 43% (BNP) and 23% (NT-proBNP). IOI was 0.14 for BNP and 0.03 for NT-proBNP and N was 1 for BNP and 1 for NT-proBNP. Conclusions: Our data demonstrate that unexplained variation of BNP and NT-proBNP is low in CHF patients during steady state, which is a prerequisite for the use of these peptides for monitoring of the disease.

To determine the prognosis, total mortality and cardiac morbidity, of patients with left ventricular systolic dysfunction and heart failure (HF) in a general population sample.A total of 764 subjects, 432 females and 332 males, median age (range) 66 years (50-89), participated in this cross sectional survey. The study population was recruited from randomly selected general practitioners and stratified to include a minimum of 150 persons in each age decade stratum. Each participant filled in a heart failure questionnaire and ECG, blood tests and echocardiography were performed. Median (range) follow-up was 1145 (51-1197) days. Subjects with LVEFor = 0.40 had a significantly higher all-cause mortality (27.8% vs. 5.6%, P0.0001), admission rate for HF (25.0% vs. 1.9%, P0.0001) and for other cardiac causes (25.0% vs. 6.3%, P0.0001) than in subjects with LVEF0.40. The age and gender adjusted 2-year relative risk of death was 4.6 (95% C.I.=1.6-13.2). No significant difference in mortality was found between subjects with or without heart failure symptoms.Significantly higher mortality as well as cardiac morbidity was found in subjects with symptomatic and asymptomatic LV systolic dysfunction compared to those with normal systolic function. These conditions were among the strongest predictors of all-cause mortality and cardiac morbidity.

Summary objective N-terminal B-type natriuretic peptide (NT-pro-BNP) is secreted from the cardiac ventricles in response to volume expansion and pressure overload, and serum levels are elevated in systolic heart failure. The aim of this study was to evaluate the influence of thyroid function on NT-pro-BNP. design Patients with overt or subclinical thyroid disease were evaluated before and after treatment for their dysthyroid state. patients Seventeen overt and 21 subclinical hypothyroid patients together with six subclinical and 13 overt hyperthyroid patients without cardiac disease were included. Subclinical states had, by definition, free T4 and free T3 estimates within reference ranges. measurements Serum levels of NT-pro-BNP and thyroid hormones were measured, and in 31 patients resting cardiac output was measured by impedance cardiography in the untreated state. results NT-pro-BNP levels were more than four times higher in hyperthyroid than hypothyroid patients, with mean values of 30 and 7 pmol/l, respectively (P

Patients with diabetes mellitus have a high morbidity and mortality from acute myocardial infarction, the reason for which is not fully understood. The relationship between congestive heart failure symptoms, left ventricular ejection fraction, and long-term mortality was examined in 578 hospital survivors of acute myocardial infarction, 47 of whom had Type 2 (non-insulin-dependent) diabetes mellitus. None of the patients were treated with insulin. The prevalence of congestive heart failure during hospitalization was similar in patients with and without diabetes, although mean diuretic dose was higher in the former patients. Left and right ventricular ejection fraction was measured with radionuclide ventriculography in the second week after acute myocardial infarction. At discharge from the coronary care unit, patients with and without diabetes had similar left ventricular ejection fraction (with diabetes: median 46% vs without diabetes: median 43%; p = 0.89). Median right ventricular ejection fraction (62%) was within normal limits in both groups and did not differ statistically. Survival data were obtained for all patients. The 5-year mortality was increased in patients with diabetes compared with non-diabetic patients independent of left ventricular ejection fraction. Univariate analysis showed that the cumulative 5-year mortality rate was 53% in the group with diabetes compared with 43% in the non-diabetic group (p = 0.007). Using multivariate regression analysis presence of diabetes was found to have a significant association with long-term mortality after myocardial infarction, that was independent of age, history of hypertension, congestive heart failure symptoms during hospitalization or of either left or right ventricular ejection fractions at discharge. We conclude that the excess mortality in patients with non-insulin-dependent diabetes mellitus is not explained by available risk markers after myocardial infarction. Even though left ventricular ejection fraction and serum creatinine did not differ significantly, the apparent higher dose of Frusemide in patients with than without non-insulin-dependent diabetes mellitus might indicate that heart failure, it present, is more severe in patients with than in those without diabetes. The importance of diastolic dysfunction in this context needs to be determined.

Summary. A TV-game of tennis of 20 min duration was used to study the influence of mild mental stress on subcutaneous blood-flow (SBF), blood-pressure and heart rate in nine insulin-dependent diabetics and nine healthy subjects. SBF was measured on the thigh by local clearance of xenon-133. Measurements were made before, during and after the period of stress. During stress, SBF increased significantly by 26% in the healthy subjects, while SBF remained unchanged in the diabetics. The difference between the two groups was significant (P