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Background and aims: Clinical practice before 2019 suggests a substantial proportion of high and very high CV risk patients taking lipid-lowering therapy (LLT) would not achieve the new LDL-C goals recommended in the 2019 ESC/EAS guidelines (18 years of age with high and very high CV risk (as assigned by the investigators) requiring LLT, with no formal patient or comparator groups. The primary objective is to document, in the real-world setting, the effectiveness of current treatment modalities in managing plasma levels of LDL-C in high-and very high-risk patients requiring LLT. Key secondary effectiveness objectives include documenting the relationship between LLT and levels of other plasma lipids, high sensitivity C-reactive protein (hsCRP) and overall predicted CV risk over one year. Health economics and patient-relevant parameters will also be assessed. Conclusions: The SANTORINI study, which commenced after the 2019 ESC/EAS guidelines were published, is ideally placed to provide important contemporary insights into the evolving management of LLT in Europe and highlight factors contributing to the low levels of LDL-C goal achievement among high and very high CV risk patients. It is hoped the findings will help enhance patient management and reduce the burden of ASCVD in Europe. ' (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background: The DANISH study (Danish Study to Assess the Efficacy of ICDs [Implantable Cardioverter Defibrillators] in Patients With Non-Ischemic Systolic Heart Failure on Mortality) did not demonstrate an overall effect on all-cause mortality with ICD implantation. However, the prespecified subgroup analysis suggested a possible age-dependent association between ICD implantation and mortality with survival benefit seen only in the youngest patients. The nature of this relationship between age and outcome of a primary prevention ICD in patients with nonischemic systolic heart failure warrants further investigation. Methods: All 1116 patients from the DANISH study were included in this prespecified subgroup analysis. We assessed the relationship between ICD implantation and mortality by age, and an optimal age cutoff was estimated nonparametrically with selection impact curves. Modes of death were divided into sudden cardiac death and nonsudden death and compared between patients younger and older than this age cutoff with the use of χ 2 analysis. Results: Median age of the study population was 63 years (range, 21–84 years). There was a linearly decreasing relationship between ICD and mortality with age (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.003–1.06; P =0.03). An optimal age cutoff for ICD implantation was present at ≤70 years. There was an association between reduced all-cause mortality and ICD in patients ≤70 years of age (HR, 0.70; 95% CI, 0.51–0.96; P =0.03) but not in patients >70 years of age (HR, 1.05; 95% CI, 0.68–1.62; P =0.84). For patients ≤70 years old, the sudden cardiac death rate was 1.8 (95% CI, 1.3–2.5) and nonsudden death rate was 2.7 (95% CI, 2.1–3.5) events per 100 patient-years, whereas for patients >70 years old, the sudden cardiac death rate was 1.6 (95% CI, 0.8–3.2) and nonsudden death rate was 5.4 (95% CI, 3.7–7.8) events per 100 patient-years. This difference in modes of death between the 2 age groups was statistically significant ( P =0.01). Conclusions: In patients with systolic heart failure not caused by ischemic heart disease, the association between the ICD and survival decreased linearly with increasing age. In this study population, an age cutoff for ICD implantation at ≤70 years yielded the highest survival for the population as a whole. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00542945.

AIM: The Danish Study to Assess the Efficacy of Implantable Cardioverter-Defibrillators (ICD) in Patients with Non-ischaemic Systolic Heart Failure (HF) on Mortality (DANISH) found no overall effect on all-cause mortality. The effect of ICD implantation on health-related quality of life (HRQoL) remains to be established as previous trials have demonstrated conflicting results. We investigated the impact of ICD implantation on HRQoL in patients with non-ischaemic systolic HF, a prespecified secondary endpoint in DANISH.METHODS AND RESULTS: In DANISH, a total of 1116 patients with non-ischaemic systolic HF were randomly assigned (1:1) to ICD implantation or usual clinical care (control). Patients completed disease-specific HRQoL as assessed by Minnesota Living with Heart Failure Questionnaire (MLHFQ; 0-105, high indicating worse). Changes in HRQoL 8 months after randomization were assessed with a mixed-effects model. At randomization, MLHFQ was completed by 935 (84%) patients (n = 472 in the ICD group and n = 463 in the control group) and was reassessed in 274 (58%) and 292 (63%) patients, respectively after 8 months for the primary analysis. Patients in the ICD group vs. the control group had similar improvements in MLHFQ after 8 months [least square mean -7.0 vs. -4.2 (P = 0.13)]. A clinically relevant improvement (decrease ≥5) in the MLHFQ overall score at 8 months was observed in 151 patients in the ICD group and 148 patients in the control group [55% vs. 51%, respectively (P = 0.25)].CONCLUSION: Implantable cardioverter-defibrillator implantation in patients with non-ischaemic systolic HF did not significantly alter HRQoL compared with patients randomized to usual clinical 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.

Background The benefit of an implantable cardioverter-defibrillator (ICD) in patients with symptomatic systolic heart failure caused by coronary artery disease has been well documented. However, the evidence for a benefit of prophylactic ICDs in patients with systolic heart failure that is not due to coronary artery disease has been based primarily on subgroup analyses. The management of heart failure has improved since the landmark ICD trials, and many patients now receive cardiac resynchronization therapy (CRT). Methods In a randomized, controlled trial, 556 patients with symptomatic systolic heart failure (left ventricular ejection fraction, ≤35%) not caused by coronary artery disease were assigned to receive an ICD, and 560 patients were assigned to receive usual clinical care (control group). In both groups, 58% of the patients received CRT. The primary outcome of the trial was death from any cause. The secondary outcomes were sudden cardiac death and cardiovascular death. Results After a median follow-up period of 67.6 months, the primary outcome had occurred in 120 patients (21.6%) in the ICD group and in 131 patients (23.4%) in the control group (hazard ratio, 0.87; 95% confidence interval [CI], 0.68 to 1.12; P=0.28). Sudden cardiac death occurred in 24 patients (4.3%) in the ICD group and in 46 patients (8.2%) in the control group (hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P=0.005). Device infection occurred in 27 patients (4.9%) in the ICD group and in 20 patients (3.6%) in the control group (P=0.29). Conclusions In this trial, prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. (Funded by Medtronic and others; DANISH ClinicalTrials.gov number, NCT00542945 .).

Our aim was to assess the prognostic impact of a high-sensitivity cardiac troponin T (hs-cTnT) assay in an outpatient population with chronic systolic left ventricular heart failure (HF). Four hundred sixteen patients with chronic HF and left ventricular ejection fraction ≤ 45% were enrolled in a prospective cohort study. In addition to hs-cTnT, plasma amino-terminal pro-B-type natriuretic peptide was measured at baseline. Mean age was 71 years, 29% were women, 62% had coronary artery disease (CAD), mean left ventricular ejection fraction was 31%, and 57% had abnormal level of hs-cTnT. During 4.4 years of follow-up, 211 (51%) patients died. In multivariate Cox regression models, hs-cTnT was categorized as quartiles or dichotomized by the 99th percentile of a healthy population. Adjusted hazard ratios for all-cause mortality for quartiles 2 to 4, with quartile 1 as reference, were 1.4 (95% confidence interval 0.9 to 2.4, p = 0.16) for quartile 2, 1.7 (0.9 to 2.5, p = 0.12) for quartile 3, and 2.6 (1.6 to 4.4, p0.001) for quartile 4 and 1.7 (1.2 to 2.5, p = 0.003) for abnormal versus normal level of hs-cTnT. In patients without CAD, quartile 4 of hs-cTnT was associated with an adjusted hazard ratio of 6.8. In conclusion, hs-cTnT is increased in most outpatients with chronic systolic HF and carries prognostic information beyond clinical parameters and amino-terminal pro-B-type natriuretic peptide. Increased hs-cTnT indicated a particularly deleterious prognosis in patients without CAD.

Copeptin, a stable fragment of the vasopressin prohormone, has been shown to be a significant biomarker for morbidity and mortality in heart failure. The aims of this study were to evaluate the influence of plasma sodium on the prognostic significance of copeptin concentrations in heart failure outpatients and to determine whether increased copeptin concentrations predict future development of hyponatremia.A total of 340 heart failure patients with left ventricular systolic dysfunction were followed for 55 months (median) in a Danish heart failure clinic. A baseline measurement of plasma copeptin, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and sodium was performed, and the sodium concentrations were recorded during 3 months after the baseline visit in the heart failure clinic. Patients were divided into 3 groups according to copeptin tertiles. In multivariate Cox proportional hazard models adjusted for confounders, including plasma sodium, loop diuretic dose, and NT-proBNP, copeptin was a significant predictor of hospitalization or death (hazard ratio 1.4, 95% confidence interval 1.1-1.9; P.019) but did not predict mortality independently from NT-proBNP. Additionally, copeptin concentrations did not predict future development of hyponatremia.Plasma copeptin levels predict mortality in outpatients with chronic heart failure independently from clinical variables, plasma sodium, and loop diuretic doses. Furthermore, copeptin predicts the combined end point of hospitalization or death independently from NT-proBNP.

No consensus exists whether subclinical thyroid disease should be treated or just observed. Untreated overt thyroid disease is associated with increased risk of cardiovascular disease, and this study was conducted to assess the risk of cardiovascular events in subclinical thyroid disease. The population-based prospective study was conducted in Denmark. A total of 609 subjects from general practice aged 50 years or above with normal left ventricular function were examined. During a median of 5 years of follow-up, major cardiovascular events were documented. In subjects with abnormal TSH at baseline, information about potential thyroid treatment during follow-up was obtained from case reports and mailings. At baseline, 549 (90.7%) were euthyroid (TSH 0.40-4.00 mU/l), 31 (5.1%) were subclinical hypothyroid (TSH4.00 mU/l), and 25 (4.1%) were subclinical hyperthyroid (TSH0.40 mU/l). 1 overt hyperthyroid and 3 overt hypothyroid participants were excluded from the analyses. At baseline, the levels of NT-proBNP were inversely associated with the levels of TSH; the lower the levels of TSH, the higher the NT-proBNP concentration. During follow-up, 88 participants died, 81 had a major cardiovascular event, and 28 had a stroke. The incidence of stroke was increased among subjects with subclinical hyperthyroidism, HR 3.39 (95% CI 1.15-10.00, p=0.027) after adjusting for sex, age, and atrial fibrillation. Subclinical hypothyroidism was not related with any of the outcome measurements. Subclinical hyperthyroidism seems to be a risk factor of developing major cardiovascular events, especially stroke in older adults from the general population with normal left ventricular function.

Pregnancy associated plasma protein-A (PAPP-A) is a potential new marker for vulnerable plaques in the coronary arteries only examined in stable coronary disease (CAD) in patients undergoing coronary angiography. Here we address the prognostic value of serum PAPP-A in unselected stable CAD patients.Blood samples were drawn at study entry. Serum PAPP-A values ≥4mIU/L were considered elevated. Mortality and non-fatal myocardial infarction was prospectively registered. The primary outcome was the composite outcome of myocardial infarction and all-cause mortality, secondary outcomes were all-cause mortality and myocardial infarction.Patients (n=4243) were followed for a median of 2.8 years. In a Cox analysis, elevated PAPP-A was significantly related to the composite outcome of myocardial infarction and death (HR 1.99, 95% CI 1.62-2.45, p0.0005), all-cause mortality (HR 2.42, 1.92-3.06, p0.0005), and myocardial infarction (HR 1.40, 1.01-1.94, p=0.046). After Holm's correction, the latter significance disappeared. After adjustment for risk factors and medication at entry, elevated PAPP-A remained significantly related to the composite outcome (HR 1.51, 1.22-1.86, p0.0005) and all-cause mortality (HR 1.68, 1.32-2.13, p0.0005).In patients with stable CAD elevated serum PAPP-A seems promising as aid in identifying patients at high risk for death.

Background Low grade inflammation is of pathogenic importance in the development of cardiovascular disease (CVD) and type 2 diabetes. The inflammation marker YKL-40 correlates with insulin resistance and is highly expressed in atherosclerotic plaques. We aimed to investigate whether YKL-40 could predict overall and cardiovascular (CV) mortality in a 50+ years population without known CVD. Methods A representative population sample of 639 individuals aged 50–89 years was recruited from general practices. Examination at baseline included echocardiography and blood and urine samples for CV risk factors and markers including lipids, high sensitive C-reactive protein (hsCRP), N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) and urinary albumin/creatinine-ratio (UACR). Median follow-up period was 5.0 (0.17–5.28) years. Results In subjects without diabetes and CVD at baseline, increasing YKL-40 levels independently predicted overall and CV mortality rate with hazard ratios of 1.58 (95% confidence interval (CI), 1.12–2.23, p =0.009) and 1.57 (95% CI, 1.00–2.46, p =0.049) after adjustment for age, sex, smoking, total cholesterol, hsCRP, NT-proBNP and UACR. In combined Kaplan–Meier analyses, baseline values of both YKL-40 and UACR above median significantly predicted increased cumulative overall and CV mortality rates in subjects without diabetes or CVD at baseline (30.6% vs. ≤8%, respectively 10.6%≤3%, p Conclusions YKL-40 seems to be an independent predictor of overall and CV mortality in an elderly part of the general population without diabetes and CVD. YKL-40 and UACR are both independent predictors, that seem to predict overall and CV mortality in a synergistic way.

In order to prioritize limited health resources in a time of increasing demands optimal cardiovascular risk stratification is essential. We tested the additive prognostic value of 3 relatively new, but established cardiovascular risk markers: N-terminal pro brain natriuretic peptide (Nt-proBNP), related to hemodynamic cardiovascular risk factors, high sensitivity C-reactive protein (hsCRP), related to metabolic cardiovascular risk factors and urine albumin/creatinine ratio (UACR), related to hemodynamic as well as metabolic risk factors. In healthy subjects with a 10-year risk of cardiovascular death lower than 5% based on HeartScore and therefore not eligible for primary prevention, the actual 10-year risk of cardiovascular death exceeded 5% in a small subgroup of subjects with UACR higher than the 95-percentile of approximately 1.6 mg/mmol. Combined use of high UACR or high hsCRP identified a larger subgroup of 16% with high cardiovascular risk in which primary prevention may be advised despite low-moderate cardiovascular risk based on HeartScore. Furthermore, combined use of high UACR or high Nt-proBNP in subjects with known cardiovascular disease or diabetes identified a large subgroup of 48% with extremely high cardiovascular risk who should be referred for specialist care to optimize treatment.

Objectives Insulin-like growth factor I (IGF-I) is an anabolic growth factor that seems to increase cardiac contractility. Reduced levels of IGF-I may be implicated in progression of CHF. The objective was to compare plasma IGF-I in CHF patients with healthy controls, and to examine the associations between baseline IGF-I levels, cardiac contractility and the prognosis as judged by all cause mortality and progression of CHF requiring admission to hospital. Methods A prospective study comprising 194 CHF outpatients, and 169 matched controls. All patients and controls underwent echocardiographic examination at baseline. Patients were followed for a median of 30 months. Results There was no difference in IGF-I levels between patients and controls (median and interquartile range), 78 (58–91) vs. 77 (57–94) ng/mL ( P = 0.92). Age-adjusted IGF-I levels were not related to left ventricular ejection fraction (LVEF) ( P = 0.58) or levels of N-terminal B-Type natriuretic peptide (NT-proBNP) ( P = 0.42). During follow-up 44 patients died and 94 were admitted to hospital due to worsening of CHF. Adjusted for cardiovascular risk factors (age, gender, NT-proBNP, lipids, diabetes mellitus, blood pressure, renal function and LVEF) IGF-I levels did not influence the overall mortality risk or the admission rate to hospital, hazard ratio (HR) (95% confidence intervals) 1.05 (0.75–1.47) ( P = 0.77) and 1.00 (0.80–1.26) ( P = 0.96), respectively per each SD increase in log IGF-I levels. Conclusions IGF-I levels were not reduced in patients with CHF and did not influence cardiac status at baseline or the prognosis.

Diabetes is associated with left ventricular hypertrophy (LVH) and impaired systolic function in hypertensive patients, but less is known about its impact on LVH regression and functional improvement during antihypertensive treatment.We performed annual echocardiography in 730 non-diabetic and 93 diabetic patients (aged 55-80 years) with hypertension and electrocardiographic LVH during 4.8-year losartan- or atenolol-based treatment in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Baseline mean blood pressure (BP) and LV mass did not differ between groups. Diabetic patients had higher body mass index and pulse pressure, and lower LV ejection fraction, midwall shortening, stress-corrected midwall shortening, and estimated glomerular filtration rate (all p0.05), and were more likely to have albuminuria. Despite comparable BP reduction in diabetic and non-diabetic groups during treatment (33/18 vs. 28/16mmHg (ns)), diabetes was associated with higher prevalence of persistent LVH (47 vs. 39%, p0.05). In multivariate analyses, diabetes independently predicted less LV mass reduction and less improvement in stress-corrected LV midwall shortening (both p0.01).Among hypertensive patients with LVH, diabetes is associated with more residual LVH and less improvement in systolic LV function by echocardiography over 4.8 years of antihypertensive treatment.

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.

BackgroundIGF1 is believed to influence ageing and development of cardiovascular disease (CVD) through complex mechanisms. Reduced IGF1 levels might be causally associated with conditions accompanying ageing including development of CVD. However, in animal models reduced GH–IGF1 signalling increases lifespan. Reduced IGF1 activity might also be associated with longevity in humans.ObjectiveThe objective was to investigate if plasma IGF1 levels were associated with all cause mortality, and the development of chronic heart failure (CHF) and a major CV event.Patients and designA population based study of 642 individuals, aged 50–89 years. Development of CHF was evaluated in 576 individuals with normal systolic function assessed by echocardiography and without the history of CHF or myocardial infarction. Development of the first major CV event was evaluated in 504 individuals with normal systolic function and without prevalent CVD. Outcomes were ascertained after 5 years using hospital discharge diagnoses.ResultsAdjustment for risk factors IGF1 values in the fourth quartile versus values below the fourth quartile was associated with increased mortality (n=103), hazard ratio (HR) 1.52 (95% confidence interval (CI) 1.01–2.28;P=0.044). IGF1 in the fourth quartile was also independently associated with risk of development of CHF (n=19), HR 5.02 (95% CI 2.00–12.64;P=0.001) but showed no association with the overall incidence of major CV events (n=58), HR 1.05 (95% CI 0.59–1.90;P=0.861).ConclusionsHigh IGF1 levels were independently associated with increased all cause mortality and risk of development of CHF, whereas no relation with the overall incidence of CVD was observed.

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.

Background: Obesity is a state characterized by glomerular hyperfiltration and age-related decreases in glomerular filtration rate (GFR). Body mass index (BMI), age, and GFR are associated with plasma concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) in chronic heart failure (CHF) patients. We hypothesized that the effects of BMI and age on plasma concentrations of NT-proBNP are associated with GFR.Methods: We obtained clinical data and laboratory test results from 345 CHF patients at the baseline visit in our heart failure clinic and examined the hypothesis using multiple linear regression models.Results: Age (P = 0.0184), BMI (P = 0.0098), hemoglobin (P = 0.0043), heart rhythm (P Conclusions: In CHF patients, the effect of age on NT-proBNP is associated with estimates for GFR derived from serum creatinine, and the significance of the effects of BMI on NT-proBNP depends on the method by which GFR is estimated.

Aim Serum N-terminal pro-brain natriuretic peptide (Nt-proBNP), high sensitivity (hs)-C-reactive protein, and urine albumin/creatinine ratio (UACR) are cardiovascular (CV) risk markers in the general population. The aim of this study was to determine whether they predicted CV events independently of established CV risk factors and whether they did so in an additive fashion. Methods and results In a population-based sample of 2656 individuals, 41, 51, 61, and 71 years old, we measured UACR, serum Nt-proBNP, hs-C-reactive protein, insulin, lipids and plasma glucose, clinic blood pressures, body composition, left ventricular (LV) mass index, and ejection fraction (EF) by echocardiography and pulse wave velocity. During the following 9.4 years, the combined CV endpoint (CEP) of CV death (136), non-fatal stroke, or non-fatal myocardial infarction occurred in 219 subjects. After adjustment for established CV risk factors using Cox-regression analyses, CEP and CV death were predicted by log(Nt-proBNP)/SD [hazard ratio (HR) = 1.58 and HR = 1.80, both P < 0.001] and by log(UACR)/SD (HR = 1.44 and HR = 1.52, both P < 0.001) in an additive fashion, but not by log(hs-C-reactive protein)/SD (HR = 1.17, P = 0.06 and HR = 1.13, NS). CV risk functions were constructed on the basis of Cox-regression analyses. Inclusion of Nt-proBNP and UACR did not increase the area under the receiver-operating characteristic plots. Conclusion Serum Nt-proBNP and UACR, but not hs-C-reactive protein, predicted CV events after adjustment for established CV risk factors including LV EF and relative wall thickness. However, more studies in relevant subgroups are needed before Nt-proBNP and UACR can be recommended for risk prediction in the general population to select subjects for primary prevention.

Brain natriuretic peptides are elevated in patients with systolic heart failure (HF) as well as in patients with atrial fibrillation (AF) and normal left ventricular ejection fraction (LVEF) and are strong predictors of death in HF patients. The aim of our study was to examine the levels of N-terminal pro brain natriuretic peptide (NT-proBNP) in patients with HF and AF versus HF and sinus rhythm (SR) and if NT-proBNP has prognostic influence in patients with AF.We included 245 patients (72% men, 70 years) with HF referred to a HF clinic. NT-proBNP was measured at referral (baseline).At baseline, 26% had AF and at follow-up 35% of the surviving patients. Patients with AF were older than patients with SR (p=0.009), but LVEF and NYHA distribution were similar. Median NT-proBNP levels were higher: 2528 vs. 899 pg/ml (p0.001). NT-proBNP was significantly correlated with AF at baseline (p0.001), age (p=0.001), P-creatinine (p0.001) and reduced LVEF (p=0.002). NT-proBNP was an independent predictor of death in patients with AF, adjusted HR 4.0 (95% CI 1.6-10.2) (p=0.003).NT-proBNP levels are higher in HF patients with AF than in HF patients with SR and has prognostic value despite the presence of AF.

ObjectivesThis study investigated the effects of rosiglitazone (RSG) on left ventricular ejection fraction (LVEF) in subjects with type 2 diabetes (T2DM) and pre-existing chronic heart failure (CHF) (New York Heart Association [NYHA] functional class I to II).BackgroundFluid retention is an important consideration in the use of thiazolidinediones in T2DM patients because it could exacerbate symptoms or precipitate decompensation in those with previously stable CHF.MethodsA total of 224 patients with T2DM and NYHA functional class I to II CHF with LVEF ≤45% were randomized to a 52-week treatment with RSG (4 to 8 mg daily, n = 110) or placebo (PLB) (n = 114) in addition to background antidiabetes therapy. Treatment was uptitrated to achieve target fasting plasma glucose

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.

BACKGROUND: The effect of an implantable cardioverter defibrillator (ICD) in patients with symptomatic systolic heart failure (HF) caused by coronary artery disease is well documented. However, the effect of primary prophylactic ICDs in patients with systolic HF not due to coronary artery disease is much weaker. In addition, HF management has improved, since the landmark ICD trials and a large proportion of patients now receive cardiac resynchronization therapy (CRT) where the effect of ICD treatment is unknown.METHODS: In the DANISH study, 1,116 patients with symptomatic systolic HF not caused by coronary artery disease have been randomized to receive an ICD or not, in addition to contemporary standard therapy. The primary outcome of the trial is time to all-cause death. Follow-up will continue until June 2016 with a median follow-up period of 5 years. Baseline characteristics show that enrolled patients are treated according to current guidelines. At baseline, 97% of patients received an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 92% received a β-blocker, 58% a mineralocorticoid receptor antagonist, and 58% were scheduled to receive CRT. Median age was 63 years (range, 21-84 years) at baseline, and 28% were women.CONCLUSION: DANISH will provide pertinent information about the effect on all-cause mortality of a primary prophylactic ICD in patients with symptomatic systolic HF not caused by coronary artery disease on contemporary standard therapy including CRT.

N-terminal pro-brain natriuretic peptide (Nt-proBNP) and high-sensitivity C-reactive protein (hsCRP) are cardiovascular risk markers in various populations, but are not well examined in hypertension. Therefore, we wanted to investigate whether high Nt-proBNP or hsCRP predicted the composite endpoint of cardiovascular death, non-fatal stroke or non-fatal myocardial infarction independently of traditional cardiovascular risk factors and the urine albumin: creatinine ratio (UACR), which is a well established cardiovascular risk factor in hypertension.In 945 hypertensive patients from the LIFE study with electrocardiographic left ventricular (LV) hypertrophy, we measured traditional cardiovascular risk factors including electrocardiography, morning UACR, hsCRP by immunoturbidimetry assay and Nt-proBNP by immunoassay after 2 weeks of placebo treatment. During 55 months' follow-up 80 patients suffered a composite endpoint.HsCRP as well as Nt-proBNP above the median values of 3.0 mg/l and 170 pg/ml, respectively, was associated with a higher incidence of composite endpoint (13.1 versus 3.8%, P0.01, and 11.5 versus 5.4%, P0.01). In Cox regression analyses, standardized log(hsCRP)/SD predicted a composite endpoint [hazard ratio (HR) 1.3 per SD = 0.47 log(mg/l), P0.05] after adjustment for traditional cardiovascular risk factors, but not after further adjustment for UACR. Standardized log(Nt-proBNP)/SD predicted a composite endpoint after adjustment for traditional cardiovascular risk factors [HR 1.9 per SD = 0.49 log(pg/ml), P0.05] as well as after further adjustment for UACR [HR 1.5 per SD = 0.49 log(pg/ml), P0.01]. Log(Nt-proBNP) added significantly to the Cox regression models using traditional cardiovascular risk factors with and without UACR (both P0.001).Nt-proBNP predicted a composite endpoint after adjustment for traditional risk factors, UACR and a history of diabetes or cardiovascular disease and added significantly to the prediction of composite endpoint, whereas hsCRP did not.

Aims Here, the aim is to assess long-term clinical variation (CV) of N-terminal pro-brain natriuretic peptide (NT-proBNP) in stable chronic heart failure (CHF) patients. The proposed use of NT-proBNP for monitoring of CHF patients will require accurate information about long-term CV of the peptide. Methods and results Medication, biochemical variables, and NYHA class were recorded at 1-year and 2-year follow-up in patients treated in our heart failure clinic. Only patients without changes in medication and the NYHA class who were not hospitalized or died in the period from first follow-up to 12 months after the second follow-up were included. A total of 78 patients fulfilled the criteria, and year-to-year CV was calculated to 30% (median) (range: 0–111%) (% changes range: −87 to 397%). Log transformation of NT-proBNP (skewed to the right) reduced the year-to-year CV to 4.7% (range: 0–22%) (% changes range: −18 to 38%). Conclusion Long-term CV of plasma concentrations of NT-proBNP in stable CHF patients is 30%, but the variation is substantial. Therefore, high long-term CV of NT-proBNP does not necessarily carry prognostic significance within the subsequent 12 months. Plasma concentrations of NT-proBNP followed a lognormal distribution, and the low CV of log(NT-proBNP) indicate that NT-proBNP levels are constant during stable conditions.

The aim of this study was to investigate the effects of losartan- vs atenolol-based antihypertensive treatment on circulating collagen markers beyond the initial blood pressure (BP) reduction.In 204 patients with hypertension and left ventricular (LV) hypertrophy we measured serum concentration of carboxy-terminal telopeptide of type I procollagen (ICTP), carboxy-terminal propeptide of type I procollagen (PICP), amino-terminal propeptide of type III procollagen (PIIINP), amino-terminal propeptide of type I procollagen (PINP) and LV mass by echocardiography at baseline and annually during 4 years of losartan- or atenolol-based antihypertensive treatment; 185 patients completed the study.Beyond the first year of treatment systolic and diastolic BP, LV mass index (LVMI) as well as collagen markers did not change significantly and were equal in the two treatment groups. Changes in PICP during first year of treatment were related to subsequent changes in LV mass index after 2 and 3 years of treatment (r=0.28 and r=0.29, both p0.05) in patients randomized to losartan, but not atenolol.Long-term losartan- vs atenolol-based antihypertensive treatment did not influence collagen markers differently, making a BP-independent effect of losartan on collagen markers unlikely. However, initial reduction in circulating PICP may predict later regression of LV hypertrophy during losartan-based antihypertensive treatment.

Metolazone is a potent thiazide-like diuretic. It is recommended in severe congestive heart failure (HF). We conducted a review of the existing literature and found that the available information on the use of metolazone in HF is based on studies containing less than 250 patients in total. Nevertheless, metolazone is widely used, often in combination with a loop diuretic. Absorption of metolazone seems to be reduced in HF. Metolazone produces a diuretic response despite a low glomerular filtration rate. A wide dose range of metolazone has been investigated (≤2.5 to 200 mg), leaving no clear dosing recommendation. However, in most studies a low starting dose (≤5 mg) was used. We further report an observational study on 21 patients with refractory systolic HF from our specialized outpatient HF clinic. The aim was to evaluate the effects of metolazone in combination with a loop diuretic in contemporary HF patients. Results: We registered 42 episodes of treatment with metolazone. The maximal dose of metolazone was 5 mg. NYHA functional class improved. A significant reduction during treatment in weight, blood pressure, plasma-sodium and –potassium was seen whereas plasma-BUN and –creatinine increased significantly. Clinically important hypokalemia (

N-terminal pro-brain natriuretic peptide (NT-proBNP) provides important prognostic information in patients with chronic heart failure and in the general population. The aim of this study was to evaluate NT-proBNP as a prognostic marker of cardiovascular morbidity and death in a sample of subjects with hypertension and preserved left ventricular systolic function from the general population.The study population was recruited from 4 general practitioners. The study participants (n = 569 subjects; ages, 50-89 years) completed a heart failure questionnaire and were submitted to blood pressure measurement, electrocardiography, echocardiography, and blood sampling. After exclusion of subjects with left ventricular ejection fraction of50%, 270 subjects fulfilled the following criteria for hypertension: history of hypertension or blood pressure150/90 mmHg. During 3 years of follow-up, 28 subjects (10.4%) reached the composite end point of death, stroke/transient ischemic attack, or myocardial infarction. After adjustment for cardiovascular risk factors, NT-proBNP (logarithmically transformed) independently predicted the risk of experiencing a composite end point (hazard ratio, 1.94; P.0001), and death (hazard ratio, 2.28; P.0001). The risk of having a composite end point (21 vs 7; P = .005) was significantly higher for subjects with NT-proBNP above the study median than for subjects with NT-proBNP below the study median.In this sample of subjects with hypertension and preserved left ventricular systolic function from the general population, plasma NT-proBNP was found to be a valuable cardiovascular risk marker, independently of traditional risk factors and prevalent cardiovascular disease.

The value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in terms of diagnosis and prognosis in congestive heart failure (CHF) and left ventricular systolic dysfunction (LVSD) has been demonstrated previously in various populations, but data on primary care patients are sparse. The aim of this study was to evaluate the diagnostic and prognostic performance of NT-proBNP in primary care patients with suspected CHF.Three hundred sixty-seven consecutive patients (mean age, 68.8 years; range, 39.0-84.0 years) who had been referred by their general practitioner for echocardiographic evaluation because of suspected CHF. In all patients, NT-proBNP was measured at baseline and left ventricular ejection fraction (LVEF) was estimated with echocardiography. LVSD (LVEFor =0.40) was found in 9% of the patients. NT-proBNP was significantly higher in patients with LVSD (P.0001). With predefined cut off values for NT-proBNP (125 pg/mL), the sensitivity, specificity, positive predictive value, and negative predictive value for the detection of LVSD were 0.97, 0.46, 0.15 and 0.99, respectively. Area under the receiver operating characteristic curve was 0.87. The application of an age-differentiated cut-off value for NT-proBNP (125 pg/mL for75 years old and 450 pg/mL foror =75 years old) did not increase diagnostic performance. Patients were followed for a median of 778 days; 8% of the patients died during the follow-up period. The mortality rate was higher in patients with NT-proBNP of125 pg/mL than in patients with normal values (P.002, log rank), and the difference persisted after controlling for age, gender, and LVEF (hazard ratio per unit increase in log NT-proBNP, 2.2; range, 1.2-4.1; P = .015).In primary care patients who were referred for echocardiography because of suspected CHF, NT-proBNP values125 pg/mL effectively rule out LVSD. Furthermore low NT-proBNP values are associated with a lower risk of death, independently of age, gender, and LVEF.

Patients with diabetes have an unfavourable prognosis after an acute myocardial infarction. In the first DIGAMI study, an insulin-based glucose management improved survival. In DIGAMI 2, three treatment strategies were compared: group 1, acute insulin-glucose infusion followed by insulin-based long-term glucose control; group 2, insulin-glucose infusion followed by standard glucose control; and group 3, routine metabolic management according to local practice.DIGAMI 2 recruited 1253 patients (mean age 68 years; 67% males) with type 2 diabetes and suspected acute myocardial infarction randomly assigned to groups 1 (n=474), 2 (n=473), and 3 (n=306). The primary endpoint was all-cause mortality between groups 1 and 2, and a difference was hypothesized as the primary objective. The secondary objective was to compare total mortality between groups 2 and 3, whereas morbidity differences served as tertiary objectives. The median study duration was 2.1 (interquartile range 1.03-3.00) years. At randomization, HbA1c was 7.2, 7.3, and 7.3% in groups 1, 2, and 3, respectively, whereas blood glucose was 12.8, 12.5, and 12.9 mmol/L, respectively. Blood glucose was significantly reduced after 24 h in all groups, more in groups 1 and 2 (9.1 and 9.1 mmol/L) receiving insulin-glucose infusion than in group 3 (10.0 mmol/L). Long-term glucose-lowering treatment differed between groups with multidose insulin (or =3 doses/day) given to 15 and 13% of patients in groups 2 and 3, respectively compared with 42% in group 1 at hospital discharge. By the end of follow-up, HbA1c did not differ significantly among groups 1-3 ( approximately 6.8%). The corresponding values for fasting blood glucose were 8.0, 8.3, and 8.6 mmol/L. Hence, the target fasting blood glucose for patients in group 1 of 5-7 mmol/L was never reached. The study mortality (groups 1-3 combined) was 18.4%. Mortality between groups 1 (23.4%) and 2 (22.6%; primary endpoint) did not differ significantly (HR 1.03; 95% CI 0.79-1.34; P=0.831), nor did mortality between groups 2 (22.6%) and 3 (19.3%; secondary endpoint) (HR 1.23; CI 0.89-1.69; P=0.203). There were no significant differences in morbidity expressed as non-fatal reinfarctions and strokes among the three groups.DIGAMI 2 did not support the fact that an acutely introduced, long-term insulin treatment improves survival in type 2 diabetic patients following myocardial infarction when compared with a conventional management at similar levels of glucose control or that insulin-based treatment lowers the number of non-fatal myocardial reinfarctions and strokes. However, an epidemiological analysis confirms that the glucose level is a strong, independent predictor of long-term mortality in this patient category, underlining that glucose control seems to be an important part of their management.

background The level of the inactive N-terminal fragment of pro–brain (B-type) natriuretic peptide (BNP) is a strong predictor of mortality among patients with acute coronary syndromes and may be a strong prognostic marker in patients with chronic coronary heart disease as well. We assessed the relationship between N-terminal pro-BNP (NT-pro-BNP) levels and long-term mortality from all causes in a large cohort of patients with stable coronary heart disease. methods NT-pro-BNP was measured in baseline serum samples from 1034 patients referred for angiography because of symptoms or signs of coronary heart disease. The rate of death from all causes was determined after a median follow-up of nine years. results At follow-up, 288 patients had died. The median NT-pro-BNP level was significantly lower among patients who survived than among those who died (120 pg per milliliter [interquartile range, 50 to 318] vs. 386 pg per milliliter [interquartile range, 146 to 897], P

To evaluate the impact of obesity on mortality in patients with acute myocardial infarction.This study comprises 6676 consecutive patients with acute myocardial infarction screened for entry into the Danish Trandolapril Cardiac Evaluation (TRACE) study. At baseline, body mass index (BMI) and waist to hip ratio (WHR) were measured. Survival status was determined after 8-10 years.BMI was used to divide patients into 4 groups: underweight, normal weight, overweight and obese. The normal weight group was used as reference for the other groups. WHR was divided in quartiles and the lowest quartile was used as reference for the three other quartiles. The prevalence of overweight (BMI 25-29.9 kg/m(2)) and obesity (BMI30 kg/m(2)) were 48% and 13% in males and 31% and 13% in females. Obese patients were younger, less often smokers and more frequently suffered from diabetes and hypertension. In both men and women, there was no association between obesity assessed as BMI and mortality [men: adjusted RR=0.99 (0.85-1.14, p=0.3); women: adjusted RR=0.90 (0.74-1.10, p=0.2)]. Men with WHR in the upper quartile had an increased mortality [adjusted RR=1.21 (1.07-1.37, p0.01)]. Increasing WHR in women showed a trend of increased mortality, although this was not significant [adjusted RR=1.13 (0.95-1.34, p=0.2)].In patients with acute myocardial infarction overall obesity as assessed by body mass index is inversely related to mortality. However, abdominal obesity appears to be an independent predictor of all-cause mortality in men and perhaps also in women.

Treatment with spironolactone (SPL) is beneficial in patients with severe congestive heart failure (CHF). In the Randomized Aldactone Evaluation Study SPL was well tolerated, particularly with regard to renal function and serum K(+) levels. Our aim was to investigate whether the reported low frequency of adverse effects during SPL treatment in a heart failure study population could be confirmed in an unselected heart failure outpatient cohort and to identify potential predictors of harmful effects.We investigated 125 consecutive patients with CHF recruited from our heart failure clinic. Inclusion criteria were LVEF (left ventricular ejection fraction)/=45% and treatment with SPL. Blood tests were performed bimonthly or more frequently if necessary. Outcomes measures were (1) increases in serum K(+) to5,0, 5.5, 6.0, or 6.5 mmol/L, respectively, and (2) rise in serum creatinine to 120%, 150%, and 200% of baseline, respectively. Mean age was 72.9 years (range 46.5 to 90.6 years); 27% were women. The New York Heart Association class distribution was: I, 6%; II, 44%; III, 46%; and IV, 4%. Mean LVEF was 29+/-5%. Other medication included angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in 86% and beta-blockers in 39%. At baseline, serum creatinine levels were 117.6+/-6.5 (mean+/-standard deviation; micromol/L, normal130) and serum K(+) was 4.2+/-0.3 mmol/L. The mean follow-up period was 11 months, and the cumulative observation period was 73 SPL treatment years. Mean peak serum-creatinine was 167.6 micromol/L+/-11.9 (45% increase from baseline) and mean peak serum K(+) was 5.0+/-0.4 mmol/L (21% increase from baseline). Sixty patients were already on SPL when admitted to the CHF clinic. The remainder were initiated on SPL. During the follow-up period 36% of the patients developed hyperkalemia (5 mmol/L), with 10% having serum K(+)6 mmol/L. An increase in serum creatinine of20% was seen in 55%, and in 24% an increase of50% was found. These alterations in serum creatinine and serum K(+) were not significantly more frequent in patients treated with angiotensin-converting enzyme inhibitors or beta-blockers or different doses of SPL.SPL adverse effects (impaired renal function, increase in serum K(+)) are much more prevalent in our elderly CHF patient population than previously reported. The recommendations from our study are that (1) particular caution is mandated in elderly patients with an LVEF20%, (2) potassium supplementation should be discontinued, (3) changes in body weight should raise concern, and (4) a dose-adjustment of the concomitant conventional diuretic regime should be considered. Care should be given to the frequent monitoring of electrolytes and renal parameters.

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.

BACKGROUND N-terminal pro-brain natriuretic peptide (Nt-proBNP) and N-terminal pro-atrial natriuretic peptide (Nt-proANP) are strong cardiovascular risk markers in patients with chronic heart failure, as well as in the general population. We investigated whether high Nt-proBNP or Nt-proANP could also predict the composite endpoint (CEP) of cardiovascular death, non-fatal stroke or non-fatal myocardial infarction in patients with hypertension and left ventricular (LV) hypertrophy. METHODS After 2 weeks of placebo treatment, clinical, laboratory and echocardiographic variables were assessed in 183 hypertensive participants in the LIFE echo substudy with electrocardiographic LV hypertrophy. Nt-proBNP and Nt-proANP were measured by immunoassay at baseline. The patients were followed for 60 +/- 5 months. RESULTS Using Cox regression analysis, the 25 CEP were predicted by ln(Nt-proBNP) (hazard ratio 1.61 per 2.73-fold increase, P < 0.01) as well as ln(Nt-proANP) (hazard ratio 2.93, P < 0.05). Nt-proBNP above the median value of 21.8 pmol/ml was associated with higher incidence of CEP (19.6 versus 7.7%, P < 0.05). Nt-proBNP above the median value was associated with higher incidence of CEP in the 123 patients without history of diabetes or cardiovascular disease (14.8 versus 4.3%, P < 0.05), but the association was insignificant in the 60 patients with a history of diabetes or cardiovascular disease (26.3 versus 18.2%, NS). Nt-proANP showed the same tendency. CONCLUSION Nt-proBNP, more than Nt-proANP, strongly predicts cardiovascular events in patients with hypertension and LV hypertrophy, especially in patients without diabetes or clinically overt cardiovascular disease.

Heart failure (HF) treatment guidelines of the ESC recommend ACE-inhibitors (ACE-I) as first-line treatment and beta-blockers added if patients remain symptomatic. CARMEN explored the need for combined treatment for remodelling and order of introduction by comparing the ACE-I enalapril against carvedilol and their combination.In a parallel-group, 3-arm study of 18 months duration, 572 mild heart failure patients were randomly assigned to carvedilol (N = 191), enalapril (N = 190) or their combination (N = 191). In the latter, carvedilol was up-titrated before enalapril. Left ventricular (LV) remodelling was assessed by transthoracic echocardiography (biplane, modified Simpson) at baseline and after 6, 12 and 18 months of maintenance therapy. Primary comparisons considered the change in LV end-systolic volume index (LVESVI) from baseline to month 18 between the combination and enalapril, and between carvedilol and enalapril.In the first primary comparison, LVESVI was reduced by 5.4 ml/m2 (p = 0.0015) in favour of combination therapy compared to enalapril. The second primary comparison tended to favour carvedilol to enalapril (NS). In the within treatment arm analyses, carvedilol significantly reduced LVESVI by 2.8 ml/m2 (p = 0.018) compared to baseline, whereas enalapril did not. LVESVI decreased by 6.3 ml/m2 (p = 0.0001) with combination therapy. All three arms showed similar safety profiles and withdrawal rates.CARMEN is the first study to demonstrate that early combination of ACE-I and carvedilol reverses LV remodelling in patients with mild to moderate HF and LV systolic dysfunction. The results of the CARMEN study support a therapeutic strategy in which the institution of beta-blockade should not be delayed.

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

Background Studies on the effect of heart failure clinics have been encouraging and convincing with respect to reduced hospitalizations, improved quality of life, and reduced cost. However, previous results have been derived from patient populations either recently discharged and with specific exclusion criteria or from heart transplant lists. We here report the establishment of a heart failure clinic that offers an integrated approach to both diagnosing and managing heart failure patients, the baseline characteristics of the first 283 patients treated, and the impact on heart failure hospitalizations during establishment. Methods Since September 1, 1999, a heart failure clinic has been in operation at Frederiksberg University Hospital. The clinic was designed with both a diagnostic and a therapeutic unit. The diagnostic unit offers open access to all patients with suspected heart failure, either through referral from general practitioners or from the medical departments of the hospital. In the case of confirmed systolic heart failure, the patient is referred to the therapeutic unit for (1) uptitration and optimization of medical therapy and thorough information and education. In addition, the unit offers a rapid access track and the possibility of intravenous diuretic treatment. Results During the 21 months of operation, a total of 460 patients were referred to the clinic. Of these, 320 (70%) were found to have clinical evidence of heart failure, and 283 (88% of the patients with heart failure) had left ventricular systolic dysfunction (defined by an ejection fraction of ≤45%). These patients were seen in the clinic for education, control of fluid retention, and uptitration of medications. These patients with left ventricular dysfunction were predominantly elderly (aged 72.7 ± 10.7 y) and most often male (73%). Ischemic heart disease was the most common etiology (55%). Before referral, most patients with left ventricular dysfunction had been treated with none or only low-dose angiotensin-converting enzyme inhibitor (55%), and fewer than one third received β-blockers (29%). During the first year of operation of the clinic, there was a 23% decline of heart failure-related hospital admissions to the department of cardiology (from 396 to 306). Conclusion Patients with systolic heart failure are not always optimally treated. The establishment of a heart failure clinic, which offers the combination of diagnosing and managing congestive heart failure, appears to be efficient both in terms of therapy optimization and with respect to a concomitant decline in hospitalization for heart failure. (Am Heart J 2002;144:e2.)

OBJECTIVES The purpose of the study was to investigate the effects of beta 1 -blockade on left ventricular (LV) size and function for patients with chronic heart failure. BACKGROUND Large-scale trials have shown that a marked decrease in mortality can be obtained by treatment of chronic heart failure with beta-adrenergic blocking agents. Possible mechanisms behind this effect remain yet to be fully elucidated, and previous studies have presented insignificant results regarding suspected LV antiremodeling effects. METHODS In this randomized, placebo-controlled and double-blind substudy to the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF), 41 patients were examined with magnetic resonance imaging three times in a six-month period, assessing LV dimensions and function. RESULTS Decreases in both LV end-diastolic volume index (150 ml/m 2 at baseline to 126 ml/m 2 after six months, p = 0.007) and LV end-systolic volume index (107 ml/m 2 to 81 ml/m 2 , p = 0.001) were found, whereas LV ejection fraction increased in the metoprolol CR/XL group (29% to 37%, p = 0.005). No significant changes were seen in the placebo group regarding these variables. Left ventricular stroke volume index remained unchanged, whereas LV mass index decreased in both groups (175 g/m 2 to 160 g/m 2 in the placebo group [p = 0.005] and 179 g/m 2 to 164 g/m 2 in the metoprolol CR/XL group [p = 0.01]). CONCLUSIONS This study is the first randomized study to demonstrate that the beta 1 -blocker metoprolol CR/XL has antiremodeling effects on the LV in patients with chronic heart failure and consequently provides an explanation for the highly significant decrease in mortality from worsening heart failure found in the MERIT-HF trial.

OBJECTIVE: Impairment of left ventricular diastolic function, possibly caused by increased collagen cross-linking of the cardiac muscle, is common in patients with type 1 diabetes even without coronary artery disease. Advanced glycation end products (AGEs) cross-link tissue collagen and are found within myocardial fibers. The aim of this study was to examine for a possible association between circulating AGEs and left ventricular cardiac function. RESEARCH DESIGN AND METHODS: Left ventricular diastolic and systolic function were assessed by M-mode and Doppler echocardiography in 52 patients with type 1 diabetes, age 40 +/- 13 (mean +/- SD) years, diabetes duration 17 +/- 13 years, and HbA1c 8.3 +/- 1.1%. Serum levels of AGEs and N epsilon-(carboxymethyl)lysine (CML) were measured by newly developed competitive immunoassays. RESULTS: A positive correlation was found between serum levels of AGEs and isovolumetric relaxation time (IVRT), r = 0.46 (P < 0.0008), and left ventricular diameter during diastole, r = 0.37 (P < 0.008). The systolic parameters did not correlate with serum levels of AGEs. Stepwise regression analysis showed that 21% of the IVRT variation could be explained by serum levels of AGEs (F = 11.4, P < 0.002), whereas serum levels of CML, HbA1c, albumin excretion rate, diabetes duration, and mean arterial blood pressure were of no importance. AGE levels were significantly increased in men compared with women (P < 0.03) and present or former smokers (P < 0.04). CONCLUSIONS: Increased serum levels of AGEs, unlike serum levels of CML, are associated with heart stiffness in patients with type 1 diabetes, possibly mediated by the cross-linking properties of AGEs.

Endothelial dysfunction is a well-established aspect of the pathophysiology of patients with systolic heart failure. We have previously reported that patients who have had multiple current or previous hospital admissions for decompensated heart failure have consistently shown abnormal levels of plasma von Willebrand factor (vWf, an index of endothelial damage/dysfunction) and soluble E-selectin (E-sel, an index of endothelial activation), as well as other indices of endothelial perturbation.To investigate if endothelial abnormalities extend to CHF outpatients who have only been recently diagnosed or have relatively mild or few, stable symptoms (at baseline), given the better prognosis in these patients, we performed a cross-sectional analysis of CHF patients, where vWf and E-sel levels (as indices of endothelial perturbation) were measured (ELISA) and related to left ventricular ejection fraction (LVEF), exercise capacity (6-min walk test) and N-terminal pro-Brain Natiuretic Peptide (NT-proBNP).There were no statistically significant differences in vWf and E-sel levels amongst patients with systolic heart failure compared to controls. Plasma NT-proBNP levels in patients with CHF were significantly elevated compared to controls (p0.0001). Among the patients with CHF, higher NT-proBNP levels correlated with poorer LVEF [Spearman r=-0.244, p0.004] and shorter 6-min walk distance [Spearman r=-0.226, p=0.045] but not NYHA class. Plasma vWf or E-sel levels did not correlate with LVEF, 6-min walk test or NYHA class. NT-proBNP levels correlated weakly with E-sel [Spearman r=-0.211, p=0.015] but not vWf.The present observation suggests that stable CHF outpatients with few symptoms may in fact have less severe endothelial perturbation, as reflected by plasma indices such as vWf and E-selectin. There was limited association of endothelial indices to LVEF, exercise capacity, NYHA class and NT-proBNP levels.

Ramipril 10 mg/day reduced regurgitation in chronic mitral regurgitation secondary to mitral valve prolapse in patients with sinus rhythm.

Aim The aim of this study was to estimate the prognostic information to be gained from ventricular fibrillation in patients with myocardial infarction. Methods and results We studied 4259 consecutive patients with myocardial infarction admitted to one centre in 1977–1988. Five hundred and twenty-eight (12·4%) of the patients had ventricular fibrillation in hospital. The following risk factors were included in multivariate models to estimate their importance for 30-day and long-term (median 7 year) prognosis: age, gender, ventricular fibrillation, congestive heart failure, pulmonary oedema, cardiogenic shock, other cardiac arrest and atrial fibrillation. We found that the odds ratio for death on days 6–30 was 6·34 (3·55–11·30, 95% confidence limits, P

Background— Renal dysfunction is an important prognostic factor in heart failure (HF), but whether this dysfunction progresses to end-stage renal disease (ESRD) is unknown. Therefore, we examined incidence and predictors of ESRD in outpatients with HF. Methods and Results— Patients with systolic HF were identified in The Danish Heart Failure database and new-onset ESRD from the Danish Registry on Dialysis. Renal function was estimated by The Chronic Kidney Disease Epidemiology Collaboration equation and patients grouped by estimated glomerular filtration rate (eGFR)—group I: ≥60 mL/min per 1.73 m 2 , group II: 30 to 59 mL/min per 1.73 m 2 , group III: 15 to 29 mL/min per 1.73 m 2 , group IV: 2 . Cox hazard models for time to ESRD, to death, and the composite end point of ESRD or death were constructed and predictors of ESRD identified. A total of 8204 patients were included in the analyses. Median age was 70 years (Q, 61–77), 28% were women, median left ventricular ejection fraction was 30% (Q, 24–40), and median eGFR was 68 (Q, 51–85) mL/min per 1.73 m 2 . Forty-one patients developed ESRD (1.3/1000 patient-years). Baseline eGFR group II ( P P P P =0.049), need of diuretics, and age P =0.016) were associated with time to ESRD. Conclusions— ESRD is rare in outpatients with systolic HF and is mainly observed in patients with an eGFR 2 . A low eGFR, age

AIMS: Low prevalence of detectable cardiac troponin in healthy people and low-risk patients previously curtailed its use. With a new high-sensitive cardiac troponin assay (hs-cTnT), concentrations below conventional detection may have prognostic value, notably in combination with N-terminal pro-B-type natriuretic peptide (NT-pro-BNP). METHODS AND RESULTS: Biomarker concentrations were determined from serum obtained at enrolment in the CLARICOR trial involving 4197 patients with stable coronary artery disease (CAD) followed for 2.6 years. Serum hs-cTnT was detectable (above 3 ng/l) in 78% and above the conventional 99th percentile (13.5 ng/l) in 23%. Across all levels of hs-cTnT there was a graded increase in the risk of cardiovascular death after adjustment for known prognostic indicators: hazard ratio (HR) per unit increase in the natural logarithm of the hs-cTnT level, 1.49; 95% confidence interval (CI), 1.23-1.81; similarly for all-cause mortality (HR 1.48, 95% CI 1.29-1.70) and myocardial infarction (HR 1.37, 95% CI 1.13-1.67). Increasing values of hs-cTnT were associated with increased mortality across all values of NT-pro-BNP, but this was particularly prominent when NT-pro-BNP >400 ng/l. CONCLUSIONS: In patients with stable CAD, any detectable hs-cTnT level is significantly associated with all-cause mortality, cardiovascular death, and myocardial infarction after adjustment for traditional risk factors and NT-pro-BNP. Excess mortality is particularly pronounced in patients with NT-pro-BNP >400 ng/l.

Aims This study was designed to evaluate a new NT-proBNP monitoring concept in outpatients with systolic heart failure (HF). Methods and results This was a multicentre, prospective randomized open-label blinded endpoint study. A total of 407 systolic HF patients were allocated to either clinical management (n = 208) or clinical management + NT-proBNP monitoring (n = 199) and followed for 2.5 years. If NT-proBNP increased >30%, a clinical checklist was completed and treatment initiated. The patients were matched at randomization and were 73 years old, 25% were females, 85% were NYHA class I–II, LVEF was 30%, and NT-proBNP 1955 pg/mL. NT-proBNP monitoring did not improve outcome, the hazard ratio for the primary composite endpoint (death or a cardiovascular admission) being 0.96 [95% confidence interval (CI) 0.71–1.29, P = 0.766]. NT-proBNP monitoring did not induce a significant change in the pharmacological strategy (P > 0.05 for all comparisons). In patients in whom NT-proBNP increased >30% (25% of the patients) during follow-up, a higher frequency of admission (69% vs. 47%, P = 0.002), a higher number of admission days (14 vs. 5 days, P = 0.003) and number of admissions (2 vs. 1, P = 0.009), and a lower quality of life (P = 0.032) and a poorer functional class (37% vs. 18% in NYHA class III–IV, P < 0.001) were observed. Conclusions Adding serial measurements of NT-proBNP to optimal clinical management was not associated with a change in pharmacological strategy and did not improve outcome. However, survivors in whom NT-proBNP increased >30% showed a poorer functional class, clinical outcome, and quality of life. Trial registration www.centerwatch: 173491 (NorthStar).

Background Outpatient follow-up in specialized heart failure clinics (HFCs) is recommended by current guidelines and implemented in most European countries, but the optimal duration of HFC programmes has not been established. Nor is it known whether all or only high-risk patients, e.g. identified by NT-proBNP, might benefit from an extended HFC follow-up. Methods and results In a multi-centre setting, we randomly assigned 921 clinically stable systolic heart failure (HF) outpatients on optimal medical therapy to undergo either an extended follow-up in the HFC ( n = 461) or referral back to their general practitioner (GP) ( n = 460). The primary composite endpoint was death or a cardiovascular admission. Secondary endpoints included mortality, an HF admission, quality of life, number of days admitted, and number of admissions. The median age of the patients was 69 years; 23% were females; the median left ventricular ejection fraction was 0.30; and the median NT-proBNP was 801 pg/mL; 89% were in NYHA class I–II. The median follow-up was 2.5 years. Time-to-event did not differ between groups (HFC vs. GP) (HR: 1.17, 95% CI: 0.95–1.45, P = 0.149). The two groups did not differ with respect to any of the secondary endpoints at the follow-up ( P > 0.05 for all). In high-risk patients identified by NT-proBNP ≥1000 pg/mL, no benefit from HFC follow-up was found ( P = 0.721). Conclusion Irrespective of the level of NT-proBNP stable HF patients on optimal medical therapy do not benefit from long-term follow-up in a specialized HFC in a publicly funded universal access healthcare system. Heart failure patients on optimal medical therapy with mild or moderate symptoms are safely managed by their personal GP. Trial Registration: www.Centerwatch.com: 173491 (NorthStar).

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.

Objective Individuals with diabetes mellitus (DM) have a considerably elevated risk of developing serious health problems including cardiovascular disease (CVD). Long-term elevated levels of blood glucose in nondiabetic individuals may also be associated with increased risk of CVD. The aim of this study was to investigate the relationships between glycated haemoglobin A1c (HbA1c) and CVD, DM and all-cause mortality. Subjects and design The Copenhagen City Heart Study is a prospective study of individuals from the Danish general population. The cohort was followed for 10 years via national registers with respect to incident CVD, DM and all-cause mortality. Follow-up was 100% complete. Results A total of 5127 subjects were included, of whom 597 had DM. In the nondiabetic population, HbA1c was significantly associated with incident CVD events in both univariate [hazard ratio (HR) 1.38, 95% CI 1.11–1.71] and multivariate analyses (HR 1.31, 95% CI 1.05–1.64). In the nondiabetic population, increased levels of HbA1c were correlated with developing DM. There was a threefold increase in risk of incident DM per unit increase in HbA1c with a univariate HR of 3.83 (95% CI 1.96–7.51). This relationship was essentially unchanged after multivariate adjustments (HR 4.19, 95% CI 2.01–8.71). Furthermore, we found that net reclassification improvement for diagnosed DM and CVD was significantly improved with the addition of HbA1c in the analyses. Although not statistically significant, we found a strong trend towards an association between HbA1c and all-cause mortality (HR 1.21, 95% CI 0.99–1.47). We did not find the same associations amongst the population with DM. Conclusion In the Danish general population, HbA1c was strongly associated with CVD in individuals without DM.

Aim α-Defensins are part of the innate immune system. Low-grade inflammation seems to play a crucial role in development and progression of chronic heart failure (CHF). The aims of the present study were to compare plasma levels of α-defensins in CHF patients and healthy controls and to examine the predictive ability of α-defensins, alone and combined with N-terminal pro brain natriuretic peptide (NT-proBNP), with respect to all-cause mortality. Methods and results In a prospective observational study lasting 2.6 years we examined the prognostic value of plasma α-defensins with respect to mortality in 194 CHF patients, and compared plasma levels with those of 98 age-matched healthy controls. α-Defensin levels were twice as high among CHF patients in New York Heart Association (NYHA) functional class III–IV than in patients in NYHA class I–II and healthy controls (P = 0.001). The absolute increase in risk of mortality for patients with α-defensin levels in the upper tertile vs. the lowest tertile was 30% (P = 0.002). After adjusting for potential confounders including NT-proBNP, plasma α-defensins remained independently associated with an increased risk of all-cause mortality (hazard ratio 1.65, 95% confidence interval 1.19–2.28, P = 0.002) per 1 standard deviation increment in Ln (natural logarithm)-transformed α-defensin values. The combination of high α-defensins and NT-proBNP levels provided incremental prognostic information independent of well-known prognostic biomarkers in heart failure. Conclusion Plasma α-defensins appear to have prognostic information regarding mortality among patients with CHF and seem to provide incremental information to established clinical risk markers.