Management of heart failure in the Netherlands

In The Netherlands, the incidence and prevalence of heart failure are rising as is the case in most other European countries. Overall, there are 200,000 patients with heart failure in The Netherlands and around 25,000 hospitalisations annually with a discharge diagnosis of heart failure. Most of these patients are managed in primary care, often together with a cardiologist.There is an active guideline program in different professional organisations (e.g. general practitioners, cardiologists) and in 2002 a collaborative multidisciplinary guideline for management of chronic heart failure was developed. However, there is clearly room for improvement in the adherence to these guidelines both with regard to the diagnosis and the treatment of HF patients. For example, ACE-I and beta-blockers are still under-prescribed. In particular, the more severely ill patients seem to be under treated. At present, general practitioners and cardiologists differ in their views on heart failure, resulting in differences in diagnosis and management. In addition to the multidisciplinary guidelines, several other initiatives have been developed to improve outcomes in these patients, such as rapid access clinics and outpatient heart failure clinics. (C) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.</p

Virtual Machining: Capabilities and Challenges of Process Simulations in the Aerospace Industry

AbstractMilling processes for the manufacturing of parts for aerospace applications can be influenced by various effects. When machining structural parts with high material removal rates, the stiffness of the machine tool can be a limiting factor because chatter vibrations. Additionally, vibrations of thin-walled structures, e. g., the blades of impellers or turbines, can lead to chatter vibrations and surface location errors. Thermo-mechanical deformations are another cause for violations of given shape tolerances. Geometric physically-based process simulations can be used to analyze milling processes with regard to these effects in order to optimize the process parameters. In this paper, an overview of several applications of a geometric physically-based simulation system for analyzing different effects during milling processes is presented. Depending on the relevant effects, process forces, the dynamic behaviour of the tool-spindle-machine system, vibrations of workpieces and fixture systems, as well as thermo-mechanical deformations are calculated

Quantitative projections of a quality measure: Performance of a complex task

AbstractComplex data series that arise during interaction between humans (operators) and advanced technology in a controlled and realistic setting have been explored. The purpose is to obtain quantitative measures that reflect quality in task performance: on a ship simulator, nine crews have solved the same exercise, and detailed maneuvering histories have been logged. There are many degrees of freedom, some of them connected to the fact that the vessels may be freely moved in any direction. To compare maneuvering histories, several measures were used: the time needed to reach the position of operation, the integrated angle between the hull direction and the direction of motion, and the extent of movement when the vessel is to be manually kept in a fixed position. These measures are expected to reflect quality in performance. We have also obtained expert quality evaluations of the crews. The quantitative measures and the expert evaluations, taken together, allow a ranking of crew performance. However, except for time and integrated angle, there is no correlation between the individual measures. This may indicate that complex situations with social and man–machine interactions need complex measures of quality in task performance. In general terms, we have established a context-dependent and flexible framework with quantitative measures in contact with a social-science concept that is hard to define. This approach may be useful for other (qualitative) concepts in social science that contain important information on the society

Identification of genomic loci associated with resting heart rate and shared genetic predictors with all-cause mortality

Resting heart rate is a heritable trait correlated with life span. Little is known about the genetic contribution to resting heart rate and its relationship with mortality. We performed a genome-wide association discovery and replication analysis starting with 19.9 million genetic variants and studying up to 265,046 individuals to identify 64 loci associated with resting heart rate (P < 5 × 10$^{-8}$); 46 of these were novel. We then used the genetic variants identified to study the association between resting heart rate and all-cause mortality. We observed that a genetically predicted resting heart rate increase of 5 beats per minute was associated with a 20% increase in mortality risk (hazard ratio 1.20, 95% confidence interval 1.11-1.28, P = 8.20 × 10$^{-7}$) translating to a reduction in life expectancy of 2.9 years for males and 2.6 years for females. Our findings provide evidence for shared genetic predictors of resting heart rate and all-cause mortality.This research was conducted using the UK Biobank Resource. This project is supported by the Netherlands organization for health research and development (ZonMw grant 90.700.441). S.B. is supported by the Wellcome Trust (grant 100114). P.B.M. acknowledges support from the NIHR Cardiovascular Biomedical Research Unit at Barts and the London School of Medicine and Dentistry, Queen Mary University of London. N.V. is supported by Netherlands Heart Institute and Marie Sklodowska-Curie Global Fellowship (grant 661395)

Erythropoietin induces neovascularization and improves cardiac function in rats with heart failure after myocardial infarction

ObjectivesWe assessed the effects of erythropoietin (EPO) treatment in a rat model of post-myocardial infarction (MI) heart failure.BackgroundErythropoietin, traditionally known as a hematopoietic hormone, has been linked to neovascularization. Whereas administration of EPO acutely after MI reduces infarct size and improves cardiac function, its role in the failing heart is unknown.MethodsRats underwent coronary ligation or sham surgery. Rats with MI were randomly assigned to: untreated (MI), a single bolus of EPO immediately after MI induction (MI-EPO-early), EPO treatment immediately after MI and once every three weeks (MI-EPO-early+late), and EPO treatment starting three weeks after induction of MI, once every three weeks (MI-EPO-late). After nine weeks, hemodynamics, infarct size, myosin heavy chain (MHC) isoforms, myocyte hypertrophy, and capillary density were measured.ResultsErythropoietin treatment started immediately after MI (MI-EPO-early and MI-EPO-early+late) resulted in a 23% to 30% reduction in infarct size (p < 0.01) and, accordingly, hemodynamic improvement. Erythropoietin treatment, started three weeks after MI (MI-EPO-late), did not affect infarct size, but resulted in an improved cardiac performance, reflected by a 34% reduction in left ventricular end-diastolic pressure (p < 0.01), and 46% decrease in atrial natriuretic peptide levels (p < 0.05). The improved cardiac function was accompanied by an increased capillary density (p < 0.01), an increased capillary-to-myocyte ratio (p < 0.05), and a partial reversal of beta-MHC (p < 0.05) in all treated groups.ConclusionsIn addition to its effect on infarct size reduction, EPO treatment improves cardiac function in a rat model of post-MI heart failure. This observation may be explained by neovascularization, associated with an increased alpha-MHC expression

Impact of Renal Impairment on Beta-Blocker Efficacy in Patients With Heart Failure.

BACKGROUND: Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy. OBJECTIVES: This study sought to investigate patient prognosis and the efficacy of beta-blockers according to renal function using estimated glomerular filtration rate (eGFR). METHODS: Analysis of 16,740 individual patients with left ventricular ejection fraction <50% from 10 double-blind, placebo-controlled trials was performed. The authors report all-cause mortality on an intention-to-treat basis, adjusted for baseline covariates and stratified by heart rhythm. RESULTS: Median eGFR at baseline was 63 (interquartile range: 50 to 77) ml/min/1.73 m2; 4,584 patients (27.4%) had eGFR 45 to 59 ml/min/1.73 m2, and 2,286 (13.7%) 30 to 44 ml/min/1.73 m2. Over a median follow-up of 1.3 years, eGFR was independently associated with mortality, with a 12% higher risk of death for every 10 ml/min/1.73 m2 lower eGFR (95% confidence interval [CI]: 10% to 15%; p < 0.001). In 13,861 patients in sinus rhythm, beta-blockers reduced mortality versus placebo; adjusted hazard ratio (HR): 0.73 for eGFR 45 to 59 ml/min/1.73 m2 (95% CI: 0.62 to 0.86; p < 0.001) and 0.71 for eGFR 30 to 44 ml/min/1.73 m2 (95% CI: 0.58 to 0.87; p = 0.001). The authors observed no deterioration in renal function over time in patients with moderate or moderately severe renal impairment, no difference in adverse events comparing beta-blockers with placebo, and higher mortality in patients with worsening renal function on follow-up. Due to exclusion criteria, there were insufficient patients with severe renal dysfunction (eGFR <30 ml/min/1.73 m2) to draw conclusions. In 2,879 patients with atrial fibrillation, there was no reduction in mortality with beta-blockers at any level of eGFR. CONCLUSIONS: Patients with heart failure, left ventricular ejection fraction <50% and sinus rhythm should receive beta-blocker therapy even with moderate or moderately severe renal dysfunction

High-efficiency Rosa26 knock-in vector construction for Cre-regulated overexpression and RNAi

Patients with heart failure (HF) and anaemia have greater functional impairment, worse symptoms, increased rates of hospital admission, and a higher risk of death, compared with non-anaemic HF patients. Whether correcting anaemia can improve outcomes is unknown. The Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF; Clinical Trials.gov NCT 003 58215) was designed to evaluate the effect of the long-acting erythropoietin-stimulating agent darbepoetin alfa on mortality and morbidity (and quality of life) in patients with HF and anaemia. Approximately 2600 patients with New York Heart Association class II-IV, an ejection fraction = 9.0 g/dL will be enrolled. Patients are randomized 1:1 to double-blind subcutaneous administration of darbepoetin alfa or placebo. Investigators are also blinded to Hb measurements and darbepoetin alfa is dosed to achieve an Hb concentration of 13.0 g/dL (but not exceeding 14.5 g/dL) with sham adjustments of the dose of placebo. The primary endpoint is the time to death from any cause or first hospital admission for worsening HF, whichever occurs first. The study will complete when similar to 1150 subjects experience a primary endpoint

Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST)

Background: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. Aims: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. Methods: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. Baseline results: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021. Conclusion: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856)