Association between loop diuretic dose changes and outcomes in chronic heart failure: observations from the ESC-EORP Heart Failure Long-Term Registry

[Abstract] Aims. Guidelines recommend down-titration of loop diuretics (LD) once euvolaemia is achieved. In outpatients with heart failure (HF), we investigated LD dose changes in daily cardiology practice, agreement with guideline recommendations, predictors of successful LD down-titration and association between dose changes and outcomes. Methods and results. We included 8130 HF patients from the ESC-EORP Heart Failure Long-Term Registry. Among patients who had dose decreased, successful decrease was defined as the decrease not followed by death, HF hospitalization, New York Heart Association class deterioration, or subsequent increase in LD dose. Mean age was 66±13 years, 71% men, 62% HF with reduced ejection fraction, 19% HF with mid-range ejection fraction, 19% HF with preserved ejection fraction. Median [interquartile range (IQR)] LD dose was 40 (25–80) mg. LD dose was increased in 16%, decreased in 8.3% and unchanged in 76%. Median (IQR) follow-up was 372 (363–419) days. Diuretic dose increase (vs. no change) was associated with HF death [hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.12–2.08; P = 0.008] and nominally with cardiovascular death (HR 1.25, 95% CI 0.96–1.63; P = 0.103). Decrease of diuretic dose (vs. no change) was associated with nominally lower HF (HR 0.59, 95% CI 0.33–1.07; P = 0.083) and cardiovascular mortality (HR 0.62 95% CI 0.38–1.00; P = 0.052). Among patients who had LD dose decreased, systolic blood pressure [odds ratio (OR) 1.11 per 10 mmHg increase, 95% CI 1.01–1.22; P = 0.032], and absence of (i) sleep apnoea (OR 0.24, 95% CI 0.09–0.69; P = 0.008), (ii) peripheral congestion (OR 0.48, 95% CI 0.29–0.80; P = 0.005), and (iii) moderate/severe mitral regurgitation (OR 0.57, 95% CI 0.37–0.87; P = 0.008) were independently associated with successful decrease. Conclusion. Diuretic dose was unchanged in 76% and decreased in 8.3% of outpatients with chronic HF. LD dose increase was associated with worse outcomes, while the LD dose decrease group showed a trend for better outcomes compared with the no-change group. Higher systolic blood pressure, and absence of (i) sleep apnoea, (ii) peripheral congestion, and (iii) moderate/severe mitral regurgitation were independently associated with successful dose decrease

Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry

Aims: This study aimed to assess age- and sex-related differences in management and 1-year risk for all-cause mortality and hospitalization in chronic heart failure (HF) patients. Methods and results: Of 16 354 patients included in the European Society of Cardiology Heart Failure Long-Term Registry, 9428 chronic HF patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates of use of guideline-directed medical therapy (GDMT) were high (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively). Crude GDMT utilization rates were lower in women than in men (all differences: P\ua0 64 0.001), and GDMT use became lower with ageing in both sexes, at baseline and at 1-year follow-up. Sex was not an independent predictor of GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all-cause mortality were lower in women than in men (7.1% vs. 8.7%; P\ua0=\ua00.015), as were rates of all-cause hospitalization (21.9% vs. 27.3%; P\ua075 years. Conclusions: There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all-cause mortality in patients with LVEF 6445%

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Dimensionless Analysis of Stirling Engine using Optimization Methods

The hot-gas engine known as the Stirling engine is a promising heat engine with a high efficiency, multi-fuel capability, low emission, quiet operation, very low maintenance requirement and long life. The Stirling engine works by using the pressure p changes resulting from cyclically heating and cooling the enclosed charge gas. The ideal Stirling machines can be considered as a cylinder containing two opposite pistons, with a regenerator between the pistons. One of the two volumes between the regenerator and the pistons is the expansion space (E-space) at a high heater temperature TE. The other one is the compression space (C-space) at a low cooler temperature TC. The engine operates on a closed regenerative thermodynamic cycle, with the same ideal efficiency as the Carnot cycle. In the ideal Stirling engine, as the motion of the pistons is discontinuous, the process of compression takes place wholly in cold space and the process of expansion takes place wholly in hot space. In practice the pistons, connected with crankshaft by means of a wide spectrum of mechanical linkage, move in quasi-sinusoidal mode. Working fluid flow is controlled by volume changes, so that there is a net conversion of heat to work. Both power and efficiency strongly depends on control of volume variations over the engine cycle. This paper presents a new Stirling engine model based on dimensionless analysis. The proposed model assumes sinusoidal variations of hot and cold swept volumes with a phase angle ƒÒ between their minimal values. Other engine control parameters are relative ones, which enable to obtain general directions for rough optimal calibration of wide spectrum of actual Stirling machines. Two constrained optimization problems of two and five parameters are formulated and solved using the model. Maximized criterion ƒ¶ is cycle work per unit of mean pressure and total swept volume. The optimal values of volume control such as phase angle, amplitude ratio of swept volumes are presented for different constraints imposed on temperature ratio and relative dead volumes. The elaborated non-dimensional Stirling model is a suitable tool for preliminary design. The maximization of the index ƒ¶ enables to determine the optimal division of total dead and swept volumes as well as the optimal volume phase angle ƒÒƒx. The obtained results show that volumes (both dead and swept) of hot cells of hot-gas engines should be greater than cold parts. The angle ƒÒƒx approaches ƒà/2 as dead volume increases

An Interactive System for Mobile Robot Navigation

In this paper we discuss an approach, based on Virtual Reality application, to interactive prototyping and real-time controlling a mobile robot. It consists in construction of two robots: real one moving in actual world and virtual one existing in three dimensional reconstruction of the same environment. A teleoperation system, based on virtual images generated by 3D computer graphics, allows to compensate for delayed or incomplete data set from real world. The system hardware and multilayer software architecture is discussed. The performance of the developed system has been examined through experiments with a mobile platform. A method, based on Dijkstra's algorithm, for the shortest-route and collision - free navigation was also elaborated and described in the paper

Chemical composition of coriander essential oil and its effect on growth of selected lactic acid bacteria

Celem pracy było oznaczenie związków lotnych metodą GC/MS w olejkach eterycznych wyekstrahowanych z nasion kolendry dwiema metodami oraz określenie wpływu tych olejków na wzrost wybranych szczepów bakterii fermentacji mlekowej z rodzaju Lactobacillus. Olejki eteryczne otrzymano metodą destylacji z parą wodną przy użyciu zestawu do destylacji prostej oraz w aparacie Derynga. W olejku eterycznym wyodrębnionym pierwszą metodą zidentyfikowano 31 związków, a w olejku z aparatu Derynga – 25 związków. Olejek eteryczny otrzymany podczas destylacji prostej zawierał takie związki, jak: linalol (31,80 %), kamfora (11,88 %), octan geranylu (8,29 %), geraniol (7,28 %), limonen (7,81 %) oraz γ-terpinen (6,45 %), a wyekstrahowany przy użyciu aparatu Derynga charakteryzował się największym udziałem linalolu (48,89 %), kamfory (10,50 %), octanu geranylu (9,69 %) oraz p-cymenu (6,60 %). Do oceny aktywności tych olejków wobec szczepów bakterii fermentacji mlekowej zastosowano metodę dyfuzji studzienkowej. Stwierdzono, że wielkość stref zahamowania wzrostu badanych szczepów bakterii zależała od stężenia zastosowanych olejków. Wielkości tych stref zawierały się w przedziale 0,1 ÷ 5,8 mm. Olejki eteryczne z kolendry użyte w stężeniu powyżej 50 % hamowały wzrost wszystkich badanych szczepów bakterii kwasu mlekowego. Użyte natomiast w stężeniu poniżej 50 % działały tylko na wybrane szczepy bakterii z rodzaju Lactobacillus.The objective of the study was to determine, using a GC/MS method, the volatile compounds in the coriander essential oils extracted from coriander seeds by two methods, and to determine their effect on the growth of selected bacteria strains of the Lactobacillus genus. The essential oils were produced by a steam distillation method with the use of a straight distillation set and in a Deryng apparatus. 31 compounds were identified in the essential oil extracted by the first method and 25 compounds in the oil from the Deryng apparatus. The essential oil obtained by the straight distillation contained such compounds as: linalool (31.80 %), camphor (11.88 %), geranyl acetate (8.29 %), geraniol (7.28 %), limonene (7.81 %), and γ-terpinene (6.45 %). The oil extracted using the Deryng apparatus was characterized by the highest percent content of linalool (48.89 %), camphor (10.50 %), geranyl acetate (9.69 %), and p-cymene (6.60 %). A well diffusion method was applied to assess the activity of those oils against the strains of lactic acid bacteria. It was found that the size of the zones of the growth inhibition of tested bacterial strains depended on the concentration of the essential oils used. The sizes of those zones ranged between 0.1 ÷ 5.8 mm. The coriander essential oils used at the concentrations above 50 % inhibited the growth of all the tested strains of lactic acid bacteria. When the concentrations of coriander essential oils used were below 50 %, the oils affected only some selected bacterial strains of the Lactobacillus genus