Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in PARADIGM-HF

Aims: Elevated serum uric acid concentration (SUA) has been associated with an increased risk of cardiovascular disease, but this may be due to unmeasured confounders. We examined the association between SUA and outcomes as well as the effect of sacubitril/valsartan on SUA in patients with heart failure with reduced ejection fraction (HFrEF) in PARADIGM-HF. Methods and results: The association between SUA and the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization, its components, and all-cause mortality was examined using Cox regression analyses among 8213 patients using quintiles (Q1–Q5) of SUA adjusted for baseline prognostic variables including estimated glomerular filtration rate (eGFR), diuretic dose, and log N-terminal pro-brain natriuretic peptide. Change in SUA from baseline over 12 months was also evaluated in each treatment group. Patients in Q5 (SUA ≥8.6 mg/dL) compared with Q1 (<5.4 mg/dL) were younger (62.8 vs. 64.2 years), more often male (88.7% vs. 63.1%), had lower systolic blood pressure (119 vs. 123 mmHg), lower eGFR (57.4 vs. 76.6 mL/min/1.73 m2), and greater diuretic use. Higher SUA was associated with a higher risk of the primary outcome (adjusted hazard ratios) Q5 vs. Q1 = 1.28 [95% confidence intervals (1.09–1.50), P = 0.003], cardiovascular death [1.44 (1.11–1.77), P = 0.001], HF hospitalization [1.37 (1.11–1.70), P = 0.004], and all-cause mortality [1.36 (1.13–1.64), P = 0.001]. Compared with enalapril, sacubitril/valsartan reduced SUA by 0.24 (0.17–0.32) mg/dL over 12 months (P < 0.0001). Sacubitril/valsartan improved outcomes, irrespective of SUA concentration. Conclusion: Serum uric acid concentration was an independent predictor of worse outcomes after multivariable adjustment in patients with HFrEF. Compared with enalapril, sacubitril/valsartan reduced SUA and improved outcomes irrespective of SUA

Renal effects and associated outcomes during angiotensin-neprilysin inhibition in heart failure

Objectives: The purpose of this study was to evaluate the renal effects of sacubitril/valsartan in patients with heart failure and reduced ejection fraction. Background: Renal function is frequently impaired in patients with heart failure with reduced ejection fraction and may deteriorate further after blockade of the renin–angiotensin system. Methods: In the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, 8,399 patients with heart failure with reduced ejection fraction were randomized to treatment with sacubitril/valsartan or enalapril. The estimated glomerular filtration rate (eGFR) was available for all patients, and the urinary albumin/creatinine ratio (UACR) was available in 1872 patients, at screening, randomization, and at fixed time intervals during follow-up. We evaluated the effect of study treatment on change in eGFR and UACR, and on renal and cardiovascular outcomes, according to eGFR and UACR. Results: At screening, the eGFR was 70 ± 20 ml/min/1.73 m2 and 2,745 patients (33%) had chronic kidney disease; the median UACR was 1.0 mg/mmol (interquartile range: 0.4 to 3.2 mg/mmol) and 24% had an increased UACR. The decrease in eGFR during follow-up was less with sacubitril/valsartan compared with enalapril (−1.61 ml/min/1.73 m2/year; [95% confidence interval: −1.77 to −1.44 ml/min/1.73 m2/year] vs. −2.04 ml/min/1.73 m2/year [95% CI: −2.21 to −1.88 ml/min/1.73 m2/year ]; p < 0.001) despite a greater increase in UACR with sacubitril/valsartan than with enalapril (1.20 mg/mmol [95% CI: 1.04 to 1.36 mg/mmol] vs. 0.90 mg/mmol [95% CI: 0.77 to 1.03 mg/mmol]; p < 0.001). The effect of sacubitril/valsartan on cardiovascular death or heart failure hospitalization was not modified by eGFR, UACR (p interaction = 0.70 and 0.34, respectively), or by change in UACR (p interaction = 0.38). Conclusions: Compared with enalapril, sacubitril/valsartan led to a slower rate of decrease in the eGFR and improved cardiovascular outcomes, even in patients with chronic kidney disease, despite causing a modest increase in UACR

The use of pulse-compression thermography for detecting defects in paintings

Interest in the conservation of paintings grows year by year. Their periodic inspection is essential for their conservation over the time. Thermographic non-destructive inspection is one technique useful for paintings, but it is essential to be able to detect buried defects while minimising the level of thermal stimulus. This paper describes a pulse-compression infrared thermography technique whereby defect detection is optimized while minimising the rise in temperature. To accomplish this task, LED lamps driven by a coded waveform based on a linear frequency modulated chirp signal have been used on paintings on both a wooden panel and a canvas layer. These specimens contained artificially fabricated defects. Although the physical condition of each painting was different, the experimental results show that the proposed signal processing procedure is able to detect defects using a low temperature contrast

Rationale for and Practical Use of Sacubitril/Valsartan in the Patient’s Journey with Heart Failure and Reduced Ejection Fraction

Sacubitril with valsartan (sacubitril/valsartan) is a relatively novel compound that has become a milestone in the treatment of patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) in the last decade. Contemporary data suggest that sacubitril/valsartan is associated with improved outcomes compared with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and has a greater beneficial effect on myocardial reverse remodelling. Additionally, two recent trials have shown that sacubitril/valsartan is well-tolerated even in the acute HF setting, thus enabling a continuum of use in the patient’s journey with HFrEF. This article summarises available data on the effectiveness and tolerability of sacubitril/valsartan in patients with HFrEF, and provides the clinician with practical insights to facilitate the use of this drug in every setting, with an emphasis on acute HF, hypotension, electrolyte imbalance and renal insufficiency

Mid infrared tomography of polymer pipes

Mid-infrared signals in the 2–5 μm wavelength range have been transmitted through samples of polymer pipes, as commonly used in the water supply industry. It is shown that simple through-transmission images can be obtained using a broad spectrum source and a suitable camera. This leads to the possibility of tomography, where images are obtained as the measurement system is rotated with respect to the axis of the pipe. The unusual 3D geometry created by a source of finite size and the imaging plane of a camera, plus the fact that refraction at the pipe wall would cause significant ray bending, meant that the reconstruction of tomographic images had to be considered with some care. A result is shown for a thinning defect on the inner wall of a polymer water pipe, demonstrating that such changes can be reconstructed successfully

The Heart Failure Epidemic

Heart failure has been singled out as an emerging epidemic, which could be the result of increased incidence and/or increased survival leading to increased prevalence. Knowledge of the responsibility of each factor in the genesis of the epidemic is crucial for prevention. Population-based studies have shown that, over time, the incidence of heart failure remained overall stable, while survival improved. Therefore, the heart failure epidemic is chiefly one of hospitalizations. Data on temporal trends in the incidence and prevalence of heart failure according to ejection fraction and how it may have changed over time are needed while interventions should focus on reducing the burden of hospitalizations in hear failure

Geographic variations in the PARADIGM-HF heart failure trial

Aims: The globalization of clinical trials has highlighted geographic variations in patient characteristics, event rates, and treatment effects. We investigated these further in PARADIGM-HF, the largest and most globally representative trial in heart failure (HF) to date. Methods and results: We looked at five regions: North America (NA) 622 (8%), Western Europe (WE) 1680 (20%), Central/Eastern Europe/Russia (CEER) 2762 (33%), Latin America (LA) 1413 (17%), and Asia-Pacific (AP) 1487 (18%). Notable differences included: WE patients (mean age 68 years) and NA (65 years) were older than AP (58 years) and LA (63 years) and had more coronary disease; NA and CEER patients had the worst signs, symptoms, and functional status. North American patients were the most likely to have a defibrillating-device (53 vs. 2% AP) and least likely prescribed a mineralocorticoid receptor antagonist (36 vs. 61% LA). Other evidence-based therapies were used most frequently in NA and WE. Rates of the primary composite outcome of cardiovascular (CV) death or HF hospitalization (per 100 patient-years) varied among regions: NA 13.5 (95% CI 11.7–15.6), WE 9.6 (8.6–10.6), CEER 12.3 (11.4–13.2), LA 11.2 (10.0–12.5), and AP 12.5 (11.3–13.8). After adjustment for prognostic variables, relative to NA, the risk of CV death was higher in LA and AP and the risk of HF hospitalization lower in WE. The benefit of sacubitril/valsartan was consistent across regions. Conclusion: There were many regional differences in PARADIGM-HF, including in age, symptoms, comorbidity, background therapy, and event-rates, although these did not modify the benefit of sacubitril/valsartan

Platelet lysate-based pro-angiogenic nanocoatings

Human platelet lysate (PL) is a cost-effective and human source of autologous multiple and potent pro-angiogenic factors, such as vascular endothelial growth factor A (VEGF A), fibroblast growth factor b (FGF b) and angiopoietin-1. Nanocoatings previously characterized were prepared by layer-by-layer assembling incorporating PL with marine-origin polysaccharides and were shown to activate human umbilical vein endothelial cells (HUVECs). Within 20 h of incubation, the more sulfated coatings induced the HUVECS to the form tube-like structures accompanied by an increased expression of angiogenicassociated genes, such as angiopoietin-1 and VEGF A. This may be a cost-effective approach to modify 2D/3D constructs to instruct angiogenic cells towards the formation of neo-vascularization, driven by multiple and synergistic stimulations from the PL combined with sulfated polysaccharides. Statement of Significance The presence, or fast induction, of a stable and mature vasculature inside 3D constructs is crucial for new tissue formation and its viability. This has been one of the major tissue engineering challenges, limiting the dimensions of efficient tissue constructs. Many approaches based on cells, growth factors, 3D bioprinting and channel incorporation have been proposed. Herein, we explored a versatile technique, layer-by-layer assembling in combination with platelet lysate (PL), that is a cost-effective source of many potent pro-angiogenic proteins and growth factors. Results suggest that the combination of PL with sulfated polyelectrolytes might be used to introduce interfaces onto 2D/3D constructs with potential to induce the formation of cell-based tubular structures.The research leading to these results has received funding from European Union's Seventh Framework Program (FP7/2007-2013) under grant agreement na REGPOT-CT2012-316331 - POLARIS and FP7-KBBE-2010-4-266033 - SPECIAL. This work was also supported by the European Research Council grant agreement ERC-2012-ADG-20120216-321266 for the project ComplexiTE. Portuguese Foundation for Science and Technology is gratefully acknowledged for fellowship of Sara M. Oliveira (SFRH/BD/70107/2010). The researcher contract of R.P. Pirraco through RL3-TECT-NORTE-01-0124-FEDER-000020, co-financed by North Portugal Regional Operational Program (ON.2-O Novo Norte), under the National Strategic Reference Framework, through the European Regional Development Fund is also acknowledged

Sympathoinhibitory effect of statins in chronic heart failure

Contains fulltext : 89087.pdf (publisher's version ) (Closed access)OBJECTIVES: Increased (central) sympathetic activity is a key feature of heart failure and associated with worse prognosis. Animal studies suggest that statin therapy can reduce central sympathetic outflow. This study assessed statin effects on (central) sympathetic activity in human chronic heart failure (CHF) patients. METHODS: Sympathetic activity was measured in eight patients with CHF patients during 8 weeks after discontinuation and 4 weeks after restart of statin therapy by microneurography for direct muscle sympathetic nerve recording (MSNA) and measurement of arterial plasma norepinephrine concentrations. RESULTS: During discontinuation of statin therapy, MSNA was significantly increased (73 +/- 4 vs. 56 +/- 5 and 52 +/- 6 bursts/100 beats, p = 0.01). Burst frequency was significantly higher after statin discontinuation (42 +/- 3 burst/min without statin vs. 32 +/- 3 and 28 +/- 3 burst/min during statin therapy, p = 0.004). Mean normalized burst amplitude and total normalized MSNA were significantly higher after statin discontinuation (mean normalized burst amplitude 0.36 +/- 0.04 without statin vs. 0.29 +/- 0.04 and 0.22 +/- 0.04 during statin, p < 0.05; total normalized MSNA 15.70 +/- 2.78 without statin, vs. 9.28 +/- 1.41 and 6.56 +/- 1.83 during statin, p = 0.009). Arterial plasma norepinephrine levels and blood pressure were unaffected. INTERPRETATION: Statin therapy inhibits central sympathetic outflow in CHF patients, as measured by MSNA.1 april 201

A framework to assess the resilience of farming systems

Agricultural systems in Europe face accumulating economic, ecological and societal challenges, raising concerns about their resilience to shocks and stresses. These resilience issues need to be addressed with a focus on the regional context in which farming systems operate because farms, farmers’ organizations, service suppliers and supply chain actors are embedded in local environments and functions of agriculture. We define resilience of a farming system as its ability to ensure the provision of the system functions in the face of increasingly complex and accumulating economic, social, environmental and institutional shocks and stresses, through capacities of robustness, adaptability and transformability. We (i) develop a framework to assess the resilience of farming systems, and (ii) present a methodology to operationalize the framework with a view to Europe’s diverse farming systems. The framework is designed to assess resilience to specific challenges (specified resilience) as well as a farming system’s capacity to deal with the unknown, uncertainty and surprise (general resilience). The framework provides a heuristic to analyze system properties, challenges (shocks, long-term stresses), indicators to measure the performance of system functions, resilience capacities and resilience-enhancing attributes. Capacities and attributes refer to adaptive cycle processes of agricultural practices, farm demographics, governance and risk management. The novelty of the framework pertains to the focal scale of analysis, i.e. the farming system level, the consideration of accumulating challenges and various agricultural processes, and the consideration that farming systems provide multiple functions that can change over time. Furthermore, the distinction between three resilience capacities (robustness, adaptability, transformability) ensures that the framework goes beyond narrow definitions that limit resilience to robustness. The methodology deploys a mixed-methods approach: quantitative methods, such as statistics, econometrics and modelling, are used to identify underlying patterns, causal explanations and likely contributing factors; while qualitative methods, such as interviews, participatory approaches and stakeholder workshops, access experiential and contextual knowledge and provide more nuanced insights. More specifically, analysis along the framework explores multiple nested levels of farming systems (e.g. farm, farm household, supply chain, farming system) over a time horizon of 1-2 generations, thereby enabling reflection on potential temporal and scalar trade-offs across resilience attributes. The richness of the framework is illustrated for the arable farming system in Veenkoloniën, the Netherlands. The analysis reveals a relatively low capacity of this farming system to transform and farmers feeling distressed about transformation, while other members of their households have experienced many examples of transformation