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Soil biodiversity, like terrestrial biodiversity, is currently under threat by changes in land use. Intensively managed farming activities with agrochemicals have degraded both soil biodiversity and health. However, little is known about how these changes in land use affect the distribution of earthworm biomass in Southeast Asia. We conducted earthworm sampling across multiple habitats, including lowland forests, exotic monoculture plantations (e.g., oil palm and rubber tree), and agroforestry orchards. To survey earthworm populations, we excavated the top 30 cm of soil at 18 sites encompassing 399 plots distributed across natural and human-modified ecosystems in Selangor and Negeri Sembilan, Peninsular Malaysia. We found that earthworm abundance was negatively related to increasing soil compaction, leaf litter weight, soil pH, and undergrowth height, whereas it was positively associated with increasing undergrowth and canopy cover. Our findings demonstrated that agroforestry orchards, rubber tree plantations, and mature oil palm plantations had higher earthworm abundance than those in logged lowland forests. Earthworm abundance in unlogged lowland forests and young oil palm plantations, on the other hand, was lower than in logged lowland forests. Overall earthworm weight was greater in rubber tree plantations, agroforestry orchards, mature oil palm plantations, and unlogged lowland forests than those in logged lowland forests, while young oil palm plantations exhibited lower earthworm weight than logged lowland forests. Our data indicate that increases in soil compaction and leaf litter weight were associated with decreased earthworm weight. These results demonstrate the importance of site-level habitat management for maintaining healthy earthworm populations and soil biodiversity. • Land use changes have a negative impact on earthworm populations. • Earthworms dislike compacted soil, heavy litter, soil pH, and undergrowth height. • Earthworms favour increasing undergrowth and canopy. • Rubber, mature oil palm, and agroforestry have more earthworms than logged forests. • Unlogged forests and immature oil palms have fewer earthworms than logged forests. [ABSTRACT FROM AUTHOR]

Background: Ischemia and subsequent reperfusion cause myocardial injury in patients presenting with ST-segment elevation myocardial infarction (STEMI). Hydrogen sulfide (H2S) reduces "ischemia-reperfusion injury" in various experimental animal models, but has not been evaluated in humans. This trial will examine the efficacy and safety of the H2S-donor sodium thiosulfate (STS) in patients presenting with a STEMI.Study Design: The Groningen Intervention study for the Preservation of cardiac function with STS after STEMI (GIPS-IV) trial (NCT02899364) is a double-blind, randomized, placebo-controlled, multicenter trial, which will enroll 380 patients with a first STEMI. Patients receive STS 12.5 grams intravenously or matching placebo in addition to standard care immediately at arrival at the catheterization laboratory after providing consent. A second dose is administered 6 hours later at the coronary care unit. The primary endpoint is myocardial infarct size as quantified by cardiac magnetic resonance imaging 4 months after randomization. Secondary endpoints include the effect of STS on peak CK-MB during admission and left ventricular ejection fraction and NT-proBNP levels at 4 months follow-up. Patients will be followed-up for 2 years to assess clinical endpoints.Conclusions: The GIPS-IV trial is the first study to determine the effect of a H2S-donor on myocardial infarct size in patients presenting with STEMI. [ABSTRACT FROM AUTHOR]

The Phase 3, placebo-controlled APOLLO-B study (NCT03997383) is evaluating the efficacy and safety of patisiran in patients (pts) with ATTR cardiac amyloidosis in a 12-month (M) double-blind (DB) period followed by an open-label extension (OLE) period when all pts receive patisiran. During the DB period, patisiran demonstrated statistically significant differences vs placebo in change from baseline (CFB) to M12 in 6-minute walk test (6MWT) and KCCQ-OS, and nominal significance in NT-proBNP and troponin I. Patisiran preserved functional capacity, health status and quality of life (QoL), while placebo was associated with steady worsening. Here, we describe data during the APOLLO-B OLE period. TTR reduction by RNAi therapeutic patisiran provides long-term benefit in pts with ATTR cardiac amyloidosis. Eligible pts (18-85 yrs) had echocardiographic evidence of cardiac amyloidosis and either ATTR amyloid detected in tissue biopsy or diagnosed by nonbiopsy criteria. Medical history of heart failure (HF) due to ATTR amyloidosis with ≥1 prior HF hospitalization or current clinical evidence of HF was required. Pts were randomized 1:1 to patisiran 0.3 mg/kg or placebo every 3 weeks for 12M. All pts completing the 12M DB period were eligible to receive patisiran in the OLE for up to 36M. Pts are summarized based on DB treatment assignment. Assessments in the OLE include CFB in 6MWT, KCCQ-OS, NT-proBNP, and troponin I, among other endpoints. At baseline, 359 pts (placebo, n=178; patisiran, n=181) received study drug in DB period: median (range) age, 76.0 (41, 85) yrs; male, 89%; wtATTR, 80%; receiving tafamidis, 25%. Of these, 334 (93%) pts entered the OLE. Preliminary data show that CFB to M18 in the patisiran arm were similar to results at M12 for 6MWT, KCCQ-OS, NT-proBNP, and troponin I. In the placebo arm, patisiran initiation was associated with a slower rate of worsening (6MWT) or relative stability (KCCQ-OS, NT-proBNP, troponin I) in each endpoint from M12 to M18 vs DB period. Differences between patisiran and placebo groups at M12 persisted at M18 (Table). Patisiran demonstrated an acceptable safety profile, with no new safety concerns. Data collection during the OLE and their analyses are ongoing. Preservation of functional capacity, health status and QoL by patisiran has been observed to date to be sustained through 18M of treatment in pts with ATTR cardiac amyloidosis. Placebo-treated pts initiating patisiran at M12 appear to show stabilization in these endpoints at M18. Early treatment initiation is important, as differences across evaluated endpoints persisted between patisiran and placebo arms after placebo-treated pts initiated patisiran. Data collection in the study is ongoing. [ABSTRACT FROM AUTHOR]

Obesity is an ongoing pandemic and is associated with the development of heart failure (HF), and especially HF with preserved ejection fraction. The definition of obesity is currently based on anthropometric measurements but neglects the location and molecular properties of excess fat. Important depots associated with HF development are subcutaneous adipose tissue and visceral adipose tissue, both located in the abdominal region, and epicardial adipose tissue (EAT) surrounding the myocardium. However, mechanisms linking these different adipose tissue depots to HF development are incompletely understood. EAT in particular is of great interest because of its close proximity to the heart. In this review, we therefore focus on the characteristics of different adipose tissue depots and their response to obesity. In addition, we evaluate how different mechanisms associated with EAT expansion potentially contribute to HF and in particular HF with preserved ejection fraction development. • Obesity is a major contributor to the development of HFpEF, but pathophysiological mechanisms remain elusive. • Fat localization is an important consideration because subcutaneous, visceral, and epicardial adipose tissue respond differently in obesity. • Epicardial adipose tissue potentially contributes to HFpEF development through proinflammatory paracrine effects, lipid infiltration, and pericardial constraint. • Targeting unique properties of different adipose tissues is a potential approach to reduce incident HFpEF. [ABSTRACT FROM AUTHOR]

Background: Elevated plasma interleukin-6 (IL-6) concentrations are frequently observed in patients with acute heart failure (AHF). However, the predictive value of serial IL-6 measurements beyond brain natriuretic peptide (BNP) remains poorly characterized.Methods and Results: This was a retrospective analysis of the PROTECT cohort (2033 patients with AHF). Plasma IL-6 and BNP levels were determined on days 1, 2, 7 and 14 after admission for AHF in 1591 (78.3%), 1462 (71.9%), 1445 (71.1%) and 1451 (71.4%) patients, respectively. The primary endpoint was 180-day all-cause mortality. The median day-1 IL-6 concentration was 11.1 pg/mL (IQR: 6.6, 20.9) and decreased to 10.1 pg/mL (IQR: 5.6-18.5) at day-7. Higher cross-sectional IL-6 concentrations at all time-points predicted the primary endpoint, independent of a risk model for this cohort and changes in BNP. Each doubling of IL-6 between day-1 and day-7 predicted the primary endpoint independent of baseline IL-6 concentrations, the risk model, baseline BNP and changes in BNP [HR (95% CI): 1.18 (1.07-1.30), p=0.0013]. Collectively, 214 (17%) patients experienced at least a doubling of their IL-6 concentrations between day-1 and day-7.Conclusions: We demonstrate that the temporal evolution patterns of IL-6 in patients with AHF have additive prognostic value independent of changes in BNP. [ABSTRACT FROM AUTHOR]

Background: Changes in renal function have been associated with differential outcomes in patients with acute heart failure (HF). However, individual trajectories of changes in renal function are unknown, and it is unclear whether they relate to different clinical characteristics and clinical outcomes. Our aim was to investigate the prognostic importance of individual trajectories of change in renal function in acute HF.Methods: This was a retrospective, observational analysis from the double-blind, randomized, placebo-controlled PROTECT trial in patients with acute HF. We identified and internally validated 8 different renal trajectories among 1897 patients by visual inspection of inhospital serum creatinine changes. The primary outcome measure was all-cause mortality at 180 days. Mean age was 70 ± 12 years; 70% were male, and mean baseline estimated glomerular filtration rate was 49.0 mL/min/1.73m2.Results: A total of 8 different trajectories was established. The most prevalent trajectories were an inhospital bump (19.0%), a sustained increase (17.6%) and a dip (14.5%) in serum creatinine. Overall, the clinical characteristics of patients in different trajectories were remarkably similar. Crude 180-day mortality rates ranged from 12.0% in the trajectory, with no significant changes to 18.3% in the trajectory of sustained increase without significant differences. Overall, after multivariable adjustment, there was no trajectory of changes in renal function that was associated with significantly better or worse outcomes.Conclusions: Trajectories of changes in renal function in acute HF differ considerably on the patient level. Despite these differences, clinical characteristics and outcomes were similar, therefore, questioning the prognostic importance of changes in renal function in acute HF. [ABSTRACT FROM AUTHOR]

The 2013 (with updates in 2016 and 2017) American College of Cardiology/American Heart Association and 2016 European Society of Cardiology guidelines provide practical evidence-based clinical guidelines for the diagnosis and treatment of both acute and chronic heart failure (HF). Both guidelines address noninvasive and invasive testing to establish the diagnosis of HF with reduced ejection fraction and HF with preserved ejection fraction. Extensive trial evidence supports the use of guideline-directed medical therapy and device-based therapies for the optimal management of patients with HF with reduced ejection fraction. Specific recommendations are also provided for HF with preserved ejection fraction although the evidence is substantially weaker. Management of medical comorbidities is now addressed in both guidelines. Acute HF and end-stage disease requiring advanced therapies are also discussed. This review compares specific recommendations across the spectrum of HF phenotypes and disease severity, highlights areas where differences exist, and lists consequential studies published since the latest guidelines. [ABSTRACT FROM AUTHOR]

Smallholders, who cultivate ±30% of the global palm oil land, are critical to the realization of a sustainable palm oil sector. However, particularly independent smallholders, untied to mills, lag behind in yields and experience challenges to market their produce. Sustainability certification, such as by the Roundtable on Sustainable Palm Oil (RSPO), is proposed as a way to improve smallholder livelihoods, while protecting the environment. However, independent smallholders experience barriers to obtain certification. Through interviews with 18 RSPO certified independent smallholder groups in Indonesia and 9 certification facilitators, this study examines how pre-certification conditions regarding smallholders' socio-economic backgrounds, legality, group organization, planation management practices, and local supply chain conditions impact prospects for RSPO certification, and how groups who successfully achieved certification have dealt with challenges during the certification process. We found that the majority (77%) of RSPO certified independent smallholders in Indonesia consists of 'former scheme' smallholders. These smallholders often have clear land legality and are organized in groups prior to certification, which increases their eligibility for RSPO certification. However, due to upfront and recurrent costs for certification, as well as complexities in meeting RSPO standards, access to certification is strongly dependent on external facilitators. To up-scale certification for independent oil palm smallholders, and include more non-scheme smallholders, certification projects should involve more local actors including local governments and certified smallholder groups. In addition, certification should focus on core social and environmental concerns for smallholders, while being flexible with regards to the forms of proof needed to fulfil legality requirements. • Most RSPO certified independent smallholder groups are former outgrowers. • Certification is facilitated by their prior land rights and group organization. • Plantation and environmental licences remain barriers: too complex and costly. • Access to certification depends on external facilitators. • Sustainability certification should focus on core social and environmental issues. [ABSTRACT FROM AUTHOR]

Background: Impaired exercise capacity is one of the hallmarks of heart failure with preserved ejection fraction (HFpEF), but the clinical and hemodynamic correlates and prognostic value of exercise testing in patients with HFpEF is unknown.Methods: Patients with HFpEF (left ventricular ejection fraction [LVEF] ≥45%) and pulmonary hypertension underwent cardiopulmonary exercise test (CPX) to measure maximal (peak VO2) and submaximal (ventilatory equivalent for carbon dioxide [VE/VCO2] slope) exercise capacity. In addition, right heart catheterization was performed. Patients were grouped in tertiles based on the VE/VCO2 slope. Univariate and multivariate regression analyses were performed. A Cox regression analysis was performed to determine the mortality during follow-up.Results: We studied 88 patients: mean age 73 ± 9 years, 67% female, mean LVEF 58%, median N-terminal pro-B-type natriuretic peptide (NT-proBNP) 840 (interquartile range 411-1938) ng/L. Patients in the highest VE/VCO2 tertile had the most severe HF, as reflected in higher New York Heart Association functional class and higher NT-proBNP plasma levels (all P < .05 for trend), whereas LVEF was similar between the groups. Multivariable regression analysis with backward elimination on invasive hemodynamic measurements showed that VE/VCO2 slope was independently associated with pulmonary vascular resistance (PVR). Cox regression analysis showed that increased VE/VCO2 slope (but not peak VO2) was independently associated with increased mortality.Conclusion: Increased VE/VCO2 slope was associated with more severe disease and higher PVR and was independently associated with increased mortality in patients with HFpEF. [ABSTRACT FROM AUTHOR]

Background: Proenkephalin (pro-ENK) has emerged as a novel biomarker associated with both renal function and cardiac function. However, its clinical and prognostic value have not been well evaluated in symptomatic patients with heart failure.Methods and Results: The association between pro-ENK and markers of renal function was evaluated in 95 patients with chronic heart failure who underwent renal hemodynamic measurements, including renal blood flow (RBF) and glomerular filtration rate (GFR) with the use of 131I-Hippuran and 125I-iothalamate clearances, respectively. The association between pro-ENK and clinical outcome in acute heart failure was assessed in another 1589 patients. Pro-ENK was strongly correlated with both RBF (P < .001) and GFR (P < .001), but not with renal tubular markers. In the acute heart failure cohort, pro-ENK was a predictor of death through 180 days, heart failure rehospitalization through 60 days, and death or cardiovascular or renal rehospitalization through day 60 in univariable analyses, but its predictive value was lost in a multivariable model when other renal markers were entered in the model.Conclusions: In patients with chronic and acute heart failure, pro-ENK is strongly associated with glomerular function, but not with tubular damage. Pro-ENK provides limited prognostic information in patients with acute heart failure on top of established renal markers. [ABSTRACT FROM AUTHOR]

Background: Sleep apnea is an important comorbidity in heart failure (HF) and is associated with an adverse outcome. Diagnosing sleep apnea is difficult, and polysomnography, considered to be the criterion standard, is not widely available. We assessed the validity of a portable 2-channel sleep-screening tool for the identification of sleep apnea in patients with HF.Methods and Results: One hundred patients with stable HF had simultaneous recordings of home-based polysomnography and the screening tool (Apnealink). To compare the apnea-hypopnea index of the screening tool with polysomnography, intraclass correlation (ICC), sensitivity, and specificity were calculated, and a Bland-Altman plot and receiver operating characteristic (ROC) curves were constructed. Ninety valid measurements with the screening tool were obtained (mean age 65.5 ± 11.0 y, 72% male, mean left ventricular ejection fraction 34.6 ± 11.0%). Agreement between the screening tool and polysomnography was high (ICC 0.85). The optimal cutoff value was apnea-hypopnea index ≥15/h (area under the ROC curve 0.94). Sensitivity and specificity were 92.9% and 91.9%, respectively.Conclusions: The screening tool is useful in excluding the presence of sleep apnea in HF patients to refer only high-risk patients for more extensive polysomnography. This method may potentially reduce the need for the more expensive polysomnography. [ABSTRACT FROM AUTHOR]

Objectives: The study sought to investigate the clinical correlates and prognostic role of anemia and changes in hemoglobin in patients hospitalized for acute decompensated heart failure (AHF). Background: Anemia is related to a poor outcome in patients with heart failure. In addition, an increase in hemoglobin during hospitalization might be a sign of effective decongestion and therefore related to improved outcome. Methods: This is a post hoc analysis of the PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) study in 1,969 patients with AHF and mild to moderate impaired renal function. Hemoglobin levels were measured daily for the first 4 days and at day 7. The endpoint was 180-day all-cause mortality. Results: Anemia at baseline was observed in 50.3% of the patients. During follow-up, 359 patients (18.2%) died. Hemoglobin increased in 69.1% and was associated with a better renal function at baseline and more weight loss, but was associated with a deterioration of renal function (p = 0.01), whereas total dose diuretics was lower in patients with hemoconcentration (p < 0.01). Interaction analysis showed that greater weight loss and better baseline renal function were associated with a more rapid increase in hemoglobin concentration (p < 0.01 for both). The absolute change in hemoglobin (g/dl) independently predicted outcome (hazard ratio: 0.66; 95% confidence interval: 0.51 to 0.86; p = 0.002), whereas baseline hemoglobin levels did not. Conclusions: Patients with AHF and preserved renal function are decongested better, as shown by an increase in hemoglobin. A rapid increase in hemoglobin during the first week is independently associated with a favorable outcome, despite a slight decrease in renal function. [ABSTRACT FROM AUTHOR]

This paper proposes and uses a new test to discriminate between on the one hand the human capital model and on the other hand the credentialists and signalling models. Previous tests used only one source of variation between years spend in education and obtained degrees. Most use the variation among degree holders in the number of years they spend at school and some use the variation in the degrees obtained given the years spend in school. This paper uses both sources of variation in a combined method, It further tests the Stiglitz model of signalling, which hypothesizes that signalling will have positive external effects against other signalling and credentialist model, which hypothesize that signalling, will have negative external effects. Dutch data from the Amenities and services utilisation surveys of 1999 and 2003 (AVO'99, AVO'03) conducted by the `Sociaal en Cultureel Planbureau' of the Netherlands is used to test the hypotheses. The main findings of the analysis is that on the one hand degrees are seen as a credential, i.e. the effects of educational degrees outweigh the effect of years of education, but that on the other hand investments in education lead to positive external effects. So the social return of education is higher than the privatereturn, supporting Stiglitz (1975) idea of signalling. [ABSTRACT FROM AUTHOR]

Abstract: We report on a study of regeneration of Mountain Ash (Eucalyptus regnans) forest in S.E. Australia in artificially created canopy gaps (0.01–2ha) and clearfelled coupes (4–27ha) with different seedbed treatments. Treatments were applied in 1988, 1989, and 1990. Our results are based on measurements 8 years after harvesting. Gap size had a significant influence on sapling height and diameter growth. The effect was substantial for the canopy openings larger than 2ha, but inconsistent across the smaller gap sizes. Mean height of the largest diameter saplings was significantly greater in the clearfells (13.2m) than in the 2ha gaps (10.7m), while mean heights in the smaller gaps ranged from 6 to 8.8m. Mean sapling diameters (at 1.3m) in clearfells and 2ha gaps were 9.6 and 7.9cm respectively compared with 3.8–5.8cm for the smaller gaps. There was lower stocking in all treatments for the third regeneration year (1990), when regeneration operations were delayed by high summer and autumn rainfall. Stocking ranged from 12 to 33% for the smallest gaps, increasing with increasing gap size to 34–64% for 2ha gaps and 48–76% for clearfells. Results were consistent with a previous study 3 years after treatment, indicating that stocking at 8 years is still dominated by initial stand establishment rather than by stand development processes. There was no significant influence of seedbed preparation on any of the variables tested at year 8; this was in contrast with earlier findings at year 3 when seedling height was significantly higher on burnt sites compared with mechanically disturbed sites. The growth of non-eucalypt competitors was also influenced by gap size and year of regeneration treatment. The main competitor species differed between larger and smaller clearings and between sites. Results indicate that using a silvicultural system based on smaller gaps (<2ha) in this forest type is likely to result in reduced timber production potential compared with clearfelling. [Copyright &y& Elsevier]

Abstract: In this paper we investigate the validity of two education requirement measures. This is important because a key part of the ongoing discussion concerning overeducation is about measurement. Thanks to the Dutch Institute for Labour Studies, we have been given a unique opportunity to compare two education requirement measures: first, Huijgen''s rather dated measure and, second, the new measure of Statistics Netherlands. To investigate the validity of these two measures we apply two existing methods as well as develop and apply a new method. This new method can also be used when only one measure is available. In the end, the Statistics Netherlands measure proved to be more valid than the Huijgen measure. [Copyright &y& Elsevier]

Objectives: We assessed the effects of erythropoietin (EPO) treatment in a rat model of post-myocardial infarction (MI) heart failure. Background: Erythropoietin, 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. Methods: Rats 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. Results: Erythropoietin treatment started immediately after MI (MI-EPO-early and MI-EPO-early+late) resulted in a 23% to 30% reduction in infarct size (p &#60; 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 &#60; 0.01), and 46% decrease in atrial natriuretic peptide levels (p &#60; 0.05). The improved cardiac function was accompanied by an increased capillary density (p &#60; 0.01), an increased capillary-to-myocyte ratio (p &#60; 0.05), and a partial reversal of beta-MHC (p &#60; 0.05) in all treated groups. Conclusions: In 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. [Copyright &y& Elsevier]

Objectives: This study aimed to investigate the prognostic importance of plasma erythropoietin (EPO) levels in chronic heart failure (CHF) patients.Background: Anemia is common and is associated with an impaired survival in patients with CHF. Erythropoietin is a hematopoietic growth factor, upregulated in anemic conditions. Little is known about the pathophysiology of anemia in CHF and the prognostic importance of plasma EPO levels in CHF patients.Methods: In 74 patients with CHF (age, 61 ± 2 years; left ventricular ejection fraction, 0.31 ± 0.01; peak oxygen consumption, 19.1 ± 0.6 [mean ± SEM]) and in 15 control patients, hemoglobin levels and plasma concentrations of EPO and brain natriuretic peptide were measured.Results: During a mean follow-up of 3.0 years (range, 2.3 to 5.3 years), 22 patients (30%) died. Anemia was present in 24% of the patients. Multivariate analysis showed that plasma EPO (p = 0.026) and hemoglobin levels (p = 0.005) were independent predictors of survival in this CHF population. We observed only a mild inverse correlation between the logarithm of EPO and hemoglobin levels (r2 = 0.08, p = 0.02) in CHF patients, whereas the control group showed a clear significant inverse correlation (r2 = 0.44, p = 0.007).Conclusions: Elevated plasma EPO levels are associated with an impaired prognosis independent of hemoglobin levels and other established markers of CHF severity. Furthermore, in the CHF patients, EPO levels poorly correlate with the hemoglobin levels, in contrast with the control group. [Copyright &y& Elsevier]

Hyperkalemia (HK) is associated with suboptimal renin–angiotensin system (RAS) inhibitor and mineralocorticoid receptor antagonist (MRA) use in heart failure with reduced ejection fraction (HFrEF). This study sought to assess characteristics and RAS inhibitor/MRA use in patients receiving patiromer during the DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) run-in phase. Patients with HFrEF and HK or past HK entered a run-in phase of ≤12 weeks with patiromer-facilitated RAS inhibitor/MRA optimization to achieve ≥50% recommended RAS inhibitor dose, 50 mg/d MRA, and normokalemia. Patients achieving these criteria (randomized group) were compared with the run-in failure group (patients not meeting the randomization criteria). Of 1,038 patients completing the run-in, 878 (84.6%) were randomized and 160 (15.4%) were run-in failures. Overall, 422 (40.7%) had HK entering run-in with a similar frequency in the randomized and run-in failure groups (40.3% vs 42.5%; P = 0.605). From start to the end of run-in, in the randomized group, an increase was observed in target RAS inhibitor and MRA use in patients with HK (RAS inhibitor: 76.8% to 98.6%; MRA: 35.9% to 98.6%) and past HK (RAS inhibitor: 60.5% to 98.1%; MRA: 15.6% to 98.7%). Despite not meeting the randomization criteria, an increase after run-in was observed in the run-in failure group in target RAS inhibitor (52.5% to 70.6%) and MRA use (15.0% to 48.1%). This increase was observed in patients with HK (RAS inhibitor: 51.5% to 64.7%; MRA: 19.1% to 39.7%) and past HK (RAS inhibitor: 53.3% to 75.0%; MRA: 12.0% to 54.3%). In patients with HFrEF and HK or past HK receiving suboptimal RAS inhibitor/MRA therapy, RAS inhibitor/MRA optimization increased during patiromer-facilitated run-in. [ABSTRACT FROM AUTHOR]

Patients who sustain an acute myocardial infarction (AMI), including ST-segment elevation myocardial infarction (STEMI) and non–ST-segment elevation myocardial infarction (NSTEMI), remain at high risk for heart failure (HF), coronary events, and death. Angiotensin-converting enzyme inhibitors have been shown to significantly decrease the risk for cardiovascular events in both STEMI and NSTEMI patients. The objectives were to determine whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan, compared with ramipril, has impact on reducing cardiovascular events according to the type of AMI. The PARADISE-MI (Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction) trial enrolled patients with AMI complicated by left ventricular dysfunction and/or pulmonary congestion and at least 1 risk-enhancing factor. Patients were randomized to either sacubitril/valsartan or ramipril. The primary endpoint was death from cardiovascular causes or incident HF. In this prespecified analysis, we stratified patients according to AMI type. Of 5,661 enrolled patients, 4,291 (75.8%) had STEMI. These patients were younger and had fewer comorbidities and cardiovascular risk factors than NSTEMI patients. After adjustment for potential confounders, the risk for the primary outcome was marginally higher in NSTEMI vs STEMI patients (adjusted HR: 1.19; 95% CI: 1.00-1.41), with borderline statistical significance (P = 0.05). The primary composite outcome occurred at similar rates in patients randomized to sacubitril/valsartan vs ramipril in STEMI (10% vs 12%; HR: 0.87; 95% CI: 0.73-1.04; P = 0.13) and NSTEMI patients (17% vs 17%; HR: 0.97; 95% CI: 0.75-1.25; P = 0.80; P interaction = 0.53). Compared with ramipril, sacubitril/valsartan did not significantly decrease the risk for cardiovascular death and HF in patients with AMI complicated by left ventricular dysfunction, irrespective of the type of AMI. (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI; NCT02924727) [Display omitted] [ABSTRACT FROM AUTHOR]

Many therapies for heart failure (HF) have shown differential impact across the spectrum of left ventricular ejection fraction (LVEF). In this prespecified analysis, the authors assessed the effects of semaglutide across the baseline LVEF strata in patients with the obesity phenotype of HF with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF) trial. STEP-HFpEF randomized 529 patients (263 semaglutide; 266 placebo). For this prespecified analysis, patients were categorized into 3 groups based on LVEF: 45% to 49% (n = 85), 50% to 59% (n = 215), and ≥60% (n = 229). At 52 weeks, semaglutide improved the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (estimated treatment difference: EF [ejection fraction] 45%-49%: 5.0 points [95% CI: −2.7 to 12.8 points], EF 50%-59%: 9.8 points [95% CI: 5.0 to 14.6 points], and EF ≥60%: 7.4 points [95% CI: 2.8 to 12.0 points]; P interaction = 0.56) and body weight (EF: 45%-49%: −7.6 [95% CI: −10.7 to −4.4], EF 50%-59%: −10.6 [95% CI: −12.6 to −8.6] and EF ≥60%: −11.9 [95% CI: −13.8 to −9.9]; P interaction = 0.08), to a similar extent across LVEF categories. Likewise, LVEF did not influence the benefit of semaglutide on confirmatory secondary endpoints: 6-minute walk distance (P interaction = 0.19), hierarchal composite endpoint (P interaction = 0.43), and high-sensitivity C-reactive protein (P interaction = 0.26); or exploratory endpoint of N-terminal pro-brain natriuretic peptide (P interaction = 0.96). Semaglutide was well-tolerated across LVEF categories. In patients with HFpEF and obesity, semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight to a similar extent across LVEF categories. These data support treatment with semaglutide in patients with the obesity phenotype of HFpEF regardless of LVEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511) [Display omitted] [ABSTRACT FROM AUTHOR]

Background Diuretic unresponsiveness often occurs during hospital admission for acute heart failure (AHF) and is associated with adverse outcome. This study aims to investigate determinants, clinical outcome, and the effects of nesiritide on diuretic response early after admission for AHF. Methods Diuretic response , defined as weight loss per 40 mg of furosemide or equivalent, was examined from hospital admission to 48 hours in 4,379 patients from the ASCEND-HF trial. As an additional analysis, a urinary diuretic response metric was investigated in 5,268 patients using urine volume from hospital admission to 24 hours per 40 mg of furosemide or equivalent. Results Mean diuretic response was −0.42 kg/40 mg of furosemide (interquartile range −1.0, −0.05). Poor responders had lower blood pressure, more frequent diabetes, long-term use of loop diuretics, poorer baseline renal function, and lower urine output (all P < .01). Randomized nesiritide treatment was not associated with diuretic response ( P = .987). Good diuretic response was independently associated with a significantly decreased risk of 30-day all-cause mortality or heart failure rehospitalization (odds ratio 0.44, 95% CI 0.29-0.65, highest vs lowest quintile, P < .001). Diuretic response based on urine output per 40 mg of furosemide showed similar results in terms of clinical predictors, association with outcome, and the absence of an effect of nesiritide. Conclusions Poor diuretic response early after hospital admission for AHF is associated with low blood pressure, renal impairment, low urine output, and an increased risk of death or rehospitalization early after discharge. Nesiritide had a neutral effect on diuretic response. [ABSTRACT FROM AUTHOR]

Background In established cardiovascular disease and heart failure (HF), low hemoglobin levels are associated with unfavorable outcome. Whether hemoglobin levels are associated with the development of new-onset HF in the population is unclear. This study sought to investigate the relationship between hemoglobin levels and development of new-onset HF in the community. Methods In 6,744 patients from PREVEND, a prospective, community-based, cohort study, we analyzed the relationship between hemoglobin levels and the risk of new-onset HF. Results Mean age (±SD) was 53 ± 12 years, 49.8% was male, and mean hemoglobin level was 13.7 ± 1.2 g/dL. During a median follow-up of 8.3 years (interquartile range 7.8-8.9), 217 subjects (3.2%) were newly diagnosed with HF. The association between hemoglobin levels and the risk for new-onset HF was U shaped ( P < .001), remaining significant after full adjustment in a multivariable model with established cardiovascular risk factors ( P = .015). Furthermore, a increased annual HF incidence was already observed in subjects with high-normal hemoglobin levels (men >16 g/dL or women >15 g/dL; P = .041), whereas on the other side of the distribution, only severe anemia (men <11 g/dL or women <10 g/dL; P = .018) was associated with a higher annual incidence. Conclusions The impact of hemoglobin level on the risk of new-onset HF in the community is best described as U shaped. Interestingly, higher hemoglobin levels, already within the high-reference range, are associated with an increased incidence. This in contrast to anemia, where a higher annual HF incidence was only observed for severe anemia. [ABSTRACT FROM AUTHOR]

Background Erythropoiesis-stimulating agents (ESAs) have been investigated in small studies in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Erythropoiesis-stimulating agents did not show a clear effect on left ventricular function or clinical outcome, but some studies suggested an increased risk of thromboembolic events. Methods A systematic literature search in MEDLINE was performed, until December 2012. We included randomized clinical trials investigating the effect of ESAs in STEMI patients undergoing primary PCI, with ≥30 days of follow-up. The primary end point was a composite of all-cause mortality, myocardial infarction, and stent thrombosis after PCI. Secondary end point was all-cause mortality. Results Individual patient data were obtained from 10 of 11 trials, including 97.3% (1,242/1,277) of all patients randomized to control (n = 600) or to ESAs (n = 642). Baseline characteristics were well balanced between the treatment allocations. Mean follow-up time was 248 (±131) days. The primary end point occurred in 3.5% (20/577) in the control group and in 2.1% (13/610) in the ESA group (hazard ratio for ESAs, 0.63; 95% CI [0.31-1.27]; P = .20). Mortality occurred in 13 (2.3%) in the control group and 5 (0.8%) in the ESA group (hazard ratio for ESAs, 0.38; 95% CI [0.13-1.06]; P = .06). Conclusions Erythropoiesis-stimulating agent administration does not result in an increased risk of adverse cardiac events in STEMI patients undergoing primary PCI. Results of ongoing studies may provide further insight to the potential beneficial clinical effects of ESAs in STEMI patients. [ABSTRACT FROM AUTHOR]

Background: Iron deficiency (ID) is an emerging problem in patients with chronic heart failure (HF) and can be a potential therapeutic target. However, not much is known about the prevalence, predictors, and prognosis of ID in patients with chronic HF. Methods: In an international pooled cohort comprising 1,506 patients with chronic HF, we studied the clinical associates of ID and its prognostic consequences. Results: Iron deficiency (defined as a ferritin level <100 μg/L or ferritin 100-299 μg/L with a transferrin saturation <20%) was present in 753 patients (50%). Anemic patients were more often iron deficient than nonanemic patients (61.2% vs 45.6%, P < .001). Other independent predictors of ID were higher New York Heart Association class, higher N-terminal pro-brain-type natriuretic peptide levels, lower mean corpuscular volume levels, and female sex (all P < .05). During follow-up (median 1.92 years, interquartile range 1.18-3.26 years), 440 patients died (29.2%). Kaplan-Meier survival analysis revealed ID as a strong predictor for mortality (log rank χ2 10.2, P = .001). In multivariable hazard models, ID (but not anemia) remained a strong and independent predictor of mortality (hazard ratio 1.42, 95% confidence interval 1.14-1.77, P = .002). Finally, the presence of ID significantly enhanced risk classification and integrated discrimination improvement when added to a prediction model with established risk factors. Conclusions: Iron deficiency is common in patients with chronic HF, relates to disease severity, and is a strong and independent predictor of outcome. In this study, ID appears to have greater predictive power than anemia. [Copyright &y& Elsevier]

Background Chemotherapy and radiotherapy for breast cancer may lead to cardiac dysfunction, but the prevalence of long-term echocardiographic evidence of cardiac dysfunction is unknown among survivors. Methods In a cross-sectional study in primary care, we included 350 women who survived breast cancer for at least 5 years after diagnosis (treated with chemotherapy and/or radiotherapy) and 350 matched women (age and primary care physician). The primary outcome was cardiac dysfunction, defined as a left ventricular ejection fraction (LVEF) < 54% and an age-corrected decreased left ventricular (LV) diastolic function. Secondary outcomes included serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, newly diagnosed cardiovascular diseases and cardiovascular medication. Results The median age at diagnosis was 63 (interquartile range (IQR) 57–68) years for the breast cancer survivors. Median follow-up after diagnosis was 10 (IQR 7–14) years. LVEF < 54% was present in 52 (15.3%) survivors and 24 (7%) controls (OR 2.4, 95%CI 1.4–4.0), but there was no significant increased prevalence of either LVEF < 50% or LV diastolic dysfunction. Serum NT-proBNP levels were increased, cardiovascular disease was more frequently diagnosed and cardiovascular medication use was more frequent among survivors compared with controls. These associations remained after adjustment for relevant covariates at diagnosis and at follow-up. Conclusions In the long term, breast cancer survivors are at increased risk of mild LV systolic dysfunction, increased NT-proBNP levels, and cardiovascular disease compared with matched controls, even after adjustment for cardiovascular risk factors. Previous breast cancer treatment with chemotherapy, radiotherapy or both should be considered when assessing a patient's cardiovascular risk profile. [ABSTRACT FROM AUTHOR]

Introduction: Advanced glycation end products (AGEs) are increased in patients with heart failure (HF). We studied the predictive value of plasma AGEs N ε-(carboxymethyl)lysine (CML), pentosidine, and the soluble form of its receptor (sRAGE) in a large HF population. Methods: In 580 patients hospitalized with HF, plasma AGEs were measured before discharge when patients were clinically stable. Patients were followed for a period of 18 months. Primary end point was a composite of death and HF admissions. CML was determined by liquid chromatography mass spectrometry, pentosidine by high-performance liquid chromatography and sRAGE by sequential sandwich immunoassay. Results: Mean age was 71 ± 11 years, 62% were men, and mean left ventricular ejection fraction was 0.32 ± 0.14. At baseline, mean CML level was 2.16 ± 0.73 μmol/L, median pentosidine was 0.043 (0.030-0.074) μmol/L, and median sRAGE level was 2.92 (1.90-4.59) ng/mL. CML and pentosidine levels were independently related to the composite end-point (HR, 1.20 per SD; 95% CI,1.05-1.37; P = .01 and HR, 1.15 per SD; 95% CI, 1.00-1.31; P = .045, respectively) and HF hospitalization (HR, 1.27 per SD; 95% CI, 1.10-1.48; P = .001 and HR, 1.27 per SD; 95% CI, 1.10-1.47; P = .001, respectively). Furthermore, CML levels were independently related to increased mortality (P = .006). Whereas sRAGE levels were univariately predictive for outcome, in multivariate models sRAGE did not reach statistical significance. Discussion: In HF patients, both CML and pentosidine predict HF hospitalization and the combined primary end-point (mortality or HF-hospitalization), whereas sRAGE did not predict events. In addition, CML was significantly and independently associated with a higher risk for mortality. [Copyright &y& Elsevier]

Erythropoietin (EPO) is a hypoxia-induced hormone produced in the kidneys that stimulates hematopoiesis in the bone marrow. However, recent studies have also shown important nonhematopoietic effects of EPO. A functional EPO receptor is found in the cardiovascular system, including endothelial cells and cardiomyocytes. In animal studies, treatment with EPO during ischemia/reperfusion in the heart has been shown to limit the infarct size and the extent of apoptosis. In the longer term, EPO may promote ischemia-induced neovascularization, either by stimulating endothelial cells in situ or by mobilizing endothelial progenitor cells from bone marrow. The effects of EPO in the ischemic heart support the concept of EPO as a pleiotropic, tissue-protective agent for other organs expressing the EPO receptor. We recently performed a first randomized clinical study showing the safety and feasibility of EPO administration in patients with acute myocardial infarction. Future clinical studies are warranted to translate the beneficial effects of EPO from basic experiments to cardiac patients. [Copyright &y& Elsevier]