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Stated preference studies in which information on the willingness to trade-off between the benefits and harms of medicines is elicited from patients or other stakeholders are becoming increasingly mainstream. Such trade-offs can mathematically be represented by a weighted additive function, with the weights, whose ratios determine how much an individual is willing to trade-off between the treatment attributes, being the response vector for the statistical analysis. One way of eliciting trade-off information is through multi-dimensional thresholding (MDT), which is a bisection-based approach that results in increasingly tight bounds on the values of the weights ratios. While MDT is cognitively less demanding than other, more direct elicitation methods, its use complicates the statistical analysis as it results in weights data that are region censored. In this article, we present a simulated maximum likelihood (SML) procedure for fitting a Dirichlet population model directly to the region-censored weights data and perform a series of computational experiments to compare the proposed SML procedure to a naive approach in which a Dirichlet distribution is fitted to the centroids of the weights boundaries obtained with MDT. The results indicate that the SML procedure consistently outperformed the centroid-based approach, with the centroid-based approach requiring three bisection steps per trade-off to achieve a similar precision as the SML procedure with one bisection step per trade-off. Using the newly proposed SML procedure, MDT can be applied with smaller sample sizes or with fewer questions compared to the more naive centroid-based approach that was applied in previous applications of MDT.

Background Recent data suggest different causes of renal dysfunction between heart failure with reduced (HFrEF) versus preserved ejection fraction (HFpEF). We therefore studied a wide range of urinary markers reflecting different nephron segments in heart failure patients. Methods In 2070, in chronic heart failure patients, we measured several established and upcoming urinary markers reflecting different nephron segments. Results Mean age was 70 ± 12 years, 74% was male and 81% (n = 1677) had HFrEF. Mean estimated glomerular filtration rate (eGFR) was lower in patients with HFpEF (56 ± 23 versus 63 ± 23 ml/min/1.73 m2, P = 0.001). Patients with HFpEF had significantly higher values of NGAL (58.1 [24.0–124.8] versus 28.1 [14.6–66.9] μg/gCr, P P = 0.001). These differences were more pronounced in patients with an eGFR > 60 ml/min/1.73m2. Conclusions HFpEF patients showed more evidence of tubular damage and/or dysfunction compared with HFrEF patients, in particular when glomerular function was preserved.

OBJECTIVES This study sought to estimate and compare the aggregate treatment benefit of pharmacological therapy for heart failure (HF) with reduced ejection fraction. BACKGROUND The estimated treatment effects of various combinations of contemporary HF medical therapies are not well characterized. METHODS We performed a systematic network meta-analysis, using MEDLINE/EMBASE and the Cochrane Central Register of Controlled Trials for randomized controlled trials published between January 1987 and January 2020. We included angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers (BB), mineralocorticoid receptor antagonists (MRAs), digoxin, hydralazine-isosorbide dinitrate, ivabradine, angiotensin receptor-neprilysin inhibitors (ARNi), sodium glucose cotransporter-2 inhibitors (SGLT2i), vericiguat, and omecamtiv-mecarbil. The primary outcome was all-cause death. We estimated the life-years gained in 2 HF populations (BIOSTAT-CHF [BIOlogy Study to TAilored Treatment in Chronic Heart Failure] and ASIAN-HF [Asian Sudden Cardiac Death in Heart Failure Registry]). RESULTS We identified 75 relevant trials representing 95,444 participants. A combination of ARNi, BB, MRA, and SGLT2i was most effective in reducing all-cause death (HR: 0.39; 95% CI: 0.31-0.49); followed by ARNi, BB, MRA, and vericiguat (HR: 0.41; 95% CI: 0.32-0.53); and ARNi, BB, and MRA (HR: 0.44; 95% CI: 0.36-0.54). Results were similar for the composite outcome of cardiovascular death or first hospitalization for HF (HR: 0.36; 95% CI: 0.29-0.46 for ARNi, BB, MRA, and SGLT2i; HR: 0.44; 95% CI: 0.35-0.56 for ARNi, BB, MRA, and omecamtiv-mecarbil; and HR: 0.43; 95% CI: 0.34-0.55 for ARNi, BB, MRA, and vericiguat). The estimated additional number of life-years gained for a 70-year-old patient on ARNi, BB, MRA, and SGLT2i was 5.0 years (2.5-7.5 years) compared with no treatment in secondary analyses. CONCLUSIONS In patients with HF with reduced ejection fraction, the estimated aggregate benefit is greatest for a combination of ARNi, BB, MRA, and SGLT2i. (J Am Coll Cardiol HF 2022;10:73-84) (c) 2022 by the American College of Cardiology Foundation.

ObjectivesThis study aimed to provide a perspective for the interpretation of exercise capacity (peakVO2) in patients with repaired Tetralogy of Fallot (patients with rTOF) by describing the course of peakVO2from patients aged 6–63 years.MethodsA retrospective study was performed between September 2001 and December 2016 in the German Heart Centre Munich, Germany, and in the University Medical Centre Groningen, the Netherlands. A total of 1175 cardiopulmonary exercise tests (CPETs) were collected from 586 patients with rTOF, 46% female. Maximal exertion was verified using a respiratory exchange ratio ≥1.00. PeakVO2was modelled using time-dependent multilevel models for repeated measurements (n=889 in 300 patients), and compared with subject-specific reference values calculated by the models of Bongerset aland Myliuset al.ResultsThe peakVO2of patients with rTOF was reduced at all ages. At the age of 6, the peakVO2was 614 mL/min (70% of predicted (95% CI 67 to 73)). The reduced increase in peakVO2during adolescence resulted in a significant lower maximum peakVO2of 1209 mL/min at 25 years (65% predicted, pConclusionsThis study provides a context for peakVO2across ages in patients with rTOF under contemporary treatment strategies. It showed that the reduction in peakVO2originates from childhood and declines over time. Sex differences in patients with rTOF were similar to natural existing sex differences.

RATIONALE: There is currently no data supporting specific dosing and weaning strategies for parental prostanoid therapy in children with pulmonary arterial hypertension (PAH).OBJECTIVES: To describe the clinical practice of intravenous (IV) or subcutaneous (SC) prostanoid therapy in pediatric PAH and identify dosing strategies associated with favorable outcome.METHODS: From an international multicenter cohort of 275 children with PAH, 98 patients that received IV/SC prostanoid therapy were retrospectively analyzed.RESULTS: IV/SC prostanoids were given as monotherapy (20%), or combined with other PAH-targeted drugs as dual (46%) or triple therapy (34%). The median time-averaged dose was 37 ng/kg/min, ranging 2-136 ng/kg/min. During follow up, IV/SC prostanoids were discontinued and transitioned to oral or inhaled PAH-targeted therapies in 29 patients. Time-dependent ROC analyses showed specific hemodynamic criteria at discontinuation of IV/SC prostanoids (mean pulmonary arterial pressure (mPAP)25 ng/kg/min), early start after diagnosis and combination with other PAH-targeted drugs were associated with better transplant-free survival.CONCLUSIONS: Early initiation of IV/SC prostanoids, higher doses of IV/SC prostanoids and combination with additional PAH-targeted therapy were associated with favorable outcome. Transition from IV/SC prostanoid therapy to oral or inhaled therapies is safe on the long-term in selected children, identified by reaching hemodynamic criteria for durable IV/SC prostanoid discontinuation while on IV/SC prostanoid therapy.

BackgroundLimited data exist on transitions across Kidney Disease Improving Global Outcomes (KDIGO) risk stages and association with new-onset heart failure (HF) in the general population.MethodsData were extacted from the first four clinical examinations of the PREVEND study. Participants were categorized into eGFR and albuminuria risk stages according to KDIGO Guideline. Multi-state model was fitted to estimate the transition rates across consecutive KDIGO risk stages and the association with new-onset HF.Results8569 participants were included at baseline. During a median follow-up of 12.6 years, 373 participants were diagnosed with new-onset HF and 710 participants had died before new-onset HF. The transition rate from low risk to intermediate risk stage did not differ between women and men; it increased from 0 to 10 transitions per 100 person-years from age 50 to 75 years. The transition rate from intermediate risk to high or very high risk stage increased exponentially with age, with women having lower rates (HR: 0.50, 95%CI: 0.34-0.76). Younger subjects and women were more likely to make a backward transition from intermediate risk to low risk stage. More advanced KDIGO risk stages were associated with increased risk of new-onset HF, and the risk association attenuates with age on the relative scale but strengthens with age on the absolute scale.ConclusionsSlowing the progression of KDIGO risk stages may result in an important reduction in the incidence of new-onset heart failure in this population of middle-aged subjects.

Background: Studies on serially measured GDF-15 (growth differentiation factor 15) in acute heart failure (HF) are limited. Moreover, several pathophysiological pathways contribute to HF. Therefore, we aimed to explore the (additional) prognostic value of serially measured GDF-15 using a multi-marker approach to more accurately predict HF risk. Methods: TRIUMPH (Translational Initiative on Unique and Novel Strategies for Management of Patients With Heart Failure) is a prospective cohort of 496 patients with acute HF who were enrolled in 14 hospitals in the Netherlands between 2009 and 2014. Blood sampling was scheduled at 7 moments during 1-year follow-up. GDF-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), ST2 (suppression of tumorigenicity 2), galectin-3, troponin I, and creatinine were measured in a central laboratory. We associated repeated measurements of these biomarkers with the composite primary end point of all-cause mortality and HF rehospitalization, using multivariable joint modeling. Results: Median age was 74 years, and 37% were women. Median baseline GDF-15 was 4632 pg/mL. The primary end point was reached in 188 (40%) patients. The average estimated GDF-15 level increased weeks before the primary end point was reached. The hazard ratio per 1 SD difference in log-GDF-15 was 2.14 (95% CI, 1.78–2.57) unadjusted, 1.96 (1.49–2.53) after adjustment for clinical confounders and 1.44 (1.05–1.91) when jointly modeled with all biomarkers. The adjusted HRs for NT-proBNP were 2.38 (1.78–3.33) and 1.52 (1.15–2.08), respectively. The multimarker model combining GDF-15, NT-proBNP, and troponin I provided a favorable risk discrimination (area under the curve=0.785). Conclusions: Sequentially measured GDF-15 independently and dynamically predicts risk of adverse outcomes during 1-year follow-up after index admission for acute HF. NT-proBNP remains a robust predictor among potential candidates. Multiple biomarkers should be considered for stratification in clinical practice. Registration: URL: https://www.trialregister.nl/trial/1783 ; Unique Identifier: NTR1893. (The trial can be found temporarily at https://trialsearch.who.int/Trial2.aspx?TrialID=NTR1893 .)

Albuminuria is an under-recognized component of chronic kidney disease definition, staging, and prognosis. Guidelines, particularly for hypertension, conflict on recommendations for urine albumin-to-creatinine ratio (ACR) measurement. Separately among 1 344 594 adults with diabetes and 2 334 461 nondiabetic adults with hypertension from the chronic kidney disease Prognosis Consortium, we assessed ACR testing, estimated the prevalence and incidence of ACR ≥30 mg/g and developed risk models for ACR ≥30 mg/g. The ACR screening rate (cohort range) was 35.1% (12.3%–74.5%) in diabetes and 4.1% (1.3%–20.7%) in hypertension. Screening was largely unrelated to the predicted risk of prevalent albuminuria. The median prevalence of ACR ≥30 mg/g across cohorts was 32.1% in diabetes and 21.8% in hypertension. Higher systolic blood pressure was associated with a higher prevalence of albuminuria (odds ratio [95% CI] per 20 mm Hg in diabetes, 1.50 [1.42–1.60]; in hypertension, 1.36 [1.28–1.45]). The ratio of undetected (due to lack of screening) to detected ACR ≥30 mg/g was estimated at 1.8 in diabetes and 19.5 in hypertension. Among those with ACR

Background: \ud 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.\ud \ud Methods and Results: \ud 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.\ud \ud Conclusions: \ud We demonstrate that the temporal evolution patterns of IL-6 in patients with AHF have additive prognostic value independent of changes in BNP.

Aims The relation between non-cardiac comorbidities and health-related quality of life (HRQoL) in patients with heart failure (HF) has been studied to a limited extent. To investigate the HRQoL and their determinants among HF patients with and without comorbidities. Methods and results TRIUMPH (TRanslational Initiative on Unique and novel strategies for Management of Patients with Heart failure) is a Dutch prospective, multicentre study enrolling 496 acute HF patients between 2009 and 2014. We included 334 patients who had completed the HRQoL questionnaires at baseline. The HRQoL was measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) en EuroQuality-of-life five Dimensions (EQ-5D). Comorbidity was defined as having a history of at least one of the following comorbidities: chronic kidney disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and/or cerebrovascular accident. Patients with comorbidity (n = 205, 61%) had lower scores on the physical limitation scale and clinical summary score of the KCCQ (P = 0.03 and P = 0.01, respectively). Female sex, COPD, previous HF, increasing body mass index (BMI), elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), high systolic blood pressure, and the presence of anxiety and/or depression negatively influenced the HRQoL among HF patients with comorbidity. Besides anxiety and depression, we hardly found any other determinant of HRQoL in patients without comorbidity. Conclusion Heart failure patients without comorbidity had better HRQoL than patients with comorbidity. Sex, previous HF, BMI, COPD, systolic blood pressure, NT-proBNP levels, and also anxiety and depression were determinants of HRQoL in patients with comorbidity. In those without comorbidity, apart from anxiety and depression, no further determinants of HRQoL were found.

Aims:\ud Severe deficiency of the essential trace element selenium can cause myocardial dysfunction although the mechanism at cellular level is uncertain. Whether, in clinical practice, moderate selenium deficiency is associated with worse symptoms and outcome in patients with heart failure is unknown.\ud \ud Methods and results:\ud BIOSTAT‐CHF is a multinational, prospective, observational cohort study that enrolled patients with worsening heart failure. Serum concentrations of selenium were measured by inductively coupled plasma mass spectrometry. Primary endpoint was a composite of all‐cause mortality and hospitalization for heart failure; secondary endpoint was all‐cause mortality. To investigate potential mechanisms by which selenium deficiency might affect prognosis, human cardiomyocytes were cultured in absence of selenium, and mitochondrial function and oxidative stress were assessed. Serum selenium concentration (deficiency) was

Background Loop diuretics are frequently prescribed to patients with heart failure and reduced ejection fraction (HFrEF) for the treatment of congestion; however, they might hamper uptitration of inhibitors of the renin–angiotensin system. Methods Loop diuretic dose at baseline was recorded in 2338 patients with HFrEF enrolled in BIOSTAT-CHF, an international study of HF patients on loop diuretic therapy who were eligible for uptitration of angiotensin-converting enzyme inhibitors (ACEi)/mineralocorticoid receptor antagonists (MRA). The association between loop diuretic dose and uptitration of ACEi/MRA to percentage of target dose was adjusted for a previously published model for likelihood of uptitration and a propensity score. Results Baseline median loop diuretic dose was 40 [40–100] mg of furosemide or equivalent. Higher doses of loop diuretics were associated with higher NYHA class and higher levels of NT-proBNP, more severe signs and symptoms of congestion, more frequent MRA use, and lower doses of ACEi reached at 3 and 9 months (all P P = 0.021), but not with uptitration of MRAs (P = 0.758). Higher doses of loop diuretics were independently associated with an increased risk of all-cause mortality or HF hospitalization [HR per doubling of loop diuretic dose: 1.06 (1.01–1.12), P = 0.021]. Conclusions Higher doses of loop diuretics limited uptitration of ACEi in patients with HFrEF and were associated with a higher risk of death and/or HF hospitalization, independent of their lower likelihood of uptitration and higher baseline risk. Graphic abstract This figure was created with images adapted from Servier Medical Art licensed under a Creative Commons Attribution 3.0

Objective:N-terminal pro-brain natriuretic peptide has an established role in the diagnosis and prognosis of heart failure. In Fontan patients, this peptide is often increased, but its diagnostic value in this particular non-physiologic, univentricular circulation is unclear. We investigated whether N-terminal pro-brain natriuretic peptide represents ventricular function or other key variables in Fontan patients.Methods and results:Ninety-five consecutive Fontan patients ≥10 years old who attended the outpatient clinic of the Center for Congenital Heart Diseases in 2012–2013 were included. Time since Fontan completion was 16 ± 9 years. Median N-terminal pro-brain natriuretic peptide was 114 (61–264) ng/l and was higher than gender-and age-dependent normal values in 54% of the patients. Peptide Z-scores were higher in patients in NYHA class III/IV compared to those in class I/II, but did not correlate with ventricular function assessed by MRI and echocardiography, nor with peak exercise capacity. Instead, peptide Z-scores significantly correlated with follow-up duration after Fontan completion (p < 0.001), right ventricular morphology (p = 0.004), indexed ventricular mass (p = 0.001), and inferior caval vein diameter (p < 0.001) (adjustedR2= 0.615).Conclusions:N-terminal pro-brain natriuretic peptide levels in Fontan patients correlate with functional class, but do not necessarily indicate ventricular dysfunction. Increased peptide levels were associated with a longer existence of the Fontan circulation, morphologic ventricular characteristics, and signs of increased systemic venous congestion. Since the latter are known to be key determinants of the performance of the Fontan circulation, these findings suggest increase in N-terminal pro-brain natriuretic peptide levels to indicate attrition of the Fontan circulation, independent of ventricular function.

Background It is uncertain that chronic heart failure (CHF) patients are susceptible to renal tubular damage with that of worsening renal function (WRF) preceding clinical outcomes.Hypothesis Changes in tubular damage biomarkers are stronger predictors of subsequent clinical events than changes in creatinine (Cr), and both have different clinical determinants.Methods During 2.2 years, we repeatedly simultaneously collected a median of 9 blood and 8 urine samples per patient in 263 CHF patients. We determined the slopes (rates of change) of the biomarker trajectories for plasma (Cr) and urinary tubular damage biomarkers N-acetyl-beta-d-glucosaminidase (NAG), and kidney-injury-molecule (KIM)-1. The degree of tubular injury was ranked according to NAG and KIM-1 slopes: increase in neither, increase in either, or increase in both; WRF was defined as increasing Cr slope. The composite endpoint comprised HF-hospitalization, cardiac death, left ventricular assist device placement, and heart transplantation.Results Higher baseline NT-proBNP and lower eGFR predicted more severe tubular damage (adjusted odds ratio, adj. OR [95%CI, 95% confidence interval] per doubling NT-proBNP: 1.26 [1.07-1.49]; per 10 mL/min/1.73 m(2) eGFR decrease 1.16 [1.03-1.31]). Higher loop diuretic doses, lower aldosterone antagonist doses, and higher eGFR predicted WRF (furosemide per 40 mg increase: 1.32 [1.08-1.62]; spironolactone per 25 mg decrease: 1.76 [1.07-2.89]; per 10 mL/min/1.73 m(2) eGFR increase: 1.40 [1.20-1.63]). WRF and higher rank of tubular injury individually entailed higher risk of the composite endpoint (adjusted hazard ratios, adj. HR [95%CI]: WRF 1.9 [1.1-3.4], tubular 8.4 [2.6-27.9]; when combined risk was highest 15.0 [2.0-111.0]).Conclusion Slopes of tubular damage and WRF biomarkers had different clinical determinants. Both predicted clinical outcome, but this association was stronger for tubular injury. Prognostic effects of both appeared independent and additive.

OBJECTIVE: To assess the association between serially measured N-terminal pro-B-type natriuretic peptide (NT-proBNP) serum levels and disease severity in children with pulmonary arterial hypertension (PAH), and to assess its predictive value for death or (heart-)lung transplantation.STUDY DESIGN: This was a longitudinal cohort study of the Dutch National Network for Pediatric Pulmonary Hypertension conducted between 2003 and 2017. Data on NT-proBNP and disease severity markers (World Health Organization Functional Class [WHO-FC], 6-minute walking distance [6MWD], and tricuspid annular plane systolic excursion [TAPSE]) were collected every 3 to 6 months from 82 children with PAH. The outcome measure was death or (heart-)lung transplantation. Also, NT-proBNP levels over time were compared between survivors and nonsurvivors.RESULTS: The median patient age was 8.8 years (IQR, 4.6-13.5 years), and 61% were female. The median duration of follow-up was 4.8 years (IQR, 1.9-10.0 years). At all times during the course of disease, higher NT-proBNP levels were associated with higher WHO-FC (β = 0.526; 95% CI, 0.451-0.600), lower 6MWD z-score (β = -0.587; 95% CI, -0.828 to -0.346), lower TAPSE z-score (β = -0.783; 95% CI, -1.016 to -0.549), and elevated risk of death or (heart-)lung transplantation (hazard ratio 16.61; 95% CI, 7.81-35.33). Compared with survivors, nonsurvivors had NT-proBNP levels that were higher at first measurement and increased exponentially over time (P = .005). Changes in NT-proBNP serum level over time were predictive of outcome.CONCLUSIONS: Throughout the disease course of pediatric PAH, serial measurements of NT-proBNP are associated with disease severity and transplant-free survival. Monitoring NT-proBNP levels over time provides important prognostic information that can support clinical decision making in combination with other established prognostic markers.

Comparability is a key concept in the evaluation of both manufacturing changes and biosimilars. It constitutes a pragmatic and flexible approach which recognises that biologicals are inherently variable and that minor variations in quality attributes are often clinically irrelevant. In this discussion paper, we argue that comparability exercises rely on a number of pragmatic criteria. These criteria have been remarkably robust for 20 years of comparability exercises; however, the increased scrutiny of biosimilar applications provides an impetus for both codification and improvement of criteria for establishing comparability. Such a more rigorous, methodologically sound, approach towards comparability seems both feasible and beneficial.

Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

BACKGROUND: Guideline-recommended doses of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), and β blockers are similar for men and women with heart failure with reduced ejection fraction (HFrEF), even though there are known sex differences in pharmacokinetics of these drugs. We hypothesised that there might be sex differences in the optimal dose of ACE inhibitors or ARBs and β blockers in patients with HFrEF.METHODS: We did a post-hoc analysis of BIOSTAT-CHF, a prospective study in 11 European countries of patients with heart failure in whom initiation and up-titration of ACE inhibitors or ARBs and β blockers was encouraged by protocol. We included only patients with left ventricular ejection fraction less than 40%, and excluded those who died within the first 3 months. Primary outcome was a composite of time to all-cause mortality or hospitalisation for heart failure. Findings were validated in ASIAN-HF, an independent cohort of 3539 men and 961 women with HFrEF.FINDINGS: Among 1308 men and 402 women with HFrEF from BIOSTAT-CHF, women were older (74 [12] years vs 70 [12] years, pINTERPRETATION: This study suggests that women with HFrEF might need lower doses of ACE inhibitors or ARBs and β blockers than men, and brings into question what the true optimal medical therapy is for women versus men.FUNDING: European Commission.

AIMS: Atrial fibrillation (AF) reduces quality of life (QoL). We aim to evaluate effects of targeted therapy of underlying conditions on QoL in patients with AF and heart failure (HF). METHODS AND RESULTS: The Routine versus Aggressive risk factor driven upstream rhythm Control for prevention of Early atrial fibrillation in heart failure (RACE 3) study randomized patients with early persistent AF and HF to targeted or conventional therapy. Both groups received guideline-driven treatment. The targeted group received four additional therapies: mineralocorticoid receptor antagonists; statins; angiotensin converting enzyme inhibitors and/or receptor blockers; and cardiac rehabilitation including physical activity, dietary restrictions, and counselling. Quality of life was analysed in 230 patients at baseline and 1 year with available Medical Outcomes Study Short-Form Health Survey (SF-36), University of Toronto AF Severity Scale (AFSS) questionnaires, and European Heart Rhythm Association (EHRA) class. Improvements in SF-36 subscales were larger in the targeted group for physical functioning (Δ12 ± 19 vs. Δ6 ± 22, P = 0.007), physical role limitations (Δ32 ± 41 vs. Δ17 ± 45, P = 0.018), and general health (Δ8 ± 16 vs. Δ0 ± 17, P

Aims: \ud The clinical correlates and consequences of atrial fibrillation (AF) might be different between heart failure with reduced vs. preserved ejection fraction (HFrEF vs. HFpEF). Biomarkers may provide insights into underlying pathophysiological mechanisms of AF in these different heart failure (HF) phenotypes.\ud \ud Methods and results: \ud We performed a retrospective analysis of the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF), which was an observational cohort. We studied 2152 patients with HFrEF [ejection fraction (EF

BackgroundPrognostic models developed in general cohorts with a mixture of heart failure (HF) phenotypes, though more widely applicable, are also likely to yield larger prediction errors in settings where the HF phenotypes have substantially different baseline mortality rates or different predictor-outcome associations. This study sought to use individual participant data meta-analysis to develop an HF phenotype stratified model for predicting 1-year mortality in patients admitted with acute HF.MethodsFour prospective European cohorts were used to develop an HF phenotype stratified model. Cox model with two rounds of backward elimination was used to derive the prognostic index. Weibull model was used to obtain the baseline hazard functions. The internal-external cross-validation (IECV) approach was used to evaluate the generalizability of the developed model in terms of discrimination and calibration.Results3577 acute HF patients were included, of which 2368 were classified as having HF with reduced ejection fraction (EF) (HFrEF; EF ConclusionsOur HF phenotype stratified model showed excellent generalizability across four European cohorts and may provide a useful tool in HF phenotype-specific clinical decision-making.

Aims: \ud This retrospective analysis sought to identify markers that might distinguish between acute heart failure (HF) and worsening HF in chronic outpatients.\ud \ud Methods and Results: \ud The BIOSTAT‐CHF index cohort included 2516 patients with new or worsening HF symptoms: 1694 enrolled as inpatients (acute HF) and 822 as outpatients (worsening HF in chronic outpatients). A validation cohort included 935 inpatients and 803 outpatients. Multivariable models were developed in the index cohort using clinical characteristics, routine laboratory values, and proteomics data to examine which factors predict adverse outcomes in both conditions and to determine which factors differ between acute HF and worsening HF in chronic outpatients, validated in the validation cohort.\ud \ud Patients with acute HF had substantially higher morbidity and mortality (6 months mortality was 12..3% for acute HF and 4..7% for worsening HF in chronic outpatients). Multivariable models predicting 180‐day mortality and 180‐day HF re‐admission differed substantially between acute HF and worsening HF in chronic outpatients. CA‐125 was the strongest single biomarker to distinguish acute HF from worsening HF in chronic outpatients, but only yielded a C‐index of 0..71. A model including multiple biomarkers and clinical variables achieved a high degree of discrimination with a C‐index of 0..913 in the index cohort and 0..901 in the validation cohort.\ud \ud Conclusion: \ud The study identifies different characteristics and predictors of outcome in acute HF patients as compared to outpatients with chronic HF developing worsening HF. The markers identified may be useful in better diagnosing acute HF and may become targets for treatment development.

Purpose Substantial differences between sexes exist with respect to cardiovascular diseases, including congenital heart disease. Nevertheless, clinical decisions in the long-term follow-up of patients with repaired tetralogy of Fallot (rTOF) are currently based on unisex thresholds for cardiac magnetic resonance (CMR) measurements. This study aimed to assess whether sex differences exist in cardiac adaptation to hemodynamic loading conditions in patients with rTOF. Methods and Results This cross-sectional, two-center, combined pediatric and adult cohort included 320 rTOF patients (163 males, 51%) who underwent routine CMR. Despite similar age (median and interquartile range [m + IQR] 23.4 [15.2–34.4] years), surgical history, and hemodynamic loading, males with rTOF demonstrated higher biventricular CMR-derived volumes and masses, indexed for body surface area, compared to females (e.g. m + IQR right ventricular (RV) end-diastolic volume: males 123 [100–151] mL/m2, females 114 [94–131] mL/m2, P = 0.007). Sex-specific Z-scores of biventricular volumes and masses were similar for males and females. RV volumes and masses correlated with hemodynamic loading, but these relations did not differ between sexes. Biventricular ejection fraction (EF) appeared to be lower in male patients, compared to female patients (e.g. m + IQR RVEF: males 48 [43–54]%, females 52 [46–57]%, P Conclusion Indexed ventricular volumes and masses are higher in males with rTOF, compared to females, similar to the healthy population. RV hypertrophy and dilatation correlated to loading conditions similarly for both sexes. However, under comparable loading conditions, males demonstrated more severe functional impairment. These results indicate that sex-differences should no longer be ignored in treatment strategies, including timing of pulmonary valve replacement.

Background We investigated serial serum levels of GDF‐15 (growth differentiation factor 15) in Fontan patients and their relation to outcome. Methods and Results In this single‐center prospective study of consecutive Fontan patients, serial serum GDF ‐15 measurement and clinical assessment was done at baseline (n=81) and after 2 years (n=51). The association between GDF ‐15 and the combined end point of all‐cause mortality, heart transplant listing, and Fontan‐related hospitalization was investigated. Median age at baseline was 21 years (interquartile range: 15–28 years). Median GDF ‐15 serum levels at baseline were 552 pg/mL (interquartile range: 453–729 pg/mL). GDF ‐15 serum levels correlated positively with age, age at Fontan initiation, New York Heart Association class, and serum levels of NT ‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) and ɣGT (γ‐glutamyltransferase) and negatively with exercise capacity. During a median follow‐up of 4.8 years (interquartile range: 3.3–5.5 years), the combined end point occurred in 30 patients (37%). Multivariate Cox regression showed that patients with the highest baseline GDF ‐15 (n=20, defined as the upper quartile) had a higher risk of hospitalization or death than the lowest 3 quartiles (hazard ratio [HR], 2.76; 95% CI , 1.27–6.00; P =0.011). After 2 years of follow‐up, patients in whom serum level of GDF ‐15 increased to >70 pg/mL (n=13) had a higher risk of hospitalization or death than the lowest 3 quartiles (HR, 2.69; 95% CI , 1.03–6.99; P =0.043). Conclusions In Fontan patients, elevated serum levels of GDF ‐15 are associated with worse functional status and predict Fontan‐related events. Furthermore, serial measurements showed that an increase in GDF ‐15 serum level was associated with increased risk for adverse outcome.

International audience; Aims: Heart failure (HF) is frequently caused by an ischaemic event (e.g. myocardial infarction) but might also be caused by a primary disease of the myocardium (cardiomyopathy). In order to identify targeted therapies specific for either ischaemic or non-ischaemic HF, it is important to better understand differences in underlying molecular mechanisms.Methods and results: We performed a biological physical protein-protein interaction network analysis to identify pathophysiological pathways distinguishing ischaemic from non-ischaemic HF. First, differentially expressed plasma protein biomarkers were identified in 1160 patients enrolled in the BIOSTAT-CHF study, 715 of whom had ischaemic HF and 445 had non-ischaemic HF. Second, we constructed an enriched physical protein-protein interaction network, followed by a pathway over-representation analysis. Finally, we identified key network proteins. Data were validated in an independent HF cohort comprised of 765 ischaemic and 100 non-ischaemic HF patients. We found 21/92 proteins to be up-regulated and 2/92 down-regulated in ischaemic relative to non-ischaemic HF patients. An enriched network of 18 proteins that were specific for ischaemic heart disease yielded six pathways, which are related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. We identified five key network proteins: acid phosphatase 5, epidermal growth factor receptor, insulin-like growth factor binding protein-1, plasminogen activator urokinase receptor, and secreted phosphoprotein 1. Similar results were observed in the independent validation cohort.Conclusions: Pathophysiological pathways distinguishing patients with ischaemic HF from those with non-ischaemic HF were related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. The five key pathway proteins identified are potential treatment targets specifically for patients with ischaemic HF.

OBJECTIVES: The aims of this study were to compare the characteristics of patients with and without diabetes and to use network analyses to compare biomarker profiles and associated pathways in patients with diabetes compared with those without diabetes, which might offer new avenues for potential therapeutic targets.BACKGROUND: Diabetes adversely affects clinical outcomes and complicates treatment in patients with heart failure (HF). A clear understanding of the pathophysiological processes associated with type 2 diabetes in HF is lacking.METHODS: Network and pathway over-representation analyses were performed to identify unique pathological pathways in patients with and without diabetes using 92 biomarkers from different pathophysiological domains measured in plasma samples from 1,572 patients with HF (31% with diabetes) with reduced ejection fraction (left ventricular ejection fraction RESULTS: Biomarker profiles were first compared between patients with HF with and without diabetes. Patients with diabetes showed higher levels of galectin-4, growth differentiation factor 15, and fatty acid binding protein 4 and lower levels of paraoxonase 3. Network analyses were then performed, revealing that epidermal growth factor receptor and galectin-3 were the most prominent connecting proteins. Translation of these networks to biologic pathways revealed that diabetes was associated with inflammatory response and neutrophil degranulation. Diabetes conferred worse outcomes after correction for an established risk model (hazard ratio: 1.20; 95% confidence interval: 1.01 to 1.42).CONCLUSIONS: Concomitant diabetes in patients with HF with reduced ejection fraction is associated with distinct pathophysiological pathways related to inflammation, protein phosphorylation, and neutrophil degranulation. These data support the evaluation of anti-inflammatory therapeutic approaches, epidermal growth factor receptor in particular, for patients with HF and diabetes.

There is an emerging consensus that evidence on patients’ perspectives provides crucial guidance for decision making throughout the medical product lifecycle (MPLC). Consid-ering the patient voice has become increasingly important for developers of new medical products and for authorities that assess, regulate and decide which products are effective, safe, well tolerated and cost effective [1, 2]. However, as key stakeholders, we lack a shared understanding about how to consider patient preferences in the MPLC [3]. This commentary captures opinions of thought leaders presenting at the symposium on “Patient preferences in the medical product lifecycle” in Basel, Switzerland in July 2019. The symposium was jointly sponsored by the Interna-tional Academy of Health Preference Research (http://www. iahpr .org) and the research project “Patient Preferences in Benefit and Risk Assessments during the Treatment Life Cycle” (PREFER; http://www.imi-prefe r.eu). This commen-tary is one of a series of papers reporting on health pref-erence research symposiums held alongside International Academy of Health Preference Research meetings [4–6].

Introduction: Patients with symptomatic heart failure (HF) require additive therapies and have a poor prognosis. However, patient characteristics and clinical outcome between HF patients treated in the outpatient setting vs. those who are hospitalized remain scarce. Methods and results: The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT‐CHF) included 2516 patients with symptoms and/or signs of HF: 1694 as inpatients and 822 as outpatients. Compared to ambulatory HF patients, inpatients had higher heart rate, urea, N‐terminal pro‐brain natriuretic peptide, lower blood pressure, lower estimated glomerular filtration rate, sodium, potassium, high‐density lipoprotein cholesterol, had more often peripheral oedema, diabetes, anaemia, and were less often treated with beta‐blockers and angiotensin‐converting enzyme inhibitors (ACEi). Outpatients had a more frequent history of HF hospitalization and received more frequently beta‐blockers and/or ACEi/angiotensin receptor blockers up‐titrated to target doses (P

AIMS: Cathepsin D is a ubiquitous lysosomal protease that is primarily secreted due to oxidative stress. The role of circulating cathepsin D in heart failure (HF) is unknown. The aim of this study is to determine the association between circulating cathepsin D levels and clinical outcomes in patients with HF and to investigate the biological settings that induce the release of cathepsin D in HF. METHODS AND RESULTS: Cathepsin D levels were studied in 2174 patients with HF from the BIOSTAT-CHF index study. Results were validated in 1700 HF patients from the BIOSTAT-CHF validation cohort. The primary combined outcome was all-cause mortality and/or HF hospitalizations. Human pluripotent stem cell-derived cardiomyocytes were subjected to hypoxic, pro-inflammatory signalling and stretch conditions. Additionally, cathepsin D expression was inhibited by targeted short hairpin RNAs (shRNA). Higher levels of cathepsin D were independently associated with diabetes mellitus, renal failure and higher levels of interleukin-6 and N-terminal pro-B-type natriuretic peptide (P

Aims: Atrial fibrillation (AF) is a progressive disease. Targeted therapy of underlying conditions refers to interventions aiming to modify risk factors in order to prevent AF. We hypothesised that targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent AF.Methods and results: We randomized patients with early persistent AF and mild-to-moderate heart failure (HF) to targeted therapy of underlying conditions or conventional therapy. Both groups received causal treatment of AF and HF, and rhythm control therapy. In the intervention group, on top of that, four therapies were started: (i) mineralocorticoid receptor antagonists (MRAs), (ii) statins, (iii) angiotensin converting enzyme inhibitors and/or receptor blockers, and (iv) cardiac rehabilitation including physical activity, dietary restrictions, and counselling. The primary endpoint was sinus rhythm at 1 year during 7 days of Holter monitoring. Of 245 patients, 119 were randomized to targeted and 126 to conventional therapy. The intervention led to a contrast in MRA (101 [85%] vs. 5 [4%] patients, P Conclusions: RACE 3 confirms that targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent AF.Trial Registration number: Clinicaltrials.gov NCT00877643.

Aims: A higher body mass index (BMI) is associated with better survival in heart failure (HF) patients, also known as the obesity paradox. However, BMI does not account for body composition. We therefore analysed the association between abdominal fat, measured via waist‐to‐hip ratio (WHR), BMI and all‐cause mortality in patients with HF. Methods and results: For this analysis, 1738 patients from the Scottish BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT‐CHF) validation study were included. Patients without waist and hip measurements were excluded. WHR was defined as waist circumference/hip circumference, divided into tertiles and split for sex. A linear regression of principal components from an extensive panel of biomarkers was performed to provide insight in the pathophysiology behind a higher WHR. In total, 1479 patients were included, of which 33% were female and mean age was 75 ±11 years. A higher WHR was independently associated with a higher BMI, a higher prevalence of diabetes and higher New York Heart Association functional class. There was a significant interaction between sex and WHR on its association with mortality (P

Edita Lycholip,1,2 Ina Thon Aamodt,3,4 Irene Lie,3 Toma Šimbelytė,5 Roma Puronaitė,2,6,7 Hans Hillege,8 Arjen de Vries,8 Imke Kraai,9 Anna Stromberg,10 Tiny Jaarsma,11 Jelena Čelutkienė1,2 1Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania; 2Center of Cardiology and Angiology, Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania; 3Centre for Patient-Centered Heart and Lung Research, Department of Cardiothoracic Surgery, Division of Cardiovascular and Pulmonary Diseases, Oslo University Hospital, Oslo, Norway; 4Department of Nursing Science, Institute of Health and Society, Faculty of Medicine, University of Oslo, Oslo, Norway; 5Clinic of Internal Medicine, Centre of Family and Internal Medicine, Vilnius University Santaros Clinics, Vilnius University, Vilnius, Lithuania; 6Centre of Informatics and Development, Vilnius University Hospital Santaros Clinics, Vilnius, Lithuania; 7Institute of Mathematics and Informatics, Vilnius University, Vilnius, Lithuania; 8Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 9PRA Health Sciences – Early Development Services, Groningen, the Netherlands; 10Department of Medical and Health Sciences, Linkoping University, Linkoping, Sweden; 11Department of Social and Welfare Studies, Linkoping University, Norrkoping, Sweden Introduction: Self-care is an important patient-reported outcome (PRO) for heart failure (HF) patients, which might be affected by disease management and/or telemonitoring (TM). The number of studies reporting the influence of TM on self-care is limited.Aims: This study aimed: to assess whether TM, in addition to information-and-communication-technology (ICT)-guided disease management system (ICT-guided DMS), affects self-care behavior; to evaluate the dynamics of self-care during the study; to investigate factors contributing to self-care changes; and to identify a patient profile that predisposes the patient to improvement in self-care. Methods: In the INnovative ICT-guided-DMS combined with Telemonitoring in OUtpatient clinics for Chronic HF patients (IN TOUCH) study, 177 patients were randomized to either ICT-guided DMS or TM+ICT-guided DMS, with a follow-up of 9months. The current analysis included 118 participants (mean age: 69±11.5years; 70% male) who filled the following PRO instruments: the nine-item European Heart Failure Self-care Behaviour scale (EHFScBs), Hospital Anxiety and Depression scale (HADs), and Minnesota Living with HF Questionnaire (MLHFQ). Results: The baseline level of self-care was better in the TM+ICT-guided-DMS group (n=58) compared to ICT-guided-DMS group (n=60, p=0.023). Self-care behavior improved in the ICT-guided-DMS group (p28, or from 17 to 28 with concomitant HADs depression subscale (HADs_D) score ≤8, demonstrated the greatest potential to improve self-care during the study. Conclusion: TM did not have an advantage on self-care improvement. Poor physical aspect of quality of life, lower LVEF, and lower NYHA class were associated with self-care worsening. The greatest self-care improvement may be achieved in those patients who have low or medium initial self-care level in the absence of depression. Keywords: heart failure, self-care, telemonitoring, disease management, patient-reported outcomes

Renal dysfunction is an important component of chronic heart failure (CHF), but its single assessment does not sufficiently reflect clinically silent progression of CHF prior to adverse clinical outcome. Therefore, we aimed to investigate temporal evolutions of glomerular and tubular markers in 263 stable patients with CHF, and to determine if their patient-specific evolutions during this clinically silent period can dynamically predict clinical outcome. We determined the risk of clinical outcome (composite endpoint of Heart Failure hospitalization, cardiac death, Left Ventricular Assist Device placement, and heart transplantation) in relation to marker levels, slopes and areas under their trajectories. In each patient, the trajectories were estimated using repeatedly measured glomerular markers: creatinine/estimated glomerular filtration rate (eGFR), cystatin C (CysC), and tubular markers: urinary N-acetyl-beta-D-glucosaminidase (NAG) and kidney injury molecule (KIM)-1, plasma and urinary neutrophil gelatinase-associated lipocalin (NGAL). During 2.2 years of follow-up, we collected on average 8 urine and 9 plasma samples per patient. All glomerular markers predicted the endpoint (univariable hazard ratio [95% confidence interval] per 20% increase: creatinine: 1.18 [1.07-1.31], CysC: 2.41[ 1.81-3.41], and per 20% eGFR decrease: 1.13[1.05-1.23]). Tubular markers, NAG, and KIM-1 also predicted the endpoint (NAG: 1.06[1.01-1.11] and KIM-1: 1.08[1.04-1.11]). Larger slopes were the strongest predictors (creatinine: 1.57[1.39-1.84], CysC: 1.76 [1.52-2.09], eGFR: 1.59[1.37-1.90], NAG: 1.26[1.11-1.44], and KIM-1: 1.64[1.38-2.05]). Associations persisted after multivariable adjustment for clinical characteristics. Thus, during clinically silent progression of CHF, glomerular and tubular functions deteriorate, but not simultaneously. Hence, patient-specific evolutions of these renal markers dynamically predict clinical outcome in patients with CHF.

Background: Fibroblast growth factor (FGF) 23 is a hormone that increases urinary phosphate excretion and regulates renal sodium reabsorption and plasma volume. We studied the role of plasma FGF23 in therapy optimization and outcomes in patients with new-onset and worsening heart failure (HF).Methods: We measured plasma C-terminal FGF23 levels at baseline in 2399 of the 2516 patients included in the BIOlogy Study to Tailored Treatment in Chronic HF (BIOSTAT-CHF) trial. The association between FGF23 and outcome was evaluated by Cox regression analysis adjusted for potential confounders.Results: Median FGF23 was 218.0 [IQR: 117.1-579.3] RU/ml; patients with higher FGF23 levels had a worse NYHA class, more signs of congestion, and were less likely to use an ACE-inhibitor (ACEi) or angiotensin receptor blocker (ARBs) at baseline (all P Conclusions: In patients with new-onset and worsening HF, higher plasma FGF23 levels were independently associated with volume overload, less successful uptitration of ACEi/ARBs and an increased risk of all-cause mortality and HF hospitalization. (c) 2017 Elsevier B.V. All rights reserved.

Prognosis in children with pulmonary vascular disease (PVD) is closely linked to right ventricular (RV) failure due to increased RV-afterload. Pulmonary arterial (PA) stiffening is known to occur early in the course of PVD and constitutes a main component of RV-afterload. This study aimed to evaluate the clinical value of PA-stiffness in children with PVD by determining its association with advanced pulmonary arterial hypertension (PAH) and mortality at long-term follow-up.Forty-one children with various stages of arterial PVD, defined as mean PA-pressure ≥20 mmHg and/or pulmonary-to-systemic flow-ratio ≥1.2, and mean pulmonary capillary wedge pressure 15 mmHg, underwent cardiac catheterization with intravascular ultrasound (IVUS) imaging between 1994 and 1997 with follow-up until 2015. PA-stiffness indices evaluated were PA-area-compliance (PA-compliance) and PA-area-distensibility (PA-distensibility). During follow-up, advanced PAH was determined by echocardiography and cardiac catheterization. During a median follow-up of 19 years, in 31 (76%) patients PVD had reversed and 10 (24%) had advanced PAH. Six (15%) died due to PVD. In addition to conventional haemodynamics, PA-compliance and PA-distensibility were associated with advanced PAH at long-term follow-up (adjusted OR [95% CI] 0.56 [0.37-0.85] and 0.52 [0.31-0.86]), and mortality (adjusted HR [95% CI] 0.60 [0.41-0.87] and 0.67 [0.49-0.90]). Also in a subgroup of patients with favourable haemodynamics, baseline PA-compliance and PA-distensibility were lower in patients with advanced PAH at follow-up (P = 0.002 /P = 0.030).In children with PVD, PA-stiffness indices assessed by IVUS predict advanced PAH and mortality at long term follow-up. Especially in patients with favourable haemodynamics, assessment of intrinsic PA-stiffness may enhance the prognostication of disease progression and survival.

Background: Hyperkalaemia is a common co-morbidity in patients with heart failure with reduced ejection fraction (HFrEF). Whether it affects the use of renin–angiotensin–aldosterone system inhibitors and thereby negatively impacts outcome is unknown. Therefore, we investigated the association between potassium and uptitration of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and its association with outcome. Methods and results: Out of 2516 patients from the BIOSTAT-CHF study, potassium levels were available in 1666 patients with HFrEF. These patients were sub-optimally treated with ACEi/ARB or beta-blockers and were anticipated and encouraged to be uptitrated. Potassium levels were available at inclusion and at 9 months. Outcome was a composite of all-cause mortality and heart failure hospitalization at 2 years. Patients' mean age was 67 ± 12 years and 77% were male. At baseline, median serum potassium was 4.3 (interquartile range 3.9–4.6) mEq/L. After 9 months, 401 (24.1%) patients were successfully uptitrated with ACEi/ARB. During this period, mean serum potassium increased by 0.16 ± 0.66 mEq/L (P 0.5 for all). Conclusion: Higher potassium levels are an independent predictor of enduring lower dosages of ACEi/ARB. Higher potassium levels do not attenuate the beneficial effects of ACEi/ARB uptitration.

Background: Comorbidities play a major role in heart failure. Whether prevalence and prognostic importance of comorbidities differ between heart failure with preserved ejection fraction (HFpEF), mid-range (HFmrEF) or reduced ejection fraction (HFrEF) is unknown.Methods: Patients from index (n=2516) and validation cohort (n=1738) of The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) were pooled. Eight non-cardiac comorbidities were assessed; diabetes mellitus, thyroid dysfunction, obesity, anaemia, chronic kidney disease (CKD, estimated glomerular filtration rate Results: Patients with complete comorbidity data were included (n=3499). Most prevalent comorbidity was CKD (50%). All comorbidities showed the highest prevalence in HFpEF, except for stroke. Prevalences of HFmrEF were in between the other entities. COPD was the comorbidity associated with the greatest reduction in QoL. In HFrEF, almost all were associated with a significant reduction in QoL, while in HFpEF only CKD and obesity were associated with a reduction. Most comorbidities in HFrEF were associated with an increased mortality risk, while in HFpEF only CKD, anaemia and COPD were associated with higher mortality risks.Conclusions: The highest prevalence of comorbidities was seen in patients with HFpEF. Overall, comorbidities were associated with a lower QoL, but this was more pronounced in patients with HFrEF. Most comorbidities were associated with higher mortality risks, although the associations with diabetes were only present in patients with HFrEF. (c) 2018 The Authors. Published by Elsevier B.V.

Objectives: This study evaluated the associations of obesity and cardiometabolic traits with incident heart failure with preserved versus reduced ejection fraction (HFpEF vs. HFrEF). Given known sex differences in HF subtype, we examined men and women separately.Background: Recent studies suggest that obesity confers greater risk of HFpEF versus HFrEF. Contributions of associated metabolic traits to HFpEF are less clear.Methods: We studied 22,681 participants from 4 community-based cohorts followed for incident HFpEF versus HFrEF (ejection fraction ≥50% vs. Results: The mean age was 60 ± 13 years, and 53% were women. Over a median follow-up of 12 years, 628 developed incident HFpEF and 835 HFrEF. Greater BMI portended higher risk of HFpEF compared with HFrEF (hazard ratio [HR]: 1.34 per 1-SD increase in BMI; 95% confidence interval [CI]: 1.24 to 1.45 vs. HR: 1.18; 95% CI: 1.10 to 1.27). Similarly, insulin resistance (homeostatic model assessment of insulin resistance) was associated with HFpEF (HR: 1.20 per 1-SD; 95% CI: 1.05 to 1.37), but not HFrEF (HR: 0.99; 95% CI: 0.88 to 1.11; p < 0.05 for difference HFpEF vs. HFrEF). We found that the differential association of BMI with HFpEF versus HFrEF was more pronounced among women (p for difference HFpEF vs. HFrEF = 0.01) when compared with men (p = 0.34).Conclusions:Obesity and related cardiometabolic traits including insulin resistance are more strongly associated with risk of future HFpEF versus HFrEF. The differential risk of HFpEF with obesity seems particularly pronounced among women and may underlie sex differences in HF subtypes.

Background Heart failure guidelines recommend up-titration of angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) to doses used in randomized clinical trials, but these recommended doses are often not reached. Up-titration may, however, not be necessary in all patients. Objectives This study sought to establish the role of blood biomarkers to determine which patients should or should not be up-titrated. Methods Clinical outcomes of 2,516 patients with worsening heart failure from the BIOSTAT-CHF (BIOlogy Study to Tailored Treatment in Chronic Heart Failure) were compared between 3 theoretical treatment scenarios: scenario A, in which all patients are up-titrated to >50% of recommended doses; scenario B, in which patients are up-titrated according to a biomarker-based treatment selection model; and scenario C, in which no patient is up-titrated to >50% of recommended doses. The study conducted multivariable Cox regression using 161 biomarkers and their interaction with treatment, weighted for treatment-indication bias to estimate the expected number of deaths or heart failure hospitalizations at 24 months for all 3 scenarios. Results Estimated death or hospitalization rates in 1,802 patients with available (bio)markers were 16%, 16%, and 26%, respectively, in the ACE inhibitor/ARB up-titration scenarios A, B, and C. Similar rates for beta-blocker and MRA up-titration scenarios A, B, and C were 23%, 19%, and 24%, and 12%, 11%, and 24%, respectively. If up-titration was successful in all patients, an estimated 9.8, 1.3, and 12.3 events per 100 treated patients could be prevented at 24 months by ACE inhibitor/ARB, beta-blocker, and MRA therapy, respectively. Similar numbers were 9.9, 4.7, and 13.1 if up-titration treatment decision was based on a biomarker-based treatment selection model. Conclusions Up-titrating patients with heart failure based on biomarker values might have resulted in fewer deaths or hospitalizations compared with a hypothetical scenario in which all patients were successfully up-titrated.

Aims: Previously, low high-density lipoprotein (HDL) cholesterol was found to be one of the strongest predictors of mortality and/or heart failure (HF) hospitalisation in patients with HF. We therefore performed in-depth investigation of the multifunctional HDL proteome to reveal underlying pathophysiological mechanisms explaining the association between HDL and clinical outcome. Methods and results: We selected a cohort of 90 HF patients with 1:1 cardiovascular death/survivor ratio from BIOSTAT-CHF. A novel optimised protocol for selective enrichment of lipoproteins was used to prepare plasma. Enriched lipoprotein content of samples was analysed using high resolution nanoscale liquid chromatography-mass spectrometry-based proteomics, utilising a label free approach. Within the HDL proteome, 49 proteins significantly differed between deaths and survivors. An optimised model of 12 proteins predicted death with 76% accuracy (Nagelkerke R2=0.37, P

Aims While heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) are well described, determinants and outcomes of heart failure with mid-range ejection fraction (HFmrEF) remain unclear. We sought to examine clinical and biochemical predictors of incident HFmrEF in the community. Methods and results We pooled data from four community-based longitudinal cohorts, with ascertainment of new heart failure (HF) classified into HFmrEF [ejection fraction (EF) 41-49%], HFpEF (EF ≥50%), and HFrEF (EF ≤40%). Predictors of incident HF subtypes were assessed using multivariable Cox models. Among 28 820 participants free of HF followed for a median of 12 years, there were 200 new HFmrEF cases, compared with 811 HFpEF and 1048 HFrEF. Clinical predictors of HFmrEF included age, male sex, systolic blood pressure, diabetes mellitus, and prior myocardial infarction (multivariable adjusted P ≤ 0.003 for all). Biomarkers that predicted HFmrEF included natriuretic peptides, cystatin-C, and high-sensitivity troponin (P ≤ 0.0004 for all). Natriuretic peptides were stronger predictors of HFrEF [hazard ratio (HR) 2.00 per 1 standard deviation increase, 95% confidence interval (CI) 1.81-2.20] than of HFmrEF (HR 1.51, 95% CI 1.20-1.90, P = 0.01 for difference), and did not differ in their association with incident HFmrEF and HFpEF (HR 1.56, 95% CI 1.41-1.73, P = 0.68 for difference). All-cause mortality following the onset of HFmrEF was worse than that of HFpEF (50 vs. 39 events per 1000 person-years, P = 0.02), but comparable to that of HFrEF (46 events per 1000 person-years, P = 0.78). Conclusions We found overlap in predictors of incident HFmrEF with other HF subtypes. In contrast, mortality risk after HFmrEF was worse than HFpEF, and similar to HFrEF.