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Aims: In patients with chronic heart failure with reduced ejection fraction (HFrEF), myocardial ketone metabolism is increased and short-term treatment with the ketone body 3-hydroxy butyrate (3-OHB) has beneficial haemodynamic effects. In patients with HFrEF, we investigated whether the level of circulating 3-OHB predicted all-cause mortality and sought to identify correlations between patient characteristics and circulating 3-OHB levels., Methods and Results: We conducted a cohort study in 218 patients with HFrEF. Plasma 3-OHB levels were measured using high-performance liquid chromatography tandem mass spectrometry. Data on all-cause mortality were obtained by reviewing the patients' medical records, which are linked to the national 'Central Person Registry' that registers the timing of all deaths in the country. Mean left ventricular ejection fraction was 35 ± 8.6%, mean age was 67 ± 10 years, 54% were New York Heart Association II, and 27% had type 2 diabetes mellitus. Median follow-up time was 7.3 (interquartile range 6.3-8.4) years. We observed large variations in 3-OHB levels between patients (median 59 μM, range: 14-694 μM). Patients with 3-OHB levels above the median displayed a markedly increased risk of death compared with those with low levels {hazard ratio [HR]: 2.1 [95% confidence interval (CI): 1.3-3.5], P = 0.003}. In a multivariate analysis, 3-OHB predicted mortality independently of known chronic heart failure risk factors [HR: 1.004 (95% CI: 1.001-1.007), P = 0.02] and with a similar statistical strength as N-terminal pro-brain natriuretic peptide (NT-proBNP) [HR: 1.0005 (95% CI: 1.000-1.001), P = 0.02]. For every 100 μmol increase in plasma 3-OHB, the hazard of death increased by 49%. The following factors significantly predicted 3-OHB levels in the univariate analysis: free fatty acids (FFAs) [β: 238 (95% CI: 185-292), P < 0.0001], age [β: 2.43 (95% CI: 1.14-3.72), P < 0.0001], plasma insulin {β: -0.28 [95% CI: -0.54-(-0.02)], P = 0.036}, body mass index {β: -3.15 [95% CI: -5.26-(-0.05)], P = 0.046}, diabetes [β: 44.49 (95% CI: 14.84-74.14), P = 0.003], glycosylated haemoglobin [β: 1.92 (95% CI: 0.24-3.59), P = 0.025], New York Heart Association class [β: 26.86 (95% CI: 5.99-47.72), P = 0.012], and NT-proBNP [β: 0.03 (95% CI: 0.01-0.04), P = 0.001]. In a multivariate analysis, only FFAs predicted 3-OHB levels [β: 216 (95% CI: 165-268), P > 0.001]., Conclusions: In patients with HFrEF, circulating 3-OHB was a strong predictor of all-cause mortality independently of NT-proBNP. Circulating FFAs were the best predictor of 3-OHB levels., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Patients suffering from chronic ischaemic heart failure with reduced left ventricular ejection fraction (HFrEF) have reduced quality-of-life, repetitive hospital admissions, and reduced life expectancy. Allogeneic cell therapy is currently investigated as a potential treatment option after initially encouraging results from clinical autologous and allogeneic trials in patients with HFrEF. We aimed to investigate the allogeneic Cardiology Stem Cell Centre Adipose tissue derived mesenchymal Stromal Cell product (CSCC&#95;ASC) as an add-on therapy in patients with chronic HFrEF., Methods and Results: This is a Danish multi-centre double-blinded placebo-controlled phase II study with direct intra-myocardial injections of allogeneic CSCC&#95;ASC. A total of 81 HFrEF patients were included and randomized 2:1 to CSCC&#95;ASC or placebo injections. The inclusion criteria were reduced left ventricular ejection fraction (LVEF ≤ 45%), New York Heart Association (NYHA) class II-III despite optimal anti-congestive heart failure medication and no further revascularization options. Injections of 0.3 mL CSCC&#95;ASC (total cell dose 100 × 10 6 ASCs) (n = 54) or isotonic saline (n = 27) were performed into the viable myocardium in the border zone of infarcted tissue using the NOGA Myostar® catheter (Biological Delivery System, Cordis, Johnson & Johnson, USA). The primary endpoint, left ventricular end systolic volume (LVESV), was evaluated at 6-month follow-up. The safety was measured during a 3-years follow-up period., Results: Mean age was 67.0 ± 9.0 years and 66.6 ± 8.1 years in the ASC and placebo groups, respectively. LVESV was unchanged from baseline to 6-month follow-up in the ASC (125.7 ± 68.8 mL and 126.3 ± 72.5 mL, P = 0.827) and placebo (134.6 ± 45.8 mL and 135.3 ± 49.6 mL, P = 0.855) group without any differences between the groups (0.0 mL (95% CI -9.1 to 9.0 mL, P = 0.992). Neither were there significant changes in left ventricular end diastolic volume or LVEF within the two groups or between groups -5.7 mL (95% CI -16.7 to 5.3 mL, P = 0.306) and -1.7% (95% CI -4.4. to 1.0, P = 0.212), respectively). NYHA classification and 6-min walk test did not alter significantly in the two groups (P > 0.05). The quality-of-life, total symptom, and overall summary score improved significantly only in the ASC group but not between groups. There were 24 serious adverse events (SAEs) in the ASC group and 11 SAEs in the placebo group without any significant differences between the two groups at 1-year follow-up. Kaplan-Meier plot using log-rank test of combined cardiac events showed an overall mean time to event of 30 ± 2 months in the ASC group and 29 ± 2 months in the placebo group without any differences between the groups during the 3 years follow-up period (P = 0.994)., Conclusions: Intramyocardial CSCC&#95;ASC injections in patients with chronic HFrEF were safe but did not improve myocardial function or structure, nor clinical symptoms., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: To define plasma concentrations, determinants, and optimal prognostic cut-offs of soluble suppression of tumorigenesis-2 (sST2), high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in women and men with chronic heart failure (HF)., Methods and Results: Individual data of patients from the Biomarkers In Heart Failure Outpatient Study (BIOS) Consortium with sST2, hs-cTnT, and NT-proBNP measured were analysed. The primary endpoint was a composite of 1 year cardiovascular death and HF hospitalization. The secondary endpoints were 5 year cardiovascular and all-cause death. The cohort included 4540 patients (age 67 ± 12 years, left ventricular ejection fraction 33 ± 13%, 1111 women, 25%). Women showed lower sST2 (24 vs. 27 ng/mL, P < 0.001) and hs-cTnT level (15 vs. 20 ng/L, P < 0.001), and similar concentrations of NT-proBNP (1540 vs. 1505 ng/L, P = 0.408). Although the three biomarkers were confirmed as independent predictors of outcome in both sexes, the optimal prognostic cut-off was lower in women for sST2 (28 vs. 31 ng/mL) and hs-cTnT (22 vs. 25 ng/L), while NT-proBNP cut-off was higher in women (2339 ng/L vs. 2145 ng/L). The use of sex-specific cut-offs improved risk prediction compared with the use of previously standardized prognostic cut-offs and allowed to reclassify the risk of many patients, to a greater extent in women than men, and for hs-cTnT than sST2 or NT-proBNP. Specifically, up to 18% men and up to 57% women were reclassified, by using the sex-specific cut-off of hs-cTnT for the endpoint of 5 year cardiovascular death., Conclusions: In patients with chronic HF, concentrations of sST2 and hs-cTnT, but not of NT-proBNP, are lower in women. Lower sST2 and hs-cTnT and higher NT-proBNP cut-offs for risk stratification could be used in women., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in patients with heart failure (HF). We assessed the influence of COPD on circulating levels and prognostic value of three HF biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), and soluble suppression of tumorigenesis-2 (sST2)., Methods: Individual data from patients with chronic HF, known COPD status, NT-proBNP and hs-TnT values (n = 8088) were analysed. A subgroup (n = 3414) had also sST2 values., Results: Patients had a median age of 66 years (interquartile interval 57-74), 77% were men and 82% had HF with reduced ejection fraction. NT-proBNP, hs-TnT and sST2 were 1207 ng/l (487-2725), 17 ng/l (9-31) and 30 ng/ml (22-44), respectively. Patients with COPD (n = 1249, 15%) had higher NT-proBNP (P = 0.042) and hs-TnT (P < 0.001), but not sST2 (P = 0.165). Over a median 2.0-year follow-up (1.5-2.5), 1717 patients (21%) died, and 1298 (16%) died from cardiovascular causes; 2255 patients (28%) were hospitalized for HF over 1.8 years (0.9-2.1). NT-proBNP, hs-TnT and sST2 predicted the three end points regardless of COPD status. The best cut-offs from receiver-operating characteristics analysis were higher in patients with COPD than in those without. Patients with all three biomarkers higher than or equal to end-point- and COPD-status-specific cut-offs were also those with the worst prognosis., Conclusions: Among patients with HF, those with COPD have higher NT-proBNP and hs-TnT, but not sST2. All these biomarkers yield prognostic significance regardless of the COPD status., (Copyright © 2021 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Objectives: The goal of this study was to assess the predictive power of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the decision cutoffs in heart failure (HF) across body mass index (BMI) categories., Background: Concentrations of NT-proBNP predict outcome in HF. Although the influence of BMI to reduce levels of NT-proBNP is known, the impact of obesity on prognostic value remains uncertain., Methods: Individual data from the BIOS (Biomarkers In Heart Failure Outpatient Study) consortium were analyzed. Patients with stable HF were classified as underweight (BMI <18.5 kg/m 2 ), normal weight (BMI 18.5-24.9 kg/m 2 ), overweight (BMI 25-29.9 kg/m 2 ), and mildly (BMI 30-34.9 kg/m 2 ), moderately (BMI 35-39.9 kg/m 2 ), or severely (BMI ≥40 kg/m 2 ) obese. The prognostic role of NT-proBNP was tested for the endpoints of all-cause and cardiac death., Results: The study population included 12,763 patients (mean age 66 ± 12 years; 25% women; mean left ventricular ejection fraction 33% ± 13%). Most patients were overweight (n = 5,176), followed by normal weight (n = 4,299), mildly obese (n = 2,157), moderately obese (n = 612), severely obese (n = 314), and underweight (n = 205). NT-proBNP inversely correlated with BMI (β = -0.174 for 1 kg/m 2 ; P < 0.001). Adding NT-proBNP to clinical models improved risk prediction across BMI categories, with the exception of severely obese patients. The best cutoffs of NT-proBNP for 5-year all-cause death prediction were lower as BMI increased (3,785 ng/L, 2,193 ng/L, 1,554 ng/L, 1,045 ng/L, 755 ng/L, and 879 ng/L, for underweight, normal weight, overweight, and mildly, moderately, and severely obese patients, respectively) and were higher in women than in men., Conclusions: NT-proBNP maintains its independent prognostic value up to 40 kg/m 2 BMI, and lower optimal risk-prediction cutoffs are observed in overweight and obese patients., Competing Interests: Funding Support and Author Disclosures Dr Januzzi is supported in part by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; has received grant support from Novartis Pharmaceuticals, Roche Diagnostics, Abbott, Singulex and Prevencio; has received consulting income from Abbott, Janssen, Novartis, Pfizer, Merck, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Boehringer Ingelheim, Janssen, and Takeda. Dr Richards has sat on advisory boards and/or received speakers honoraria, travel support, and/or grants from Novartis, Roche Diagnostics, Abbott Laboratories, Thermo Fisher, and Critical Diagnostics. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; has served as consultant or on the Advisory Board/ Steering Committee/Executive Committee for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, WebMD Global LLC, Radcliffe Group Ltd, and Corpus. Dr Latini has received grant support and travel reimbursements from Roche Diagnostics. Dr Brunner-La Rocca reports unrestricted research grants and consulting fees from Roche Diagnostics, as well as unrestricted research grants from Novartis and GlaxoSmithKline outside this work. Dr Bayes-Genis has received grant support from Roche Diagnosis, lecture honoraria from Roche Diagnostics and Critical Diagnostics, and consulting income from Roche Diagnostics, Critical Diagnostics, and Novartis. Dr Lupón has received lecture honoraria from Roche Diagnostics and Critical Diagnostics. The University Medical Centre Groningen, which employs Drs De Boer and Meems, has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche. Dr de Boer received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche, outside the submitted work. Dr Gaggin has received grant support from Roche and Portola; consulting income from Roche Diagnostics, Amgen, and Ortho Clinical; and research payments for clinical endpoint committees for EchoSense and Radiometer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Higher body mass index (BMI) is associated with better outcome compared with normal weight in patients with HF and other chronic diseases. It remains uncertain whether the apparent protective role of obesity relates to the absence of comorbidities. Therefore, we investigated the effect of BMI on outcome in younger patients without co-morbidities as compared to older patients with co-morbidities in a large heart failure (HF) population., Methods: In an individual patient data analysis from pooled cohorts, 5,819 patients with chronic HF and data available on BMI, co-morbidities and outcome were analysed. Patients were divided into four groups based on BMI (i.e. ≤ 18.5 kg/m 2 , 18.5-25.0 kg/m 2 ; 25.0-30.0 kg/m 2 ; 30.0 kg/m 2 ). Primary endpoints included all-cause mortality and HF hospitalization-free survival., Results: Mean age was 65 ± 12 years, with a majority of males (78%), ischaemic HF and HF with reduced ejection fraction. Frequency of all-cause mortality or HF hospitalization was significantly worse in the lowest two BMI groups as compared to the other two groups; however, this effect was only seen in patients older than 75 years or having at least one relevant co-morbidity, and not in younger patients with HF only. After including medications and N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin concentrations into the model, the prognostic impact of BMI was largely absent even in the elderly group with co-morbidity., Conclusions: The present study suggests that obesity is a marker of less advanced disease, but does not have an independent protective effect in patients with chronic HF. Categories of BMI are only predictive of poor outcome in patients aged > 75 years or with at least one co-morbidity (bottom), but not in those aged < 75 years without co-morbidities (top). The prognostic effect largely disappears in multivariable analyses even for the former group. These findings question the protective effect of obesity in chronic heart failure (HF)., (© 2021. The Author(s).)

Background: SGLT2 inhibitors are a promising treatment option in patients with heart failure and reduced ejection fraction. We aimed to investigate the effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate (GFR) in patients with heart failure and reduced ejection fraction., Methods: Empire HF Renal was a prespecified substudy of the investigator-initiated, double-blind, randomised, placebo-controlled Empire HF trial. The study was done at Herlev and Gentofte University Hospital (Herlev, Denmark), with patients recruited from four Danish heart failure outpatient clinics. Patients with New York Heart Association class I-III symptoms, with a left ventricular ejection fraction of 40% or lower, and on guideline-directed heart failure therapy were randomly assigned (1:1) to receive either oral empagliflozin 10 mg or matched placebo once daily for 12 weeks. The allocation sequence was computer-generated. Patients and study investigators were masked to treatment allocation. The coprimary prespecified renal outcomes were the between-group difference in the changes in estimated extracellular volume, estimated plasma volume, and measured GFR from baseline to 12 weeks. All analyses were done in the intention-to-treat population (apart from safety analyses, which were done in patients who received at least one dose of study drug), with no interim analyses done during the trial. The Empire HF trial is registered with ClinicalTrials.gov, NCT03198585, and EudraCT, 2017-001341-27., Findings: Between June 29, 2017, and July 15, 2019, we assessed 391 patients for eligibility, of whom 120 (31%) were randomly assigned to empagliflozin or placebo, including 105 (88%) without diabetes. In intention-to-treat analyses, 60 (100%) patients in the empagliflozin group and 59 (98%) patients in the placebo group were included for estimated extracellular volume and estimated plasma volume, and 59 (98%) patients in the empagliflozin group and 58 (97%) patients in the placebo group were included for measured GFR. Empagliflozin treatment resulted in reductions in estimated extracellular volume (adjusted mean difference -0·12 L, 95% CI -0·18 to -0·05; p=0·00056), estimated plasma volume (-7·3%, -10·3 to -4·3; p<0·0001), and measured GFR (-7·5 mL/min, -11·2 to -3·8; p=0·00010) compared with placebo. Five (8%) of 60 patients in the empagliflozin group and three (5%) of 60 patients in the placebo group had one or more serious adverse events., Interpretation: In patients with heart failure and reduced ejection fraction, empagliflozin reduced estimated extracellular volume, estimated plasma volume, and measured GFR after 12 weeks. Fluid volume changes might be an important mechanism underlying the beneficial clinical effects of SGLT2 inhibitors., Funding: Research Council at Herlev and Gentofte University Hospital, Research and Innovation Foundation of the Department of Cardiology at Herlev and Gentofte University Hospital, Capital Region of Denmark, Danish Heart Foundation, and AP Møller Foundation for the Advancement of Medical Science., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aim: To assess the effect of liraglutide, a glucagon-like peptide-1 receptor agonist, on urinary sodium excretion as well as on circulating adrenomedullin and copeptin levels in patients with type 2 diabetes (T2D)., Materials and Methods: In the LIVE study, patients (n = 241) with left ventricular ejection fraction ≤45% were randomized to liraglutide 1.8 mg daily or placebo for 24 weeks, and 30% had a concomitant diagnosis of T2D. Plasma levels of N-terminal brain-natriuretic-peptide (NT-proBNP) (a predefined secondary endpoint), midregional pro-atrial-natriuretic-peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM) and copeptin were measured at baseline and after 24 weeks in this substudy. The potential effect modification of T2D was assessed., Results: In the eligible subgroup of 231 patients with available biomarkers (115 randomized to liraglutide and 116 to placebo), MR-proANP decreased by 12% (P = .002) and NT-proBNP by 9% (P = .009) during liraglutide treatment compared with placebo at week 24. Interaction with T2D for the treatment effect of change in MR-proANP and NT-proBNP levels was P = .003 and P = .03, respectively. Consequently, in patients with T2D, liraglutide decreased MR-proANP by 27% (P < .001) and NT-proBNP by 25% (P = .02) compared with placebo, whereas no change was observed in patients without T2D. There was no effect of liraglutide on MR-proADM (P = .10) or copeptin (P = .52)., Conclusion: Liraglutide decreased the A- and B-type natriuretic peptides significantly in patients with heart failure with reduced ejection fraction (HFrEF) and concomitant T2D, suggesting a beneficial mechanism of liraglutide in T2D patients with HFrEF., (© 2020 John Wiley & Sons Ltd.)

Aims: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT) and soluble suppression of tumorigenesis-2 (sST2) predict outcome in chronic heart failure (HF). We assessed the influence of age on circulating levels and prognostic significance of these biomarkers., Methods and Results: Individual data from 5301 patients with chronic HF and NT-proBNP, hs-TnT, and sST2 data were evaluated. Patients were stratified according to age: <60 years (n = 1332, 25%), 60-69 years (n = 1628, 31%), 70-79 years (n = 1662, 31%), and ≥ 80 years (n = 679, 13%). Patients (median age 66 years, 75% men, median left ventricular ejection fraction 28%, 64% with ischaemic HF) had median NT-proBNP 1564 ng/L, hs-TnT 21 ng/L, and sST2 29 ng/mL. Age independently predicted NT-proBNP and hs-TnT, but not sST2. The best NT-proBNP and hs-TnT cut-offs for 1-year and 5-year all-cause and cardiovascular mortality and 1- to 12-month HF hospitalization increased with age, while the best sST2 cut-offs did not. When stratifying patients according to age- and outcome-specific cut-offs, this stratification yielded independent prognostic significance over NT-proBNP levels only, or the composite of NT-proBNP and hs-TnT, and improved risk prediction for most endpoints. Finally, absolute NT-proBNP, hs-TnT, and sST2 levels predicted outcomes independent of age, sex, left ventricular ejection fraction category, ethnic group, and other variables., Conclusions: Soluble ST2 is less influenced by age than NT-proBNP or hs-TnT; all these biomarkers predict outcome regardless of age. The use of age- and outcome-specific cut-offs of NT-proBNP, hs-TnT and sST2 allows more accurate risk stratification than NT-proBNP alone or the combination of NT-proBNP and hs-TnT., (© 2019 European Society of Cardiology.)

Aims: To investigate the effect of the sodium-glucose co-transporter-2 inhibitor empagliflozin on N-terminal pro-b-type natriuretic peptide (NT-proBNP) in patients with heart failure (HF) and reduced ejection fraction (HFrEF)., Methods and Results: Empire HF was an investigator-initiated, multi-center, double-blinded, placebo-controlled, randomized trial. Patients with mildly symptomatic HFrEF, mean (standard deviation (SD)) age 64 (11) years, 85% male, and mean left ventricular ejection fraction 29% (8), on recommended HF therapy were assigned to receive either empagliflozin 10 mg once daily or placebo for 12 weeks. The primary endpoint was the between-group difference in the change of NT-proBNP from baseline to 12 weeks. In total, 95 patients were assigned to empagliflozin and 95 to placebo. No significant difference in the change of NT-proBNP with empagliflozin versus placebo was observed [Empagliflozin: baseline, median (interquartile range (IQR)) 582 (304-1020) pg/mL, 12 weeks, 478 (281-961) pg/mL; Placebo: baseline, 605 (322-1070) pg/mL, 12 weeks, 520 (267-1075) pg/mL, adjusted ratio of change empagliflozin/placebo 0.98; 95% confidence interval (CI) 0.82-1.11, P = 0.7]. Further, no significant difference was observed in accelerometer-measured daily activity level [adjusted mean difference of change, empagliflozin versus placebo, -26.0 accelerometer counts; 95% CI -88.0 to 36.0, P = 0.4] or Kansas City Cardiomyopathy Questionnaire Overall Summary Score [adjusted mean difference of change, empagliflozin versus placebo 0.8; 95% CI -2.3 to 3.9, P = 0.6]., Conclusion: In low-risk patients with HFrEF with mild symptoms and on recommended HF therapy, empagliflozin did not change NT-proBNP after 12 weeks. Further, no change in daily activity level or health status was observed., Competing Interests: Declaration of competing interest Dr Jensen reports grants from the Research Council at Herlev and Gentofte University Hospital, Denmark, grants from the Research and Innovation Foundation of the Department of Cardiology ((FUHAS, formerly FUKAP), Herlev and Gentofte University Hospital, Denmark, grants from the A.P. Møller Foundation for the Advancement of Medical Science, Denmark, during the conduct of the study. Dr Omar reports grants from The Steno Diabetes Center Odense, Denmark, during the conduct of the study. Dr Kistorp reports personal fees from scientific advisory panel and speaker fees from Boehringer Ingelheim, Merck, Sharp & Dohme, AstraZeneca, Amgen, Novartis, Novo Nordisk and Shire, outside the submitted work. Dr Poulsen has nothing to disclose. Dr Tuxen has nothing to disclose. Dr I. Gustafsson has nothing to disclose. Dr Køber reports personal fees from speaker honorarium from Novartis, AstraZeneca and Boehringer Ingelheim, outside the submitted work. Dr F. Gustafsson reports personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Novartis, grants and personal fees from Pfizer, personal fees from Orion Pharma Abbott, Bayer, AstraZeneca and Carmat, outside the submitted work. Dr Faber has nothing to disclose. Dr Fosbøl has nothing to disclose. Dr Bruun has nothing to disclose. Dr Brønd has nothing to disclose. Dr Forman has nothing to disclose. Dr Videbæk has nothing to disclose. Dr Møller reports grants and personal fees from Abiomed, personal fees from Novartis and Orion Pharma, outside the submitted work. Dr Schou reports grants from The Capital Region of Denmark, grants from The Danish Heart Foundation, during the conduct of the study; personal fees and non-financial support from AstraZeneca, personal fees from Novo Nordisk and Boehringer Ingelheim, outside the submitted work., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background . Liraglutide, a glucagon-like peptide-1 agonist, is used for treatment of type 2 diabetes and has beneficial cardiovascular properties. However, treatment increases heart rate (HR) and possibly the risk of cardiovascular events in chronic heart failure (CHF) patients. We investigated potential associations between HR changes and clinical, laboratory and echocardiographic parameters and clinical events in liraglutide treated CHF patients. Methods . This was a sub-study of the LIVE study. CHF patients ( N  = 241) with a left ventricular ejection fraction ≤45% were randomised to 1.8 mg liraglutide daily or placebo for 24 weeks. Electrocardiograms ( N  = 117) and readouts from cardiac implanted electronic devices ( N  = 20) were analysed for HR and arrhythmias. Results . In patients with sinus rhythm (SR), liraglutide increased HR by 8 ± 9 bpm (pulse measurements), 9 ± 9 bpm (ECG measurements) and 9 ± 6 bpm (device readouts) versus placebo (all p <.005). Increases in HR correlated with liraglutide dose ( p =.01). HR remained unchanged in patients without SR. Serious cardiac adverse events were not associated with HR changes. Conclusions . During 6 months of treatment, HR increased substantially in CHF patients with SR treated with liraglutide but was not associated with adverse events. The long-term clinical significance of increased HR in liraglutide treated CHF patients needs to be determined.

According to the World Health Organization, palliative care must be available for everyone with life-threatening diseases. However, in daily practice the primary focus worldwide is on cancer patients. The aim of the article was to generate a national position statement as the first step in implementing palliative care in severe heart disease with focus on advanced heart failure, including tools to identify the need for and timing of palliative care and how palliative care could be organized in Denmark. A task force was formed in the Danish Society of Cardiology Heart Failure Working Group, and the position statement was prepared in collaboration with members from a broad group of specialties, including palliative medicine. Because of major gaps in evidence, the position statement was based on small and low-quality studies and clinical practice statements. This position statement was aligned with the European Society of Cardiology recommendation, focusing on relieving suffering from the early disease stages parallel to standard care and supplementing life-prolonging treatment. The statement delivers practical guidance on clinical aspects and managing symptoms during the three stages of advanced heart disease. Furthermore, the statement describes the importance of communication and topics to be broached, including deactivating implantable cardioverter defibrillators. The statement recommends a targeted effort on organizational strategies using high-quality assessment tools and emphasizes multidisciplinary and intersectoral collaboration. Danish cardiologists supported by allied professionals acknowledge the importance of palliative care in advanced heart disease. This national position statement intended to inform and influence policy and practice and can hopefully inspire other countries to take action toward implementing palliative care in advanced heart disease.

Aims: Obesity defined by body mass index (BMI) is characterized by better prognosis and lower plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) in heart failure. We assessed whether another anthropometric measure, per cent body fat (PBF), reveals different associations with outcome and heart failure biomarkers (NT-proBNP, high-sensitivity troponin T (hs-TnT), soluble suppression of tumorigenesis-2 (sST2))., Methods: In an individual patient dataset, BMI was calculated as weight (kg)/height (m) 2 , and PBF through the Jackson-Pollock and Gallagher equations., Results: Out of 6468 patients (median 68 years, 78% men, 76% ischaemic heart failure, 90% reduced ejection fraction), 24% died over 2.2 years (1.5-2.9), 17% from cardiovascular death. Median PBF was 26.9% (22.4-33.0%) with the Jackson-Pollock equation, and 28.0% (23.8-33.5%) with the Gallagher equation, with an extremely strong correlation ( r  = 0.996, p  < 0.001). Patients in the first PBF tertile had the worst prognosis, while patients in the second and third tertile had similar survival. The risks of all-cause and cardiovascular death decreased by up to 36% and 27%, respectively, per each doubling of PBF. Furthermore, prognosis was better in the second or third PBF tertiles than in the first tertile regardless of model variables. Both BMI and PBF were inverse predictors of NT-proBNP, but not hs-TnT. In obese patients (BMI ≥ 30 kg/m 2 , third PBF tertile), hs-TnT and sST2, but not NT-proBNP, independently predicted outcome., Conclusion: In parallel with increasing BMI or PBF there is an improvement in patient prognosis and a decrease in NT-proBNP, but not hs-TnT or sST2. hs-TnT or sST2 are stronger predictors of outcome than NT-proBNP among obese patients.

Background: Data from recent cardiovascular outcome trials in patients with type 2 diabetes (T2D) suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors can prevent development of heart failure (HF) and prolong life in patients without HF. Ongoing event-driven trials are investigating whether the same effect is present in patients with well-defined HF. The mechanism behind the effect of SGLT2 inhibitors in patients with T2D and the potential effect in patients with overt HF is presently unknown., Methods: This is a randomized, double-blinded, placebo-controlled, parallel group, clinical trial including HF patients with reduced left ventricular ejection fraction (HFrEF) with an ejection fraction ≤ 40% on optimal therapy recruited from specialized HF clinics in Denmark. The primary aim is to investigate the effect of the SGLT2 inhibitor empagliflozin on N-terminal pro-brain natriuretic peptide (NT-proBNP). Secondary endpoints include cardiac biomarkers, function and hemodynamics, metabolic and renal parameters, daily activity level, and quality of life. Patients are assigned 1:1 to 90 days treatment with empagliflozin 10 mg daily or placebo. Patients with T2D are required to be on recommended doses of anti-glycemic therapy with a hemoglobin A1c (HbA1c) of 6.5-10.0% (48-86 mmol/mol). To show a between-group difference in the change of NT-proBNP of 30%, a total of 189 patients will be included., Discussion: The Empire HF trial will elucidate the effects and modes of action of empagliflozin in HFrEF patients with and without T2D and provide important mechanistic data which will complement ongoing event-driven trials., Trial Registration: Clinicaltrialsregister.eu, EudraCT Number 2017-001341-27 . Registered on 29 May 2017. ClinicalTrials.gov, NCT03198585 . Registered on 26 June 2017.

Background: The glucagon-like peptide-1 analog liraglutide increases heart rate and may be associated with more cardiac events in chronic heart failure (CHF) patients. We studied whether this could be ascribed to effects on myocardial glucose uptake (MGU), myocardial blood flow (MBF) and MBF reserve (MFR)., Methods and Results: CHF patients with left ventricular ejection fraction ≤45% and without type 2 diabetes were randomized to liraglutide (N = 18) 1.8 mg once daily or placebo (N = 18) for 24 weeks in a double-blinded design. Changes in MGU during an oral glucose tolerance test (OGTT) and changes in MBF and MFR from baseline to follow-up were measured quantitatively by 18 F-FDG and 15 O-H 2 O positron emission tomography. Compared with placebo, liraglutide reduced weight (P = 0.03), HbA1c (P = 0.03) and the 2-hour glucose value during the OGTT (P = 0.004). Despite this, changes in MGU (P = 0.98), MBF (P = 0.76) and MFR (P = 0.89) from baseline to follow-up did not differ between groups. Furthermore, there was no association between the level of insulin resistance at baseline and changes in MGU in patients treated with liraglutide., Conclusion: Liraglutide did not affect MGU, MBF, or MFR in non-diabetic CHF patients. Any potential increase in cardiac events in these patients seems not to involve changes in MGU, MBF, or MFR., Trial Registration: Trial registry: http://www.ClinicalTrials.org . Identifier: NCT01472640. Url: https://clinicaltrials.gov/ct2/show/NCT01472640?term=NCT01472640&rank=1.

Background: In a recent individual patient data meta-analysis, high-sensitivity troponin T (hs-TnT) emerged as robust predictor of prognosis in stable chronic heart failure (HF). In the same population, we compared the relative predictive performances of hs-TnT, N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP), hs-C-reactive protein (hs-CRP), and estimated glomerular filtration rate (eGFR) for prognosis., Methods and Results: 9289 patients (66 ± 12 years, 77% men, 85% LVEF <40%, 60% ischemic HF) were evaluated over a 2.4-year median follow-up. Median eGFR was 58 mL/min/1.73 m 2 (interquartile interval 46-70; n = 9220), hs-TnT 16 ng/L (8-20; n = 9289), NT-proBNP 1067 ng/L (433-2470; n = 8845), and hs-CRP 3.3 mg/L (1.4-7.8; n = 7083). In a model including all 3 biomarkers, only hs-TnT and NT-proBNP were independent predictors of all-cause and cardiovascular mortality and cardiovascular hospitalization. hs-TnT was a stronger predictor than NT-proBNP: for example, the risk for all-cause death increased by 54% per doubling of hs-TnT vs. 24% per doubling of NT-proBNP. eGFR showed independent prognostic value from both hs-TnT and NT-proBNP. The best hs-TnT and NT-proBNP cut-offs for the prediction of all-cause death increased progressively with declining renal function (eGFR ≥ 90: hs-TnT 13 ng/L and NT-proBNP 825 ng/L; eGFR < 30: hs-TnT 40 ng/L and NT-proBNP 4608 ng/L). Patient categorization according to these cut-offs effectively stratified patient prognosis across all eGFR classes., Conclusions: hs-TnT conveys independent prognostic information from NT-proBNP, while hs-CRP does not. Concomitant assessment of eGFR may further refine risk stratification. Patient classification according to hs-TnT and NT-proBNP cut-offs specific for the eGFR classes holds prognostic significance., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Most patients with chronic heart failure have detectable troponin concentrations when evaluated by high-sensitivity assays. The prognostic relevance of this finding has not been clearly established so far. We aimed to assess high-sensitivity troponin assay for risk stratification in chronic heart failure through a meta-analysis approach., Methods: Medline, EMBASE, Cochrane Library, and Scopus were searched in April 2017 by 2 independent authors. The terms were "troponin" AND "heart failure" OR "cardiac failure" OR "cardiac dysfunction" OR "cardiac insufficiency" OR "left ventricular dysfunction." Inclusion criteria were English language, clinical stability, use of a high-sensitivity troponin assay, follow-up studies, and availability of individual patient data after request to authors. Data retrieved from articles and provided by authors were used in agreement with the PRISMA statement. The end points were all-cause death, cardiovascular death, and hospitalization for cardiovascular cause., Results: Ten studies were included, reporting data on 11 cohorts and 9289 patients (age 66±12 years, 77% men, 60% ischemic heart failure, 85% with left ventricular ejection fraction <40%). High-sensitivity troponin T data were available for all patients, whereas only 209 patients also had high-sensitivity troponin I assayed. When added to a prognostic model including established risk markers (sex, age, ischemic versus nonischemic etiology, left ventricular ejection fraction, estimated glomerular filtration rate, and N-terminal fraction of pro-B-type natriuretic peptide), high-sensitivity troponin T remained independently associated with all-cause mortality (hazard ratio, 1.48; 95% confidence interval, 1.41-1.55), cardiovascular mortality (hazard ratio, 1.40; 95% confidence interval, 1.33-1.48), and cardiovascular hospitalization (hazard ratio, 1.42; 95% confidence interval, 1.36-1.49), over a median 2.4-year follow-up (all P <0.001). High-sensitivity troponin T significantly improved risk prediction when added to a prognostic model including the variables above. It also displayed an independent prognostic value for all outcomes in almost all population subgroups. The area under the curve-derived 18 ng/L cutoff yielded independent prognostic value for the 3 end points in both men and women, patients with either ischemic or nonischemic etiology, and across categories of renal dysfunction., Conclusions: In chronic heart failure, high-sensitivity troponin T is a strong and independent predictor of all-cause and cardiovascular mortality, and of hospitalization for cardiovascular causes, as well. This biomarker then represents an additional tool for prognostic stratification., (© 2018 American Heart Association, Inc.)

Aims: To determine the effect of the glucagon-like peptide-1 analogue liraglutide on left ventricular function in chronic heart failure patients with and without type 2 diabetes., Methods and Results: LIVE was an investigator-initiated, randomised, double-blinded, placebo-controlled multicentre trial. Patients (n = 241) with reduced left ventricular ejection fraction (LVEF ≤45%) were recruited (February 2012 to August 2015). Patients were clinically stable and on optimal heart failure treatment. Intervention was liraglutide 1.8 mg once daily or matching placebo for 24 weeks. The LVEF was similar at baseline in the liraglutide and the placebo group (33.7 ± 7.6% vs. 35.4 ± 9.4%). Change in LVEF did not differ between the liraglutide and the placebo group; mean difference (95% confidence interval) was -0.8% (-2.1, 0.5; P = 0.24). Heart rate increased with liraglutide [mean difference: 7 b.p.m. (5, 9), P < 0.0001]. Serious cardiac events were seen in 12 (10%) patients treated with liraglutide compared with 3 (3%) patients in the placebo group (P = 0.04)., Conclusion: Liraglutide did not affect left ventricular systolic function compared with placebo in stable chronic heart failure patients with and without diabetes. Treatment with liraglutide was associated with an increase in heart rate and more serious cardiac adverse events, and this raises some concern with respect to the use of liraglutide in patients with chronic heart failure and reduced left ventricular function. More data on the safety of liraglutide in different subgroups of heart failure patients are needed., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Background: Diabetes mellitus (DM) is associated with an adverse outcome in heart failure (HF). Increased concentrations of midregional proadrenomedullin (MR-proADM) have been associated with DM and are predictors of mortality in HF patients. The aim of this study was to elucidate the impact of DM on MR-proADM concentrations and the prognostic value regarding all-cause mortality and hospitalization among HF patients., Methods and Results: We included 366 patients from an HF clinic; 69 (19%) had a history of DM and 40 (11%) had newly diagnosed DM (HbA1c ≥48 mmol/mol). The median MR-proADM concentration was unaffected by DM status (P = .20) but increased in HF patients with impaired renal function (P < .001). During a median follow-up of 55 months, 189 died, and 292 either died or were hospitalized. After adjustment for clinically relevant parameters, MR-proADM was associated with all-cause mortality (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.1-1.4; P = .01) and the combined end point of death and hospitalization (HR 1.2, 95% CI 1.1-1.4; P = .02) per 1 SD increment of ln-transformed variable. No interaction between DM and MR-proADM was found regarding mortality or hospitalization., Conclusions: Diabetes status had no impact on MR-proADM concentrations or in the predictive ability of MR-proADM in HF patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Heart failure is one of the most common cardiovascular complications of diabetes and the most disabling and deadly complication too. Many antidiabetic agents have been associated with increased morbidity and mortality in a subset of patients with chronic heart failure (CHF); thus, new treatment modalities are warranted. Interestingly, a beneficial effect of the incretin hormone, GLP-1, on cardiac function has been suggested in patients with diabetes and patients without diabetes. Liraglutide (Victoza) is a GLP-1 analogue developed for the treatment of type 2 diabetes (T2D); however, its impact on cardiac function has not previously been investigated in patients with CHF. This prompted us to investigate whether liraglutide treatment for 24 weeks improves left ventricular ejection fraction (LVEF) in patients with CHF with and without T2D compared with placebo treatment., Methods and Analysis: An investigator-initiated, multicentre, randomised, double-blind, parallel, placebo-controlled intervention trial. In total, 240 patients with CHF (with and without T2D) with LVEF≤45% will be randomised to either subcutaneous injection of liraglutide 1.8 mg or matching placebo once daily for 24 weeks. The effect of liraglutide on left ventricular function will be evaluated by advanced echocardiography, including three-dimensional contrast echocardiography., Ethics and Dissemination: The study will be performed and monitored according to the Good Clinical Practice-International Conference on Harmonisation (GCP-ICH) regulations and conducted according to the principles of the Helsinki Declaration. The Danish Medicines Agency, the local Research Ethics Committee and the Danish Data Protection Agency have approved the study., Trial Registration Number: ClinicalTrials.gov Identifier: NCT01472640., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Copeptin, a stable fragment of the vasopressin prohormone, has been shown to be a significant biomarker for morbidity and mortality in heart failure. The aims of this study were to evaluate the influence of plasma sodium on the prognostic significance of copeptin concentrations in heart failure outpatients and to determine whether increased copeptin concentrations predict future development of hyponatremia., Methods and Results: A total of 340 heart failure patients with left ventricular systolic dysfunction were followed for 55 months (median) in a Danish heart failure clinic. A baseline measurement of plasma copeptin, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and sodium was performed, and the sodium concentrations were recorded during 3 months after the baseline visit in the heart failure clinic. Patients were divided into 3 groups according to copeptin tertiles. In multivariate Cox proportional hazard models adjusted for confounders, including plasma sodium, loop diuretic dose, and NT-proBNP, copeptin was a significant predictor of hospitalization or death (hazard ratio 1.4, 95% confidence interval 1.1-1.9; P < .019) but did not predict mortality independently from NT-proBNP. Additionally, copeptin concentrations did not predict future development of hyponatremia., Conclusions: Plasma copeptin levels predict mortality in outpatients with chronic heart failure independently from clinical variables, plasma sodium, and loop diuretic doses. Furthermore, copeptin predicts the combined end point of hospitalization or death independently from NT-proBNP., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to investigate the influence of diabetes on long-term mortality in a large cohort of patients hospitalized with heart failure (HF)., Background: Diabetes is common in HF patients, but information on the prognostic effect of diabetes is sparse., Methods: The study is an analysis of survival data comprising 5,491 patients consecutively hospitalized with new or worsening HF and screened for entry into the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND). Screening, which included obtaining an echocardiogram in 95% of the patients, took place at Danish hospitals between 1993 and 1995. The follow-up time was five to eight years., Results: A history of diabetes was found in 900 patients (16%), 41% of whom were female. Among the diabetic patients, 755 (84%) died during follow-up, compared with 3,200 (70%) among the non-diabetic patients, resulting in a risk ratio (RR) of death in diabetic patients of 1.5 (95% confidence interval [CI] 1.4 to 1.6, p < 0.0001). In a multivariate analysis, the RR of death in diabetic patients was 1.5 (CI 1.3 to 1.76, p < 0.0001), but a significant interaction between diabetes and gender was found. Diabetes increased the mortality risk more in women than in men, with the RR for diabetic men being 1.4 (95% CI 1.3 to 1.6, p < 0.0001) and 1.7 for diabetic women (95% CI 1.4 to 1.9, p < 0.0001). The effect of diabetes on mortality was similar in patients with depressed and normal left ventricular systolic function., Conclusions: Diabetes is a potent, independent risk factor for mortality in patients hospitalized with HF. The excess risk in diabetic patients appears to be particularly prominent in females.

Aims: Results of previous studies on the influence of gender on prognosis in heart failure have been conflicting and most studies have been conducted in selected populations. The aim of this study was determine whether mortality risk in women and men hospitalized with congestive heart failure is different., Methods and Results: Survival analysis of 5491 consecutive patients admitted with congestive heart failure to 34 Danish hospitals between 1993-1996. Follow-up time was 5-8 years. Forty percent of the patients were female. Females were older, had less evidence of ischaemic heart disease and their left ventricular systolic function was preserved to a greater extent than in males. Men were more often treated with ACE inhibitors. During the follow-up period 1569 women (72%) and 2386 (72%) of the men died. When the age difference between men and women was adjusted for, male gender was associated with an increased risk of death (RR 1.25 (1.17-1.34)) and the increased risk was confirmed in a multivariate model containing several covariates., Conclusions: In patients hospitalized with congestive heart failure male gender is an independent predictor of mortality. Female heart failure patients may be under-treated with ACE inhibitors.

Aims To investigate the associations between glucose metabolism, left ventricular (LV) contractile reserve, and exercise capacity in patients with chronic systolic heart failure (HF). Methods and results From an outpatient HF clinic, 161 patients with systolic HF were included (mean age 70 ± 10 years, 69% male, 59% had ischaemic heart disease, mean LV ejection fraction (LVEF) 37 ± 9%). Thirty-four (21%) patients had known diabetes mellitus (DM). Oral glucose tolerance testing (OGTT) classified patients without a prior DM diagnosis as normal glucose tolerance (NGT), impaired glucose tolerance or new DM. All patients completed low-dose dobutamine echocardiography (LDDE) and 154 patients a 6-min walking distance test (6MWD). Compared with patients with NGT, patients with known DM had lower resting LVEF (33.4 vs. 39.1%, P < 0.05) and higher E/e′ (13.9 vs. 11.4, P < 0.05). During LDDE, an increase in LVEF could be observed in all glycemic groups (mean 8.2% absolute increase), but the contractile reserve was lower in patients with known DM (−5.4%, P = 0.001) and new DM (−3.5%, P = 0.035) compared to patients with NGT. 6MWD was lower in known DM (349 m) and new DM (379 m) compared with NGT (467 m) (P < 0.001). Differences in clinical variables, resting echocardiographic parameters or contractile reserve, did not explain the exercise intolerance related to diabetes. Conclusion Diabetes, known or newly detected by OGTT, is independently associated with reduced LV contractile reserve and exercise intolerance in outpatients with systolic HF. These findings may offer one explanation for the excess mortality related to diabetes in HF. [ABSTRACT FROM AUTHOR]

An abstract of the study "Male Sex Is an Independent Predictor of Mortality in Hospitalized Heart Failure Patients," by P. Buch and L. Kober, is presented.