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Aims: In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, the soluble guanylate cyclase stimulator vericiguat reduced the risk of hospitalization for heart failure (HHF) or cardiovascular death in patients with heart failure (HF) and reduced ejection fraction (HFrEF) with recent worsening HF. The effect of vericiguat in patients with HFrEF without recent worsening HF remains unknown. The VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial was designed to assess the efficacy and safety of vericiguat in patients with ejection fraction ≤40% without recent worsening HF on a background of current foundational HFrEF therapy., Methods: The primary endpoint for VICTOR is time to first event for the composite of HHF or cardiovascular death. The trial will also assess the effect of vericiguat on time to cardiovascular death, time to HHF, total HHF, and all-cause death. As an event-driven trial, at least 1080 primary events are expected, but follow-up will continue until the targeted number of at least 590 cardiovascular deaths has been reached. Approximately 6000 participants will be randomized to vericiguat or placebo., Conclusion: VICTOR is the first large event-driven HFrEF trial performed in the contemporary era of quadruple foundational guideline-directed medical therapy, in a compensated ambulatory HF population. VICTOR will add important information to the evidence of the effects of vericiguat across the spectrum of patients with HFrEF., (© 2024 Bayer AG, Merck Sharp & Dohme LLC and The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background and Aims: There is a gap in knowledge about implementing diagnostic tools and therapy for heart failure with preserved ejection fraction (HFpEF) in clinical practice. This survey aimed to assess real-world practice in HFpEF diagnosis and treatment in the international medical community., Methods: An independent academic web-based 29-question survey was designed by a group of heart failure specialists and posted by email and through scientific societies and social networks to a broad community of physicians worldwide., Results: 1.460 physicians from 95 countries answered the survey, with a mean age of 42.2±10.4 years, 39.4 % females, and 85.1 % were cardiologists. The left ventricular ejection fraction cut-off value selected for HFpEF diagnosis was 50 % for 89 % of participants. The scores for the probability of diagnosis of HFpEF were used only by 47.2 %, and H2FPEF was the most used score (31 %). Natriuretic peptides were used by 87.4 % of participants for the diagnostic workup, while the diastolic stress test was only used by 26.2 %. 54.4 % of participants chose SGLT2 inhibitors as their first drug treatment, followed by diuretics (18.6 %) and ACE inhibitors (8.4 %)., Conclusions: In an international academic survey on HFpEF management, the criteria for screening and diagnosis of HFpEF patients remain aligned with classic international guidelines with a low use of diagnostic scores. SGLT2i is the leading therapeutic drug class used for this heterogeneous patient population. These results raise the need to improve education and awareness on diagnosing and managing HFpEF patients., Competing Interests: Declaration of competing interest CS has received honoraria as speaker for Speaker for Novartis, Servier, Merck, Sanofi Pfizer, Astrazeneca, Boehringer Ingelheim, Novo Nordisk, Ely Lilly and as advisor for Bayer, Merck and Novo Nordisk, CF has received travel fees from Pfizer, NM has received consulting fees from Bayer and Amgen and as speaker for Astrazeneca, Novartis and Boehringer Ingelheim, support for attending meetings from Astrazeneca and Novartis, FR has not received personal payments by pharmaceutical companies or device manufacturers in the last 3 years (remuneration for the time spent in activities, such as participation as steering committee member of clinical trials and member of the Pfizer Research Award selection committee in Switzerland, were made directly to the University of Zurich). The Department of Cardiology (University Hospital of Zurich/University of Zurich) reports research-, educational- and/or travel grants from Abbott, Abiomed, Alnylam,Amarin, Amgen, Astra Zeneca, At the Limits Ltd., Bayer, Biotronik, BMS, Boehringer Ingelheim, Boston Scientific, Bracco, CM Microport, Concept Medical, CTI, Daiichi Sankyo, Edwards Lifesciences, FomF GmbH, Hamilton Health Sciences, IHF, Innosuisse, IumiraDX, Kantar, LabPoint, MedAlliance, Medcon International, Medical Education Global Solutions, Medtronic, MicroPort, Monocle, Novartis, Novo Nordisk, OM Pharma, Pfizer, Quintiles Switzerland Sarl, RecorMedical, Roche Diagnostics, Roche Pharma, Sahajanand IN, Sanofi, Sarstedt AG, Servier, Terumo Deutschland, Trama Solutions, V- Wave, Vifor, ZOLL. These grants do not impact on Prof. Ruschitzka`s personal remuneration. IJI received support for travel to meetings from Novartis. DM received payment as a speaker for Novartis, Pfizer, Astra Zeneca and support for attending meetings from Pfizer, Astrazeneca and abbot. GR reports grants and personal fees from Astra Zeneca, personal fees and other from Boheringer Ingelheim, other from Bayer, personal fees from Anlylam, other from Medtronic, grants from Servier, grants and non-financial support from Menarini, personal fees from Viatris, grants from Vifor Pharma, outside the submitted work. GGR reports personal fees from Pfizer, personal fees from CSL Vifor, personal fees from Astra Zeneca, personal fees from PTC therapeutics, personal fees from Bristol MS, personal fees from Boehringer Ingelheim, personal fees from Servier, outside the submitted work; GE reports personal fees from NOVO NORDISK, during the conduct of the study; IM reports grants from Boehringer Ingelheim, during the conduct of the study, SZ Served on advisory boards for, or speaker engagements with Abbott, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Eli Lilly, GSK, Medtronic, Merck, Novartis, Novo-Nordisk, Pfizer and Vifor Pharma; and serves on a clinical trial committee or as a national lead for studies sponsored by AstraZeneca, Boehringer Ingelheim, Merck, Novartis, Pfizer, Salubris Bio and Served on advisory boards for, or speaker engagements with Abbott, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Eli Lilly, GSK, Medtronic, Merck, Novartis, Novo-Nordisk, Pfizer and Vifor Pharma., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: We analysed baseline characteristics and guideline-directed medical therapy (GDMT) use and decisions in the European Society of Cardiology (ESC) Heart Failure (HF) III Registry., Methods and Results: Between 1 November 2018 and 31 December 2020, 10 162 patients with acute HF (AHF, 39%, age 70 [62-79], 36% women) or outpatient visit for HF (61%, age 66 [58-75], 33% women), with HF with reduced (HFrEF, 57%), mildly reduced (HFmrEF, 17%) or preserved (HFpEF, 26%) ejection fraction were enrolled from 220 centres in 41 European or ESC-affiliated countries. With AHF, 97% were hospitalized, 2.2% received intravenous treatment in the emergency department, and 0.9% received intravenous treatment in an outpatient clinic. AHF was seen by most by a general cardiologist (51%) and outpatient HF most by a HF specialist (48%). A majority had been hospitalized for HF before, but 26% of AHF and 6.1% of outpatient HF had de novo HF. Baseline use, initiation and discontinuation of GDMT varied according to AHF versus outpatient HF, de novo versus pre-existing HF, and by ejection fraction. After the AHF event or outpatient HF visit, use of any renin-angiotensin system inhibitor, angiotensin receptor-neprilysin inhibitor, beta-blocker, mineralocorticoid receptor antagonist and loop diuretics was 89%, 29%, 92%, 78%, and 85% in HFrEF; 89%, 9.7%, 90%, 64%, and 81% in HFmrEF; and 77%, 3.1%, 80%, 48%, and 80% in HFpEF., Conclusion: Use and initiation of GDMT was high in cardiology centres in Europe, compared to previous reports from cohorts and registries including more primary care and general medicine and regions more local or outside of Europe and ESC-affiliated countries., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Several mechanisms have been identified in the aetiopathogenesis of heart failure with preserved ejection fraction (HFpEF). Among these, coronary microvascular dysfunction (CMD) may play a key pathophysiological role. We performed a systematic review and meta-analysis to investigate the prevalence, echocardiographic correlates, and prognostic implications of CMD in patients with HFpEF., Methods and Results: A systematic search for articles up to 1 May 2023 was performed. The primary aim was to assess the prevalence of CMD. Secondary aims were to compare key echocardiographic parameters (E/e' ratio, left atrial volume index [LAVi], and left ventricular mass index [LVMi]), clinical outcomes [death and hospitalization for heart failure (HF)], and prevalence of atrial fibrillation (AF) between patients with and without CMD. Meta-regressions according to baseline patient characteristics and study features were performed to explore potential heterogeneity sources. We identified 14 observational studies, enrolling 1138 patients with HFpEF. The overall prevalence of CMD was 58%. Compared with patients without CMD, patients with HFpEF and CMD had larger LAVi [mean difference (MD) 3.85 confidence interval (CI) 1.19-6.5, P < 0.01)], higher E/e' ratio (MD 2.76 CI 1.54-3.97; P < 0.01), higher prevalence of AF (odds ratio 1.61 CI 1.04-2.48, P = 0.03) and higher risk of death or hospitalization for HF [hazard ratio 3.19, CI 1.04-9.57, P = 0.04]., Conclusions: CMD is present in little more than half of the patients with HFpEF and is associated with echocardiographic evidence of more severe diastolic dysfunction and a higher prevalence of AF, doubling the risk of death or HF hospitalization., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Guideline-directed medical therapy (GDMT) in patients with heart failure and reduced ejection fraction (HFrEF) reduces morbidity and mortality, but its implementation is often poor in daily clinical practice. Barriers to implementation include clinical and organizational factors that might contribute to clinical inertia, i.e. avoidance/delay of recommended treatment initiation/optimization. The spectrum of strategies that might be applied to foster GDMT implementation is wide, and involves the organizational set-up of heart failure care pathways, tailored drug initiation/optimization strategies increasing the chance of successful implementation, digital tools/telehealth interventions, educational activities and strategies targeting patient/physician awareness, and use of quality registries. This scientific statement by the Heart Failure Association of the ESC provides an overview of the current state of GDMT implementation in HFrEF, clinical and organizational barriers to implementation, and aims at suggesting a comprehensive framework on how to overcome clinical inertia and ultimately improve implementation of GDMT in HFrEF based on up-to-date evidence., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Recent guidelines recommend four core drug classes (renin-angiotensin system inhibitor/angiotensin receptor-neprilysin inhibitor [RASi/ARNi], beta-blocker, mineralocorticoid receptor antagonist [MRA], and sodium-glucose cotransporter 2 inhibitor [SGLT2i]) for the pharmacological management of heart failure (HF) with reduced ejection fraction (HFrEF). We assessed physicians' perceived (i) comfort with implementing the recent HFrEF guideline recommendations; (ii) status of guideline-directed medical therapy (GDMT) implementation; (iii) use of different GDMT sequencing strategies; and (iv) barriers and strategies for achieving implementation., Methods and Results: A 26-question survey was disseminated via bulletin, e-mail and social channels directed to physicians with an interest in HF. Of 432 respondents representing 91 countries, 36% were female, 52% were aged <50 years, and 90% mainly practiced in cardiology (30% HF). Overall comfort with implementing quadruple therapy was high (87%). Only 12% estimated that >90% of patients with HFrEF without contraindications received quadruple therapy. The time required to initiate quadruple therapy was estimated at 1-2 weeks by 34% of respondents, 1 month by 36%, 3 months by 24%, and ≥6 months by 6%. The average respondent favoured traditional drug sequencing strategies (RASi/ARNi with/followed by beta-blocker, and then MRA with/followed by SGLT2i) over simultaneous initiation or SGLT2i-first sequences. The most frequently perceived clinical barriers to implementation were hypotension (70%), creatinine increase (47%), hyperkalaemia (45%) and patient adherence (42%)., Conclusions: Although comfort with implementing all four core drug classes in patients with HFrEF was high among physicians, a majority estimated implementation of GDMT in HFrEF to be low. We identified several important perceived clinical and non-clinical barriers that can be targeted to improve implementation., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: We assessed eligibility for omecamtiv mecarbil (OM) in a real-world cohort with heart failure with reduced ejection fraction (HFrEF) according to the selection criteria of the GALACTIC-HF trial (trial scenario) and selected trial´s criteria more likely to impact real-world use (pragmatic scenario)., Methods and Results: We included 31,015 patients with HFrEF lasting ≥3 months and registered in the Swedish HF registry between 2000-2021. Trial eligibility was calculated by applying all the GALACTIC-HF selection criteria. The pragmatic scenario considered only the New York Heart Association class, history of worsening HF, N-terminal pro-B-type natriuretic peptides (NT-proBNP), blood pressure and renal failure criteria defined as in the trial. Eligibility for OM in chronic HFrEF was 21% and 36% in the trial and pragmatic scenarios, respectively. Eligibility was higher in those with EF<30% (trial: 27%, pragmatic: 44%), in-patients (trial:30%, pragmatic:57%), severe HF (trial: 35%, pragmatic: 60%), NYHA class III-IV (trial: 26%, pragmatic: 45%), and NT-proBNP≥5,000pg/mL (trial: 30%, pragmatic: 51%). The criteria that most limited eligibility were history of a recent worsening HF event (60% eligible in chronic HFrEF), elevated NT-proBNP (82% eligible), and deviating blood pressure (82% eligible). Overall, eligible patients were characterized by more severe HF and higher CV event-rates in both scenarios, and higher comorbidity burden in the pragmatic scenario., Conclusion: Approximately 21% of real-world chronic HFrEF patients would be eligible for OM according to the GALACTIC-HF selection criteria, and 36% according to the criteria more likely to affect OM use in clinical practice. Criteria in both scenarios identified a patient-group with severe HF and high CV event-rates., Competing Interests: FL has no conflicts of interest to declare. NØ has no conflicts of interest to declare. MM reports grants and other from Amgen, Abbott Vascular, Edwards Therapeutics, Servier, WindTree Therapeutics, Actelion, Livanova, Vifor Pharma. GR reports no conflicts of interest. UD reports research grants from AstraZeneca, Boehringer Ingelheim, Pfizer, Vifor, Boston Scientific, Roche Diagnostics and honoraria/consultancies from Amgen, Pfizer and AstraZeneca all outside the present manuscript. PM has no conflicts of interest to declare. CH none related to the present work; unrelated to the present work: consulting fees from Novartis, Roche Diagnostics, and AnaCardio; speaker fees from Novartis and Merck Sharp & Dohme. LHL none related to the present work; unrelated to the present work: grants, consulting, honoraria: Abbot, Alleviant, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Edwards, FineHeart, MedScape/WebMD, Merck/MSD, Novartis, Novo Nordisk, OrionPharma, Pharmacosmos, Radcliffe Cardiology, Roche, Sanofi, Servier, Translational Medicines Academy, Vifor; Stock ownership: AnaCardio. GS received financial support from Cytokinetics for performing this investigator-initiated study. GS reports grants and personal fees from Vifor, personal fees and grants from Boehringer Ingelheim, grants and personal fees from AstraZeneca, personal fees from Roche, grants and personal fees from Servier, grants and personal fees from Novartis, grants and personal fees from Cytokinetics, personal fees from Medtronic, grants from Boston Scientific, grants and personal fees from Pharmacosmos, grants from Merck, grants from Bayer, personal fees from INTAS, personal fees from Abbott, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials, (Copyright: © 2024 Lindberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: The aim of this analysis was to provide data on the overall comorbidity burden, both cardiovascular (CV) and non-CV, in a large real-world heart failure (HF) population across the ejection fraction (EF)., Methods and Results: Patients with HF from the Swedish HF Registry between 2000 and 2021 were included. Of 91 463 patients (median age 76 years [interquartile range 67-82]), 98% had at least one among the 17 explored comorbidities (94% at least one CV and 85% at least one non-CV comorbidity). All comorbidities, except for coronary artery disease (CAD), were more frequent in HF with preserved EF (HFpEF). Patients with multiple comorbidities were older, more likely female, inpatients, with HFpEF, worse New York Heart Association class and higher N-terminal pro-B-type natriuretic peptide levels. In a multivariable Cox model, 12 comorbidities were independently associated with a higher risk of death from any cause. The highest risk was associated with dementia (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.45-1.65), chronic kidney disease (HR 1.37, 95% CI 1.34-1.41), chronic obstructive pulmonary disease (HR 1.32, 95% CI 1.28-1.35). Obesity was associated with a lower risk of all-cause death (HR 0.81, 95% CI 0.79-0.84). CAD and valvular heart disease were associated with a higher risk of all-cause and CV mortality, but not non-CV mortality, whereas cancer and musculo-skeletal disease increased the risk of non-CV mortality. A significant interaction with EF was observed for several comorbidities. Occurrence of CV and non-CV outcomes was related to the number of CV and non-CV comorbidities, respectively., Conclusion: The burden of both CV and non-CV comorbidities was high in HF regardless of EF, but overall higher in HFpEF. Multimorbidity was associated with a high risk of death with a different burden on CV or non-CV outcomes., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Early start and patient profile-oriented heart failure (HF) management has been recommended. In this post hoc analysis from the SHIFT trial, we analysed the treatment effects of ivabradine in HF patients with systolic blood pressure (SBP) < 110 mmHg, resting heart rate (RHR) ≥ 75 b.p.m., left ventricular ejection fraction (LVEF) ≤ 25%, New York Heart Association (NYHA) Class III/IV, and their combination., Methods and Results: The SHIFT trial enrolled 6505 patients (LVEF ≤ 35% and RHR ≥ 70 b.p.m.), randomized to ivabradine or placebo on the background of guideline-defined standard care. Compared with placebo, ivabradine was associated with a similar relative risk reduction of the primary endpoint (cardiovascular death or HF hospitalization) in patients with SBP < 110 and ≥110 mmHg [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.74-1.08 vs. HR 0.80, 95% CI 0.72-0.89, P interaction = 0.34], LVEF ≤ 25% and >25% (HR 0.85, 95% CI 0.72-1.01 vs. HR 0.80, 95% CI 0.71-0.90, P interaction = 0.53), and NYHA III-IV and II (HR 0.83, 95% CI 0.74-0.94 vs. HR 0.81, 95% CI 0.69-0.94, P interaction = 0.79). The effect was more pronounced in patients with RHR ≥ 75 compared with <75 (HR 0.76, 95% CI 0.68-0.85 vs. HR 0.97, 95% CI 0.81-0.1.16, P interaction = 0.02). When combining these profiling parameters, treatment with ivabradine was also associated with risk reductions comparable with patients with low-risk profiles for the primary endpoint (relative risk reduction 29%), cardiovascular death (11%), HF death (49%), and HF hospitalization (38%; all P values for interaction: 0.40). No safety concerns were observed between study groups., Conclusions: Our analysis shows that RHR reduction with ivabradine is effective and improves clinical outcomes in HF patients across various risk indicators such as low SBP, high RHR, low LVEF, and high NYHA class to a similar extent and without safety concern., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: This study assessed sex-related differences in a large cohort of unselected patients with heart failure (HF) across the ejection fraction (EF) spectrum., Background: Females are under-represented in randomized clinical trials. Potential sex-related differences in HF may question the generalizability of trials., Methods: In the Swedish Heart Failure Registry population multivariate Cox and logistic regression models were fitted to investigate differences in prognosis, prognostic predictors, and treatments across males and females., Results: Of 42,987 patients, 37% were females (55% with HF with preserved EF [HFpEF], 39% with HF with mid-range EF [HFmrEF], and 29% with HF with reduced EF [HFrEF]). Females were older and more symptomatic and more likely to have hypertension and kidney disease but less likely to have diabetes and ischemic heart disease. After adjustments, females were more likely to use beta-blockers and digoxin but less likely to receive HF device therapy. Crude mortality/HF hospitalization rates for HFpEF (hazard ratio [HR]: 1.16) and HFmrEF (HR: 1.14) were significantly higher in females but lower in females with HFrEF (HR: 0.95). After adjustments, the risk was significantly lower in females regardless of EF (HR: 0.80 in HFrEF, HR: 0.91 in HFmrEF, and HR: 0.93 in HFpEF). The main sex-related differences in prognostic predictors concerned diabetes in HFrEF and anemia in HFmrEF., Conclusions: Males and females with HF showed different characteristics across the EF spectrum. Males reported a lower crude risk of mortality/morbidity in HFpEF and HFmrEF but higher risk of HFrEF, although after adjustments, prognosis was better in females regardless of EF. The observed sex-related differences highlight the need for an adequate representation of females in HF randomized controlled trials to improve generalizability., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aim: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in heart failure with reduced ejection fraction (HFrEF), but are underutilized. Hyperkalaemia may be one reason, but the underlying reasons for underuse are unknown. The aim of this study was to investigate the independent predictors of MRA underuse in a large and unselected HFrEF cohort., Methods and Results: We included patients with HFrEF (ejection fraction <40%), New York Heart Association (NYHA) class II-IV and heart failure (HF) duration ≥6 months from the Swedish HF Registry. Logistic regression analysis identified independent associations between 39 demographic, clinical, co-treatment, and socioeconomic predictors and MRA non-use. Of 11 215 patients, 27% were women; mean age was 75 ± 11 years; only 4443 (40%) patients received MRA. Selected characteristics independently associated with MRA non-use were in descending order of magnitude: lower creatinine clearance (<60 mL/min), no need for diuretics, no cardiac resynchronization therapy/implantable cardioverter-defibrillator, higher blood pressure, no digoxin use, higher ejection fraction, outpatient setting, older age, lower income, ischaemic heart disease, male sex, follow-up in primary vs. specialty care, lower NYHA class, and absence of hypertension diagnosis. Plasma potassium and N-terminal pro B-type natriuretic peptide levels were not associated with MRA non-use., Conclusion: Mineralocorticoid receptor antagonists remain underused in HFrEF. Their use does not decrease with elevated potassium but does with impaired renal function, even in the creatinine clearance 30-59.9 mL/min range where MRAs are not contraindicated. MRA underuse may be further related to non-specialist care, milder HF and no use of other HF therapy., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Background: The aim of this study was to characterize N-terminal pro-B-type natriuretic peptide (NT-proBNP) in terms of determinants of levels and of its prognostic and discriminatory role in heart failure with mid-range (HFmrEF) versus preserved (HFpEF) and reduced (HFrEF) ejection fraction., Methods and Results: In 9847 outpatients with HFpEF (n = 1811; 18%), HFmrEF (n = 2122; 22%) and HFrEF (n = 5914; 60%) enrolled in the Swedish Heart Failure Registry, median NT-proBNP levels were 1428, 1540, and 2288 pg/mL, respectively. Many determinants of NT-proBNP differed by ejection fraction, with atrial fibrillation (AF) more important in HFmrEF and HFpEF, diabetes and hypertension in HFmrEF, and age and body mass index in HFrEF and HFmrEF, whereas renal function, New York Heart Association functional class, heart rate, and anemia were similar. Hazard ratios for death and death/HF hospitalization for NT-proBNP above the median ranged from 1.48 to 2.00 and were greatest for HFmrEF and HFpEF. Areas under the receiver operating characteristic curve for death and death/HF hospitalization were greater in HFmrEF than in HFpEF and HFrEF and were reduced by AF in HFpEF and HFmrEF but not in HFrEF., Conclusions: In HFpEF and especially HFmrEF, NT-proBNP was more prognostic and discriminatory, but also more affected by confounders such as AF. These data support the use of NT-proBNP for eligibility, enrichment, and surrogate end points in HFpEF and HFmrEF trials, and suggest that cutoff levels for eligibility should be carefully tailored to comorbidity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: In heart failure with mid-range ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF), feasible surrogate end points are needed for phase II trials. The aim was to assess whether a reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with improved mortality/morbidity in an unselected population of HFmrEF and HFpEF patients., Methods and Results: In the Swedish Heart Failure Registry, HFmrEF (EF=40%-49%) and HFpEF (EF≥50%) patients reporting at least 2 consecutive outpatient NT-proBNP assessments were prospectively studied. Associations between reduction in NT-proBNP and overall mortality, HF hospitalization, and their composite were assessed by multivariable Cox regressions, with NT-proBNP changes modeled as binary (decrease/increase) or quantitative predictor by restricted cubic splines. In 650 patients, at a median of 7 months between the 2 measurements of NT-proBNP and over a median follow-up of 1.65 years, 361 patients (55%) showed a reduction and 289 patients (45%) an increase in NT-proBNP. Change in NT-proBNP was associated with risk of outcomes. Fifty-seven patients (16%) who decreased their NT-proBNP versus 78 patients (27%) who increased it died from any cause (adjusted hazard ratio=0.53; 95% confidence interval=0.36-0.77), 61 (17%) versus 86 (30%) were hospitalized for HF (hazard ratio=0.41; 95% confidence interval=0.29-0.60), and 96 (27%) versus 125 (43%) reported the composite outcome (hazard ratio=0.46; 95% confidence interval=0.34-0.62). These findings were replicated in HFmrEF and HFpEF separately., Conclusions: In HFmrEF and HFpEF during routine care, decreases in NT-proBNP were associated with improved mortality and morbidity. Studies to determine whether NT-proBNP changes in response to therapy predict drug efficacy are needed., (© 2016 American Heart Association, Inc.)

The role of spironolactone and eplerenone in patients with Heart Failure with preserved Ejection Fraction (HFpEF) is not well defined. Since a growing medical literature has suggested that mineralocorticoid receptor antagonists may be beneficial for patients with HFpEF, this review gives an in-depth update on the role of spironolactone and eplerenone and their implications for therapy in the setting of HFpEF. Eleven clinical studies, including seven randomized trials, were reviewed. Two randomized controlled trials evaluated the effect of eplerenone on different end-points, including 6 minute walk distance (6 MWD), cardiovascular mortality, non-fatal reinfarction, hospitalization for unstable angina and congestive heart failure. Eplerenone did not affect either 6 MWD or event-free survival rates in the overall study population in these two reports. The effects of spironolactone on similar composite endpoints were evaluated in 7 studies in patients with HFpEF. Compared to placebo, hospitalization for heart failure was significantly lower in the spironolactone group and spironolactone was also shown to improve diastolic function and induced beneficial remodeling through a reduction in myocardial fibrosis. The safety profile of spironolactone and eplerenone has been assessed in two recent studies. Data showed that eplerenone and spironolactone are both associated with the occurrence of gynecomastia, mastodynia, and abnormal vaginal bleeding and in addition, they can increase natriuresis and cause renal retention of potassium; furthermore, eplerenone may cause hyperkalemia and promote the onset of metabolic acidosis or hyponatremia. In conclusion although the mineralocorticoid receptor antagonists eplerenone and spironolactone improve clinical outcomes in patients with HFrEF, additional data will be necessary to better define their risk-benefit profile, especially for eplerenone, in the treatment of HFpEF., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The primary objective of this study was to assess the effect of a 6-month testosterone supplementation therapy on functional capacity and insulin resistance in female patients with chronic heart failure (CHF)., Background: Patients with CHF show decreased exercise capacity and insulin sensitivity. Testosterone supplementation improves these variables in men with CHF. No study has evaluated the effects of testosterone supplementation on female patients with CHF., Methods: Thirty-six elderly female patients with stable CHF, (ejection fraction 32.9 ± 6) were randomly assigned (2:1 ratio) to receive testosterone transdermal patch (T group, n = 24) or placebo (P group, n = 12), both on top of optimal medical therapy. At baseline and after 6 months, patients underwent 6-min walking test (6MWT), cardiopulmonary exercise test, echocardiogram, quadriceps maximal isometric voluntary contraction, dynamic quadriceps isokinetic strength (peak torque), and insulin resistance assessment by homeostasis model., Results: Distance walked at 6MWT as well as peak oxygen consumption significantly improved in the T group, whereas they were unchanged in the P group (p < 0.05 for all comparisons). The homeostasis model was significantly reduced in the T group in comparison with the P group (-16.5% vs. +5%, respectively; p < 0.05). Maximal voluntary contraction and peak torque increased significantly in the T group but did not change in the P group. Increase in distance walked at 6MWT was related to the increase in free testosterone levels (r = 0.593, p = 0.01). No significant changes in echocardiographic parameters were observed in either group. No side effects requiring discontinuation of T were detected., Conclusions: Testosterone supplementation improves functional capacity, insulin resistance, and muscle strength in women with advanced CHF. Testosterone seems to be an effective and safe therapy for elderly women with CHF., (Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)