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Aims: We explored timing, settings and predictors of angiotensin receptor-neprilysin inhibitor (ARNI) initiation in a large, nationwide cohort of patients with heart failure (HF) with reduced ejection fraction (HFrEF)., Methods and Results: Patients with HFrEF (ejection fraction <40%) registered in the Swedish HF Registry in 2017-2021 and naïve to ARNI were evaluated for timing and location of, and their characteristics at ARNI initiation. ARNI use increased from 8.3% in 2017 to 26.7% in 2021. Among 3892 hospitalized patients, 8% initiated ARNI in-hospital or ≤14 days after discharge, 4% between 15 and 90 days, and 88% >90 days after discharge or never initiated. Factors associated with earlier initiation included follow-up in specialized HF care, more severe HF, previous HF treatment use and higher income, whereas older age, higher comorbidity burden and living alone were associated with later/no initiation. Of 16 486 HFrEF patients, 8.1% inpatients and 5.9% outpatients initiated an ARNI at the index date. Factors associated with initiation in outpatients were overall consistent with those linked with an in-hospital/earlier ARNI initiation; 4.9% of 10 209 with HF duration <6 months and 9.1% of 5877 with HF duration ≥6 months initiated ARNI. Predictors of ARNI initiation in HF duration <6 months were inpatient status, lower ejection fraction, hypertension, whereas previous angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use was associated with less likely initiation. Discontinuation at 1 year ranged between 13% and 20% across the above-reported analyses., Conclusions: In-hospital and early initiation of ARNI are limited in real-world care but still slightly more likely than in outpatients. ARNI were more likely initiated in patients with more severe HF, which might suggest its use as a second-line treatment and only following worsening of clinical status. One-year discontinuation rates were consistent regardless of the timing/setting of ARNI initiation., (© 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.)

Background: The cardiotoxic effects of anthracyclines therapy are well recognized, both in the short and long term. Echocardiography allows monitoring of cancer patients treated with this class of drugs by serial assessment of left ventricle ejection fraction (LVEF) as a surrogate of systolic function. However, changes in myocardial function may occur late in the process when cardiac damage is already established. Novel cardiac magnetic resonance (CMR) parametric techniques, like native T1 mapping and extra-cellular volume (ECV), may detect subclinical myocardial damage in these patients, recognizing early signs of cardiotoxicity before development of overt cancer therapy-related cardiac dysfunction (CTRCD) and prompting tailored therapeutic and follow-up strategies to improve outcome., Methods and Results: We conducted a systematic review and a meta-analysis to investigate the difference in CMR derived native T1 relaxation time and ECV values, respectively, in anthracyclines-treated cancer patients with preserved EF versus healthy controls. PubMed, Embase, Web of Science and Cochrane Central were searched for relevant studies. A total of 6 studies were retrieved from 1057 publications, of which, four studies with 547 patients were included in the systematic review on T1 mapping and five studies with 481 patients were included in the meta-analysis on ECV. Three out of the four included studies in the systematic review showed higher T1 mapping values in anthracyclines treated patients compared to healthy controls. The meta-analysis demonstrated no statistically significant difference in ECV values between the two groups in the main analysis (Hedges´s g =3.20, 95% CI -0.72-7.12, p =0.11, I 2 =99%), while ECV was significantly higher in the anthracyclines-treated group when sensitivity analysis was performed., Conclusions: Higher T1 mapping and ECV values in patients exposed to anthracyclines could represent early biomarkers of CTRCD, able to detect subclinical myocardial changes present before the development of overt myocardial dysfunction. Our results highlight the need for further studies to investigate the correlation between anthracyclines-based chemotherapy and changes in CMR mapping parameters that may guide future tailored follow-up strategies in this group of patients., Competing Interests: Declaration of competing interest CBD is the chief executive officer (part-time) for the Society for Cardiovascular Magnetic Resonance (SCMR), she has received speakers’ fees from Circle Cardiovascular Imaging, Siemens Healthineers, Bayer and GE HealthCare. The other Authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.)

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: 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.)

Background: Hospitalization for heart failure (HHF) is associated with poor postdischarge outcomes but the role of time since most recent HHF and potential treatment interactions are unknown. We aimed to assess history of and time since previous HHF, associations with composite of cardiovascular (CV) death and total HHF, first HHF and interactions with randomization to spironolactone, in heart failure with preserved ejection fraction., Methods and Results: We assessed these objectives using uni- and multivariable regressions and spline analyses in TOPCAT-Americas. Among 1,765 patients, 66% had a previous HHF. Over a median of 2.9 years, 1,064 composite events of CV death or total HHFs occurred. Previous HHF was associated with more severe HF, and was independently associated with the composite outcome (HR 1.26, 95%CI 1.05-1.52, P = .014), and all secondary outcomes. A shorter time since most recent HHF appeared to be associated with subsequent first HHF, but not the composite of CV death or total HHF. Spironolactone had a significant interaction with previous HHF (interaction-P .046). Patients without a previous HHF had a larger effect of spironolactone on the composite outcome (HR 0.63, 95%CI 0.46-0.87, P = .005) than patients with a previous HHF (HR 0.91, 95%CI 0.78-1.06, P = .224)., Conclusion: In TOPCAT-Americas, previous HHF was associated with CV death and first and total HHF. Duration since most recent HHF seemed to be associated with time to first HHF only. Spironolactone was associated with better outcomes in patients without a previous HHF. This interaction is hypothesis-generating and requires validation in future trials., Competing Interests: Conflict of interest The authors have no disclosures related to the current research. Unrelated to the present work, the authors disclose: MF: Dr Fudim was supported by the American Heart Association (20IPA35310955), Doris Duke, Bayer, Bodyport, and Verily. He received consulting fees from Abbott, Ajax, Alio Health, Alleviant, Artha, Audicor, AxonTherapies, Bayer, Bodyguide, Bodyport, Boston Scientific, Broadview, Cadence, Cardioflow, Cardionomics, Coridea, CVRx, Daxor, Deerfield Catalyst, Edwards LifeSciences, EKO, Feldschuh Foundation, Fire1, FutureCardia, Galvani, Gradient, Hatteras, HemodynamicQ, Impulse Dynamics, Intershunt, Medtronic, Merck, NIMedical, NovoNordisk, NucleusRx, NXT Biomedical, Pharmacosmos, PreHealth, ReCor, Rockley, Shifamed, Splendo, Sumacor, SyMap, Verily, Vironix, Viscardia, Zoll. GS reports grants and personal fees from Vifor, grants from Boehringer Ingelheim, personal fees from Societa´ Prodotti Antibiotici, grants and personal fees from AstraZeneca, personal fees from Roche, personal fees from Servier, grants and personal fees from Novartis, personal fees from GENESIS, 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 TEVA, outside the submitted work. CH: Grants from Bayer and speaker and honoraria from AstraZeneca and Novartis, consulting fees from Novartis, Roche Diagnostics and AnaCardio, Supported by the Swedish Research Council [grant 20180899]; BP: Dr Pitt has received consulting fees from Lexicon, Bayer, AstraZeneca, Boehringer Ingelheim, Merck, and Phasebio; has received consulting fees and/or stock options from Vifor, KBP Biosciences, Cereno Scientific, Tricida, SCPharmaceuticals, SQinnovation, G-3 Pharmaceuticals, Protonintel, and Brainstorm Medical; and holds U.S. Patent 9931412 on site-specific delivery of eplerenone to the myocardium and U.S. Patent pending 63/045,783 on histone-modulating agents for the protection and treatment of organ damage. LHL: Grants: AstraZeneca, Vifor, Boston Scientific, Boehringer Ingelheim, Novartis, MSD; Consulting: Vifor, AstraZeneca, Bayer, Pharmacosmos, MSD, MedScape, Sanofi, Lexicon, Myokardia, Boehringer Ingelheim, Servier, Edwards Life Sciences, Alleviant; Speaker's honoraria: Abbott, OrionPharma, MedScape, Radcliffe, AstraZeneca, Novartis, Boehringer Ingelheim, Bayer; Patent: AnaCardio; Stock ownership: AnaCardio, (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: To assess cause-specific death in patients with heart failure with preserved, mildly reduced, and reduced ejection fraction (HFpEF, HFmrEF, and HFrEF)., Methods and Results: Data were analysed from the Swedish Heart Failure Registry (SwedeHF) and the National Patient Register of patients enrolled in SwedeHF 2000-2021. Cox proportional hazards regression models were performed and adjusted for age, sex and time period. Among 100 584 patients (23% HFpEF, 23% HFmrEF, 53% HFrEF), median age (interquartile range) was 75 (66-82) and 36% were female. Of those who died within 5 years, most deaths were ascribed to cardiovascular (CV) causes across all ejection fraction (EF) categories. Within 5 years, HFpEF had higher adjusted risk of non-CV death (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.28-1.38, p < 0.001) and lower adjusted risk of CV death (HR 0.85, 95% CI 0.82-0.88, p < 0.001) compared to HFrEF. Ischaemic heart disease (IHD) and cancer were the most common causes of CV and non-CV death regardless of EF category. The incidence rate of CV death due to IHD was highest in HFrEF while incidence rates of CV death due to pulmonary vascular disease, stroke, valvular heart disease and atrial fibrillation increased with increasing EF. The incidence rates of non-CV deaths due to cancer, respiratory disease, and infections increased with increasing EF., Conclusion: Cardiovascular death was more common than non-CV death across all EF categories although the risk of non-CV death within 5 years was higher with increasing EF. IHD and cancer were the most common causes of CV and non-CV deaths, respectively, regardless of EF category., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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.)

Review Purpose: This review summarises key findings on treatment effects within phenotypical clusters of patients with heart failure (HF), making a distinction between patients with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF)., Findings: Treatment response differed among clusters; ACE inhibitors were beneficial in all HFrEF phenotypes, while only some studies show similar beneficial prognostic effects in HFpEF patients. Beta-blockers had favourable effects in all HFrEF patients but not in HFpEF phenotypes and tended to worsen prognosis in older, cardiorenal patients. Mineralocorticoid receptor antagonists had more favourable prognostic effects in young, obese males and metabolic HFpEF patients. While a phenotype-guided approach is a promising solution for individualised treatment strategies, there are several aspects that still require improvements before such an approach could be implemented in clinical practice. Stronger evidence from clinical trials and real-world data may assist in establishing a phenotype-guided treatment approach for patient with HF in the future., (© 2023. The Author(s).)

Review Purpose: This systematic review aims to summarise clustering studies in heart failure (HF) and guide future clinical trial design and implementation in routine clinical practice., Findings: 34 studies were identified (n = 19 in HF with preserved ejection fraction (HFpEF)). There was significant heterogeneity invariables and techniques used. However, 149/165 described clusters could be assigned to one of nine phenotypes: 1) young, low comorbidity burden; 2) metabolic; 3) cardio-renal; 4) atrial fibrillation (AF); 5) elderly female AF; 6) hypertensive-comorbidity; 7) ischaemic-male; 8) valvular disease; and 9) devices. There was room for improvement on important methodological topics for all clustering studies such as external validation and transparency of the modelling process. The large overlap between the phenotypes of the clustering studies shows that clustering is a robust approach for discovering clinically distinct phenotypes. However, future studies should invest in a phenotype model that can be implemented in routine clinical practice and future clinical trial design. HF = heart failure, EF = ejection fraction, HFpEF = heart failure with preserved ejection fraction, HFrEF = heart failure with reduced ejection fraction, CKD = chronic kidney disease, AF = atrial fibrillation, IHD = ischaemic heart disease, CAD = coronary artery disease, ICD = implantable cardioverter-defibrillator, CRT = cardiac resynchronization therapy, NT-proBNP = N-terminal pro b-type natriuretic peptide, BMI = Body Mass Index, COPD = Chronic obstructive pulmonary disease., (© 2023. The Author(s).)

Background: It is unknown if β-blockers reduce mortality/morbidity in patients with heart failure (HF) and advanced chronic kidney disease (CKD), a population underrepresented in HF trials., Methods: Observational cohort of HF patients with advanced CKD (estimated glomerular filtration rate <30 mL/min per 1.73 m 2 ) from the Swedish Heart Failure Registry between 2001 and 2016. We first explored associations between β-blocker use, 5-year death, and the composite of cardiovascular death/HF hospitalization among 3775 patients with HF with reduced ejection fraction (HFrEF) and advanced CKD. We compared observed hazards with those from a control cohort of 15 346 patients with HFrEF and moderate CKD (estimated glomerular filtration rate <60-30 mL/min per 1.73 m 2 ), for whom β-blocker trials demonstrate benefit. Second, we explored outcomes associated to β-blocker among advanced CKD participants with preserved (HFpEF; N=2009) and midrange ejection fraction (HFmrEF; N=1514)., Results: During a median follow-up of 1.3 years, 2012 patients had a subsequent HF hospitalization, and 2849 died in the HFrEF cohort, of which 2016 died due to cardiovascular causes. Among patients with HFrEF, β-blocker use was associated with lower risk of death (adjusted hazard ratio 0.85 [95% CI, 0.75-0.96]) and cardiovascular mortality/HF hospitalization (0.87 [0.77-0.98]) compared with nonuse. The magnitude of the associations was similar to that observed for HFrEF patients with moderate CKD. Conversely, no significant association was observed for β-blocker users in advanced CKD with HFpEF (death: 0.88 [0.77-1.02], cardiovascular mortality/HF hospitalization: 1.05 [0.90-1.23]) or HFmrEF (death: 0.95 [0.79-1.14], cardiovascular mortality/HF hospitalization: 1.09 [0.90-1.31])., Conclusions: In HFrEF patients with advanced CKD, the use of β-blockers was associated with lower morbidity and mortality. Although inconclusive due to limited power, these benefits were not observed in similar patients with HFpEF or HFmrEF.

Background: The role of anemia in heart failure with mid-range and preserved ejection fraction (HFmrEF, EF 40-49% and HFpEF, EF ≥50%) is unknown. We aimed to compare prevalence of, associations with, and prognostic role of anemia in HF across the EF spectrum., Methods: In patients from the Swedish HF Registry, we assessed the associations between clinical characteristics and anemia (hemoglobin <120 g/L in women and <130 g/L in men) by multivariable logistic regression, and between anemia, composite of all-cause death and HF hospitalization and all-cause death alone by multivariable Cox regression., Results: Of 49,985 patients with HF (anemia = 34%), 23% had HFpEF (anemia = 41%), 21% had HFmrEF (anemia = 35%) and 55% had HFpEF (anemia = 32%). Higher EF was independently associated with higher likelihood of concomitant anemia. Important predictors of anemia across the EF spectrum were male sex, older age, worse New York Heart Association class and renal function, lower systolic blood pressure, higher N-Terminal B-type natriuretic peptides levels, diabetes, valvular disease and in-patient status. Anemia had adjusted hazard ratios (95% CI) for mortality or HF hospitalization 1.24 (1.18-1.30) in HFpEF, 1.26 (1.19-1.34) in HFmrEF and 1.14 (1.10-1.19) in HFrEF; p interaction EF = 0.003; and for mortality 1.28 (1.20-1.36) in HFpEF, 1.21 (1.13-1.29) in HFmrEF, and 1.30 (1.24-1.35) in HFrEF; p interaction EF = 0.22., Conclusions: In this nation-wide registry, prevalence of anemia was higher in HFpEF vs. HFmrEF vs. HFrEF, but was associated with a similarly increased risk of death across the EF spectrum, with greater risk of death or HF hospitalization in HFpEF and HFmrEF vs. HFrEF., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: HFmrEF has been recently proposed as a distinct HF phenotype. How HFmrEF differs from HFrEF and HFpEF according to age remains poorly defined. We aimed to investigate age-dependent differences in heart failure with mid-range (HFmrEF) vs. preserved (HFpEF) and reduced (HFrEF) ejection fraction., Methods and Results: 42,987 patients, 23% with HFpEF, 22% with HFmrEF and 55% with HFrEF, enrolled in the Swedish heart failure registry were studied. HFpEF prevalence strongly increased, whereas that of HFrEF strongly decreased with higher age. All cardiac comorbidities and most non-cardiac comorbidities increased with aging, regardless of the HF phenotype. Notably, HFmrEF resembled HFrEF for ischemic heart disease prevalence in all age groups, whereas regarding hypertension it was more similar to HFpEF in age ≥ 80 years, to HFrEF in age < 65 years and intermediate in age 65-80 years. All-cause mortality risk was higher in HFrEF vs. HFmrEF for all age categories, whereas HFmrEF vs. HFpEF reported similar risk in ≥ 80 years old patients and lower risk in < 65 and 65-80 years old patients. Predictors of mortality were more likely cardiac comorbidities in HFrEF but more likely non-cardiac comorbidities in HFpEF and HFmrEF with < 65 years. Differences among HF phenotypes for comorbidities were less pronounced in the other age categories., Conclusion: HFmrEF appeared as an intermediate phenotype between HFpEF and HFrEF, but for some characteristics such as ischemic heart disease more similar to HFrEF. With aging, HFmrEF resembled more HFpEF. Prognosis was similar in HFmrEF vs. HFpEF and better than in HFrEF.

Aims: This study aims to assess prognostic impact of Framingham criteria for heart failure (FC-HF) in patients with stable heart failure (HF) with preserved ejection fraction (HFpEF)., Methods and Results: In the prospective Karolinska-Rennes (KaRen) study, we assessed stable HFpEF patients after an acute HF episode. We evaluated associations between the four descriptive models of HFpEF and the composite endpoint of all-cause mortality and HF hospitalization. The descriptive models were FC-HF alone, FC-HF + natriuretic peptides (NPs) according to the PARAGON trial, FC-HF + NPs + echocardiographic HFpEF criteria according to European Society of Cardiology HF guidelines, and FC-HF + NPs + echocardiographic criteria according to the PARAGON trial. Out of the 539 patients enrolled in KaRen, 438 returned for the stable state revisit after 4-8 weeks, 13 (2.4%) patients died before the planned follow-up, and 88 patients (16%) declined or were unable to return. Three hundred ninety-nine patients have FC registered at follow-up, and among these, the four descriptive models were met in 107 (27%), 82 (22%), 61 (21%), and 69 (22%) patients, and not met in 292 (73%). The 107 patients that had FC-HF at stable state (descriptive model 1) could also be part of the other models because all patients in models 1-4 had to fulfil the FC-HF. The patients in model 0 did not fulfil the criteria for FC-HF but could have single FC. Of single FC, only pleural effusion predicted the endpoint [hazard ratio (HR) 3.38, 95% confidence interval (CI) 1.47-7.76, P = 0.004]. Patients without FC-HF had better prognosis than patients meeting FC-HF. The unadjusted associations between the four HFpEF descriptive models and the endpoint were HR 1.54, 95% CI 1.14-2.09, P = 0.005; HR 1.71, 95% CI 1.24-2.36, P = 0.002; HR 1.95, 95% CI 1.36-2.81, P = 0.001; and HR 2.05, 95% CI 1.45-2.91, P < 0.001, for descriptive models 1-4, respectively. No descriptive model independently predicted the endpoint., Conclusions: In ambulatory HFpEF patients, a quarter met FC-HF, while most met NP and echocardiography criteria for HF. Residual FC-HF tended to be associated with increased risk for mortality and HF hospitalization, further strengthened by NPs and echocardiographic criteria, highlighting its role in clinical risk assessment., (© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Objective: The aim was to assess sex-specific differences in N-terminal B-type natriuretic peptide (NT-proBNP) regarding concentrations, predictors of high concentrations, and prognostic role, in a large and unselected population with chronic heart failure (HF) with preserved (HFpEF), mid-range (HFmrEF), and reduced ejection fraction (HFrEF)., Methods and Results: In 9847 outpatients with HFpEF, HFmrEF, and HFrEF (49 vs. 35 vs. 25% females, respectively) from the Swedish HF Registry, median NT-proBNP concentrations were 1598 ng/L in females vs. 1310 ng/L in males in HFpEF, 1764 vs. 1464 ng/L in HFmrEF, and 2543 vs. 2226 ng/L in HFrEF (p < 0.05 for all). The differences persisted after multiple adjustment. The largest sex-difference in NT-proBNP levels was observed in HFpEF with sinus rhythm, where median concentrations were 1.4 folds higher in females (923 vs. 647 ng/L). Independent predictors of NT-proBNP levels (defined as above the different medians according to sex and HF phenotype) were overall consistent across sexes and EF. NT-proBNP levels were similarly associated with risk of all-cause death/HF hospitalization in both sexes regardless of EF., Conclusion: Concentrations of NT-proBNP were higher in females across the EF spectrum, with larger relative differences in HFpEF with sinus rhythm. However, similar predictors of high levels were observed in both sexes. There were no sex-differences in the prognostic role of NT-proBNP. These findings support the use of NT-proBNP for prognostic purposes in chronic HF, regardless of sex., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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.)

Objectives: This study sought to evaluate the incidence, the predictors, and the associations with outcomes of changes in ejection fraction (EF) in heart failure (HF) patients., Background: EF determines therapy in HF, but information is scarce about incidence, determinants, and prognostic implications of EF change over time., Methods: Patients with ≥2 EF measurements were made in the Swedish Heart Failure Registry were categorized as heart failure with preserved ejection fraction (HFpEF) (EF ≥50%), heart failure with midrange ejection fraction (HFmrEF) (EF 40% to 49%), or heart failure with reduced ejection fraction (HFrEF) (EF <40%). Changes among categories were recorded, and associations among EF changes, predictors, and all-cause mortality and/or HF hospitalizations were analyzed using logistic and Cox regressions., Results: Of 4,942 patients at baseline, 18% had HFpEF, 19% had HFmrEF, and 63% had HFrEF. During follow-up, 21% and 18% of HFpEF patients transitioned to HFmrEF and HFrEF, respectively; 37% and 25% of HFmrEF patients transitioned to HFrEF and HFpEF, respectively; and 16% and 10% of HFrEF patients transitioned to HFmrEF and HFpEF, respectively. Predictors of increased EF included female sex, cases of less severe HF, and comorbidities. Predictors of decreased EF included diabetes, ischemic heart disease, and cases of more severe HF. Use of renin-angiotensin-system inhibitors was associated with lower likelihood of EF increase, but not with EF decrease, i.e., stable EF. Increased EF was associated with a lower risk (hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.55 to 0.69) and decreased EF with a higher risk (HR: 1.15; 95% CI: 1.01 to 1.30) of mortality and/or HF hospitalizations. Prognostic implications were most evident for transitions to and from HFrEF., Conclusions: Increases in EF occurred in one-fourth of HFrEF and HFmrEF patients, and decreases occurred in more than one-third of patients with HFpEF and HFmrEF. EF change was associated with a wide range of important clinical and organizational factors as well as with outcomes, particularly transitions to and from HFrEF., (Copyright © 2019. Published by Elsevier Inc.)

Aims: In heart failure with reduced ejection fraction (HFrEF), renin-angiotensin system inhibitors (RASi) improve morbidity and mortality. However, patients aged >80 years constituted a small minority in trials. We assessed the association between RASi use and mortality/morbidity in HFrEF patients aged >80 years., Methods and Results: We included patients with ejection fraction <40% and age >80 years from the Swedish Heart Failure Registry. Propensity scores for RASi use were calculated from 37 variables. Cox regression models for RASi vs. non-RASi with all-cause mortality and all-cause mortality/heart failure (HF) hospitalization as outcomes were fitted in a 1:1 propensity-score-matched cohort. To assess consistency, the same analyses were performed in a 'positive control' cohort aged ≤80 years. Of 6710 patients [median age (interquartile range) 85 (82-87) years; 38% women], 5384 (80%) received RASi. Propensity-score matching yielded 2416 patients, [age 86 (83-91) years]. RASi use was associated with hazard ratio (HR) (95% confidence interval) 0.78 (0.72-0.86) for all-cause mortality and 0.86 (0.79-0.94) for all-cause mortality/HF hospitalization. In positive control patients aged ≤80 years (17 842 patients in the overall cohort, 2126 after matching), HR for all-cause mortality was 0.81 (0.71-0.91), whereas it was 0.85 (0.76-0.94) for all-cause mortality/HF hospitalization., Conclusion: In HFrEF patients with age >80 years, RASi were relatively underused compared with in younger patients, despite similar association with reduced morbidity and mortality and no apparent association with risk of syncope-related hospitalization. These results may be interpreted as hypothesis generating for randomized clinical trials on RASi in this elderly HFrEF subpopulation.

Background: Professional guidelines are based on the best available evidence. However, patients treated in clinical practice may differ from those included in reference trials., Objective: The aim of this study was to evaluate the effects of cardiac resynchronization therapy (CRT) in a large population of patients implanted with a CRT device stratified in accordance with the 2016 European heart failure (HF) guidelines., Methods: We collected data on 930 consecutive patients from the Cardiac Resynchronization Therapy MOdular REgistry. The primary end point was a composite of death and HF hospitalization., Results: Five hundred sixty-three (60.5%) patients met class I indications, 145 (15.6%) class IIa, 108 (11.6%) class IIb, and 114 (12.3%) class III. After a median follow-up of 1001 days, 120 (14.7%) patients who had an indication to CRT had died and 71 (8.7%) had been hospitalized for HF. The time to the end point was longer in patients with a class I indication (hazard ratio 0.55; 95% confidence interval 0.39-0.76; P = .0001). After 12 months, left ventricular (LV) end-systolic volume had decreased by ≥15% in 61.5% (320/520) of patients whereas in 57.5% (389/676) of patients the absolute LV ejection fraction improvement was ≥5%. Adherence to class I was also associated with an absolute LV ejection fraction increase of >5% (P = .0142) and an LV end-systolic volume decrease of ≥15% (P = .0055)., Conclusion: In our population, ∼60% of patients underwent implantation according to the 2016 European HF guidelines class I indication. Adherence to class I was associated with a lower death and HF hospitalization rates and better LV reverse remodeling., (Copyright © 2018 Heart Rhythm Society. 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.)

Aims: Clinical features and outcomes in the novel phenotype heart failure with mid-range ejection fraction [HFmrEF, ejection fraction (EF) 40-49%] were compared with heart failure with reduced EF (HFrEF, EF <40%) and preserved EF (HFpEF, EF ≥50%)., Methods and Results: In the Swedish Heart Failure Registry, we assessed the association between baseline characteristics and EF group using multivariable logistic regressions, and the association between EF group and all-cause mortality using multivariable Cox regressions. Of 42 061 patients, 56% had HFrEF, 21% had HFmrEF, and 23% had HFpEF. Characteristics were continuous for age (72 ± 12 vs. 74 ± 12 vs. 77 ± 11 years), proportion of women (29% vs. 39% vs. 55%), and 13 other characteristics. Coronary artery disease (CAD) was distinctly more common in HFrEF (54%) and HFmrEF (53%) vs. HFpEF (42%); adjusted odds ratio for CAD in HFmrEF vs. HFpEF was 1.52 [95% confidence interval (CI) 1.41-1.63]. For six additional characteristics HFmrEF resembled HFrEF, for seven characteristics HFmrEF resembled HFpEF, and for 10 characteristics there was no pattern. The adjusted hazard ratio (HR) for mortality in HFrEF vs. HFpEF was 1.35 (95% CI 1.14-1.60) at 30 days, 1.26 (95% CI 1.17-1.35) at 1 year, and 1.20 (95% CI 1.14-1.26) at 3 years. In contrast, HFmrEF and HFpEF had a similar prognosis (HR 1.06, 95% CI 0.86-1.30 at 30 days; HR 1.08, 95% CI 1.00-1.18 at 1 year; and HR 1.06, 95% CI 1.00-1.12 at 3 years). Three-year mortality was higher in HFmrEF than in HFpEF in the presence of CAD (HR 1.11, 95% CI 1.02-1.21), but not in the absence of CAD (HR 1.02, 95% CI 0.94-1.12; P for interaction <0.001)., Conclusions: HFmrEF was an intermediate phenotype, except that CAD was more common in HFmrEF and HFrEF vs. HFpEF, crude all-cause mortality was lower in HFmrEF and HFrEF, adjusted all-cause mortality was lower in HFmrEF and HFpEF, and CAD portended a higher adjusted risk of death in HFmrEF and HFrEF., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Background: The sinus node inhibitor ivabradine was approved for patients with heart failure (HF) after the ivabradine and outcomes in chronic HF (SHIFT [Systolic Heart Failure Treatment With the IF Inhibitor Ivabradine Trial]) trial. Our objective was to characterize the proportion of patients with HF eligible for ivabradine and the representativeness of the SHIFT trial enrollees compared with those in the Swedish Heart Failure Registry., Methods and Results: We examined 26 404 patients with clinical HF from the Swedish Heart Failure Registry and divided them into SHIFT type (left ventricular ejection fraction <40%, New York Heart Association class II-IV, sinus rhythm, and heart rate ≥70 beats per minute) and non-SHIFT type. Baseline characteristics and medication use were compared and change in eligibility over time was reported at 6 months and 1 year in a subset of patients. Overall, 14.2% (n=3741) of patients were SHIFT type. These patients were more likely to be younger, men, have diabetes mellitus, ischemic heart disease, lower left ventricular ejection fraction, and more recent onset HF (<6 months; all, P <0.001). Although 88.9% of SHIFT type and 88.5% of non-SHIFT type ( P =0.421) were receiving selected β-blockers, only 58.8% and 67.3% ( P <0.001) were on >50% of target dose. From those patients who had repeated visits within 6 months (n=5420) and 1 year (n=6840), respectively, 10.2% (n=555) and 10.6% (n=724) of SHIFT-type patients became ineligible, 77.3% (n=4188) and 77.3% (n=5287) remained ineligible, and 4.6% (n=252) and 4.9% (n=335) of non-SHIFT-type patients became eligible for initiation of ivabradine., Conclusions: From the Swedish Heart Failure Registry, 14.2% of patients with HF were eligible for ivabradine. These patients more commonly were not receiving target β-blocker dose. Over time, a minority of patients became ineligible and an even smaller minority became eligible., (© 2017 American Heart Association, Inc.)

Background: The pathogenic role of ischemic heart disease (IHD) in heart failure (HF) with reduced ejection fraction (HFrEF; EF <40%) is well established, but its pathogenic and prognostic significance in HF with midrange (HFmrEF; EF 40%-50%) and preserved EF (HFpEF; EF ≥50%) has been much less explored., Methods and Results: We evaluated 42 987 patients from the Swedish Heart Failure Registry with respect to baseline IHD, outcomes (IHD, HF, cardiovascular events, and all-cause death), and EF change during a median follow-up of 2.2 years. Overall, 23% had HFpEF (52% IHD), 21% had HFmrEF (61% IHD), and 55% had HFrEF (60% IHD). After multivariable adjustment, associations with baseline IHD were similar for HFmrEF and HFrEF and lower in HFpEF (risk ratio, 0.91 [0.89-0.93] versus HFmrEF and risk ratio, 0.90 [0.88-0.92] versus HFrEF). The adjusted risk of IHD events was similar for HFmrEF versus HFrEF and lower in HFpEF (hazard ratio, 0.89 [0.84-0.95] versus HFmrEF and hazard ratio, 0.84 [0.80-0.90] versus HFrEF). After adjustment, prevalent IHD was associated with increased risk of IHD events and all other outcomes in all EF categories except all-cause mortality in HFpEF. Those with IHD, particularly new IHD events, were also more likely to change to a lower EF category and less likely to change to a higher EF category over time., Conclusions: HFmrEF resembled HFrEF rather than HFpEF with regard to both a higher prevalence of IHD and a greater risk of new IHD events. Established IHD was an important prognostic factor across all HF types., (© 2017 American Heart Association, Inc.)

Background: In acute decompensated heart failure (ADHF) with preserved ejection fraction (HFpEF) there are no surrogate endpoints for early phase trials. The aim of the current study was to evaluate whether a reduction in natriuretic peptides (NP) between acute hospital presentation to stable follow-up is associated with improved mortality and morbidity., Methods: Patients presenting acutely to the hospital for ADHF with HFpEF enrolled in the Karolinska Rennes (KaRen) study and reporting N-terminal pro-B-type NP or B-type NP assessment at baseline hospital presentation and at 4-8weeks follow-up were prospectively studied. Logistic regression analyses were performed to detect the predictors of baseline and changes in NPs. Cox regression models were performed to assess the impact of NP reductions on mortality and the composite of mortality and HF hospitalization., Results: Of 361 patients (median follow-up 585days), 267 (74%) reported an improvement in NPs, while 94 (26%) reported worsening. At baseline, the independent predictors of lower NPs were higher glomerular filtration rate (Odds Ratio [OR] per unit: 1.013; 95% Confidence Interval [CI]: 1.005-1.021) and younger age (OR per year: 0.972; CI: 0.947-0.998). Improvement in NPs at follow-up was predicted by higher heart rate at baseline (OR per bpm: 1.014; CI: 1.003-1.025). After adjustments, the hazard ratio for all-cause death was 0.730 (CI: 0.456-1.169) and for the composite outcome 0.814 (CI: 0.582-1.139) for patients who improved vs. worsened in NP levels., Conclusions: In patients presenting acutely to the hospital with HFPEF, an improvement in NP levels did not independently and significantly predict improved mortality and/or morbidity. NPs as surrogate endpoints in acute HFpEF require further study., (Copyright © 2016 Elsevier Ireland Ltd. 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.)

Heart failure with reduced ejection fraction is a common and malignant condition, which recognizes a lot of causes and that carries a poor long-term prognosis. All patients with reduced left ventricular ejection fraction, both asymptomatic and symptomatic, should be evaluated with transthoracic echocardiography as a depth analysis of first level, due to its characteristics of accuracy, availability, safety and low costs. In fact, echocardiography is an essential tool to establish not only the diagnosis, but also the aetiology and the understanding pathophysiology of heart failure. Moreover, by the new more sensitive and more specific echocardiographic technologies, such as tissue Doppler imaging or strain rate or speckle tracking or three-dimensional echocardiography, it is possible to identify other recognized high-risk parameters associated with adverse outcome, which are useful to guide therapy and follow-up management of heart failure patients. Therefore, this review would underline the prognostic role of some echocardiographic parameters in the evaluation and management of patients with heart failure and reduced ejection fraction.