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© 2015 Bentham Science Publishers.Acute decompensated heart failure (ADHF) continues to increase in prevalence and is associated with substantial mortality and morbidity including frequent hospitalizations. The American Heart Association is predicting that

Aims Serelaxin is effective in relieving dyspnoea and improving multiple outcomes in acute heart failure (AHF). Many AHF patients have preserved ejection fraction (HFpEF). Given the lack of evidence-based therapies in this population, we evaluated the effe

© 2014 The Authors European Journal of Heart Failure.Aims We studied the characteristics and clinical outcome related to diuretic response and the effects of serelaxin in patients hospitalized for acute heart failure (AHF).Methods and results RELAX-AHF was

Background: Adenosine exerts actions in multiple organ systems, and adenosine receptors are a therapeutic target in many development programmes.Objective: The aim of this analysis was to evaluate the safety of rolofylline, an adenosine A(1)-receptor antagonist, in patients with acute heart failure.Methods: The effect of rolofylline was investigated in patients hospitalized for acute heart failure with impaired renal function. Intravenous rolofylline 30 mg or placebo was infused over 4 hours daily for up to 3 days. Adverse events (AEs) and serious AEs (SAEs) were recorded from baseline through 7 and 14 days, respectively, and clinical events were adjudicated through 60 days.Results: Of 2033 patients enrolled, 2002 received study drug randomized 2 : 1 to rolofylline or placebo. Rolofylline and placebo were associated with a similar risk of pre-specified groups of AEs or SAEs, other than selected neurological events. Investigator-reported seizures occurred in 11 (0.8%) rolofylline-treated patients and zero patients receiving placebo (p = 0.02). Stroke occurred in 21 (1.6%) patients assigned to rolofylline compared with 3 (0.5%) placebo-treated patients through 60 days with a greater risk for stroke in the rolofylline group (hazard ratio 3.49; 95% CI 1.04, 11.71; p = 0.043). There was no temporal relation to rolofylline administration and no specific stroke subtype or clinical characteristics that predicted stroke in the rolofylline group.Conclusions: Rolofylline treatment was associated with an increased seizure rate, an anticipated complication of A(1)-receptor antagonists. An unanticipated, disproportionate increase in strokes in the rolofylline-treated patients emerged, although no clear temporal relation, aetiology, stroke subtype or interacting factor suggestive of a causal mechanism was identified. Further research into stroke as a potential complication of adenosine-modulating therapies is required. Additionally, this study underscores the value of longer follow-up durations for AEs, even for agents with short treatment periods, such as in acute heart failure. [ABSTRACT FROM AUTHOR]

Cardiac resynchronization therapy (CRT) improves survival, symptoms, quality of life, exercise capacity, and cardiac structure and function in patients with New York Heart Association (NYHA) functional class II or ambulatory class IV heart failure (HF) with wide QRS complex. The totality of evidence supports the use of CRT in patients with less severe HF symptoms. CRT is recommended for patients in sinus rhythm with a widened QRS interval (>=150 ms) not due to right bundle branch block (RBBB) who have severe left ventricular (LV) systolic dysfunction and persistent NYHA functional class II-III symptoms despite optimal medical therapy (strength of evidence A). CRT may be considered for several other patient groups for whom evidence of benefit is clinically significant but less substantial, including patients with a QRS interval of >=120 to <150 ms and severe LV systolic dysfunction who have persistent mild to severe HF despite optimal medical therapy (strength of evidence B), some patients with atrial fibrillation, and some with ambulatory class IV HF. Several evidence gaps remain that need to be addressed, including the ideal threshold for QRS duration, QRS morphology, lead placement, degree of myocardial scarring, and the modality for evaluating dyssynchrony. Recommendations will evolve over time as additional data emerge from completed and ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Treatment with inotropic agents is one of the most controversial topics in heart failure. Initial enthusiasm, based on strong pathophysiological rationale and apparent empirical efficacy, has been progressively limited by results of controlled trials and registries showing poorer outcomes of the patients on inotropic therapy. The use of these agents remains, however, potentially indicated in a significant proportion of patients with low cardiac output, peripheral hypoperfusion and end-organ dysfunction caused by heart failure. Limitations of inotropic therapy seem to be mainly related to their mechanisms of action entailing arrhythmogenesis, peripheral vasodilation, myocardial ischemia and damage, and possibly due to their use in patients without a clear indication, rather than to the general principle of inotropic therapy itself. This review will discuss the characteristics of the patients with a potential indication for inotropic therapy, the main data from registries and controlled trials, the mechanism of the untoward effects of these agents on outcomes and, lastly, perspectives with new agents with novel mechanisms of action. [ABSTRACT FROM AUTHOR]

Relaxin is a naturally occurring peptide hormone that plays a central role in the hemodynamic and renovascular adaptive changes that occur during pregnancy. Triggering similar changes could potentially be beneficial in the treatment of patients with heart failure. The effects of relaxin include the production of nitric oxide, inhibition of endothelin, inhibition of angiotensin II, production of VEGF, and production of matrix metalloproteinases. These effects lead to systemic and renal vasodilation, increased arterial compliance, and other vascular changes. The recognition of this has led to the study of relaxin for the treatment of heart failure. An initial pilot study has shown favorable hemodynamic effects in patients with heart failure, including reduction in ventricular filling pressures and increased cardiac output. The ongoing RELAX-AHF clinical program is designed to evaluate the effects of relaxin on the symptoms and outcomes in a large group of patients admitted to hospital for acute heart failure. This review will summarize both the biology of relaxin and the data supporting its potential efficacy in human heart failure. [ABSTRACT FROM AUTHOR]

Decreased systolic function is a central factor in the pathogenesis of heart failure, yet there are no safe medical therapies to improve cardiac function in patients. Currently available inotropes, such as dobutamine and milrinone, increase cardiac contractility at the expense of increased intracellular concentrations of calcium and cAMP, contributing to increased heart rate, hypotension, arrhythmias, and mortality. These adverse effects are inextricably linked to their inotropic mechanism of action. A new class of pharmacologic agents, cardiac myosin activators, directly targets the kinetics of the myosin head. In vitro studies have demonstrated that these agents increase the rate of effective myosin cross-bridge formation, increasing the duration and amount of myocyte contraction, and inhibit non-productive consumption of ATP, potentially improving myocyte energy utilization, with no effect on intracellular calcium or cAMP. Animal models have shown that this novel mechanism increases the systolic ejection time, resulting in improved stroke volume, fractional shortening, and hemodynamics with no effect on myocardial oxygen demand, culminating in significant increases in cardiac efficiency. A first-in-human study in healthy volunteers with the lead cardiac myosin activator, CK-1827452, as well as preliminary results from a study in patients with stable chronic heart failure, have extended these findings to humans, demonstrating significant increases in systolic ejection time, fractional shortening, stroke volume, and cardiac output. These studies suggest that cardiac myosin activators offer the promise of a safe and effective treatment for heart failure. A program of clinical studies are being planned to test whether CK-1827452 will fulfill that promise. [ABSTRACT FROM AUTHOR]

Although we have recently witnessed substantial progress in management and outcome of patients with chronic heart failure, acute heart failure (AHF) management and outcome have not changed over almost a generation. Vasodilators are one of the cornerstones of AHF management; however, to a large extent, none of those currently used has been examined by large, placebo-controlled, non-hemodynamic monitored, prospective randomized studies powered to assess the effects on outcomes, in addition to symptoms. In this article, we will discuss the role of vasodilators in AHF trying to point out which are the potentially best indications to their administration and which are the pitfalls which may be associated with their use. Unfortunately, most of this discussion is only partially evidence based due to lack of appropriate clinical trials. In general, we believe that vasodilators should be administered early to AHF patients with normal or high blood pressure (BP) at presentation. They should not be administered to patients with low BP since they may cause hypotension and hypoperfusion of vital organs, leading to renal and/or myocardial damage which may further worsen patients' outcome. It is not clear whether vasodilators have a role in either patients with borderline BP at presentation (i.e., low-normal) or beyond the first 1-2 days from presentation. Given the limitations of the currently available clinical trial data, we cannot recommend any specific agent as first line therapy, although nitrates in different formulations are still the most widely used in clinical practice. [ABSTRACT FROM AUTHOR]

BACKGROUND: Heart failure is a major cause of morbidity and mortality and is increasing in prevalence. Treatments for heart failure permit a growing number of persons to live with the illness for many years. The burden of symptoms in persons with advanced heart failure is high. Fatigue, limited exertion, dyspnea, and depression are commonly associated with heart failure, but pain is common as well. METHODS AND RESULTS: Although it is known that underlying comorbidities modify the response to and experience of pain, the interaction between pain and the clinical syndrome of heart failure has not been studied to date. The Pain Assessment, Incidence & Nature in Heart Failure (PAIN-HF) study will evaluate pain in patients with advanced heart failure. Specifically, PAIN-HF will examine the anatomical location of pain, prevalence of pain, its association with aspects of patients' heart failure and comorbid conditions, and its relation to interventions and medications to treat pain. CONCLUSIONS: This study to identify the nature, incidence, and character of pain is an important step in relieving distress and discomfort in persons with heart failure. [ABSTRACT FROM AUTHOR]

Objectives: We sought to investigate the efficacy and safety of tezosentan, a dual endothelin receptor antagonist, in patients hospitalized for acute heart failure (HF).Background: Tezosentan has been previously shown to improve hemodynamics in patients with stable chronic HF.Methods: In a double-blind fashion, 292 patients (cardiac index < or =2.5 l/min per m(2) and pulmonary capillary wedge pressure (PCWP) > or =15 mm Hg) who were admitted to the hospital and in need of intravenous treatment for acute HF and central hemodynamic monitoring were randomized to 24-h intravenous treatment with tezosentan (50 or 100 mg/h) or placebo. Central hemodynamic variables, the dyspnea score, and safety variables were measured.Results: After 6 h of treatment, significantly greater increases in the cardiac index and decreases in PCWP were observed with both tezosentan dosages than with placebo (mean treatment effects at 0.38 and 0.37 l/min per m(2) with 50 and 100 mg/h and -3.9 mm Hg for each dose, respectively; p < 0.0001). This effect was maintained during the remaining infusion and for > or =6 h after treatment cessation. A tendency for an improved dyspnea score and a decreased risk of clinical worsening was observed after 24 h of treatment with each tezosentan dose. Adverse events, more frequent with tezosentan than with placebo (headache, asymptomatic hypotension, early worsening of renal function, nausea, vomiting), were dose-related.Conclusions: Intravenous tezosentan rapidly and effectively improved hemodynamics in these patients. The similar beneficial effects of the two dosages and the increased dose-related adverse events with the higher dosage suggest that the optimal dosing regimen is <50 mg/h. [ABSTRACT FROM AUTHOR]

Background: Multimorbidity frequently occurs in patients with acute heart failure (AHF). The co-occurrence of comorbidities often follows specific patterns., Objectives: This study investigated multimorbidity subtypes and their associations with clinical outcomes., Methods: From the prospective RELAX-AHF-2 (Relaxin for the Treatment of Acute Heart Failure-2) trial, 6,545 patients (26% with HF with preserved ejection fraction, defined as LVEF ≥50%) were classified into multimorbidity groups using latent class analysis. The association between subgroups and clinical outcomes was examined. Validation of these findings was conducted in the RELAX-AHF trial, which comprised 1,161 patients., Results: Five distinct multimorbidity groups emerged: 1) diabetes and chronic kidney disease (CKD) (often male, high prevalence of CKD and diabetes mellitus); 2) ischemic (ischemic HF); 3) elderly/atrial fibrillation (AF) (oldest, high prevalence of AF); 4) metabolic (obese, hypertensive, more often HF with preserved ejection fraction); and 5) young (fewest comorbidities). After adjusting for confounders, patients in the diabetes and CKD (HR: 1.80; 95% CI: 1.50-2.20), elderly/AF (HR: 1.42; 95% CI: 1.20-1.70), and metabolic (HR: 1.40; 95% CI: 1.20-1.80) groups had higher rates of the composite outcome than patients in the young group, primarily driven by differences in rehospitalization. Treatment allocation (placebo or serelaxin) modified these associations (P interaction  <0.001). Serelaxin-treated patients in the young group were associated with a lower risk for all-cause mortality (HR: 0.59; 95% CI: 0.40-0.90). Similarly, patients from the RELAX-AHF trial clustered in 5 multimorbidity groups. The clinical characteristics and associations with outcomes could also be validated., Conclusions: Comorbidities naturally clustered into 5 mutually exclusive groups in RELAX-AHF-2, showing variations in clinical outcomes. These data emphasize that the specific combination of comorbidities can influence adverse outcomes and treatment responses in patients with AHF., Competing Interests: Funding Support and Author Disclosures This study was funded by the PROMINENT project (funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement number 754425). Dr Tromp is supported by the National University of Singapore Start-up grant, the tier 1 grant from the ministry of education, and the CS-IRG New Investigator Grant from the National Medical Research Council; has received consulting or speaker fees from Daiichi Sankyo, Boehringer Ingelheim, Roche Diagnostics, and Us2.ai; and owns patent US-10702247-B2 unrelated to the present work. Drs Cotter and Davison are employees of Momentum Research, Inc, which has received grants from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics Inc, Corteria Pharmaceuticals, Roche Diagnostics Inc, Sanofi, Windtree Therapeutics Inc, and XyloCor Therapeutics. Dr Felker has received research grants from the National Heart, Lung, and Blood Institute, the American Heart Association, Amgen, Bayer, BMS, Merck, Cytokinetics, and CSL-Behring; has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Boehringer Ingelheim, American Regent, Abbott, AstraZeneca, Reprieve, Myovant, Sequana, Windtree Therapeutics, and Whiteswell; and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. Dr Gimpelewicz is an employee of Novartis. Dr Greenberg is a consultant for or on the advisory board of AstraZeneca, Bayer, Ionis, Merck, Mesoblast, and Tenaya; and has been on the Data Safety Monitoring Board of ACI, Axon, AstraZeneca, Bayer, Cytokinetics, Boehringer Ingelheim, EBR Systems, Faraday, Inventiva, Impulse Dynamics, Ionis, Salubris, Vifor, Viking, and Windtree. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, ProSciento Inc, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as co-founder and nonexecutive director of Us2.ai. Dr Voors has received research support and/or has been a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Cytokinetics, Merck, MyoKardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr Metra received personal fees of minimal amounts in the last 3 years from Actelion, Amgen, LivaNova, and Vifor pharma as a member of Executive or Data Monitoring Committees of sponsored clinical trials; and from AstraZeneca, Abbott Vascular, Bayer, Boehringer Ingelheim, and Edwards Therapeutics for participation on advisory boards and/or speeches at sponsored meetings. Dr Teerlink has received research support and/or has been a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics. Dr van der Meer received grant support and/or consultancy fees from Novartis, Pharma Nord, Pfizer, Ionis, Astra Zeneca, Vifor Pharma, Pharmacosmos, BridgeBio, and Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Patients hospitalized for acute heart failure (HF) could be enrolled in EMPULSE (NCT04157751) upon haemodynamic stabilization and between 24 h and 5 days after hospital admission. The timing of treatment initiation may influence the efficacy and safety of drugs such as empagliflozin. The aim of this study was to evaluate patient characteristics, clinical events, and treatment effects according to time from admission to randomization., Methods and Results: The EMPULSE population was dichotomized by median time from hospital admission to randomization (1-2 days vs. 3-5 days). The primary outcome was a hierarchical composite endpoint of time to all-cause death, number of HF events, time to first HF event, and a ≥5-point difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline after 90 days, analysed using the win ratio (WR) method. Patients randomized later (3-5 days, average time 3.9 days; n = 312) had a higher risk of experiencing clinical events than patients randomized earlier (1-2 days, average time 1.7 days; n = 215). The treatment effect favoured empagliflozin versus placebo in patients randomized later (3-5 days: WR 1.69, 95% confidence interval [CI] 1.26-2.25) but was attenuated in patients randomized earlier (1-2 days: WR 1.04, 95% CI 0.74-1.44) (interaction p = 0.029). A similar pattern was observed for the composite of HF hospitalization or cardiovascular death and all-cause hospitalizations (interaction p < 0.1 for both). The reduction of N-terminal pro-B-type natriuretic peptide levels was more pronounced with empagliflozin among patients randomized later than in patients randomized earlier (interaction p = 0.004)., Conclusions: Among patients hospitalized for acute HF enrolled in EMPULSE, those randomized later after hospital admission (3-5 days) experienced greater clinical benefit with empagliflozin than those randomized earlier (1-2 days). These findings should be confirmed in future studies before clinical application., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Inadequate inclusion in clinical trial enrollment may contribute to health inequities by evaluating interventions in cohorts that do not fully represent target populations., Objectives: The aim of this study was to determine if characteristics of patients with heart failure (HF) enrolled in a pivotal trial are associated with who receives an intervention after approval., Methods: Demographics from 2,017,107 Medicare patients hospitalized for HF were compared with those of the first 10,631 Medicare beneficiaries who received implantable pulmonary artery pressure sensors. Characteristics of the population studied in the pivotal CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) clinical trial (n = 550) were compared with those of both groups. All demographic data were analyzed nationally and in 4 U.S. regions., Results: The Medicare HF cohort included 80.9% White, 13.3% African American, 1.9% Hispanic, 1.3% Asian, and 51.5% female patients. Medicare patients <65 years of age were more likely to be African American (33%) and male (58%), whereas older patients were mostly White (84%) and female (53%). Forty-one percent of U.S. HF hospitalizations occurred in the South; demographic characteristics varied significantly across all U.S. regions. The CHAMPION trial adequately represented African Americans (23% overall, 35% <65 years of age), Hispanic Americans (2%), and Asian Americans (1%) but underrepresented women (27%). The trial's population characteristics were similar to those of the first patients who received pulmonary artery sensors (82% White, 13% African American, 1% Asian, 1% Hispanic, and 29% female)., Conclusions: Demographics of Centers for Medicare and Medicaid Services beneficiaries hospitalized with HF vary regionally and by age, which should be considered when defining "adequate" representation in clinical studies. Enrollment diversity in clinical trials may affect who receives early application of recently approved innovations., Competing Interests: Funding Support and Author Disclosures Abbott provided resources for access and analyses of CMS claims data and demographic information from the CHAMPION trial. Dr Adamson is an employee of Abbott. Dr Echols is a consultant to Abbott. Dr DeFilippis serves on a clinical trial committee for Abiomed. Dr Morris has received research funding from the Agency for Healthcare Research and Quality (HS026081), the American Heart Association, Google, and Merck; and has received consulting fees from Abbott, Acorai, Boehringer Ingelheim, Eli Lilly, Cytokinetics, Edwards Lifesciences, Ionis, Merck, and Regeneron. Dr Bennett has received consulting fees and speaker honoraria from Abbott. Dr Abraham has received consulting fees from Abbott Vascular, AquaPass, Boehringer Ingelheim, Impulse Dynamics, Sensible Medical Innovations, V-Wave, and Zoll Respicardia. Dr Lindenfeld has received consulting and/or research support from Abbott, AstraZeneca, Boehringer Ingelheim, Boston Scientific, CVRx, Edwards Lifesciences, Impulse Dynamics, Merck, Medtronic, V-Wave, Vifor, and Volumetrix. Dr Teerlink has received research support from 3ive Labs, AstraZeneca, Bayer, Boehringer Ingelheim, Cardurion, Cytokinetics, EBR Systems, Edwards Lifesciences, Impulse Dynamics, Kaiser Permanente, LivaNova, Medtronic, Myovant Sciences, the Patient-Centered Outcomes Research Institute, RECARDIO, and V-Wave; and is a consultant for 3ive Labs, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, CorHepta, Cytokinetics, Daiichi-Sankyo, EBR Systems, Edwards Lifesciences, Eli Lilly Impulse Dynamics, JuvLabs, Kaiser Permanente, LivaNova, Medtronic, Myovant Sciences, Novartis, the Patient-Centered Outcomes Research Institute, Pfizer, ReCor Medical, Regeneron, Reprieve, Tectonic, V-Wave, Verily, ViCardia, and Windtree Therapeutics. Dr O’Connor has received research funding from Merck; and has received consulting fees from Bayer and Dey. Dr Connolly is an employee of Abbott. Dr Li is an employee of Abbott. Dr. Vaduganathan has received research grant support from, served on advisory boards for, or has had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer, Baxter Healthcare, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer, Occlutech, and Impulse Dynamics. Dr Batchelor has received consulting fees from Boston Scientific, Medtronic, Edwards Lifesciences, V-Wave, Chiesi, Abbott, and Idorsia; and has received research support from Abbott and Boston Scientific. Dr McCants has received consulting fees and speaker honoraria from Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Omecamtiv mecarbil improves outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We examined the relationship between baseline troponin levels, change in troponin levels over time and the treatment effect of omecamtiv mecarbil in patients enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial (NCT02929329)., Methods: GALACTIC-HF was a double-blind, placebo-controlled trial that randomized 8256 patients with symptomatic HFrEF to omecamtiv mecarbil or placebo. High-sensitivity troponin I (cTnI) was measured serially at a core laboratory. We analyzed the relationship between both baseline cTnI and change in cTnI concentrations with clinical outcomes and the treatment effect of omecamtiv mecarbil., Results: Higher baseline cTnI concentrations were associated with a risk of adverse outcomes (hazard ratio for the primary endpoint of time to first HF event or CV death = 1.30; 95% CI 1.28, 1.33; P < 0.001 per doubling of baseline cTnI). Although the incidence of safety outcomes was higher in patients with higher baseline cTnI, there was no difference between treatment groups. Treatment with omecamtiv mecarbil led to a modest increase in cTnI that was related to plasma concentrations of omecamtiv mecarbil, and it peaked at 6 weeks. An increase in troponin from baseline to week 6 was associated with an increased risk of the primary endpoint (P < 0.001), which was similar, regardless of treatment assignment (P value for interaction = 0.2)., Conclusions: In a cohort of patients with HFrEF, baseline cTnI concentrations were strongly associated with adverse clinical outcomes. Although cTnI concentrations were higher in patients treated with omecamtiv mecarbil, we did not find a differential effect of omecamtiv mecarbil on either safety or efficacy based on baseline cTnI status or change in cTnI., Competing Interests: DISCLOSURES GMF has received research grants from NHLBI, American Heart Association, Amgen, Bayer, BMS, Merck, Cytokinetics, and CSL-Behring; he has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Boehringer-Ingelheim, American Regent, Abbott, Astra-Zeneca, Reprieve, Myovant, Sequana, Windtree Therapuetics, and Whiteswell and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. SDS reports receiving grants (via Brigham and Women's Hospital) from Amgen and Cytokinetics during the conduct of the study; grants (via Brigham and Women's Hospital) from Actelion, Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bellerophon Therapeutics, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos Therapeutics, Eli Lilly, Gilead Sciences,GlaxoSmithKline, Ionis Pharmaceuticals, Mesoblast,Myocardium, the National Heart, Lung, and Blood Institute, NeuroTronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, and Theracos; and consulting fees from Abbott Laboratories, Action Pharma, Akros Pharma, Alnylam Pharmaceuticals, American Regent, Amgen, Arena Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimensions, Cardior Pharmaceuticals, Cardurion Pharmaceuticals, CellProthera, Corvia Medical, Cytokinetics, Daiichi Sankyo, Dinaqor, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceuticals, Merck & Co, Moderna, Myokardia, Novartis, Quantum Genomics, Roche, Sanofi Pasteur, Sarepta Therapeutics, Tenaya Therapeutics, Theracos, and Tremeau Pharmaceuticals. MM reports receiving personal fees from Amgen and Servier Laboratories during the conduct of the study and personal fees from Abbott Laboratories, Actelion, AstraZeneca, Edwards Lifesciences, LivaNova, Vifor Pharma, and Windtree Therapeutics. JJVM reports receiving travel fees and nonfinancial support (via the University of Glasgow) from Amgen during the conduct of the study; travel fees and nonfinancial support (via the University of Glasgow) from Alnylam Pharmaceuticals, AstraZeneca, Bayer, Bristol Myers Squibb, Cyclerion Therapeutics, Cytokinetics, DalCor Pharmaceuticals, GlaxoSmithKline, Novartis, Pfizer, Servier Laboratories, and Theracos; and personal fees from Abbott Laboratories, Hikma Pharmaceuticals, Servier Laboratories, and Sun Pharmaceutical Industries. RD reports receiving grants from Amgen during the conduct of the study. BC reports receiving grants (via Brigham and Women's Hospital) from Amgen and Cytokinetics during the conduct of the study and consulting fees from Amgen, Boehringer Ingelheim, Corvia Medical, Myokardia, and Novartis. DEL is supported in part by grants from the National Institutes of Health (P50MD017351, R01HL132154), has received research funding or support from Amgen, Astra Zeneca, Janssen, Eli Lilly, and Somalogic, and has acted as consultant to ACI Clinical (Abbott Laboratories), AstraZeneca, Cytokinetics, Duke Clinical Research Institute (CONNECT-HF), Illumina, Janssen, Martin Pharmaceuticals, Ortho Clinical Diagnostics, and Otsuka. HV reports being a national leader of GALACTIC-HF and has received lecture fees and consultation fees from Amgen. RDL reports research grants or contracts from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi-Aventis and funding for educational activities or lectures from Pfizer and Daiichi Sankyo and funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Novo Nordisk. S-IM reports being a national leader of GALACTIC-HF and has received lecture and consultation fees from Amgen. TB-S reports being a steering committee member of the Amgen-financed GALACTIC-HF trial, chief investigator and steering committee chair of the Sanofi Pasteur-financed NUDGE-FLU trial; chief investigator and steering committee chair of the Sanofi Pasteur-financed DANFLU-1 trial; steering committee member of LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific's Investigational ICM System trial; is on the advisory boards of Sanofi Pasteur, Amgen and GSK; receives speaker honoraria from Bayer, Novartis, Sanofi Pasteur, and GSK and research grants from GE Healthcare and Sanofi Pasteur. SBH, PHD, SK, and FIM are employees of Cytokinetics. JRT reports receiving grants from Amgen and Cytokinetics, personal fees from Amgen, Cytokinetics and Servier Laboratories, and nonfinancial support from Amgen and Cytokinetics during the conduct of the study; grants from Abbott Laboratories, Bayer, Boerhinger Ingelheim, Bristol Myers Squibb, EBR Systems, LivaNova, Medtronic, Novartis, and Windtree Therapeutics; and personal fees from Amgen, AstraZeneca, Cytokinetics, Merck & Co, and Servier Laboratories. All other authors report no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: The EMPULSE (EMPagliflozin in patients hospitalised with acUte heart faiLure who have been StabilizEd) trial showed that, compared to placebo, the sodium-glucose cotransporter 2 inhibitor empagliflozin (10 mg/day) improved clinical outcomes of patients hospitalized for acute heart failure (HF). We investigated whether efficacy and safety of empagliflozin were consistent across the spectrum of left ventricular ejection fraction (LVEF)., Methods and Results: A total of 530 patients hospitalized for acute de novo or decompensated HF were included irrespective of LVEF. For the present analysis, patients were classified as HF with reduced (HFrEF, LVEF ≤40%), mildly reduced (HFmrEF, LVEF 41-49%) or preserved (HFpEF, LVEF ≥50%) ejection fraction at baseline. The primary endpoint was a hierarchical outcome of death, worsening HF events (HFE) and quality of life over 90 days, assessed by the win ratio. Secondary endpoints included individual components of the primary endpoint and safety. Out of 523 patients with baseline data, 354 (67.7%) had HFrEF, 54 (10.3%) had HFmrEF and 115 (22.0%) had HFpEF. The clinical benefit (hierarchical composite of all-cause death, HFE and Kansas City Cardiomyopathy Questionnaire total symptom score) of empagliflozin at 90 days compared to placebo was consistent across LVEF categories (≤40%: win ratio 1.35 [95% confidence interval 1.04, 1.75]; 41-49%: win ratio 1.25 [0.66, 2.37)] and ≥50%: win ratio 1.40 [0.87, 2.23], p interaction  = 0.96) with a favourable safety profile. Results were consistent across individual components of the hierarchical primary endpoint., Conclusion: The clinical benefit of empagliflozin proved consistent across LVEF categories in the EMPULSE trial. These results support early in-hospital initiation of empagliflozin regardless of LVEF., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Atrial fibrillation (AF) and heart failure (HF) are common cardiovascular conditions that frequently coexist. Among patients with HF, more than one-half also have AF. Both are associated with significant morbidity and mortality. Moreover, the prevalence of each is increasing globally, and this trend is expected to continue owing to an aging population and increased life expectancy. Diagnosis of AF in a patient with HF is associated with greater symptom burden, more frequent hospitalizations, and a worse prognosis. Guideline-directed medical therapy (GDMT) for HF can affect the incidence of AF. Once present, AF can influence the efficacy of some components of GDMT for HF. In this review, we discuss the effect of GDMT for HF across the spectrum of ejection fraction on prevention of AF as well as the benefit of GDMT in patients with vs without AF., Competing Interests: Funding Support and Author Disclosures Dr O’Meara is supported by the Montreal Heart Institute’s Carolyn & Richard J. Renaud Chair for Research in Heart Failure, with fees paid through her institution for this chair, for a Canadian Heart Function Alliance (CHFA) Team Grant, funded by the CIHR (steering committee member), and for involvement in the following trials as a steering committee member for DAPA-ACT and GARDEN-HF (TIMI group and AstraZeneca), for HEART-FID (steering committee member, American Regent), CARDINAL-HF (steering committee member, Cardurion), and HERMES (national lead investigator, Novo Nordisk); and has received consulting or speaker fees from AstraZeneca, Boehringer Ingelheim, Bayer, and Novartis. Dr Savarese has received grants and personal fees from Vifor, AstraZeneca, Pharmacosmos, and Novartis; has received grants from Boehringer Ingelheim, Boston Scientific, Merck, and Bayer; has received personal fees from Servier, Cytokinetics, Medtronic, Edwards Lifesciences, Teva, and Abbott; and receives funding through the EU Horizon Programme and the Swedish Heart and Lung Foundation. Dr Vardeny has received research support (paid to institution) from the National Institutes of Health, the Food and Drug Administration, AstraZeneca, Bayer, and Cardurion; and has received personal consulting fees from Cardior and Cytokinetics. Dr Allen has received grant funding from the Patient-Centered Outcomes Research Institute and the National Institutes of Health; and has received consulting fees from ACI Clinical, Boston Scientific, Cytokinetics, Novartis, and Quidel. Dr Gottlieb has received consulting fees from Cytokinetics. Dr Zainab serves on the Heart Failure Publication Committee of Cytokinetics. Dr Morris has received consulting fees or honoraria from Abbott, Acorai, BI Lilly, Cytokinetics, Edwards, Ionis, Merck, Novo Nordisk, and Regeneron. Dr Desai works under contract with the Centers for Medicare and Medicaid Services to develop and maintain performance measures used for public reporting and pay for performance programs; and has received research grants and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, SCPharmaceuticals, and Vifor. Dr Teerlink has received consulting fees from Cytokinetics. Dr Saldarriaga-Giraldo has served as a speaker for AstraZeneca, Novartis, Servier, Abbott, Medtronic, Pfizer, Roche, Sanofi, Boehringer Ingelheim, Elly Lilly, Bayer, and Merck; has served as a principal investigator for Amgen, Novartis, Merck, and Bayer; and has served as an advisor for Medtronic, Novartis, Bayer, AstraZeneca, Boehringer Ingelheim, Servier, and Novo Nordisk. Dr Lindenfeld has received grant funding from the National Institutes of Health, the Patient-Centered Outcomes Research Institute, and AstraZeneca; and has received consulting fees from Abbott, Alleviant, AstraZeneca, Axon, Bayer, Boehringer Ingelheim, Boston Scientific, CVRx, Edwards Lifesciences, Merck, Medtronic, VWave, and Vascular Dynamics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Tricuspid regurgitation (TR) is common and is associated with poor outcomes in patients with heart failure (HF). However, data with adjudicated events from fully characterized patients with heart failure with reduced ejection fraction (HFrEF) are lacking., Objectives: This study sought to explore the association between mild or moderate/severe TR and clinical outcomes of patients with HFrEF., Methods: GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) was a double-blind, placebo-controlled randomized trial comparing omecamtiv mecarbil vs placebo in patients with symptomatic HFrEF., Results: Among the 8,232 patients analyzed in the GALACTIC-HF trial, 8,180 (99%) had data regarding baseline TR (none: n = 6,476 [79%], mild: n = 919 [11%], and moderate/severe: n = 785 [10%]). The primary composite outcome of a first HF event or cardiovascular death occurred in 2,368 (36.6%) patients with no TR, 353 (38.4%) patients with mild TR, and 389 (49.6%) patients with moderate/severe TR. Moderate/severe TR was independently associated with a higher relative risk of the primary composite outcome compared with either no TR (adjusted HR: 1.12 [95% CI: 1.01-1.26]; P = 0.046) or no/mild TR (adjusted HR: 1.14 [95% CI: 1.02-1.27]; P = 0.025) driven predominantly by HF events. The association between moderate/severe TR and clinical outcomes was more pronounced in outpatients with worse renal function, higher left ventricular ejection fraction, and lower N-terminal pro-B-type natriuretic peptide and bilirubin levels. The beneficial treatment effect of omecamtiv mecarbil vs placebo on clinical outcomes was not modified by TR., Conclusions: In symptomatic patients with HFrEF, baseline moderate/severe TR was independently associated with cardiovascular death or HF events driven predominantly by HF events. The beneficial treatment effect of omecamtiv mecarbil on the primary outcome was not modified by TR., Competing Interests: Funding Support and Author Disclosures Dr Adamo has received specker honoraria from Abbott Vascular. Dr Metra has received consulting fees from Abbott Vascular, Actelion, Amgen, AstraZeneca, Bayer, Edwards Therapeutics, Livanova, Servier, Vifor Pharma, and WindTree Therapeutics. Dr Claggett has received consulting fees from Amgen and Myokardia. Dr Diaz has received research grants and/or consulting fees from Amgen, Cytokinetics, and Servier. Dr Felker has received grant funding to his institution from Amgen, Bayer, Cytokinetics, Merck, and Myokardia; has received consulting fees personally from Abbott, American Regent, Amgen, AstraZeneca, Becton Dickinson, Boehringer Ingelheim, Bristol Myers Squibb, Cardionomic, Cytokinetics, Medtronic, Novartis, and Sequana; and has served on the Board of Directors for the Heart Failure Society of America. Dr McMurray has received consulting fees paid to his institution from Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardialysis, Cardurion, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Merck, Novartis, Pfizer, and Theracos. Dr Solomon has received grants from Celladon, Eidos, Ionis, Lone Star Heart, Mesoblast, National Institutes of Health/National Heart, Lung, and Blood Institute, and Sanofi Pasteur; has received grants and personal fees from Alnylam, Amgen, AstraZeneca, Bayer, Bellerophon, Bristol Myers Squibb, Cytokinetics, Gilead, GlaxoSmithKline, MyoKardia, Novartis, and Theracos; and has received personal fees from Akros, AoBiome, Arena, Cardiac Dimensions, Cardior, Cardurion, Corvia, Daiichi-Sankyo, Dinaqor, Ironwood, Janssen, Merck, Moderna, Quantum Genomics, Roche, Takeda, and Tenaya. Dr Teerlink has received research grants and/or consulting fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics; has received support for attending meetings and/or travel from Abbott Laboratories, Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, EBR Systems, LivaNova, Medtronic, Servier, and WindTree Therapeutics; and has served as Treasurer to Heart Failure Society of America. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

There is waning interest among cardiology trainees in pursuing an Advanced Heart Failure/Transplant Cardiology (AHFTC) fellowship as evidenced by fewer applicants in the National Resident Matching Program match to this specialty. This trend has generated considerable attention across the heart failure community. In response, the Heart Failure Society of America convened the AHFTC Fellowship Task Force with a charge to develop strategies to increase the value proposition of an AHFTC fellowship. Subsequently, the HFSA sponsored the AHFTC Fellowship Consensus Conference April 26-27, 2023. Before the conference, interviews of 44 expert stakeholders diverse across geography, site of practice (traditional academic medical center or other centers), specialty/area of expertise, sex, and stage of career were conducted virtually. Based on these interviews, potential solutions to address the declining interest in AHFTC fellowship were categorized into five themes: (1) alternative training pathways, (2) regulatory and compensation, (3) educational improvements, (4) exposure and marketing for pipeline development, and (5) quality of life and mental health. These themes provided structure to the deliberations of the AHFTC Fellowship Consensus Conference. The recommendations from the Consensus Conference were subsequently presented to the HFSA Board of Directors to inform strategic plans and interventions. The HFSA Board of Directors later reviewed and approved submission of this document. The purpose of this communication is to provide the HF community with an update summarizing the processes used and concepts that emerged from the work of the HFSA AHFTC Fellowship Task Force and Consensus Conference., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: In the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil, compared with placebo, reduced the risk of worsening heart failure (HF) events, or cardiovascular death in patients with HF and reduced ejection fraction. The primary aim of this prespecified analysis was to evaluate the safety and efficacy of omecamtiv mecarbil by randomization setting, that is, whether participants were enrolled as outpatients or inpatients., Methods and Results: Patients were randomized either during a HF hospitalization or as an outpatient, within one year of a worsening HF event (hospitalization or emergency department visit). The primary outcome was a composite of worsening HF event (HF hospitalization or an urgent emergency department or clinic visit) or cardiovascular death. Of the 8232 patients analyzed, 2084 (25%) were hospitalized at randomization. Hospitalized patients had higher N-terminal prohormone of B-type natriuretic peptide concentrations, lower systolic blood pressure, reported more symptoms, and were less frequently treated with a renin-angiotensin system blocker or a beta-blocker than outpatients. The rate (per 100 person-years) of the primary outcome was higher in hospitalized patients (placebo group = 38.3/100 person-years) than in outpatients (23.1/100 person-years); adjusted hazard ratio 1.21 (95% confidence interval 1.12-1.31). The effect of omecamtiv mecarbil versus placebo on the primary outcome was similar in hospitalized patients (hazard ratio 0.89, 95% confidence interval 0.78-1.01) and outpatients (hazard ratio 0.94, 95% confidence interval 0.86-1.02) (interaction P = .51)., Conclusions: Hospitalized patients with HF with reduced ejection fraction had a higher rate of the primary outcome than outpatients. Omecamtiv mecarbil decreased the risk of the primary outcome both when initiated in hospitalized patients and in outpatients., Competing Interests: Declaration of Competing Interest K.F.D. has received financial support to attend educational meetings from Cytokinetics during the conduct of the study, personal fees from AstraZeneca, consulting fees from Us2.ai and research grants to his institution from AstraZeneca and Boehringer Ingelheim outside the submitted work. J.J.V.M. has received funding to his institution from Amgen and Cytokinetics for his participation in the Steering Committee for the ATOMIC-HF, COSMIC-HF, and GALACTIC-HF trials and meetings and other activities related to these trials; has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; has received personal lecture fees from the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, and Global Clinical Trial Partners (GCTP). R.D. has received research grants and other payment or honoraria from Amgen. G.M.F. has received grant funding to his institution from American Heart Association, Amgen, Bayer, Bristol Myers Squibb, CSL-Behring, Cytokinetics, Merck, Myokardia, and National Institutes of Health; has received consulting fees from Abbott, American Regent, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cardionomic, Cytokinetics, Medtronic, Myovant, Novartis, Reprieve, Sequana, Windtree Therapeutics, and WhiteSwell; and has participated on Data Safety Monitoring boards or advisory boards for EBR Systems, LivaNova, Medtronic, Siemens, Rocket Pharma, and V-Wave. M.M. has received funding to his institution from Amgen and Cytokinetics as participant to the Executive Committee during the trial and for patients’ enrolment; has received consulting fees for participation to advisory boards from AstraZeneca, Bayer, and Boehringer Ingelheim; has received personal fees as member of Executive or Data Monitoring Committees of sponsored clinical trials from LivaNova and Vifor Pharma; has received speaker fees from Abbott Vascular and Edwards Therapeutics for speeches at sponsored meetings; and has participated on Data Safety Monitoring boards for Actelion. S.D.S. has received grant funding to his institution from Actelion, Alnylam, Amgen, AstraZeneca, Bayer, Bellerophon, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis Pharmaceuticals, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has received consulting fees from Abbott, Action, Akros, Alnylam, American Regent, Amgen, Anacardio, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimensions, Cardior, Cardurion, CellProthera, Corvia, Cytokinetics, Daiichi Sankyo, Dinaqor, GlaxoSmithKline, Janssen, Lexicon, Lilly, Merck, Moderna, Myokardia, Novartis, Puretech Health, Quantum Genomics, Roche, Sanofi Pasteur, Sarepta, Tenaya, Theracos, and Tremeau. K.F.A. has received research grants from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim Pharmaceuticals Inc., Eli Lilly USA, LivaNova USA, Merck, Novartis, and Otsuka; acted as a consultant to Amgen, Cytokinetics, Inc., Novartis, Roche Diagnostics, Relypsa, and Windtree Therapeutics. M.B. has received funds from the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project No. 322900939) and personal fees from Abbott, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cytokinetics, Medtronic, Novartis, ReCor, Servier, Vifor Pharma, and Boehringer Ingelheim. A.R.G. reports consulting fees for clinical trials from Amgen, Novartis, KOWA, and Bayer outside the submitted work; personal payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk outside the submitted work; support for attending meetings and/or travel from Pfizer, AstraZeneca, and Boehringer Ingelheim; and leadership or fiduciary role as President, Bulgarian Society of Cardiology 2020-22. J.G.H. has received grants and consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Novo Nordisk, and Pfizer; has received personal fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Novo Nordisk, and Pfizer; and is Co-Chair of the Heart Failure Pathway Group of the Province of Alberta, Heart Failure lead at University of Calgary, and in the Canadian Cardiovascular Society Guidelines and Development Committees. M.L. has received grant funding and personal fees from Amgen; has received honoraria from Novartis; and has served as the New Zealand Chairperson for Cardiac Society Australia and New Zealand. P.P. has received research grants to his institution from Amgen and Vifor Pharma; and has received consulting fees or honoraria from Abbott Vascular, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Cibiem, Coridea, Impulse Dynamics, Novartis, Pfizer, Renal Guard Solutions, Servier, and Vifor Pharma. M.B.Y. reports funding to his institution from Amgen, Bayer, Novartis, and Dalcor Pharmaceuticals outside the submitted work. F.Z. reports consulting fees from Cardior, Cereno pharmaceutical, Cellprothera, Owkin, Novo Nordisk, Vifor, and Fresenius; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer and Bayer; payment for expert testimony from Cardiorentis; stock or stock options in Cereno pharmaceutical; and steering committee personal fees from Applied Therapeutics, Amgen, Bayer, Boehringer, CVRx, Novartis, and Merck. B.L.C. has received consulting fees from Amgen, Cardurion, Corvia, Myokardia, and Novartis. Z.M.M. has no conflicts of interest to disclose. S.A.A. is an employee and shareholder of Amgen. P.H.D., S.B.H., S.K., and F.I.M. are employees and shareholders of Cytokinetics. J.R.T. has received personal fees as Chairperson of the GALACTIC-HF Executive Committee from Amgen and Cytokinetics; has received personal fees for research contracts and/or consulting fees from 3ive Labs, Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Medtronic, Merck, Novartis, Verily, ViCardia, and Windtree Therapeutics; has served as Secretary and Treasurer of Heart Failure Society of America; and is currently President-Elect of the Heart Failure Society of America. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: To investigate the effects of Cimlanod, a nitroxyl donor with vasodilator properties, on water and salt excretion after an administration of an intravenos bolus of furosemide., Methods and Results: In this randomized, double-blind, mechanistic, crossover trial, 21 patients with left ventricular ejection fraction <45%, increased plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and receiving loop diuretics were given, on separate study days, either an 8 h intravenous (IV) infusion of cimlanod (12 μg/kg/min) or placebo. Furosemide was given as a 40 mg IV bolus four hours after the start of infusion. The primary endpoint was urine volume in the 4 h after the bolus of furosemide during infusion of cimlanod compared with placebo. Median NT-proBNP at baseline was 1487 (interquartile range: 847-2665) ng/L. Infusion of cimlanod increased cardiac output and reduced blood pressure without affecting cardiac power index consistent with its vasodilator effects. Urine volume in the 4 h post-furosemide was lower with cimlanod (1032 ± 393 ml) versus placebo (1481 ± 560 ml) (p = 0.002), as were total sodium excretion (p = 0.004), fractional sodium excretion (p = 0.016), systolic blood pressure (p < 0.001), estimated glomerular filtration rate (p = 0.012), and haemoglobin (p = 0.010), an index of plasma volume expansion., Conclusions: For patients with heart failure and congestion, vasodilatation with agents such as cimlanod reduces the response to diuretic agents, which may offset any benefit from acute reductions in cardiac preload and afterload., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Women with heart failure with reduced ejection fraction (HFrEF) receive less guideline-recommended therapy and experience worse quality of life than men., Objectives: The authors sought to assess differences in baseline characteristics, outcomes, efficacy, and safety of omecamtiv mecarbil between men and women enrolled in the GALACTIC-HF (Registrational Study With Omecamtiv Mecarbil [AMG 423] to Treat Chronic Heart Failure With Reduced Ejection Fraction) study., Methods: In GALACTIC-HF, patients with symptomatic heart failure with EF of 35% or less, recent heart failure event, and elevated natriuretic peptides were randomized to omecamtiv mecarbil or placebo. The current analysis investigated differences in baseline characteristics, clinical outcomes, and efficacy and safety of omecamtiv mecarbil between men and women., Results: Of 8,232 patients analyzed, 21.2% were women. Women more likely self-identified as being Black, had worse symptoms (lower Kansas City Cardiomyopathy Questionnaire Total Symptom Score [KCCQ-TSS]), and were less likely to be treated with angiotensin receptor/neprilysin inhibitor and devices at baseline. Compared with men, women had lower rates of the primary endpoint (adjusted HR: 0.80, 95% CI: 0.73-0.88). Sex did not significantly modify omecamtiv mecarbil's treatment effect (P interaction = 0.68). Women also had 20% less risk of cardiovascular death, heart failure event, and all-cause death. Women participants had lower rates of serious adverse events., Conclusions: Women participants of the GALACTIC-HF trial had worse quality of life and were less likely to be treated with guideline-based therapies at baseline. Despite KCCQ-TSS being predictive of poor outcomes in this population, women had a 20% lower risk of an HF event or cardiovascular death compared with men. The beneficial effect of omecamtiv mecarbil did not significantly differ by sex. (Registrational Study With Omecamtiv Mecarbil [AMG 423] to Treat Chronic Heart Failure With Reduced Ejection Fraction [GALACTIC-HF]; NCT02929329)., Competing Interests: Funding Support and Author Disclosures Dr Pabon is supported by the First.In.Women Fellowship Program in Sex- and Gender-Differences in Cardiovascular Diseases Connors Center for Women’s Health and Gender Biology and the John S. LaDue Memorial Fellowship at Harvard Medical School. Dr Cunnigham has consulted for Roche Diagnostics, Occlutech, and KCK. Dr Clagget has consulted for Alnylam, CVRX, Cardurion, Corvia, Cytokinetics, Intellia, Novartis, and Rocket. Dr Felker has received research grants from NHLBI, American Heart Association, Amgen, Bayer Merck, Cytokinetics, Myokardia; has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Boehringer-Ingelheim, American Regent, Abbott, AstraZeneca, Reprieve, and Sequana; and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharm. Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, and Novartis; personal consultancy fees from Alnylam Pharma, Bayer, BMS, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation; and received personal lecture fees Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, J.B. Chemicals & Pharma Ltd, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, and Translational Medicine Academy; and he is a director of Global Clinical Trial Partners Ltd. Dr Metra has received personal fees in the last 3 years from Vifor Pharma and LivaNova (Executive Committee member); and participated in advisory boards for AstraZeneca, Abbott Structural, Bayer, Boehringer Ingelheim, and Roche Diagnostics. Dr Diaz has received research grants and/or consulting fees from Amgen, Cytokinetics Inc, and Servier Laboratories. Dr Wang is supported by a T32 postdoctoral training grant from the National Heart, Lung, and Blood Institute (T32 HL094301) and by the Scott Schoen and Nancy Adams First.In.Women Cardiovascular Fellowship, Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital. Dr Crespo Leiro has received personal fees from Amgen; personal fees and/or nonfinancial support from Vifor, Novartis, MSD, AstraZeneca, Boehringer Ingelheim, and Medtronic; and grants from CIBERCV, outside the submitted work. Dr Fonseca has received personal fees from AstraZeneca, Bayer, Bial, Boehringer Ingelheim, Novartis, Pfizer, and Servier; and grants and personal fees from Vifor Pharma, outside of the submitted work. Dr Goncalvesova has received personal fees from Amgen, during the conduct of the study; personal fees from Boehringer Ingelheim, Merck; personal fees and nonfinancial support from Servier; and grants and personal fees from Novartis, outside of the submitted work. Dr Lund has received grant funding and personal fees from Amgen; has received honoraria from Novartis; and has served as the New Zealand Chairperson for Cardiac Society Australia and New Zealand. Dr O’Meara has received research funds (paid to her institution) for clinical trials from American Regent, Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis, and Pfizer; consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, and Janssen; and speaker fees from AstraZeneca, Bayer, and Boehringer Ingelheim. Dr Malik is an employee of and owns stock in Cytokinetics, Inc. Dr Solomon has received research grants from Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Cytokinetics, Eidos, GlaxoSmithKline, Ionis, Lilly, MyoKardia, National Institutes of Health/NHLBI, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr Teerlink has received personal fees as Chairperson of the GALACTIC-HF Executive Committee from Amgen and Cytokinetics; personal fees for research contracts and/or consulting fees from 3ive Labs, Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardurion, Medtronic, Merck, Novartis, Verily, ViCardia, and Windtree Therapeutics; has served as Secretary and Treasurer of the Heart Failure Society of America; and is currently President of the Heart Failure Society of America. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)