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Background: Current fiducial markers (FMs) in external-beam radiotherapy (EBRT) for prostate cancer (PCa) cannot be positively visualized on magnetic resonance imaging (MRI) and create dose perturbation and significant imaging artifacts on computed tomography (CT) and MRI. We report our initial experience with clinical imaging of a novel multimodality FM, NOVA., Methods: We tested Gold Anchor [G-FM], BiomarC [carbon, C-FM], and NOVA FMs in phantoms imaged with kilovoltage (kV) X-rays, transrectal ultrasound (TRUS), CT, and MRI. Artifacts of the FMs on CT were quantified by the relative streak artifacts level (rSAL) metric. Proton dose perturbations (PDPs) were measured with Gafchromic EBT3 film, with FMs oriented either perpendicular to or parallel with the beam axis. We also tested the performance of NOVA-FMs in a patient., Results: NOVA-FMs were positively visualized on all 4 imaging modalities tested. The rSAL on CT was 0.750 ± 0.335 for 2-mm reconstructed slices. In F-tests, PDP was associated with marker type and depth of measurement ( p < 10 -6 ); at 5-mm depth, PDP was significantly greater for the G-FM (12.9%, p = 10 -6 ) and C-FM (6.0%, p = 0.011) than NOVA (4.5%). EBRT planning with MRI/CT image co-registration and daily alignments using NOVA-FMs in a patient was feasible and reproducible., Conclusions: NOVA-FMs were positively visible and produced less PDP than G-FMs or C-FMs. NOVA-FMs facilitated MRI/CT fusion and identification of regions of interest.

Background: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience a high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity), once-weekly semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary end points across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline and on all key summary and individual KCCQ domains., Methods: STEP-HFpEF randomly assigned 529 participants with symptomatic HF, an ejection fraction of ≥45%, and a body mass index of ≥30 kg/m 2 to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary end points change in KCCQ-Clinical Summary Score (CSS) and body weight. Confirmatory secondary end points included change in 6-minute walk distance, a hierarchical composite end point (death, HF events, and change in KCCQ-CSS and 6-minute walk distance) and change in C-reactive protein. Patients were stratified by KCCQ-CSS tertiles at baseline. Semaglutide effects on the primary, confirmatory secondary, and select exploratory end points (N-terminal pro-brain natriuretic peptide) were examined across these subgroups. Semaglutide effects on additional KCCQ domains (Total Symptom Score [including symptom burden and frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score) were also evaluated., Results: Baseline median KCCQ-CSS across tertiles was 37, 59, and 77 points, respectively. Semaglutide consistently improved primary end points across KCCQ tertiles 1 to 3 (estimated treatment differences [95% CI]: for KCCQ-CSS, 10.7 [5.4 to 16.1], 8.1 [2.7 to 13.4], and 4.6 [-0.6 to 9.9] points; for body weight, -11 [-13.2 to -8.8], -9.4 [-11.5 to -7.2], and -11.8 [-14.0 to -9.6], respectively; P interaction =0.28 and 0.29, respectively); the same was observed for confirmatory secondary and exploratory end points ( P interaction >0.1 for all). Semaglutide-treated patients experienced improvements in all key KCCQ domains (estimated treatment differences, 6.7-9.6 points across domains; P ≤0.001 for all). Greater proportion of semaglutide-treated versus placebo-treated patients experienced at least 5-, 10-, 15-, and 20-point improvements in all KCCQ domains (odds ratios, 1.6-2.9 across domains; P <0.05 for all)., Conclusions: In patients with HFpEF and obesity, semaglutide produced large improvements in HF-related symptoms, physical limitations, exercise function, inflammation, body weight, and N-terminal pro-brain natriuretic peptide, regardless of baseline health status. The benefits of semaglutide extended to all key KCCQ domains., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04788511., Competing Interests: Disclosures Dr Kosiborod served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; holds stocks in Artera Health and Saghmos Therapeutics; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. He has also received other research support from AstraZeneca. Dr Verma has received research grants or consultancy fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Napp Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; has served on committees for AbbVie, Akero, Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, New Amsterdam, Novo Nordisk, Resverlogix, and Teikoku; and is Director of Global Clinical Trial Partners (GCTP). Dr Borlaug receives research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is a named inventor (US patent No. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Butler is a consultant to 3live, Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Impulse Dynamics, Imbria, Innolife, Inventiva, Janssen, Lexicon, Lilly, LivaNova, Medtronics, Merck, Novartis, Novo Nordisk, Occlutech, Pfizer, Pharmacosmos, Pharmain, Roche, Sequana, SQ Innovation, and Vifor. Dr Davies has acted as a consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; an advisory board member and speaker for AstraZeneca; an advisory board member for Medtronic, Pfizer, and ShouTi Pharma; and a speaker for Amgen, Novartis, and Sanofi. She has received grants in support of investigator and investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi-Aventis. Dr Petrie has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; and consultancy and committees payments for AbbVie, Akero, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiorentis, Horizon Therapeutics, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, Takeda, Teikoku, and Vifor. Dr Shah reports receiving consulting fees from Abbott, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, Metabolic Flux, MyoKardia, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Drs Jensen, Rasmussen, and Marstrand are employees of and hold shares in Novo Nordisk. Dr Ito reports honoraria and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Mochida, Novartis, and Novo Nordisk. Dr Schou reports speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Melenovský reports consulting fees from Bayer, MSD, and Novo Nordisk; research grants from Regeneron; and research support from the National Institute for Research of Metabolic and Cardiovascular Diseases (Programme EXCELES, ID Project No. LX22NPO5104), funded by the European Union – Next Generation EU. Dr Abhayaratna reports honoraria and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Kitzman reports receiving honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus; received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus; and has stock ownership in Gilead Sciences.

Importance: Tafamidis has been shown to improve survival in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) compared with placebo. However, its effect on cardiac function has not been fully characterized., Objective: To examine the effect of tafamidis on cardiac function in patients with ATTR-CM., Design, Setting, and Participants: This was an exploratory, post hoc analysis of the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), a multicenter, international, double-blind, placebo-controlled phase 3 randomized clinical trial conducted from December 2013 to February 2018. The ATTR-ACT included 48 sites in 13 counties and enrolled patients aged 18 to 90 years with ATTR-CM. Data were analyzed from July 2018 to September 2023., Intervention: Patients were randomized to tafamidis meglumine, 80 mg or 20 mg, or placebo for 30 months., Main Outcomes and Measures: Patients were categorized based on left ventricular (LV) ejection fraction at enrollment as having heart failure with preserved ejection fraction (≥50%), mildly reduced ejection fraction (41% to 49%), or reduced ejection fraction (≤40%). Changes from baseline to month 30 in LV ejection fraction, LV stroke volume, LV global longitudinal strain, and the ratio of early mitral inflow velocity to septal and lateral early diastolic mitral annular velocity (E/e') were compared in patients receiving tafamidis, 80 mg, vs placebo., Results: A total of 441 patients were randomized in ATTR-ACT, and 436 patients had available echocardiographic data. Of 436 included patients, 393 (90.1%) were male, and the mean (SD) age was 74 (7) years. A total of 220 (50.5%), 119 (27.3%), and 97 (22.2%) had heart failure with preserved, mildly reduced, and reduced LV ejection fraction, respectively. Over 30 months, there was less pronounced worsening in 4 of the echocardiographic measures in patients receiving tafamidis, 80 mg (n = 176), vs placebo (n = 177) (least squares mean difference: LV stroke volume, 7.02 mL; 95% CI, 2.55-11.49; P = .002; LV global longitudinal strain, -1.02%; 95% CI, -1.73 to -0.31; P = .005; septal E/e', -3.11; 95% CI, -5.50 to -0.72; P = .01; lateral E/e', -2.35; 95% CI, -4.01 to -0.69; P = .006)., Conclusions and Relevance: Compared with placebo, tafamidis, 80 mg, attenuated the decline of LV systolic and diastolic function over 30 months in patients with ATTR-CM. Approximately half of patients had mildly reduced or reduced LV ejection fraction at enrollment, suggesting that ATTR-CM should be considered as a possible diagnosis in patients with heart failure regardless of underlying LV ejection fraction., Trial Registration: ClinicalTrials.gov Identifier: NCT01994889.

Background: Heterochronic parabiosis has identified growth differentiation factor (GDF)-11 as a potential means of cardiac rejuvenation, but findings have been inconsistent. A major barrier has been lack of assay specificity for GDF-11 and its homolog GDF-8., Methods: We tested the hypothesis that GDF-11 and GDF-8, and their major antagonists follistatin and follistatin-like (FSTL)-3, are associated with incident heart failure (HF) and its subtypes in elders. Based on validation experiments, we used liquid chromatography-tandem mass spectrometry to measure total serum GDF-11 and GDF-8, along with follistatin and FSTL-3 by immunoassay, in 2 longitudinal cohorts of older adults., Results: In 2 599 participants (age 75.2 ± 4.3) followed for 10.8 ± 5.6 years, 721 HF events occurred. After adjustment, neither GDF-11 (HR per doubling: 0.93 [0.67, 1.30]) nor GDF-8 (HR: 1.02 per doubling [0.83, 1.27]) was associated with incident HF or its subtypes. Positive associations with HF were detected for follistatin (HR: 1.15 [1.00, 1.32]) and FLST-3 (HR: 1.38 [1.03, 1.85]), and with HF with preserved ejection fraction for FSTL-3 (HR: 1.77 [1.03, 3.02]). (All HRs per doubling of biomarker.) FSTL-3 associations with HF appeared stronger at higher follistatin levels and vice versa, and also for men, Blacks, and lower kidney function., Conclusions: Among older adults, serum follistatin and FSTL-3, but not GDF-11 or GDF-8, were associated with incident HF. These findings do not support the concept that low serum levels of total GDF-11 or GDF-8 contribute to HF late in life, but do implicate transforming growth factor-β superfamily pathways as potential therapeutic targets., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Inflammation is a key driver of heart failure with preserved left ventricular ejection fraction. AZD4831 inhibits extracellular myeloperoxidase, decreases inflammation, and improves microvascular function in preclinical disease models., Methods and Results: In this double-blind phase 2a study (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure [SATELLITE]; NCT03756285), patients with symptomatic heart failure, left ventricular ejection fraction of ≥40%, and elevated B-type natriuretic peptides were randomized 2:1 to once-daily oral AZD4831 5 mg or placebo for 90 days. We aimed to assess target engagement (primary end point: myeloperoxidase specific activity) and safety of AZD4831. Owing to coronavirus disease 2019, the study was terminated early after randomizing 41 patients (median age 74.0 years, 53.7% male). Myeloperoxidase activity was decreased by more than 50% from baseline to day 30 and day 90 in the AZD4831 group, with a placebo-adjusted decreased of 75% (95% confidence interval, 48, 88, nominal P < .001). No improvements were noted in secondary or exploratory end points, apart from a trend in Kansas City Cardiomyopathy Questionnaire overall summary score. No deaths or treatment-related serious adverse events occurred. AZD4831 treatment-related adverse events were generalized maculopapular rash, pruritus, and diarrhea (all n = 1)., Conclusions: AZD4831 inhibited myeloperoxidase and was well tolerated in patients with heart failure and left ventricular ejection fraction of 40% or greater. Efficacy findings were exploratory owing to early termination, but warrant further clinical investigation of AZD4831., Lay Summary: Few treatments are available for patients with the forms of heart failure known as heart failure with preserved or mildly reduced ejection fraction. Current treatments do not target inflammation, which may play an important role in this condition. We tested a new drug called AZD4831 (mitiperstat), which decreases inflammation by inhibiting the enzyme myeloperoxidase. Among the 41 patients in our clinical trial, AZD4831 had a good safety profile and inhibited myeloperoxidase by the expected amount. Results mean we can conduct further trials to see whether AZD4831 decreases the symptoms of heart failure and improves patients' ability to participate in physical exercise., Competing Interests: Declaration of Competing Interest A.A., J.v.W., and S.S. declare no conflicts of interest. A.A.V. has received research support or consultancy fees from Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. A.B. has received speaker honoraria and consultancy fees from Boehringer Ingelheim, AstraZeneca, Novartis, and Bayer. A.G., A.G., E-L.L., K.N., L-M.G., and P.G. are employees of AstraZeneca and may own stock or stock options. A.S. has received speaker's honoraria or consultancy fees from Abbot, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, and Pfizer. C.P. has received speaker's honoraria or consultancy fees from Amgen and Sanofi. D.E. has received speaker's honoraria or consultancy fees from AstraZeneca and Chiesi. E.L.G. has received speaker honoraria or consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Lundbeck Pharma, Novo Nordisk, Pfizer, and MSD; has served as an investigator in trials sponsored by AstraZeneca, Idorsia, and Bayer; and has received unrestricted grants from Boehringer Ingelheim. C.S.P.L. 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 an advisory board/steering committee/executive committee for Abbott, Actelion, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc., EchoNous Inc, 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 cofounder and nonexecutive director of Us2.ai. L.H.L. has received grants from AstraZeneca, Vifor, Boston Scientific, Boehringer Ingelheim, and Novartis; consultancy fees from Merck, Vifor, AstraZeneca, Bayer, Pharmacosmos, MedScape, Sanofi, Lexicon, Myokardia, Boehringer Ingelheim, and Servier; speaker's honoraria from Abbott, MedScape, Radcliffe, AstraZeneca, and Novartis; and holds stock and intellectual property in AnaCardio. M.S. has received speaker's honoraria and consultancy fees from Boehringer Ingelheim, AstraZeneca, Novartis, and Novo Nordisk. S.J.S. is supported by research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Shifamed, Tenax, Tenaya, and United Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Obesity is causally related to the development of heart failure with preserved ejection fraction (HFpEF) but complicates the diagnosis and treatment of this disorder. We aimed to determine the relationship between severity of obesity and clinical, echocardiographic and haemodynamic parameters in a large cohort of patients with documented HFpEF., Methods and Results: The REDUCE LAP-HF II trial randomized 626 patients with ejection fraction ≥40% and exercise pulmonary capillary wedge pressure (PCWP) ≥25 mmHg to atrial shunt or sham procedure. We tested for associations between body mass index (BMI), clinical characteristics, cardiac structural and functional abnormalities, physical limitations, quality of life and outcomes with atrial shunt therapy. Overall, 60.9% of patients had BMI ≥30 kg/m 2 . As the severity of obesity increased, symptoms (Kansas City Cardiomyopathy Questionnaire score) and 6-min walk distance worsened. More severe obesity was associated with lower natriuretic peptide levels despite more cardiac remodelling, higher cardiac filling pressures, and higher cardiac output. Lower cut points for E/e' were needed to identify elevated PCWP in more obese patients. Strain measurements in all four chambers were maintained as BMI increased. Pulmonary vascular resistance at rest and exercise decreased with higher BMI. Obesity was associated with more first and recurrent heart failure events. However, there was no significant interaction between obesity and treatment effects of the atrial shunt., Conclusions: Increasing severity of obesity was associated with greater cardiac remodelling, higher right and left ventricular filling pressures, higher cardiac output and increased subsequent heart failure events. Despite significant obesity, many HFpEF patients have preserved right heart and pulmonary vascular function and thus, may be appropriate candidates for atrial shunt therapy., (© 2023 European Society of Cardiology.)

Background: We examined the association between hypoglycemia and the occurrence of early onset sepsis (EOS) in premature infants admitted to the neonatal intensive care unit (NICU)., Methods: We included infants discharged from 358 NICUs between 1997 and 2020 with gestational age <34 weeks, ≥1 culture collected in the first 3 days of life, and ≥1 serum glucose value recorded on the day of or day prior to culture collection. We used multivariable logistic regression and inverse probability weighting (IPW) and constructed models for three definitions of hypoglycemia: American Academy of Pediatrics (AAP), Pediatric Endocrine Society, and a definition based on neurodevelopmental studies. We performed subgroup analysis in EOS episodes caused by Gram-negative and Gram-positive organisms., Results: Of the 62,178 infants and 64,559 cultures that met study inclusion criteria, 739 (1%) cultures were positive. The median (25th, 75th percentile) glucose value was 75 mg/dL (50, 106) on the day of or day prior to a positive culture versus 70 mg/dL (50, 95) on the day of or day prior to a negative culture. We found that hypoglycemia was not associated with the occurrence of EOS for all organisms and Gram-positive organisms, whereas there was a small but significant association between the lower AAP glucose cutoff value and EOS due to Gram-negative organisms (logistic regression: risk difference [RD] 0.24% [95% CI, 0.01-0.47]; IPW: RD 0.22% [95% CI, 0.00-0.43])., Conclusions: Hypoglycemia may be an early marker of EOS, particularly in episodes caused by Gram-negative organisms and when using a stricter definition of hypoglycemia., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Apparent treatment-resistant hypertension (aTRH) is prevalent and associated with adverse outcomes in heart failure with mildly reduced or preserved ejection fraction. Less is known about the potential role of sodium-glucose co-transporter 2 inhibition in this high-risk population. In this post hoc analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure), we evaluated clinical profiles and treatment effects of dapagliflozin among participants with aTRH., Methods: DELIVER participants were categorized on the basis of baseline blood pressure (BP), with aTRH defined as BP ≥140/90 mm Hg (≥130/80 mm Hg if diabetes) despite treatment with 3 antihypertensive drugs including a diuretic. Nonresistant hypertension was defined as BP above threshold but not meeting aTRH criteria. Controlled BP was defined as BP under threshold. Incidence of the primary outcome (cardiovascular death or worsening heart failure event), key secondary outcomes, and safety events was assessed by baseline BP category., Results: Among 6263 DELIVER participants, 3766 (60.1%) had controlled BP, 1779 (28.4%) had nonresistant hypertension, and 718 (11.5%) had aTRH at baseline. Participants with aTRH had more cardiometabolic comorbidities and tended to have higher left ventricular ejection fraction and worse kidney function. Rates of the primary outcome were 8.7 per 100 patient-years in those with controlled BP, 8.5 per 100 patient-years in the nonresistant hypertension group, and 9.5 per 100 patient-years in the aTRH group. Relative treatment benefits of dapagliflozin versus placebo on the primary outcome were consistent across BP categories ( P interaction =0.114). Participants with aTRH exhibited the greatest absolute reduction in the rate of primary events with dapagliflozin (4.1 per 100 patient-years) compared with nonresistant hypertension (2.7 per 100 patient-years) and controlled BP (0.8 per 100 patient-years). Irrespective of assigned treatment, participants with aTRH experienced a higher rate of reported vascular events, including myocardial infarction and stroke, over study follow-up. Dapagliflozin modestly reduced systolic BP (by ≈1 to 3 mm Hg) without increasing risk of hypotension, hypovolemia, or other serious adverse events, irrespective of BP category, but did not improve the proportion of participants with aTRH attaining goal BP over time., Conclusions: aTRH was identified in >1 in 10 patients with heart failure and left ventricular ejection fraction >40% in DELIVER. Dapagliflozin consistently improved clinical outcomes and was well-tolerated, including among those with aTRH., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03619213., Competing Interests: Disclosures Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health, and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Selvaraj was supported by the National Heart, Lung, and Blood Institute (grant K23HL161348), American Heart Association (grant 935275), Doris Duke Charitable Foundation (grant 2020061), Mandel Foundation, and Duke Heart Center. Dr Claggett has received consulting fees from Boehringer Ingelheim. Dr de Boer has received research grant support from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche, and had speaker engagements with Abbott, AstraZeneca, Bayer, Novartis, and Roche. Dr Hernandez reports research grant support from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic, and Verily; and consulting fees from Amgen, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Cytokinetics, Merck, Novartis, and Novo Nordisk. Dr Desai reports institutional grant support from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer; and consulting fees from Abbott, Alnylam, AstraZeneca, Avidity, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Medpace, Merck, New Amsterdam, Novartis, Parexel, Regeneron, River2Renal Roche, Veristat, Verily, and Zydus. Dr Jhund reports speakers’ fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals, and Intas Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and research funding from AstraZeneca, Boehringer Ingelheim, and Analog Devices Inc; and is director of Global Clinical Trial Partners. Dr Jhund’s employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Kosiborod reports research grant support from AstraZeneca and Boehringer Ingelheim and consulting fees from Alnylam, AstraZeneca, Amgen, Bayer, Boehringer-Ingelheim, Cytokinetics, Esperion, Eli Lilly, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Pharmacosmos, Novo Nordisk, Sanofi, and Vifor. 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, or 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 cofounder and non–executive director of Us2.ai. Drs Langkilde, Lindholm, and Petersson are employees of AstraZeneca. Dr Martinez has received personal fees from AstraZeneca. Dr O’Meara has received research funds (paid to her institution) for clinical trials from American Regent, Amgen, AstraZeneca, Bayer AG, Cardurion, Cytokinetics, Novartis, and Pfizer; and has received consulting fees from AstraZeneca, Bayer AG, Boehringer Ingelheim, Cytokinetics, Eli Lilly, and Janssen, as well as speaker fees from AstraZeneca, Bayer AG, and Boehringer Ingelheim. Dr Shah reports research grants from the National Institutes of Health (grants U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer, and consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr McMurray has received funding to his institution, Glasgow University, for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, Pfizer, and Theracos; and has received personal lecture fees from the Corpus, Abbott, Hickma, Sun Pharmaceuticals, and Medsca. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, 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 consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, 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, and Sarepta. The other authors report no disclosures.

Transcatheter atrial shunt therapies, designed to dynamically lower left atrial (LA) pressure by shunting blood into the larger reservoir of the right atrium and central veins, have been developed as a novel treatment for heart failure (HF) over the past 10+ years. Several atrial shunt devices and procedures are currently in development with several pivotal randomized clinical trials (RCT) underway; however, only 2 sham-controlled RCT (both with the Atrial Shunt Device [Corvia Medical] in HF with EF ≥ 40%) have been reported thus far; a mechanistic RCT (n = 44) that demonstrated a reduction in exercise LA pressure at 1 month and a pivotal RCT (n = 626) that was neutral with no difference in outcomes or health status between shunt and sham groups. Subsequent analyses of the single completed pivotal RCT found that peak exercise pulmonary vascular resistance <1.74 WU plus the absence of a cardiac rhythm management device identified a responder group that benefited from LA unloading with atrial shunt implantation, a finding that is currently being confirmed in a follow-up RCT. Here we provide a comprehensive review of the field of atrial shunt therapeutics with a description of the following: (1) current HF treatment; (2) rationale and history of atrial shunt development; (3) design of and accumulated evidence for the various atrial shunt devices and procedures under investigation; (4) unanswered questions in the field; and (5) future considerations. Atrial shunts represent a potential innovative therapeutic for HF but the optimal design/approach and phenotype of HF most likely to benefit are yet to be determined., (© 2023 The Author(s).)

Aims: In heart failure with preserved ejection fraction (HFpEF), regional heterogeneity of clinical phenotypes is increasingly recognized, with coronary microvascular dysfunction (CMD) potentially being a common shared feature. We sought to determine the regional differences in clinical characteristics and prevalence of CMD in HFpEF., Methods and Results: We analysed clinical characteristics and CMD in 202 patients with stable HFpEF (left ventricular ejection fraction ≥40%) in Finland, Singapore, Sweden, and United States in the multicentre PROMIS-HFpEF study. Patients with unrevascularized macrovascular coronary artery disease were excluded. CMD was assessed using Doppler echocardiography and defined as coronary flow reserve (adenosine-induced vs. resting flow) < 2.5. Patients from Singapore had the lowest body mass index yet highest prevalence of hypertension, dyslipidaemia, and diabetes; patients from Finland and Sweden were oldest, with the most atrial fibrillation, chronic kidney disease, and high smoking rates; and those from United States were youngest and most obese. The prevalence of CMD was 88% in Finland, 80% in Singapore, 77% in Sweden, and 59% in the United States; however, non-significant after adjustment for age, sex, N-terminal pro-brain natriuretic peptide, smoking, left atrial reservoir strain, and atrial fibrillation. Associations between CMD and clinical characteristics did not differ based on region (interaction analysis)., Conclusions: Despite regional differences in clinical characteristics, CMD was present in the majority of patients with HFpEF across different regions of the world with the lowest prevalence in the United States. This difference was explained by differences in patient characteristics. CMD could be a common therapeutic target across regions., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: COVID-19 may affect clinical risk in patients with heart failure. DELIVER began before and was conducted during the COVID-19 pandemic. This study aimed to evaluate the association between COVID-19 and clinical outcomes among DELIVER participants., Methods and Results: Participants with chronic heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) were randomized to dapagliflozin or placebo across 350 sites in 20 countries. COVID-19 was investigator-reported and the contribution of COVID-19 to death was centrally adjudicated. We assessed (i) the incidence of COVID-19, (ii) event rates before/during the pandemic, and (iii) risks of death after COVID-19 diagnosis compared to risks of death in participants without COVID-19. Further, we performed a sensitivity analysis assessing treatment effects of dapagliflozin vs. placebo censored at pandemic onset. Of 6263 participants, 589 (9.4%) developed COVID-19, of whom 307 (52%) required/prolonged hospitalization. A total of 155 deaths (15% of all deaths) were adjudicated as definitely/possibly COVID-19-related. COVID-19 cases and deaths did not differ by randomized assignment. Death rate in the 12 months following diagnosis was 56.1 (95% confidence interval [CI] 48.0-65.6) versus 6.4 (95% CI 6.0-6.8)/100 participant-years among trial participants with versus without COVID-19 (adjusted hazard ratio [aHR] 8.60, 95% CI 7.18-10.30). Risk was highest 0-3 months following diagnosis (153.5, 95% CI 130.3-180.8) and remained elevated at 3-6 months (12.6, 95% CI 6.6-24.3/100 participant-years). After excluding investigator-reported fatal COVID-19 events, all-cause death rates in the 12 months following diagnosis among COVID-19 survivors (n = 458) remained higher (aHR 2.46, 95% CI 1.83-3.33) than rates for all trial participants from randomization, with censoring of participants who developed COVID-19 at the time of diagnosis. Dapagliflozin reduced cardiovascular death/worsening HF events when censoring participants at COVID-19 diagnosis (HR 0.81, 95% CI 0.72-0.91) and pandemic onset (HR 0.72, 95% CI 0.58-0.89). There were no diabetic ketoacidosis or major hypoglycaemic events within 30 days of COVID-19., Conclusion: DELIVER is one of the most extensive experiences with COVID-19 of any cardiovascular trial, with >75% of follow-up time occurring during the pandemic. COVID-19 was common, with >50% of cases leading to hospitalization or death. Treatment benefits of dapagliflozin persisted when censoring at COVID-19 diagnosis and pandemic onset. Patients surviving COVID-19 had a high early residual risk., Clinical Trial Registration: ClinicalTrials.gov Identifier NCT03619213., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: The ICAM1 variant rs5491 ( p.K56M ) is common among Black individuals and has been associated with risk of heart failure with preserved ejection fraction (HFpEF). The pathways by which rs5491 leads to HFpEF are not known., Methods: Among Black individuals within the Multi-Ethnic Study of Atherosclerosis, we evaluated associations of rs5491 with 3 inflammatory biomarkers (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], and tumor necrosis factor-α receptor 1 [TNFR-1])., Results: Among 1558 Black participants (mean age 62 ± 10 y, 47 % female), each additional rs5491 allele was associated with higher hsCRP after covariate adjustment (β: 0.15, SE: 0.07, P = 0.02). Each additional rs5491 allele was associated with higher TNFR-1 (β: 0.06, SE: 0.02, P = 0.02), but not IL-6 (β: 0.04, SE: 0.04, P = 0.29). The association between rs5491 and HFpEF remained significant after adjustment for hsCRP., Conclusion: In Black individuals, rs5491 ( p.K56M ) is associated with higher hsCRP and higher TNFR-1, but not IL-6.

Background: Hospitalization is recognized as a sentinel event in the disease trajectory of patients with heart failure (HF), but not all patients experiencing clinical decompensation are ultimately hospitalized. Outpatient intensification of diuretics is common in response to symptoms of worsening HF, yet its prognostic and clinical relevance, specifically for patients with HF with mildly reduced or preserved ejection fraction, is uncertain., Methods: In this prespecified analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we assessed the association between various nonfatal worsening HF events (those requiring hospitalization, urgent outpatient visits requiring intravenous HF therapies, and outpatient oral diuretic intensification) and rates of subsequent mortality. We further examined the treatment effect of dapagliflozin on an expanded composite end point of cardiovascular death, HF hospitalization, urgent HF visit, or outpatient oral diuretic intensification., Results: In DELIVER, 4532 (72%) patients experienced no worsening HF event, whereas 789 (13%) had outpatient oral diuretic intensification, 86 (1%) required an urgent HF visit, 585 (9%) had an HF hospitalization, and 271 (4%) died of cardiovascular causes as a first presentation. Patients with a first presentation manifesting as outpatient oral diuretic intensification experienced rates of subsequent mortality that were higher (10 [8-12] per 100 patient-years) than those without a worsening HF event (4 [3-4] per 100 patient-years) but similar to rates of subsequent death after an urgent HF visit (10 [6-18] per 100 patient-years). Patients with an HF hospitalization as a first presentation of worsening HF had the highest rates of subsequent death (35 [31-40] per 100 patient-years). The addition of outpatient diuretic intensification to the adjudicated DELIVER primary end point (cardiovascular death, HF hospitalization, or urgent HF visit) increased the overall number of patients experiencing an event from 1122 to 1731 (a 54% increase). Dapagliflozin reduced the need for outpatient diuretic intensification alone (hazard ratio, 0.72 [95% CI, 0.64-0.82]) and when analyzed as a part of an expanded composite end point of worsening HF or cardiovascular death (hazard ratio, 0.76 [95% CI, 0.69-0.84])., Conclusions: In patients with HF with mildly reduced or preserved ejection fraction, worsening HF requiring oral diuretic intensification in ambulatory care was frequent, adversely prognostic, and significantly reduced by dapagliflozin., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03619213., Competing Interests: Disclosures Dr Chatur is supported by the Canadian Arthur J.E. Child’s Cardiology Fellowship. Dr Vaduganathan has received research grant support, has served on advisory boards, or has had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, 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 AG, Occlutech, and Impulse Dynamics. Dr Claggett has been a consultant for Amgen, AO Biome, Biogen, Boehringer Ingelheim, Corvia, Gilead, Myokardia, Cardurion, and Novartis. Dr Cunningham has been a consultant for Roche Diagnostics, Occlutech, and KCK. Dr Docherty reports receiving grant support from Novartis and lecture fees from Eli Lilly. Dr Desai has received research grant support from AstraZeneca, Alnylam, and Novartis; and has received consulting fees and honoraria from Abbott, AstraZeneca, Alnylam, Boehringer-Ingelheim, Boston Scientific, Biofourmis, Corvidia, DalCor Pharma, Novartis, Relypsa, and Regeneron. Dr Jhund has received consulting fees, advisory board fees, and lecture fees from Novartis, advisory board fees from Cytokinetics, and grant support from Boehringer Ingelheim. Dr de Boer’s institution, the University Medical Centre Groningen, has received research grants and fees (outside the submitted work) from AstraZeneca, Abbott, Boehringer Ingelheim, Cardio Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche. Dr de Boer has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche (outside the submitted work). Dr Hernandez has received research grant support from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Suib, Cytokinetics, Eidos, Intercept, Merck, and Novartis. Dr Lam is supported by a clinician scientist award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics, has served as a consultant or was on the advisory board/steering committee/executive committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research & Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, and WebMD Global LLC; and serves as the cofounder and nonexecutive director of Us2.ai. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim/Lilly, Novo Nordisk, Merck, Pfizer and Bayer; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Kosiborod has received research grant support from AstraZeneca, and Boehringer Ingelheim; has served as a consultant or on an advisory board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Martinez has received personal fees from AstraZeneca. Dr Shah has received either personal or institutional research support for DELIVER from AstraZeneca. Dr Solomon has received either personal or institutional research support for DELIVER from AstraZeneca. Drs Petersson and Langkilde are employees and shareholders of AstraZeneca. Dr McMurray has received grants from, and his employer was paid by, AstraZeneca, Theracos, and GlaxoSmithKline during the conduct of the study. His employer was paid by Novartis, Amgen, Bristol-Myers Squibb, Bayer, Abb-vie, Dal-Cor, Kidney Research UK, and Cardurion, and he received grants from the British Heart Foundation. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI, and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, 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 Puretech Health.

Background: Many therapies for heart failure (HF) have shown differential impact across the spectrum of left ventricular ejection fraction (LVEF)., Objectives: In this prespecified analysis, the authors assessed the effects of semaglutide across the baseline LVEF strata in patients with the obesity phenotype of HF with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF) trial., Methods: STEP-HFpEF randomized 529 patients (263 semaglutide; 266 placebo). For this prespecified analysis, patients were categorized into 3 groups based on LVEF: 45% to 49% (n = 85), 50% to 59% (n = 215), and ≥60% (n = 229)., Results: At 52 weeks, semaglutide improved the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (estimated treatment difference: EF [ejection fraction] 45%-49%: 5.0 points [95% CI: -2.7 to 12.8 points], EF 50%-59%: 9.8 points [95% CI: 5.0 to 14.6 points], and EF ≥60%: 7.4 points [95% CI: 2.8 to 12.0 points]; P interaction = 0.56) and body weight (EF: 45%-49%: -7.6 [95% CI: -10.7 to -4.4], EF 50%-59%: -10.6 [95% CI: -12.6 to -8.6] and EF ≥60%: -11.9 [95% CI: -13.8 to -9.9]; P interaction = 0.08), to a similar extent across LVEF categories. Likewise, LVEF did not influence the benefit of semaglutide on confirmatory secondary endpoints: 6-minute walk distance (P interaction = 0.19), hierarchal composite endpoint (P interaction = 0.43), and high-sensitivity C-reactive protein (P interaction = 0.26); or exploratory endpoint of N-terminal pro-brain natriuretic peptide (P interaction = 0.96). Semaglutide was well-tolerated across LVEF categories., Conclusions: In patients with HFpEF and obesity, semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight to a similar extent across LVEF categories. These data support treatment with semaglutide in patients with the obesity phenotype of HFpEF regardless of LVEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511)., Competing Interests: Funding Support and Author Disclosures The STEP-HFpEF trial was funded by Novo Nordisk A/S. Dr Butler is a consultant to 3live, Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronic, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Sequana, SQ Innovation, and Vifor. Dr Borlaug has received research support from the National Institutes of Health and the U.S. Department of Defense; has received research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is a named inventor (U.S. Patent number 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Davies has acted as a consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; has served as an advisory board member and speaker for AstraZeneca; has served as an advisory board member for Medtronic, Pfizer, and ShouTi Pharma; has served as a speaker for Amgen, Novartis, and Sanofi; and has received grants in support of investigator and investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi. Dr Kitzman was supported in part by the Kermit Glenn Phillips II Chair in Cardiovascular Medicine and National Institutes of Health grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, and U01HL160272; has received honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus; has received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus; and has stock ownership in Gilead Sciences. Dr Petrie has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; and has received consultancy and committee payments for AbbVie, Akero, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiorentis, Horizon Therapeutics, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, Takeda, Teikoku, and Vifor. Dr Shah has received consulting fees from Abbott, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, Metabolic Flux, MyoKardia, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Verma has received research grants or consultancy fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Napp Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; has served on committees for AbbVie, Akero, Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, New Amsterdam, Novo Nordisk, Resverlogix, and Teikoku; and is Director of Global Clinical Trial Partners (GCTP). Dr Abhayaratna has received honoraria and/or consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Chopra has received speaker fees from AstraZeneca, Boehringer Ingelheim, Cipla, Dr Reddy’s, Lupin, Mankind, Novartis, Novo Nordisk, Pfizer, Sanofi, Sun Pharma, and Torrent. Dr Ezekowitz has received research support for trial leadership from American Regent, Applied Therapeutics, Bayer, Cytokinetics, Merck, and Novo Nordisk; has received honoraria for consultancy from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, and Otsuka; and serves as an advisor to US2.ai. Dr Ito has received honoraria and/or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Mochida, Novartis, and Novo Nordisk. Dr Lelonek has received honoraria and/or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Ewopharma, Gedeon Richter, Novartis, Novo Nordisk, Roche, and Servier. Dr Núñez has received honoraria and/or consulting fees from Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Novartis, Novo Nordisk, Pfizer, Rovi, and Vifor. Dr Perna has received honoraria from Novo Nordisk. Dr Schou has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Senni has received honoraria and/or consulting fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, MSD, Novartis, Novo Nordisk, and Vifor. Dr van der Meer has received institutional payments for consultancy fees and/or grants from AstraZeneca, Boehringer Ingelheim, BridgeBio, Ionis, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharma Nord, and Vifor. Dr von Lewinski has received honoraria and/or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, MSD, Novartis, Novo Nordisk, Recardio, Sanofi, Sanova, and Vaxxinity. Dr Wolf is a member of SFB1425, funded by the Deutsche Forschungsgemeinschaft (German Research Foundation); and has received consultancy fees from Novo Nordisk and Novartis. Drs Abildstrøm, Altschul, and Rasmussen are employees of and hold shares in Novo Nordisk. Dr Kosiborod has served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; holds stocks in Artera Health and Saghmos Therapeutics; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received other research support from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Echocardiographic strain imaging reflects myocardial deformation and is a sensitive measure of cardiac function and wall-motion abnormalities. Deep learning (DL) algorithms could automate the interpretation of echocardiographic strain imaging., Methods and Results: We developed and trained an automated DL-based algorithm for left ventricular (LV) strain measurements in an internal dataset. Global longitudinal strain (GLS) was validated externally in (i) a real-world Taiwanese cohort of participants with and without heart failure (HF), (ii) a core-lab measured dataset from the multinational prevalence of microvascular dysfunction-HF and preserved ejection fraction (PROMIS-HFpEF) study, and regional strain in (iii) the HMC-QU-MI study of patients with suspected myocardial infarction. Outcomes included measures of agreement [bias, mean absolute difference (MAD), root-mean-squared-error (RMSE), and Pearson's correlation (R)] and area under the curve (AUC) to identify HF and regional wall-motion abnormalities. The DL workflow successfully analysed 3741 (89%) studies in the Taiwanese cohort, 176 (96%) in PROMIS-HFpEF, and 158 (98%) in HMC-QU-MI. Automated GLS showed good agreement with manual measurements (mean ± SD): -18.9 ± 4.5% vs. -18.2 ± 4.4%, respectively, bias 0.68 ± 2.52%, MAD 2.0 ± 1.67, RMSE = 2.61, R = 0.84 in the Taiwanese cohort; and -15.4 ± 4.1% vs. -15.9 ± 3.6%, respectively, bias -0.65 ± 2.71%, MAD 2.19 ± 1.71, RMSE = 2.78, R = 0.76 in PROMIS-HFpEF. In the Taiwanese cohort, automated GLS accurately identified patients with HF (AUC = 0.89 for total HF and AUC = 0.98 for HF with reduced ejection fraction). In HMC-QU-MI, automated regional strain identified regional wall-motion abnormalities with an average AUC = 0.80., Conclusion: DL algorithms can interpret echocardiographic strain images with similar accuracy as conventional measurements. These results highlight the potential of DL algorithms to democratize the use of cardiac strain measurements and reduce time-spent and costs for echo labs globally., Competing Interests: Conflict of interest: P.L.M. has received research grants from AstraZenca and consulting fees from Amarin, AmGen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Novartis, Novo Nordisk, Orion Pharma, Pharmacosmos, Vifor, and Us2.ai. A.S. received research grants from Academy of Finland and Finnish Foundation for Cardiovascular Research during the conduct of the study; and consulting fees from GE healthcare, Novartis, Abbot, Astra Zeneca. C.H. has received consulting fees from Novartis and MSD. M.J.F., Z.J., Y.M.H. are all employees of Us2.ai. M.L.F. is employee of AstraZeneca R&D. L.H.L. reports no disclosures related to this work. Outside the present work: Grants from AstraZeneca, Vifor, Boston Scientific, Boehringer Ingelheim, Novartis, MSD. Consulting for Vifor, AstraZeneca, Bayer, Pharmacosmos, MSD, MedScape, Sanofi, Lexicon, Myokardia, Boehringer Ingelheim, Servier, Edwards Life Sciences, Alleviant. Speaker’s honoraria from Abbott, OrionPharma, MedScape, Radcliffe, AstraZeneca, Novartis, Boehringer Ingelheim, Bayer. Patent and stock ownership for AnaCardio. S.J.S. has received research grants from Actelion, AstraZeneca, Corvia, and Novartis; and consulting fees from Actelion, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Cardiora, Eisai, Ironwood, Merck, Novartis, Sanofi, Tenax, and United Therapeutics. C.S.L. has received research support from Novo Nordisk and Roche Diagnostics; and has consulted for Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, Cytokinetics, Darma Inc., EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai. J.T. 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 research support from AstraZeneca, consulting or speaker fees from Daiichi-Sankyo, Boehringer Ingelheim, Roche diagnostics and Us2.ai, and owns patent US-10702247-B2 related to the present work. All other authors have no disclosures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Systemic inflammation has been implicated in the pathobiology of heart failure with preserved ejection fraction (HFpEF). Here, we examine the association of upstream mediators of inflammation as ascertained by fatty-acid derived eicosanoid and eicosanoid-related metabolites with HFpEF status and exercise manifestations of HFpEF. Among 510 participants with chronic dyspnea and preserved LVEF who underwent invasive cardiopulmonary exercise testing, we find that 70 of 890 eicosanoid and related metabolites are associated with HFpEF status, including 17 named and 53 putative eicosanoids (FDR q-value < 0.1). Prostaglandin (15R-PGF2α, 11ß-dhk-PGF2α) and linoleic acid derivatives (12,13 EpOME) are associated with greater odds of HFpEF, while epoxides (8(9)-EpETE), docosanoids (13,14-DiHDPA), and oxylipins (12-OPDA) are associated with lower odds of HFpEF. Among 70 metabolites, 18 are associated with future development of heart failure in the community. Pro- and anti-inflammatory eicosanoid and related metabolites may contribute to the pathogenesis of HFpEF and serve as potential targets for intervention., (© 2023. The Author(s).)

We report an unexpected rearrangement, controlled by the nature of the bridge, leading to the formation of novel, remarkably stable triply fused dinickel(II)/dicopper(II) chlorin-porphyrin dication diradical heterodimers in excellent yields. Here, a dipyrromethene bridge gets completely fused between two porphyrin macrocycles with two new C-C and one C-N bonds. The two macrocycles exhibit extensive π-conjugation through the bridge, which results in an antiferromagnetic coupling between the two π-cation radicals. In addition, the macrocyclic distortion also favours a rare intramolecular ferromagnetic interaction between the Cu II and π-cation radical spins to form a triplet state. The structural and electronic perturbation in the unconjugated dication diradical possibly enables the bridging pyrrolic nitrogen to undergo a nucleophilic attack at the nearby β-carbon of the porphyrin π-cation radical with a computed free energy barrier of >20 kcal mol -1 which was supplied in the form of reflux condition to initiate such a rearrangement process. UV-vis, EPR and ESI-MS spectroscopies were used to monitor the rearrangement process in situ in order to identify the key reactive intermediates leading to such an unusual transformation., (© 2023 Wiley-VCH GmbH.)

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are guideline recommended in the management of heart failure (HF). Although these therapies can be initiated even in patients with comorbid chronic kidney disease, some patients may face deterioration of kidney function over time., Objectives: In this study, the authors sought to examine the safety and efficacy of continuing SGLT2 inhibitors in HF when the estimated glomerular filtration rate (eGFR) falls below thresholds for initiation., Methods: Associations between a deterioration of eGFR to <25 mL/min/1.73 m 2 , efficacy, and safety outcomes and treatment with dapagliflozin were evaluated in time-updated Cox proportional hazard models in a participant-level pooled analysis of the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials., Results: Among 11,007 patients, 347 (3.2%) experienced a deterioration of eGFR to <25 mL/min/1.73 m 2 at least once in follow-up. These patients had a higher risk of the primary composite outcome (HR: 1.87; 95% CI: 1.48-2.35; P < 0.001). The risk of the primary outcome was lower with dapagliflozin compared with placebo among patients who did (HR: 0.53; 95% CI: 0.33-0.83) as well as did not (HR: 0.78; 95% CI: 0.72-0.86) experience deterioration of eGFR to <25 mL/min/1.73 m 2 (P interaction  = 0.17). The risk of safety outcomes, including drug discontinuation, was higher among patients with deterioration of eGFR to <25 mL/min/1.73 m 2 ; however, rates remained similar between treatment groups including among those who remained on study drug., Conclusions: Patients with deterioration of eGFR to <25 mL/min/1.73 m 2 had elevated risks of cardiovascular outcomes yet appeared to benefit from continuation of dapagliflozin with no excess in safety outcomes between treatment groups. The benefit-to-risk ratio may favor continuation of dapagliflozin treatment in patients with HF experiencing deterioration of kidney function. Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124; and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding Support and Author Disclosures DAPA-HF and DELIVER were funded by AstraZeneca. Dr Chatur is supported by the Canadian Arthur J.E. Child’s Cardiology Fellowship. Dr Vaduganathan has received research grant support, has served on advisory boards, or has had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer, Baxter Healthcare, Boehringer Ingelheim, 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 AG, Occlutech, and Impulse Dynamics. Dr Claggett has been a consultant for Amgen, AO Biome, Biogen, Boehringer Ingelheim, Corvia, Gilead, Myokardia, Cardurion, and Novartis. Dr Mc Causland has received research funding from NIDDK, Satellite Healthcare, Fifth Eye, Novartis, and Lexicon paid directly to his institution; and has received consulting fees from GS, and Zydus Therapeutics. Dr Desai has received research grant support from AstraZeneca, Alnylam, and Novartis; and has received consulting fees and/or honoraria from Abbott, AstraZeneca, Alnylam, Boehringer Ingelheim, Boston Scientific, Biofourmis, Corvidia, DalCor Pharma, Novartis, Relypsa, and Regeneron. Dr Jhund has received consulting fees, advisory board fees, and lecture fees from Novartis; has received advisory board fees from Cytokinetics; and has received grant support from Boehringer Ingelheim. Dr de Boer has received research grants and fees (to the institution, outside the submitted work) from AstraZeneca, Abbott, Boehringer Ingelheim, Cardio Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Novo Nordisk, and Roche; and has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche (outside the submitted work). Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Novo Nordisk, Somologic, and Verily; and has served as a consultant to or on the Advisory Board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Eidos, GlaxoSmithKline, Intercept, Merck, Novartis, Novo Nordisk, and Prolaio. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim/Lilly, Novo Nordisk, Merck, Pfizer, and Bayer; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Kosiborod receives consulting fees from Alnylam Pharmaceuticals, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Esperion Therapeutics, Janssen Global Services, Lexicon Pharmaceuticals, Merck, Novo Nordisk, Pharmacosmos, Sanofi, Vifor Pharma; and receives grant/contract or travel fees from AstraZeneca and Boehringer Ingelheim. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as a consultant or on the advisory board/steering committee/executive committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma, Us2.ai, Janssen Research and Development, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Sanofi, and WebMD Global; and serves as the cofounder and nonexecutive director of Us2.ai. Dr Martinez receives consulting fees from AstraZeneca. Dr Shah is supported by research grants from the National Institutes of Health (U54 HL160273, R01 HL140731, R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GSK, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Sabatine has received research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Boehringer-Ingelheim, Daiichi-Sankyo, Eisai, Intarcia, Ionis, Merck, Novartis, and Pfizer, as well as consulting fees from Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Boehringer Ingelheim, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, Precision Biosciences, and Silence Therapeutics; and is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from ARCA Biopharma, Janssen Research and Development, Pfizer, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, Softcell Medical, and Zora Biosciences. Dr Kober has received lecture fees from Novartis and Bristol Myers Squibb. Dr Ponikowski has received consulting fees, fees for serving on a Speakers Bureau, and fees (paid to himself and to his institution) for serving as an investigator and steering or executive committee member for clinical trials from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cibiem, Novartis, and RenalGuard; has received lecture fees from Pfizer; has received fees (paid to himself and to his institution) for serving as an investigator and steering or executive committee member for clinical trials from Amgen; has received grant support (paid to his institution), fees for serving on a Speakers Bureau, consulting fees, and fees (paid to himself and to his institution) for serving as an investigator and steering or executive committee member for clinical trials from Vifor Pharma; has received fees for serving on a Speakers Bureau and consulting fees from Servier and Respicardia; and has received fees for serving on a Speakers Bureau from Berlin-Chemie. Dr Merkely has received personal fees from AstraZeneca and Servier. Dr Petersson is an employee and shareholder of AstraZeneca. Dr Langkilde is an employee and shareholder of AstraZeneca. Dr McMurray and his institution have received grants from AstraZeneca, Theracos, and GlaxoSmithKline during the conduct of the study and from Novartis, Amgen, Bristol Myers Squibb, Bayer, Abbvie, Dal-Cor, Kidney Research UK, and Cardurion; and has received grants from the British Heart Foundation. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, Us2.ai; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, 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 Puretech Health., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

BACKGROUND: The primary end point in most heart failure (HF) trials is a composite of time to a first worsening HF event or cardiovascular death. Prevention of recurrent events and improvements in symptoms/quality of life are also important for patients but are usually analyzed separately. Win statistics can integrate all these outcomes into a single composite end point, which is analyzed in hierarchical order, reflecting the clinical importance of each component. METHODS: The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF, n=4744) and Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER, n=6263) trials enrolled patients with New York Heart Association class II, III, or IV HF, elevated natriuretic peptides, and either an ejection fraction of 40% or less (DAPA-HF) or greater than 40% and left atrial enlargement/left ventricular hypertrophy (DELIVER). We examined the effects of dapagliflozin compared with placebo on a hierarchical composite outcome, including cardiovascular death, total (first and recurrent) HF hospitalizations, total urgent HF visits, and improvement/deterioration in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS; range from 0 to 100, with a higher score indicating fewer symptoms and physical limitations) at 8 months. RESULTS: For this composite outcome, the win ratio was 1.30 (95% confidence interval [CI], 1.23 to 1.36) in the pooled cohort, 1.33 (95% CI, 1.23 to 1.43) in the DAPA-HF trial, and 1.27 (95% CI, 1.18 to 1.36) in the DELIVER trial. Win odds and net benefit in overall patients were 1.19 (95% CI, 1.14 to 1.24) and 8.7% (95% CI, 6.6 to 10.9%), respectively. In the overall pooled cohort, the majority of wins and losses were accounted for by KCCQ-TSS; 52.4% were settled by the KCCQ-TSS tier in the pooled cohort. CONCLUSIONS: In both the DAPA-HF and DELIVER trials, dapagliflozin led to a significant improvement in composite outcomes that incorporated patient-reported outcomes along with total HF events, as well as cardiovascular deaths. These analyses provided a comprehensive presentation of win statistics and illustrated the utility and flexibility of win statistics in describing the effects of dapagliflozin in two recent clinical trials in patients with HF. (Funded by British Heart Foundation Centre of Research Excellence and others; clinical trial registration numbers, NCT03036124 and NCT03619213.)

Background: Cardio-renal-metabolic (CRM) conditions are individually common among patients with heart failure (HF), but the prevalence and influence of overlapping CRM conditions in this population have not been well-studied., Objectives: This study aims to evaluate the impact of overlapping CRM conditions on clinical outcomes and treatment effects of dapagliflozin in HF., Methods: In this post hoc analysis of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we evaluated the prevalence of comorbid CRM conditions (atherosclerotic cardiovascular disease, chronic kidney disease, and type 2 diabetes), their impact on the primary outcome (cardiovascular death or worsening HF), and treatment effects of dapagliflozin by CRM status., Results: Among 6,263 participants, 1,952 (31%), 2,245 (36%), and 1,236 (20%) had 1, 2, and 3 additional CRM conditions, respectively. HF alone was uncommon (13%). Greater CRM multimorbidity was associated with older age, higher body mass index, longer-duration HF, worse health status, and lower left ventricular ejection fraction. Risk of the primary outcome increased with higher CRM overlap, with 3 CRM conditions independently associated with highest risk of primary events (adjusted HR: 2.16 [95% CI: 1.72-2.72]; P < 0.001) compared with HF alone. Relative benefits of dapagliflozin on the primary outcome were consistent irrespective of the type of CRM overlap (P interaction  = 0.773) and by the number of CRM conditions (P interaction  = 0.734), with greatest absolute benefits among those with highest CRM multimorbidity. Estimated 2-year numbers needed to treat with dapagliflozin to prevent 1 primary event were approximately 52, 39, 33, and 24 for participants with 0, 1, 2, and 3 additional CRM conditions at baseline, respectively. Adverse events between treatment arms were similar across the CRM spectrum., Conclusions: CRM multimorbidity was common and associated with adverse outcomes among patients with HF and left ventricular ejection fraction >40% in DELIVER. Dapagliflozin was safe and effective across the CRM spectrum, with greater absolute benefits among those with highest CRM overlap (Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding Support and Author Disclosures DELIVER was sponsored by AstraZeneca. Dr Claggett has received consulting fees from Boehringer Ingelheim. Dr Desai has received institutional grant support from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer; and has received consulting fees from Abbott, Alnylam, AstraZeneca, Avidity, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Medpace, Merck, New Amsterdam, Novartis, Parexel, Regeneron, River2Renal Roche, Veristat, Verily, and Zydus. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals, and Intas Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; and his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and NovoNordisk; and is the Director of Global Clinical Trial Partners (GCTP). Dr Kosiborod has received research grant support from AstraZeneca and Boehringer Ingelheim; and has received consulting fees from Alnylam, AstraZeneca, Amgen, Bayer, Boehringer-Ingelheim, Cytokinetics, Esperion, Eli Lilly, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Pharmacosmos, Novo Nordisk, Sanofi, and Vifor. Dr Lam has received support from 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 and 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 Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Martinez has received personal fees from AstraZeneca. Dr de Boer has received research grant support from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche; and has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche. Dr Hernandez has received research grant support from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic; and has received verily consulting fees from Amgen, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Cytokinetics, Merck, Novartis, and NovoNordisk. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Shifamed, Tenax, Tenaya, and United Therapeutics. Drs Petersson and Langkilde are employees of AstraZeneca. Dr McMurray has received funding to his institution, Glasgow University, for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, Pfizer, and Theracos; and has received personal lecture fees from the Corpus, Abbott, Hickma, Sun Pharmaceuticals, and Medsca. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, 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, and Sarepta. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, 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 AG, Occlutech, and Impulse Dynamics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Artificial intelligence (AI), driven by advances in deep learning (DL), has the potential to reshape the field of cardiovascular imaging (CVI). While DL for CVI is still in its infancy, research is accelerating to aid in the acquisition, processing, and/or interpretation of CVI across various modalities, with several commercial products already in clinical use. It is imperative that cardiovascular imagers are familiar with DL systems, including a basic understanding of how they work, their relative strengths compared with other automated systems, and possible pitfalls in their implementation. The goal of this article is to review the methodology and application of DL to CVI in a simple, digestible fashion toward demystifying this emerging technology., Observations: At its core, DL is simply the application of a series of tunable mathematical operations that translate input data into a desired output. Based on artificial neural networks that are inspired by the human nervous system, there are several types of DL architectures suited to different tasks; convolutional neural networks are particularly adept at extracting valuable information from CVI data. We survey some of the notable applications of DL to tasks across the spectrum of CVI modalities. We also discuss challenges in the development and implementation of DL systems, including avoiding overfitting, preventing systematic bias, improving explainability, and fostering a human-machine partnership. Finally, we conclude with a vision of the future of DL for CVI., Conclusions and Relevance: Deep learning has the potential to meaningfully affect the field of CVI. Rather than a threat, DL could be seen as a partner to cardiovascular imagers in reducing technical burden and improving efficiency and quality of care. High-quality prospective evidence is still needed to demonstrate how the benefits of DL CVI systems may outweigh the risks.

Background: Heart failure with preserved ejection fraction is associated with significant functional limitations, yet treatments for improving exercise performance have been elusive. We sought to explore the association between prespecified patient characteristics and changes in 6-minute walk distance that constitute a clinically significant response to dapagliflozin., Methods: We performed a responder analysis to understand patient characteristics associated with clinically meaningful improvement in 6-minute walk test (6MWT) distance ≥15 m among patients randomized to 12 weeks of dapagliflozin versus placebo in the double-blind PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure)., Results: A total of 289 randomized patients had 6MWT distance completed at baseline and 12 weeks. Patients randomized to dapagliflozin improved walking distance by ≥15 m more frequently than those on placebo (n=64, 44% versus n=48, 34%). After adjusting for baseline covariates, patients randomized to dapagliflozin were more likely to experience a clinically meaningful improvement in 6MWT distance compared with those that received placebo (adjusted odds ratio, 1.66 [95% CI, 1.00-2.75]; P =0.05). Dapagliflozin-treated patients were also less likely to have a ≥15 m reduction in 6MWT distance compared with placebo-treated patients (adjusted odds ratio, 0.56 [95% CI, 0.33-0.94]; P =0.03). These results were consistent across all prespecified subgroups (all P values for interaction were not significant)., Conclusions: Compared with those on placebo, patients with heart failure with preserved ejection fraction randomized to dapagliflozin were more likely to experience a clinically meaningful improvement and less likely to experience a deterioration in physical function over 12 weeks as measured by 6MWT distance. Beneficial response to dapagliflozin was consistent across prespecified subgroups., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03030235., Competing Interests: Disclosures Dr Lewis reports research funding from the National Institutes of Health (NIH) R01-HL 151841, R01-HL131029, R01-HL159514, U01-HL160278, Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, SoniVie, NXT, and Rivus. He has received honoraria for advisory boards outside of the current study from Pfizer, Merck, Boehringer-Ingelheim, NXT, American Regent, Cyclerion, Cytokinetics, Amgen, RIVUS, and NXT and receives royalties from UpToDate for scientific content authorship related to exercise physiology. Dr Nassif is a consultant to Vifor and has received research support from Cytokinetics. Dr Borlaug receives research support from the NIH (R01 HL128526, R01 HL162828, and U01 HL160226) and the US Department of Defense (W81XWH2210245), and research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax Therapeutics. Dr Borlaug has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer-Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations and is named inventor (US Patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Kitzman has received honoraria as a consultant for Boehringer-Ingelheim, Novo Nordisk, AstraZeneca, Corvia, Rivus, Keyto, Saint Luke’s Medical Center, and Novartis and grant funding from Novartis, Bayer, Novo Nordisk, Rivus, Saint Luke’s Medical Center, and AstraZeneca and stock ownership in Gilead Sciences. Dr Shah is supported by research grants from the NIH (U54 HL160273, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GSK, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Umpierrez is partly supported by research grants from the NIH/National Center for Advancing Translational Sciences (UL 3UL1TR002378-05S2) from the Clinical and Translational Science Award program, and from the NIH and National Center for Research Resources (NIH/National Institute of Diabetes and Digestive and Kidney Diseases 2P30DK111024-06). He has also received research support (to Emory University) from Dexcom, Bayer, Abbott, and AstraZeneca. Dr Sharma is an advisory board member and consultant for Alleviant, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Cytokinetics, Janssen, Novartis, Novo Nordisk, and RIVUS and receives honoraria. Dr Khan receives funding from the American Heart Association (19TPA34890060) and NIH (1R01HL159250). Dr Kosiborod receives grant/research support from AstraZeneca, Boehringer-Ingelheim, and Pfizer; honoraria from AstraZeneca, Boehringer-Ingelheim, and Novo Nordisk; is a consultant for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; and has stock options from Artera Health and Saghmos Therapeutics. Dr Sauer is a consultant for Bayer, Abbott, Acorai, Biotronik, Boston Scientific, Edwards Life Sciences, Impulse Dynamics, Medtronics, Story Health, and Vifor Pharma and owns stock in ISHI. The other authors report no disclosures.

Importance: The US Food and Drug Administration expanded labeling of sacubitril-valsartan from the treatment of patients with chronic heart failure (HF) with reduced ejection fraction (EF) to all patients with HF, noting the greatest benefits in those with below-normal EF. However, the upper bound of below normal is not clearly defined, and value determinations across a broader EF range are unknown., Objective: To estimate the cost-effectiveness of sacubitril-valsartan vs renin-angiotensin system inhibitors (RASis) across various upper-level cutoffs of EF., Design, Setting, and Participants: This economic evaluation included participant-level data from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and the PARAGON-HF (Prospective Comparison of ARNi with ARB Global Outcomes in HF With Preserved Ejection Fraction) trials. PARADIGM-HF was conducted between 2009 and 2014, PARAGON-HF was conducted between 2014 and 2019, and this analysis was conducted between 2021 and 2023., Main Outcomes and Measures: A 5-state Markov model used risk reductions for all-cause mortality and HF hospitalization from PARADIGM-HF and PARAGON-HF. Quality-of-life differences were estimated from EuroQol-5D scores. Hospitalization and medication costs were obtained from published national sources; the wholesale acquisition cost of sacubitril-valsartan was $7092 per year. Risk estimates and treatment effects were generated in consecutive 5% EF increments up to 60% and applied to an EF distribution of US patients with HF from the Get With the Guidelines-Heart Failure registry. The base case included a lifetime horizon from a health care sector perspective. Incremental cost-effectiveness ratios (ICERs) were estimated at EFs of 60% or less (base case) and at various upper-level EF cutoffs., Results: Among 13 264 total patients whose data were analyzed, for those with EFs of 60% or less, sacubitril-valsartan was projected to add 0.53 quality-adjusted life-years (QALYs) at an incremental lifetime cost of $40 892 compared with RASi, yielding an ICER of $76 852 per QALY. In a probabilistic sensitivity analysis, 95% of the values of the ICER occurred between $71 516 and $82 970 per QALY. Among patients with chronic HF and an EF of 60% or less, treatment with sacubitril-valsartan vs RASis would be at least of economic intermediate value (ICER <$180 000 per QALY) at a sacubitril-valsartan cost of $10 242 or less per year, of high economic value (ICER <$60 000 per QALY) at a cost of $3673 or less per year, and cost-saving at a cost of $338 or less per year. The ICERs were $67 331 per QALY, $59 614 per QALY, and $56 786 per QALY at EFs of 55% or less, 50% or less, and 45% or less, respectively. Treatment with sacubitril-valsartan in only those with EFs of 45% or greater (up to ≤60%) yielded an ICER of $127 172 per QALY gained; treatment was more cost-effective in those at the lower end of this range (ICER of $100 388 per QALY gained for those with EFs of 45%-55%; ICER of $84 291 per QALY gained for those with EFs of 45%-50%)., Conclusions and Relevance: Cost-effectiveness modeling provided an ICER for treatment with sacubitril-valsartan vs RASis consistent with high economic value for patients with reduced and mildly reduced EFs (≤50%) and at least intermediate value at the current undiscounted wholesale acquisition cost price at an EF of 60% or less. Treatment was more cost-effective at lower EF ranges. These findings may have implications for coverage decisions and value assessments in contemporary clinical practice guidelines.

Stereotactic radiation therapy yields high rates of local control for brain metastases, but patients in rural or suburban areas face geographic and socioeconomic barriers to its access. We conducted a phase II clinical trial of frameless, fractionated stereotactic radiation therapy for brain metastases in an integrated academic satellite network for patients 18 years of age or older with 4 or fewer brain metastases. Dose was based on gross tumor volume: less than 3.0 cm, 27 Gy in 3 fractions and 3.0 to 3.9 cm, 30 Gy in 5 fractions. Median follow-up was 10 months for 73 evaluable patients, with a median age of 68 years. Median intracranial progression-free survival was 7.1 months (95% confidence interval = 5.3 to not reached), and median survival was 7.2 months (95% confidence interval = 5.4 to not reached); there were no serious adverse events. Outcomes of this trial compare favorably with contemporary trials, and this treatment strategy provides opportunities to expand stereotactic radiation therapy access to underserved populations., (© The Author(s) 2023. Published by Oxford University Press.)

In the STEP-HFpEF trial, 2.4 mg semaglutide produced marked improvements in heart failure-related symptoms, physical limitations, and exercise function, and reduced inflammation and body weight in individuals with obesity HFpEF phenotype. These data usher in a new paradigm of targeting obesity as a therapeutic strategy in HFpEF., Competing Interests: Declaration of interests The STEP-HFpEF and STEP-HFpEF DM trials were funded by Novo Nordisk. S.V. reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management Inc, and Sanofi. B.A.B. has received research support from the National Institutes of Health and the United States Department of Defense; has received research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is named inventor (U.S. patent number 10307179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. J.B. is a consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Sequana, SQ Innovation, 3live, and Vifor. M.J.D. has acted as a consultant, advisory board member, and speaker for Boehringer Ingelheim, Lilly, Novo Nordisk, and Sanofi; is an advisory board member and speaker for AstraZeneca; is an advisory board member for Pfizer, Medtronic, and ShouTi Pharma Inc; is a speaker for Novartis, Sanofi, and Amgen; and has received grants in support of investigator and investigator-initiated trials from AstraZeneca, Sanofi-Aventis, Eli Lilly, Boehringer Ingelheim, Janssen, and Novo Nordisk. D.W.K. has been supported in part by research grants from the National Institutes of Health (U01AG076928, R01AG078153, R01AG18915, P30AG021332, U24AG059624, and U01HL160272); reports receiving consulting fees from AstraZeneca, Pfizer, Corvia Medical, Bayer, Boehringer-Ingleheim, NovoNordisk, Rivus, and St. Luke’s Medical Center; has received grant support from Novartis, AstraZeneca, Bayer, Pfizer, Novo Nordisk, Rivus, and St. Luke’s Medical Center; and owns stock in Gilead Sciences. M.C.P. has received research grants or consultancy fees from SQ Innovations, AstraZeneca, Roche, Boehringer Ingelheim, Pharmacosmos, Eli Lilly, Napp Pharmaceuticals, Novartis, and Novo Nordisk; has served on committees for AbbVie, Akero, Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Resverlogix, Teikoku, New Amsterdam, and Novo Nordisk; and is director of Global Clinical Trial Partners. S.J.S. has been supported by research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423) and reports receiving consulting fees from Abbott, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, Metabolic Flux, MyoKardia, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. M.N.K. served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research grants from AstraZeneca and Boehringer Ingelheim; holds stocks in Artera Health and Saghmos Therapeutics; has received honorarium from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received other research support from AstraZeneca., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Patients with heart failure (HF) have a high burden of multimorbidity, often necessitating numerous medications. There may be clinical concern about introducing another medication, especially among individuals with polypharmacy., Objectives: This study examined the efficacy and safety of addition of dapagliflozin according to the number of concomitant medications in HF with mildly reduced or preserved ejection fraction., Methods: In this post hoc analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, 6,263 participants with symptomatic HF with left ventricular ejection fraction >40% were randomized to dapagliflozin or placebo. Baseline medication use (including vitamins and supplements) was collected. Efficacy and safety outcomes were assessed by medication use categories ("nonpolypharmacy": <5 medications; "polypharmacy": 5 to 9 medications; and "hyperpolypharmacy": ≥10 medications) and continuously. The primary outcome was worsening HF or cardiovascular death., Results: Overall, 3,795 (60.6%) patients met polypharmacy and 1,886 (30.1%) met hyperpolypharmacy criteria. Higher numbers of medications were strongly associated with higher comorbidity burden and increased rates of the primary outcome. Compared with placebo, dapagliflozin similarly reduced the risk of the primary outcome irrespective of polypharmacy status (nonpolypharmacy HR: 0.88 [95% CI: 0.58-1.34]; polypharmacy HR: 0.88 [95% CI: 0.75-1.03]; hyperpolypharmacy HR: 0.73 [95% CI: 0.60-0.88]; P interaction  = 0.30). Similarly, benefits with dapagliflozin were consistent across the spectrum of total medication use (P interaction  = 0.06). Although adverse events increased with higher number of medications, they were not more frequent with dapagliflozin, regardless of polypharmacy status., Conclusions: In the DELIVER trial, dapagliflozin safely reduced worsening HF or cardiovascular death across a broad range of baseline medication use, including among individuals with polypharmacy (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding support and author disclosures The DELIVER trial was funded by AstraZeneca. Dr Peikert has received a research grant from the German Research Foundation. Dr Goyal has received consulting fees from Sensorum Health. Dr Vaduganathan has received research grant support; has served on advisory boards or has had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, 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 AG, Occlutech, and Impulse Dynamics. Dr Claggett has received consulting fees from Alnylam, Cardurion, Corvia, Cytokinetics, and Intellia, Rocket. Dr Vardeny has received institutional research support from AstraZeneca, Bayer, and Cardurion; and has served as a consultant or advisory board member for AstraZeneca, Cardior, Cytokinetics, and Sanofi-Pasteur. Dr Kosiborod has received research grant support from AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant or on an advisory board for 35 Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Desai has received institutional research grants from Abbott, AstraZeneca, Alnylam, Bayer, Novartis, and Pfizer; and has received personal consulting fees from Abbott, AstraZeneca, Alnylam, Avidity, Axon Therapeutics, Bayer, Biofourmis, GlaxoSmithKline, Medpace, Merck, Novartis, Parexel, Regeneron, River2Renal, Veristat, Verily, and Zydus. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; and personal fees from Roche and Intas Pharma; has served as Director of Global Clinical Trial Partners (GCTP); and his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and NovoNordisk. 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 and 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 has served as cofounder and nonexecutive director of Us2.ai. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Martinez has received personal fees from AstraZeneca. Dr de Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals Inc, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic and Verily; and has served as a consultant or on the Advisory Board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Eidos, Intercept, Merck, and Novartis. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Eli Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Drs Petersson and Langkilde are employees and shareholders of AstraZeneca. 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, River 2 Renal Corporation; personal lecture fees from 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, Translational Medicine Academy; and he is a director of Global Clinical Trial Partners Ltd. Dr Solomon has received research grants (paid to institution) from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Eli Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Eli Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Valo. 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.)

Background: Mobility loss is common in hospitalized older adults, and resources to prevent mobility impairment are finite. Our goal was to use routinely collected data to develop a risk assessment tool that identifies individuals at risk of losing the ability to walk during hospitalization on the first hospital day. Second, we determined if the tool could inform the use of mobility-preserving interventions., Methods: We included patients admitted to a general medical service, aged ≥65 years, who walked occasionally or frequently on admission (Braden Scale Activity subset > = 3). Patients were considered to have a new mobility impairment if, at discharge, their ability to walk was severely limited or nonexistent or they were confined to bed (Braden Scale Activity subset <3). We used predictors available on the first hospital day to develop (2017-18 cohort) and validate (2019 cohort) a risk assessment tool. We determined the association between predicted risk and therapy use in the validation cohort to highlight the model's clinical utility., Results: 5542 patients were included (median age 76 years, 48% women); 7.6% were discharged unable to walk. The model included 5 predictors: age, medication administrations, Glasgow Coma Scale verbal score, serum albumin, and urinary catheter presence. In the validation cohort, the model discriminated well (c-statistic 0.75) and was strongly associated with hospital-acquired mobility impairment (lowest decile 1%, highest decile 25%). In the validation cohort, therapy consultation ordering increased linearly with predicted risk; however, observed mobility impairment increased exponentially., Conclusion: The tool assesses the risk of mobility impairment in all ambulatory hospitalized older adults on the first hospital day. Further, it identifies at-risk older adults who may benefit from mobility interventions., (© 2023 The American Geriatrics Society.)

Background: Atrial fibrillation (AF) is a common comorbidity in patients with heart failure with preserved ejection fraction (HFpEF) and in heart failure with mildly reduced ejection fraction (HFmrEF)., Objectives: This study sought to describe AF burden and its clinical impact among individuals with HFpEF and HFmrEF who participated in a randomized clinical trial of atrial shunt therapy (REDUCE LAP-HF II [A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure]) and to evaluate the effect of atrial shunt therapy on AF burden., Methods: Study investigators characterized AF burden among patients in the REDUCE LAP-HF II trial by using ambulatory cardiac patch monitoring at baseline (median patch wear time, 6 days) and over a 12-month follow-up (median patch wear time, 125 days). The investigators determined the association of baseline AF burden with long-term clinical events and examined the effect of atrial shunt therapy on AF burden over time., Results: Among 367 patients with cardiac monitoring data at baseline and follow-up, 194 (53%) had a history of AF or atrial flutter (AFL), and median baseline AF burden was 0.012% (IQR: 0%-1.3%). After multivariable adjustment, baseline AF burden ≥0.012% was significantly associated with heart failure (HF) events (HR: 2.00; 95% CI: 1.17-3.44; P = 0.01) both with and without a history of AF or AFL (P for interaction = 0.68). Adjustment for left atrial reservoir strain attenuated the baseline AF burden-HF event association (HR: 1.71; 95% CI: 0.93-3.14; P = 0.08). Of the 367 patients, 141 (38%) had patch-detected AF during follow-up without a history of AF or AFL. Atrial shunt therapy did not change AF incidence or burden during follow-up., Conclusions: In HFpEF and HFmrEF, nearly 40% of patients have subclinical AF by 1 year. Baseline AF burden, even at low levels, is associated with HF events. Atrial shunt therapy does not affect AF incidence or burden. (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure [REDUCE LAP-HF II]; NCT03088033)., Competing Interests: Funding Support and Author Disclosures Corvia Medical, Inc has provided funding for this work. Dr Reddy has served as a consultant to and has equity in Corvia Medical; also, unrelated to this manuscript, has served as a consultant to and has equity in Ablacon, Acutus Medical, Affera-Medtronic, Apama Medical-Boston Scientific, APN Health, Aquaheart, Atacor, Autonomix, Axon Therapies, Backbeat, BioSig, CardiaCare, CardioNXT/AFTx, Circa Scientific, CoRISMA, Dinova-Hangzhou Dinova EP Technology, East End Medical, EPD-Philips, EP Frontiers, Epix Therapeutics-Medtronic, EpiEP, Eximo, Farapulse-Boston Scientific, Field Medical, Focused Therapeutics, HRT, Intershunt, Javelin, Kardium, Keystone Heart, LuxMed, Medlumics, Middlepeak, Neutrace, Nuvera-Biosense Webster, Oracle Health, Restore Medical, Sirona Medical, SoundCath, and Valcare; unrelated to this work, has served as a consultant to Abbott, AtriAN, Biosense Webster, BioTel Heart, Biotronik, Boston Scientific, Cairdac, Cardiofocus, Cardionomic, CoreMap, Fire1, W.L. Gore & Associates, Impulse Dynamics, Medtronic, Philips, and Pulse Biosciences; and has equity in Manual Surgical Sciences, Newpace, Nyra Medical, Surecor, and Vizaramed. Dr Komtebedde has been employed by Corvia Medical, Inc. Dr Walton has served as a proctor for Medtronic, Edwards Lifesciences, and Abbott; has served on advisory boards for Medtronic, Abbott, and Edwards Lifesciences; and has received grant support from Medtronic, Abbott, and Edwards Lifesciences. Dr Herrmann has received institutional research grants from Abbott, Bayer, Boston Scientific, Edwards Lifesciences, Highlife, Medtronic, Shockwave, and W.L. Gore & Associates; has received consultant fees from Medtronic, W.L. Gore & Associates, and Corazon; and has equity in Holistic Medical and Microinterventional Devices. Dr Trochu received consulting fees from Bayer, Bristol-Myers-Squibb, Abbott, AstraZeneca, and Novartis; lecture fees from Boehringer-Ingelheim and Vifor; and congress sponsoring from Corvia. Dr Auricchio has served as a consultant to Boston Scientific, Cairdac, Corvia, Microport CRM, EPD Philips, EP Solution, Radcliffe Publishers, and XSpline; has received speaker fees from Boston Scientific, Medtronic, and Microport CRM; has participated in clinical trials sponsored by Boston Scientific, Medtronic, EPD Philips, XSpline; and has intellectual properties with Boston Scientific, Biosense Webster, and Microport CRM. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure with preserved ejection fraction is increasing in prevalence and is associated with a high symptom burden and functional impairment, especially in persons with obesity. No therapies have been approved to target obesity-related heart failure with preserved ejection fraction., Methods: We randomly assigned 529 patients who had heart failure with preserved ejection fraction and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or higher to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The dual primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in the 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level., Results: The mean change in the KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo (estimated difference, 7.8 points; 95% confidence interval [CI], 4.8 to 10.9; P<0.001), and the mean percentage change in body weight was -13.3% with semaglutide and -2.6% with placebo (estimated difference, -10.7 percentage points; 95% CI, -11.9 to -9.4; P<0.001). The mean change in the 6-minute walk distance was 21.5 m with semaglutide and 1.2 m with placebo (estimated difference, 20.3 m; 95% CI, 8.6 to 32.1; P<0.001). In the analysis of the hierarchical composite end point, semaglutide produced more wins than placebo (win ratio, 1.72; 95% CI, 1.37 to 2.15; P<0.001). The mean percentage change in the CRP level was -43.5% with semaglutide and -7.3% with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). Serious adverse events were reported in 35 participants (13.3%) in the semaglutide group and 71 (26.7%) in the placebo group., Conclusions: In patients with heart failure with preserved ejection fraction and obesity, treatment with semaglutide (2.4 mg) led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo. (Funded by Novo Nordisk; STEP-HFpEF ClinicalTrials.gov number, NCT04788511.)., (Copyright © 2023 Massachusetts Medical Society.)

Rationale & Objective: Heart failure (HF) is an important cause of morbidity and mortality among individuals with chronic kidney disease (CKD). A large body of evidence from preclinical and clinical studies implicates excess levels of fibroblast growth factor 23 (FGF23) in HF pathogenesis in CKD. It remains unclear whether the relationship between elevated FGF23 levels and HF risk among individuals with CKD varies by HF subtype., Study Design: Prospective cohort study., Settings & Participants: A total of 3,502 participants were selected in the Chronic Renal Insufficiency Cohort study., Exposure: Baseline plasma FGF23., Outcomes: Incident HF by subtype and total rate of HF hospitalization. HF was categorized as HF with preserved ejection fraction (HFpEF, ejection fraction [EF] ≥ 50%), HF with reduced EF (HFrEF, EF < 50%) and HF with unknown EF (HFuEF)., Analytical Approach: Multivariable-adjusted cause-specific Cox proportional hazards models were used to investigate associations between FGF23 and incident hospitalizations for HF by subtype. The Lunn-McNeil method was used to compare hazard ratios across HF subtypes. Poisson regression models were used to evaluate the total rate of HF., Results: During a median follow-up time of 10.8 years, 295 HFpEF, 242 HFrEF, and 156 HFuEF hospitalizations occurred. In multivariable-adjusted cause-specific Cox proportional hazards models, FGF23 was significantly associated with the incidence of HFpEF (HR, 1.41; 95% CI, 1.21-1.64), HFrEF (HR, 1.27; 95% CI, 1.05-1.53), and HFuEF (HR, 1.40; 95% CI, 1.13-1.73) per 1 standard deviation (SD) increase in the natural log of FGF23. The Lunn-McNeil method determined that the risk association was consistent across all subtypes. The rate ratio of total HF events increased with FGF23 quartile. In multivariable-adjusted models, compared with quartile 1, FGF23 quartile 4 had a rate ratio of 1.81 (95% CI, 1.28-2.57) for total HF events., Limitations: Self-report of HF hospitalizations and possible lack of an echocardiogram at time of hospitalization., Conclusions: In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risks for all HF subtypes., Plain-Language Summary: Heart failure (HF) is a prominent cause of morbidity and mortality in individuals with chronic kidney disease (CKD). Identifying potential pathways in the development of HF is essential in developing therapies to prevent and treat HF. In a large cohort of individuals with CKD, the Chronic Renal Insufficiency Cohort (N = 3,502), baseline fibroblast growth factor-23 (FGF23), a hormone that regulates phosphorous, was evaluated in relation to the development of incident and recurrent HF with reduced, preserved, and unknown ejection fraction. In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risk of all HF subtypes. These findings demonstrate the need for further research into FGF23 as a target in preventing the development of HF in individuals with CKD.

In the STEP-HFpEF trial, semaglutide improved symptoms, physical limitations and exercise function and reduced body weight in patients with obesity phenotype of heart failure and preserved ejection fraction (HFpEF). This prespecified analysis examined the effects of semaglutide on dual primary endpoints (change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and body weight) and confirmatory secondary endpoints (change in 6-minute walk distance (6MWD), hierarchical composite (death, HF events, change in KCCQ-CSS and 6MWD) and change in C-reactive protein (CRP)) across obesity classes I-III (body mass index (BMI) 30.0-34.9 kg m - 2 , 35.0-39.9 kg m - 2 and ≥40 kg m - 2 ) and according to body weight reduction with semaglutide after 52 weeks. Semaglutide consistently improved all outcomes across obesity categories (P value for treatment effects × BMI interactions = not significant for all). In semaglutide-treated patients, improvements in KCCQ-CSS, 6MWD and CRP were greater with larger body weight reduction (for example, 6.4-point (95% confidence interval (CI): 4.1, 8.8) and 14.4-m (95% CI: 5.5, 23.3) improvements in KCCQ-CSS and 6MWD for each 10% body weight reduction). In participants with obesity phenotype of HFpEF, semaglutide improved symptoms, physical limitations and exercise function and reduced inflammation and body weight across obesity categories. In semaglutide-treated patients, the magnitude of benefit was directly related to the extent of weight loss. Collectively, these data support semaglutide-mediated weight loss as a key treatment strategy in patients with obesity phenotype of HFpEF. ClinicalTrials.gov identifier: NCT04788511 ., (© 2023. The Author(s).)

Aims: Mitiperstat (formerly AZD4831) is a novel selective myeloperoxidase inhibitor. Currently, no effective therapies target comorbidity-induced systemic inflammation, which may be a key mechanism underlying heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). Circulating neutrophils secrete myeloperoxidase, causing oxidative stress, microvascular endothelial dysfunction, interstitial fibrosis, cardiomyocyte remodelling and diastolic dysfunction. Mitiperstat may therefore improve function of the heart and other organs, and ameliorate heart failure symptoms and exercise intolerance. ENDEAVOR is a combined, seamless phase 2b-3 study of the efficacy and safety of mitiperstat in patients with HFpEF/HFmrEF., Methods: In phase 2b, approximately 660 patients with heart failure and ejection fraction >40% are being randomized 1:1:1 to mitiperstat 2.5 mg, 5 mg or placebo for 48 weeks. Eligible patients have baseline 6-min walk distance (6MWD) of 30-400 m with a <50 m difference between screening and randomization and Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) ≤90 points at screening and randomization. The dual primary endpoints are change from baseline to week 16 in 6MWD and KCCQ-TSS. The sample size provides 85% power to detect placebo-adjusted improvements of 21 m in 6MWD and 6.0 points in KCCQ-TSS at overall two-sided alpha of 0.05. Safety is monitored throughout treatment, with a focus on maculopapular rash. In phase 3 of ENDEAVOR, approximately 820 patients will be randomized 1:1 to mitiperstat or placebo., Conclusion: ENDEAVOR is the first phase 2b-3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF/HFmrEF., (© 2023 AstraZeneca. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial demonstrated the sodium-glucose cotransporter 2 inhibitor dapagliflozin to be beneficial in patients with symptomatic heart failure (HF) with improved ejection fraction (HFimpEF; those with prior left ventricular ejection fraction ≤40% that had improved to >40% by enrolment). Whether this benefit differs by background medical therapy is unclear. The current study aims to determine the efficacy and safety of dapagliflozin among patients with HFimpEF by background medical therapy., Methods and Results: Treatment effects on the primary endpoint (worsening HF or cardiovascular death) were assessed by number of background HF medical therapies (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, evidence-based beta-blocker, and mineralocorticoid receptor antagonist). Among the 6263 patients randomized in DELIVER, 1151 (18%) had HFimpEF. Of those, 21% of patients were on 0-1 therapies, 44% were on two therapies, and 35% were on three therapies. During 2.3 years of median follow-up, the incidence rate of the primary outcome was 9.7, 8.8, and 8.4 per 100 person-years for patients on 0-1, 2 and 3 HF medications at baseline, respectively. Treatment effects with dapagliflozin on the primary outcome may be greater in patients with HFimpEF on 0-1 therapies at baseline (p interaction  = 0.09), driven mostly by a significant interaction for HF hospitalization (p interaction  = 0.023) with no evidence of effect modification for cardiovascular death (p interaction  = 0.65). Treatment effects of dapagliflozin on the primary outcome were, however, consistent when assessed across the modified Heart Failure Collaboratory Medical Therapy Score integrating both therapeutic use and dosing (p interaction  = 0.39). The use of dapagliflozin was not associated with changes in use or doses of background HF therapies, and among patients on three HF medications at baseline, the addition of dapagliflozin did not lead to higher adverse events., Conclusions: In patients with HFimpEF, the safety and efficacy of dapagliflozin were largely similar by background use and dosing of HF medical therapies. The benefit of dapagliflozin in reducing HF events tended to be greater in those patients on 0-1 medications at baseline. Among patients already on three HF medical therapies, the addition of dapagliflozin was safe without requiring de-escalation of other therapies., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: It is widely held that heart failure (HF) does not cause exertional hypoxaemia, based upon studies in HF with reduced ejection fraction, but this may not apply to patients with HF and preserved ejection fraction (HFpEF). Here, we characterize the prevalence, pathophysiology, and clinical implications of exertional arterial hypoxaemia in HFpEF., Methods and Results: Patients with HFpEF (n = 539) and no coexisting lung disease underwent invasive cardiopulmonary exercise testing with simultaneous blood and expired gas analysis. Exertional hypoxaemia (oxyhaemoglobin saturation <94%) was observed in 136 patients (25%). As compared to those without hypoxaemia (n = 403), patients with hypoxaemia were older and more obese. Patients with HFpEF and hypoxaemia had higher cardiac filling pressures, higher pulmonary vascular pressures, greater alveolar-arterial oxygen difference, increased dead space fraction, and greater physiologic shunt compared to those without hypoxaemia. These differences were replicated in a sensitivity analysis where patients with spirometric abnormalities were excluded. Regression analyses revealed that increases in pulmonary arterial and pulmonary capillary pressures were related to lower arterial oxygen tension (PaO 2 ), especially during exercise. Body mass index (BMI) was not correlated with the arterial PaO 2 , and hypoxaemia was associated with increased risk for death over 2.8 (interquartile range 0.7-5.5) years of follow-up, even after adjusting for age, sex, and BMI (hazard ratio 2.00, 95% confidence interval 1.01-3.96; p = 0.046)., Conclusion: Between 10% and 25% of patients with HFpEF display arterial desaturation during exercise that is not ascribable to lung disease. Exertional hypoxaemia is associated with more severe haemodynamic abnormalities and increased mortality. Further study is required to better understand the mechanisms and treatment of gas exchange abnormalities in HFpEF., (© 2023 European Society of Cardiology.)

Written instructions improve patient comprehension of discharge instructions but are often provided only in English even for patients with a non-English language preference (NELP). We implemented standardized written discharge instructions in English, Spanish, and Chinese for hospital medicine patients at an urban academic medical center. Using an interrupted time series analysis, we assessed the impact on medication-related postdischarge questions for patients with English, Spanish, or Chinese language preferences. Of 4013 patients, ∼15% had NELP. Preintervention, Chinese-preferring patients had a 5.6 percentage point higher probability of questions (adjusted odds ratio [aOR] = 1.55, 95% confidence interval [CI]: 1.08, 2.21) compared to English-preferring patients; Spanish-preferring and English-preferring patients had similar rates of questions. Postintervention, English-preferring and Spanish-preferring patients had no significant change; Chinese-preferring patients had a significant 10.9 percentage point decrease in the probability of questions (aOR = 0.38, 95% CI: 0.21, 0.69) thereby closing the disparity. Language-concordant written discharge instructions may reduce disparities in medication-related postdischarge questions for patients with NELP., (© 2023 The Authors. Journal of Hospital Medicine published by Wiley Periodicals LLC on behalf of Society of Hospital Medicine.)

Background: Catastrophic disruptions in care delivery threaten the operational efficiency and potentially the validity of clinical research efforts, in particular randomized clinical trials. Most recently, the COVID-19 pandemic affected essentially all aspects of care delivery and clinical research conduct. While consensus statements and clinical guidance documents have detailed potential mitigation measures, few real-world experiences detailing clinical trial adaptations to the COVID-19 pandemic exist, particularly among, large, global registrational cardiovascular trials., Methods: We outline the operational impact of COVID-19 and resultant mitigation measures in the Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial, one of the largest and most globally diverse experiences with COVID-19 of any cardiovascular clinical trial to date. Specifically, we address the needed coordination between academic investigators, trial leadership, clinical sites, and the supporting sponsor to ensure the safety of participants and trial staff, to maintain the fidelity of trial operations, and to prospectively adapt statistical analyses plans to evaluate the impact of COVID-19 and the pandemic at large on trial participants. These discussions included key operational issues such as ensuring delivery of study medications, adaptations to study visits, enhanced COVID-19 related endpoint adjudication, and protocol and analytical plan revisions., Conclusion: Our findings may have important implications for establishing consensus on prospective contingency planning in future clinical trials., Clinicaltrial: gov: NCT03619213., Clinicaltrial: GOV: NCT03619213., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Artificial intelligence (AI) promises to revolutionize many fields, but its clinical implementation in cardiovascular imaging is still rare despite increasing research. We sought to facilitate discussion across several fields and across the lifecycle of research, development, validation, and implementation to identify challenges and opportunities to further translation of AI in cardiovascular imaging. Furthermore, it seemed apparent that a multidisciplinary effort across institutions would be essential to overcome these challenges. This paper summarizes the proceedings of the National Heart, Lung, and Blood Institute-led workshop, creating consensus around needs and opportunities for institutions at several levels to support and advance research in this field and support future translation., Competing Interests: Funding Support and Author Disclosures The content of this manuscript is solely the responsibility of the authors and does not necessarily reflect the official views of the National Heart, Lung, and Blood Institute, National Institutes of Health, or the United States Department of Health and Human Services. The National Heart, Lung, and Blood Institute (NHLBI) Workshop on Artificial Intelligence in Cardiovascular Imaging: Translating Science to Patient Care, held on June 27 and 28, 2022, was supported by the Division of Cardiovascular Sciences, NHLBI. Dr Antani has been supported by the Intramural Research Program of the National Library of Medicine and National Institutes of Health (NIH). Dr Arnaout has been supported by the NIH, the Department of Defense, and the Gordon and Betty Moore Foundation. Dr Dey has received software royalties from Cedars Sinai; and funding support from NIH/NHLBI grants (1R01HL148787-01A1 and 1R01HL151266). Dr Leiner has served on the Advisory Board for Cart-Tech B.V. and AI4Med; has been a clinical advisor for Quantib B.V.; has been a consultant for Guerbet; and has received funding support from the Netherlands Heart Foundation. Dr Sengupta has served on the Advisory Boards of Echo IQ and RCE Technologies; and has received funding support from NSF Award: 2125872 and NRT-HDR: Bridges in Digital Health. Dr Shah has received consulting fees from AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol Myers Squib, Cytokinetics, Edwards Lifesciences, Eidos, Gordian, Intellia, Ionis, Merck, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics; and has received funding support from the NIH (U54 HL160273, R01 HL140731, R01 HL149423), Corvia, and Pfizer. Dr Slomka has received software royalties from Cedars Sinai; and has received funding support from the NIH/NHLBI grant 1R35HL161195-01. Dr Williams has been a speaker at lectures sponsored by Canon Medical Systems and the Siemens Healthineers; and has received funding support from the British Heart Foundation (FS/ICRF/20/26002). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Recent guidelines proposed a classification for heart failure (HF) on the basis of left ventricular ejection fraction (LVEF), although it remains unclear whether the divisions chosen were biologically rational. Using patients spanning the full range of LVEF, we examined whether there was evidence of LVEF thresholds in patient characteristics or inflection points in clinical outcomes., Methods: Using patient-level information, we created a merged dataset of 33 699 participants who had been enrolled in 6 randomized controlled HF trials including patients with reduced and preserved ejection fraction. The relationship between the incidence of all-cause death (and specific causes of death) and HF hospitalization, and LVEF, was evaluated using Poisson regression models., Results: As LVEF increased, age, the proportion of women, body mass index, systolic blood pressure, and prevalence of atrial fibrillation and diabetes increased, whereas ischemic pathogenesis, estimated glomerular filtration rate, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) decreased. As LVEF increased >50%, age and the proportion of women continued to increase, and ischemic pathogenesis and NT-proBNP decreased, but other characteristics did not change meaningfully. The incidence of most clinical outcomes (except noncardiovascular death) decreased as LVEF increased, with a LVEF inflection point of around 50% for all-cause death and cardiovascular death, around 40% for pump failure death, and around 35% for HF hospitalization. Higher than those thresholds, there was little further decline in the incidence rate. There was no evidence of a J-shaped relationship between LVEF and death; no evidence of worse outcomes in patients with high-normal ("supranormal") LVEF. Similarly, in a subset of patients with echocardiographic data, there were no structural differences in patients with a high-normal LVEF suggestive of amyloidosis, and NT-proBNP levels were consistent with this conclusion., Conclusions: In patients with HF, there was a LVEF threshold of around 40% to 50% where the pattern of patient characteristics changed, and event rates began to increase compared with higher LVEF values. Our findings provide evidence to support current upper LVEF thresholds defining HF with mildly reduced ejection fraction on the basis of prognosis., Registration: URL: https://www., Clinicaltrials: gov; Unique identifiers: NCT00634309, NCT00634400, NCT00634712, NCT00095238, NCT01035255, NCT00094302, NCT00853658, and NCT01920711., Competing Interests: Disclosures T.K. received speaker fees from Abbott, Ono Pharma, Otsuka Pharma, Novartis, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, and Abiomed. I.S.A. reports receiving fees for serving on a steering committee from AstraZeneca, ARCA Biopharma, Amgen, and LivaNova; fees for serving as chair of a data and safety monitoring board from Boston Scientific; fees for serving on an end point committee from Boehringer Ingelheim; and fees for serving on an advisory board from Zensun. A.S.D. has received grants and personal fees from AstraZeneca during the conduct of the study; personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Corvidia, DalCor Pharma, Relypsa, Regeneron, and Merck; grants and personal fees from Alnylam and Novartis; and personal fees from Amgen, outside the submitted work. M.P. reports consulting fees from AbbVie, Akcea, Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. M.R.Z. reports research funding from Novartis and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and Myokardia V Wave. M.A.P. reports research grant support through Brigham and Women’s Hospital from Novartis; reports consulting fees from AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Corvidia, DalCor, GlaxoSmithKline, National Heart, Lung, and Blood Institute CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge, and Sanofi; and has equity in DalCor. S.D.S. has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, 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 consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellPro-Thera, Moderna, American Regent, and Sarepta. W.T.A. has received personal fees from Abbott; has received consulting fees from Boehringer Ingelheim, CVRx, Edwards Lifesciences, Impulse Dynamics, and Respicardia; has received salary support from V-Wave Medical; and has received research support from the National Heart, Lung, and Blood Institute, all for studies performed within the heart failure arena. S.J.S. has received either personal or institutional research support from AstraZeneca. C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Novo Nordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.AI; and serves as cofounder and nonexecutive director of Us2.AI. P.S.J. reports speakers’ fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals, and Intas Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and research funding from AstraZeneca, Boehringer Ingelheim, and Analog Devices Inc. P.S.J.’s employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk. P.S.J. is a director of Global Clinical Trial Partners Ltd. J.J.V.M. reports payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, and Novartis; and personal consultancy fees from Alnylam Pharma., Bayer, BMS, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation. J.J.V.M. receives personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma Ltd, Eris Lifesciences, European Academy of Continued Medical Education, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, JB Chemicals & Pharma Ltd, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, and Translational Medicine Academy. He is a director of Global Clinical Trial Partners Ltd. The other author reports no conflicts.

Background: Heart failure and left ventricular ejection fraction in the normal range (HFnEF) (left ventricular ejection fraction [LVEF] of ≥55% for men and ≥60% for women) is understudied., Objectives: The authors aimed to characterize patients with HFnEF compared with those with preserved (≥50%) yet below the normal LVEF., Methods: In an Asian HF registry, clinical characteristics, echocardiographic features, and outcomes were compared across: 1) HFnEF; 2) heart failure with preserved left ventricular ejection fraction (HFpEF) (LVEF of ≥50%) and below normal LVEF; and 3) community-based controls without HF. Cluster analysis of echocardiographic parameters was performed and validated in an external cohort., Results: Among 1,765 patients with HFpEF (age 68 ± 12 years; 50% women), 1,313 (74.4%) had HFnEF. Compared with patients with HFpEF and below normal LVEF, patients with HFnEF had less coronary artery disease (33.7% vs 27.9%), greater LV wall thickness, and higher stroke volume, but similar 2-year age-adjusted all-cause mortality (HR: 0.8; 95% CI: 0.6-1.2). Five echocardiographic clusters with similar 2-year mortality were identified: 1) normal LV (normal structure despite increased filling pressure; least comorbidities) in 25%; 2) restrictive (smallest stroke volume; predominantly elderly women) in 26%; 3) hypertrophic (most concentric hypertrophy; more men) in 25%; 4) high output (greatest stroke volume; predominantly obese younger men) in 10%; and 5) atrial dominant (most left atrial myopathy; mainly elderly women with multiple comorbidities) in 10%. Similar patterns were found in the validation cohort., Conclusions: The majority of patients with HFpEF had normal LVEF, which consists of patients with different patterns of cardiac features and clinical characteristics. Results may carry implications for targeted treatment approaches in HFpEF., Competing Interests: The ASIAN-HF is supported by research grants from Boston Scientific Investigator Sponsored Research Program, National Medical Research Council of Singapore (R-172-003-219-511), The ATTRaCT program (SPF2014/003, SPF2014/004, SPF2014/005), and Bayer. The PROMIS-HFpEF study was sponsored by AstraZeneca. 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, owns patent US-10702247-B2 unrelated to the present work. Dr Chandramouli has received grants from National Medical Research Council Singapore; philanthropic research grants from Lee Foundation Singapore; and consulting or speaker fees from Boehringer Ingelheim, Us2.ai, and Sanofi. Dr Anand has received consulting fees from Amgen, ARCA Pharma, AstraZeneca, Boehringer Ingelheim, Boston Scientific, LivaNova, and Novartis. Dr Lund is supported by Karolinska Institutet, the Swedish Research Council [grant 523-2014-2336], the Swedish Heart Lung Foundation [grants 20150557, 20190310], and the Stockholm County Council [grants 20170112, 20190525]; reports consultancy with AstraZeneca, Novartis, Bayer, Vifor Pharma, Sanofi, Lexicon, Myokardia, Pharmacosmos, Merck/MSD, Respicardia, Medscape; lecture fees from AstraZeneca, Novartis, Vifor Pharma, Bayer, Orion Pharma, Abbott, Medscape, Radcliffe Cardiology, research grants from AstraZeneca, Novartis, Boehringer Ingelheim, Boston Scientific, Vifor Pharma, Pharmacosmos, and stock ownership in AnaCardio. Dr Richards has received research support from Boston Scientific, Bayer, AstraZeneca, Medtronic, Roche Diagnostics, Abbott Laboratories, Thermo Fisher, and Critical Diagnostics; and has consulted for Bayer, Novartis, Merck, AstraZeneca, and Roche Diagnostics. Dr Shah has received grants from the U.S. National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/ Executive Committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc., Us2.ai, Janssen Research & Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd., Roche Diagnostics, Sanofi, and WebMD Global LLC; and serves as co-founder & non-executive director of Us2.ai. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Aims: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection fraction. In this study, the safety and efficacy of dapagliflozin according to background diuretic therapy and the influence of dapagliflozin on longitudinal diuretic use were evaluated., Methods and Results: In this pre-specified analysis of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, the effects of dapagliflozin vs. placebo were assessed in the following subgroups: no diuretic, non-loop diuretic, and loop diuretic furosemide equivalent doses of <40, 40, and >40 mg, respectively. Of the 6263 randomized patients, 683 (10.9%) were on no diuretic, 769 (12.3%) were on a non-loop diuretic, and 4811 (76.8%) were on a loop diuretic at baseline. Treatment benefits of dapagliflozin on the primary composite outcome were consistent by diuretic use categories (Pinteraction = 0.64) or loop diuretic dose (Pinteraction = 0.57). Serious adverse events were similar between dapagliflozin and placebo arms, irrespective of diuretic use or dosing. Dapagliflozin reduced new initiation of loop diuretics by 32% [hazard ratio (HR) 0.68; 95% confidence interval (CI): 0.55-0.84, P < 0.001] but did not influence discontinuations/disruptions (HR 0.98; 95% CI: 0.86-1.13, P = 0.83) in follow-up. First sustained loop diuretic dose increases were less frequent, and sustained dose decreases were more frequent in patients treated with dapagliflozin: net difference of -6.5% (95% CI: -9.4 to -3.6; P < 0.001). The mean dose of loop diuretic increased over time in the placebo arm, a longitudinal increase that was significantly attenuated with treatment with dapagliflozin (placebo-corrected treatment effect of -2.5 mg/year; 95% CI: -1.5, -3.7, P < 0.001)., Conclusion: In patients with heart failure with mildly reduced or preserved ejection fraction, the clinical benefits of dapagliflozin relative to placebo were consistent across a wide range of diuretic categories and doses with a similar safety profile. Treatment with dapagliflozin significantly reduced new loop diuretic requirement over time., Competing Interests: Conflict of interest: S.C is supported by the Canadian Arthur J.E. Child’s Cardiology Fellowship. M.V. has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. B.C. has been a consultant for Amgen, AO Biome, Biogen, Boehringer Ingelheim, Corvia, Gilead, Myokardia, Cardurion, and Novartis. O.V. has received either personal or institutional research support for DELIVER from AstraZeneca. A.S.D. has received research grant support from AstraZeneca, Alnylam, and Novartis; and has received consulting fees and/or honoraria from Abbott, AstraZeneca, Alnylam, Boehringer-Ingelheim, Boston Scientific, Biofourmis, Corvidia, DalCor Pharma, Novartis, Relypsa, and Regeneron. P.S.J. has received consulting fees, advisory board fees, and lecture fees from Novartis, advisory board fees from Cytokinetics, and grant support from Boehringer Ingelheim. R.A.D.’s institution, the UMCG, has received research grants and fees (outside the submitted work) from AstraZeneca, Abbott, Boehringer Ingelheim, Cardio Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche. R.A.d.B. has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche (outside the submitted work). C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as a consultant or on the advisory board/steering committee/executive committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research & Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, and WebMD Global LLC; and serves as the cofounder and non-executive director of Us2.ai. M.N.K. has received research grant support from AstraZeneca, and Boehringer Ingelheim; has served as a consultant or on an advisory board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca; and has received honorarium from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. S.J.S. has received either personal or institutional research support for DELIVER from AstraZeneca. F.M. has received personal fees from AstraZeneca. S.E.I. has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Merck, Pfizer and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. A.F.H. has received research grant support from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somo-logic, and Verily and has served as a consultant or on the Advisory Board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Eidos, Intercept, Merck, and Novartis. T.H. reports no disclosures. S.S.M. served on the advisory boards of BridgeBio and Alnylam Pharmaceuticals and also receives speaking fees from Alnylam Pharmaceuticals. Z.M.M. reports no disclosures. M.P. is an employee and shareholder of AstraZeneca. A.M.L. is an employee and shareholder of AstraZeneca. J.J.V.M. has received grants and his employer paid by AstraZeneca, Theracos, and GlaxoSmithKline during the conduct of the study and grants and his employer being paid by Novartis, Amgen, Bristol-Myers Squibb, Bayer, Abb-vie, Dal-Cor, Kidney Research UK, and Cardurion and grants from British Heart Foundation. S.D.S. has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, 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 Puretech Health. The remaining authors have nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Limited data exist to characterize novel measures of right ventricular (RV) function and the coupling to pulmonary circulation in patients with heart failure and preserved left ventricular ejection fraction (HFpEF)., Objectives: This study sought to assess the clinical implications of RV function, the association with N-terminal pro-B-type natriuretic peptide, and the risk for adverse events among patients with HFpEF., Methods: This study analyzed measures of RV function by assessing absolute RV free wall longitudinal strain (RVFWLS) and its ratio to estimated pulmonary artery systolic pressure (PASP) (RVFWLS/PASP ratio) in 528 patients (mean age 74 ± 8 years, 56% female) with adequate echocardiographic images quality enrolled in the PARAGON-HF trial. Associations with baseline N-terminal pro-B-type natriuretic peptide and with total HF hospitalizations and cardiovascular death were assessed, after accounting for confounders., Results: Overall, 311 patients (58%) had evidence of RV dysfunction, defined as absolute RVFWLS <20%, and among the 388 patients (73%) with normal tricuspid annular planar systolic excursion and RV fractional area change, more than one-half showed impaired RV function. Lower values of RVFWLS and RVFWLS/PASP ratios were significantly associated with higher circulating N-terminal pro-B-type natriuretic peptide. With a median follow-up of 2.8 years, there were 277 total HF hospitalizations and cardiovascular deaths. Both absolute RVFWLS (HR: 1.39; 95% CI: 1.05-1.83; P = 0.018) and RVFWLS/PASP ratio (HR: 1.43; 95% CI: 1.13-1.80; P = 0.002) were significantly associated with the composite outcome. Treatment effect of sacubitril/valsartan was not modified by measures of RV function., Conclusions: Worsening RV function and its ratio to pulmonary pressure is common and significantly associated with an increased risk of HF hospitalizations and cardiovascular death in patients with HFpEF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)., Competing Interests: Funding Support and Author Disclosures The PARAGON-HF trial was funded by Novartis. Dr Abanda received institutional support from National Institutes of Health (5HL9804812) through the Harvard T.H. Chan School of Public Health. Dr A. Shah has received research support from Novartis, through Brigham and Women’s Hospital; and has received consulting fees from Philips Ultrasound and Bellerophon Therapeutics. Dr Cikes has received grants, personal fees, and nonfinancial support (travel support) from Novartis, GE Healthcare, Abbott, Roche Diagnostics, Bayer, Pfizer, Boehringer Ingelheim, Berlin-Chemie Menarini, Servier, Corvia, AstraZeneca, Sanofi Genzyme, Sandoz, Amgen, Orion Pharma, and Teva Pharmaceutical Industries. Dr Vaduganathan has received research grants from American Regent, Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Chiesi, Cytokinetics, Novo Nordisk, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and participates in clinical trial committees for studies sponsored by AstraZeneca, Occlutech, Impulse Dynamics, Galmed, Bayer AG, and Novartis. Dr S. Shah has received research grants from the National Institutes of Health (R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, and Novartis; and has served as a consultant or an Advisory Board member for Abbott, Actelion, AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Cardiora, Coridea, CVRx, Eisai, Ionis, Ironwood, Merck, MyoKardia, Novartis, Pfizer, Sanofi, Shifamed, Tenax, and United Therapeutics. Dr Zile has received grants and personal fees from Novartis, CVRx, and Medtronic; and has received personal fees from Abbott, Boston Scientific, EBR, Endotronics, Ironwood, Merck, Myokardia, and V Wave. Dr Lam has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; has served as consultant or on Advisory Boards, Steering Committees, or Executive Committees for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research and Development, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth Bio-Therapeutics, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, WebMD Global, Radcliffe Group, and Corpus; and is a cofounder of eKo.ai. Dr Pfeffer has received research grant support through Brigham and Women’s Hospital from Novartis; and has received consulting fees from Alnylam, AstraZeneca, Boehringer Ingelheim, Eli Lilly Alliance, Corvidia, DalCor, GlaxoSmithKline, National Heart, Lung, and Blood Institute CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge, and Sanofi; and has equity in DalCor. Dr McMurray has received payment paid to his employer, Glasgow University, from Novartis for his role as co–principal investigator of PARAGON-HF; has received grants paid to his employer from AstraZeneca, Theracos, and GlaxoSmithKline during the conduct of the study; and has received grants paid to his employer from Novartis, Amgen, Bristol Myers Squibb, Bayer, Abb-vie, Dal-Cor, Kidney Research UK, and Cardurion; and has received grants from the British Heart Foundation. Dr Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has consulted for Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The majority of patients with heart failure with preserved ejection fraction (HFpEF) have the obesity phenotype, but no therapies specifically targeting obesity in HFpEF exist., Objectives: The aim of this study was to describe the design and baseline characteristics of 2 trials of semaglutide, a glucagon-like peptide-1 receptor agonist, in patients with the obesity HFpEF phenotype: STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF; NCT04788511) and STEP-HFpEF DM (Semaglutide Treatment Effect in People with obesity and HFpEF and type 2 diabetes; NCT04916470)., Methods: Both STEP-HFpEF and STEP-HFpEF DM are international multicenter, double-blind, placebo-controlled trials that randomized adults with HFpEF and a body mass index ≥30 kg/m 2 to once-weekly semaglutide at a dose of 2.4 mg or placebo. Participants were eligible if they had a left ventricular ejection fraction (LVEF) ≥45%; NYHA functional class II to IV; a Kansas City Cardiomyopathy Questionnaire (KCCQ)-Clinical Summary Score (CSS) <90 points; and ≥1 of the following: elevated filling pressures, elevated natriuretic peptides plus structural echocardiographic abnormalities, recent heart failure hospitalization plus ongoing diuretic use, and/or structural abnormalities. The dual primary endpoints are the 52-week change in the KCCQ-CSS and body weight., Results: In STEP-HFpEF and STEP-HFpEF DM (N = 529 and N = 617, respectively), nearly half were women, and most had severe obesity (median body mass index of 37 kg/m 2 ) with typical features of HFpEF (median LVEF of 57%, frequent comorbidities, and elevated natriuretic peptides). Most participants received diuretic agents and renin-angiotensin blockers at baseline, and approximately one-third were on mineralocorticoid receptor antagonists. Sodium-glucose cotransporter-2 inhibitor use was rare in STEP-HFpEF but not in STEP HFpEF DM (32%). Patients in both trials had marked symptomatic and functional impairments (KCCQ-CSS ∼59 points, 6-minute walking distance ∼300 m)., Conclusions: In total, STEP-HFpEF program randomized 1,146 participants with the obesity phenotype of HFpEF and will determine whether semaglutide improves symptoms, physical limitations, and exercise function in addition to weight loss in this vulnerable group., Competing Interests: Funding Support and Author Disclosures The STEP-HFpEF and STEP-HFpEF DM trials were funded by Novo Nordisk. Dr Kosiborod served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research grants from AstraZeneca and Boehringer Ingelheim; holds stocks in Artera Health and Saghmos Therapeutics; has received honorarium from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received other research support from AstraZeneca. Dr Abildstrøm is employed by Novo Nordisk; and has shares in Novo Nordisk. Dr Borlaug has received research support from the National Institutes of Health and the United States Department of Defense; has received research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is named inventor (U.S. patent number 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Butler is a consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Sequana, SQ Innovation, 3live, and Vifor. Dr Christensen is employed by Novo Nordisk; and has shares in Novo Nordisk. Dr Davies has acted as a consultant, advisory board member, and speaker for Boehringer Ingelheim, Lilly, Novo Nordisk, and Sanofi; is an advisory board member and speaker for AstraZeneca; is an advisory board member for Pfizer, Medtronic, and ShouTi Pharma Inc; is a speaker for Novartis, Sanofi, and Amgen; and has received grants in support of investigator and investigator-initiated trials from AstraZeneca, Sanofi-Aventis, Eli Lilly, Boehringer Ingelheim, Janssen, and Novo Nordisk. Dr Hovingh is employed by Novo Nordisk and The Amsterdam University Medical Center; and has shares in Novo Nordisk. Dr Kitzman has served as a paid consultant for Novo Nordisk; and his institution has received grant awards from Novo Nordisk. Dr Lindegaard is employed by Novo Nordisk; and has shares in Novo Nordisk. Dr Møller is employed by Novo Nordisk; and has shares in Novo Nordisk. Dr Shah has been supported by research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423); and reports receiving consulting fees from Abbott, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, Metabolic Flux, MyoKardia, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Treppendahl is employed by Novo Nordisk; and has shares in Novo Nordisk. Dr Verma has received speaking honoraria and/or consulting fees from Abbott, AstraZeneca, Bayer, Boehringer-Ingelheim, Novo Nordisk, Novartis, Merck, PhaseBio, HLS Therapeutics, Amarin, Eli Lilly, Janssen, Pfizer, TIMI, and Canadian Medical and Surgical Knowledge Translation Research Group. Dr Petrie has received research grants or consultancy fees from SQ Innovations, AstraZeneca, Roche, Boehringer Ingelheim, Pharmacosmos, Eli Lilly, Napp Pharmaceuticals, Novartis, and Novo Nordisk; has served on committees for AbbVie, Akero, Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Resverlogix, Teikoku, New Amsterdam, and Novo Nordisk; and is director of Global Clinical Trial Partners., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Dapagliflozin resulted in significant and sustained reductions in first and recurrent heart failure (HF) hospitalizations among patients with HF across the spectrum of ejection fraction. How treatment with dapagliflozin differentially impacts hospitalization for HF of varying complexity is not well studied., Methods and Results: In the DELIVER and DAPA-HF trials, we examined the effects of dapagliflozin on adjudicated HF hospitalizations of varying complexity and hospital length of stay (LOS). HF hospitalizations requiring intensive care unit stay, intravenous vasoactive therapies, invasive/non-invasive ventilation, mechanical fluid removal or mechanical circulatory support were categorized as complicated. The balance was classified as uncomplicated. Of the total 1209 HF hospitalizations reported in DELIVER, 854 (71%) were uncomplicated and 355 (29%) were complicated. Of the total 799 HF hospitalizations reported in DAPA-HF, 453 (57%) were uncomplicated and 346 (43%) were complicated. Relative to patients experiencing a first uncomplicated HF hospitalization, those with complicated HF hospitalizations had a significantly higher in-hospital mortality both in DELIVER (16.7% vs. 2.3%, p < 0.001) and DAPA-HF (15.1% vs. 3.8%, p < 0.001). Dapagliflozin similarly reduced total 'uncomplicated' (DELIVER: rate ratio [RR] 0.67, 95% confidence interval [CI] 0.55-0.82 and DAPA-HF: RR 0.69, 95% CI 0.54-0.87) and 'complicated' HF hospitalizations (DELIVER: RR 0.82, 95% CI 0.63-1.06 and DAPA-HF: RR 0.75, 95% CI 0.58-0.97). Dapagliflozin consistently reduced hospitalizations irrespective of their LOS: <5 days (DELIVER: RR 0.76, 95% CI 0.58-0.99 and DAPA-HF: RR 0.58, 95% CI 0.42-0.80) or ≥5 days (DELIVER: RR 0.71, 95% CI 0.58-0.86 and DAPA-HF: RR 0.77, 95% CI 0.62-0.94)., Conclusion: A substantial proportion of hospitalizations (∼30-40%) among patients with HF irrespective of ejection fraction required intensification of treatment beyond standard intravenous diuretics. Such patients experienced significantly higher in-hospital mortality. Treatment with dapagliflozin consistently reduced HF hospitalizations regardless of severity of inpatient course or LOS., Clinical Trial Registration: ClinicalTrials.gov, DELIVER (NCT03619213) and DAPA-HF (NCT03036124)., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Many patients with heart failure and preserved ejection fraction have no overt volume overload and normal resting left atrial (LA) pressure., Objectives: This study sought to characterize patients with normal resting LA pressure (pulmonary capillary wedge pressure [PCWP] <15 mm Hg) but exercise-induced left atrial hypertension (EILAH)., Methods: The REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc. IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) trial randomized 626 patients with ejection fraction ≥40% and exercise PCWP ≥25 mm Hg to atrial shunt or sham procedure. The primary trial outcome, a hierarchical composite of death, heart failure hospitalization, intensification of diuretics, and change in health status was compared between patients with EILAH and those with heart failure and resting left atrial hypertension (RELAH)., Results: Patients with EILAH (29%) had similar symptom severity, but lower natriuretic peptide levels, higher 6-minute walk distance, less atrial fibrillation, lower left ventricular mass, smaller LA volumes, lower E/e', and better LA strain. PCWP was lower at rest, but had a larger increase with exercise in EILAH. Neither group as a whole had a significant effect from shunt therapy vs sham. Patients with EILAH were more likely to have characteristics associated with atrial shunt responsiveness (peak exercise pulmonary vascular resistance <1.74 WU) and no pacemaker (63% vs 46%; P < 0.001). The win ratio for the primary outcome was 1.56 (P = 0.08) in patients with EILAH and 1.51 (P = 0.04) in those with RELAH when responder characteristics were present., Conclusions: Patients with EILAH had similar symptom severity but less advanced myocardial and pulmonary vascular disease. This important subgroup may be difficult to diagnose without invasive exercise hemodynamics, but it has characteristics associated with favorable response to atrial shunt therapy. (A Study to Evaluate the Corvia Medical, Inc. IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure [REDUCE LAP-HF TRIAL II]; NCT03088033)., Competing Interests: Funding Support and Author Disclosures This study was sponsored by Corvia Medical Inc. Dr Litwin has received research funding from the department of Veterans Affairs, Corvia, AstraZeneca, V-Wave, Axon Therapeutics, and Eli Lilly all paid to the institution; has received consulting fees from CVRx, Axon Therapeutics, Occlutech, Eli Lilly, and Rivus Pharmaceuticals; and has received travel grants, speaker fees, and advisory board honoraria from NovoNordisk and Roche. Dr Komtebedde is employed by Corvia. Dr Burkhoff has consulted for Corvia. Dr Hasenfuß has consulted for AstraZeneca, Boehringer Ingelheim, Corvia, Impulse Dynamics, Novartis, Servier, Vifor; has received honoraria for lectures from AstraZeneca, Bayer, Impulse Dynamics, Novartis, Pfizer, Servier, and Vifor; and is a co-principal investigator to Impulse Dynamics. Dr Borlaug has received research grants from Corvia, AstraZeneca, Medtronic, GlaxoSmithKline, Mesoblast, Novartis, and Tenax Therapeutics; and has received consulting fees from Actelion, Amgen, Aria, Axon Therapies, Boehringer Ingelheim, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, and VADovations. Dr Solomon has received research grants from Alnylam, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Cytokinetics, Eidos, GlaxoSmithKline, Ionis, Lilly, MyoKardia, the National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, 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, and Akros. Dr Mohan has received research support from Corvia and V-Wave paid to the institution. Dr Kahwash has served as a consultant for Medtronic, Impulse Dynamics, and Cardionomic. Dr Sverdlov has received research grants from the National Heart Foundation of Australia (Future Leader Fellowships 101918 and 106025), Department of Health and Aged Care (Australia): Medical Research Future Fund (MRF2017053), New South Wales Health (Australia), Novartis Australia, Biotronik, RACE Oncology, Bristol Myers Squibb, Roche Diagnostics, and Vifor Pharma; and has received personal fees from Novartis, Bayer, Bristol Myers Squibb, AstraZeneca, Corvia, and Boehringer Ingelheim. Dr Fail has received research support paid to the institution from Corvia and Alleviant. Dr Chung has served as a consultant to Intershunt. Dr Kaye has received research support from Corvia. Dr Hummel has received research grant funding from National Institutes of Health, Veterans Affairs, American Heart Association, Novartis, Pfizer, AstraZeneca, Corvia, and Axon Therapies. Dr Zirlik has received personal consulting fees and honoraria for lectures from Abbott, Abiomed, AstraZeneca, Amarin, Amgen, Bayer Healthcare, Biotronik, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimensions, Cardiorentis, Corvia, Daichi Sankyo, Edwards Lifesciences, Eli Lilly, Janssen, Merck, Neucomed, Novo Nordisk, Novartis, Rigel, and Stealth Peptides. Dr Hayward has received research support from Corvia, Medtronic, Abbott, Roche, and Procyrion. Dr Lewis has received research funding from the National Institutes of Health (R01-HL 151841, R01-HL131029, R01-HL159514), American Heart Association (15GPSGC-24800006), Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, and SoniVie; has received honoraria for advisory boards outside of the current study from Pfizer, Merck, Boehringer Ingelheim, NXT, American Regent, Cyclerion, Cytokinetics, and Amgen; and has received royalties from UpToDate for scientific content authorship related to exercise physiology. Dr Gupta has received research support from the National Institutes of Health, Imara, Corvia, and Astellas Pharma. Dr Cikes has received institutional research grants from Abbott, Novartis, and Pfizer; has received travel grants, speaker fees, and advisory board honoraria from Abbott, Abiomed, Amicus, AstraZeneca, Bayer, Boehringer Ingelheim, GE Healthcare, Krka Pharma, LivaNova, Medtronic, Novartis, Orion Corporation, Pfizer, Sanofi, Swixx BioPharma, and Teva Pharmaceutical Industries, all outside of the present study; and has received research support from Corvia. Dr Gustafsson has received honoraria outside the present study as a consultant for Abbott, Pfizer, Ionis Pharmaceuticals, Bayer, AstraZeneca, and Alnylam; has received speaker fees from Novartis and Orion Pharma; and has received research support from Corvia. Dr Silvestry has received research support from Corvia. Dr Rowin has received research support from Corvia; and has served as a consultant for Cardiovascular Clinical Sciences. Dr Cutlip has received research support from Corvia paid to the institution. Dr Kitzman has received honoraria outside the present study as a consultant for Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Rivus, Keyto, and Novartis; has received grant funding outside the present study from Novartis, Bayer, Novo Nordisk, and AstraZeneca; owns stock in Gilead Sciences; and has received research support from Corvia. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received personal fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, Intellia Therapeutics, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Shifamed, Tenax, Tenaya, and United Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Intercellular adhesion molecule-1 (ICAM-1) is a cell surface protein that participates in endothelial activation and is hypothesized to play a central role in heart failure (HF). We evaluated associations of ICAM1 missense genetic variants with circulating ICAM-1 levels and with incident HF., Methods and Results: We identified 3 missense variants within ICAM1 (rs5491, rs5498 and rs1799969) and evaluated their associations with ICAM-1 levels in the Coronary Artery Risk Development in Young Adults Study and the Multi-Ethnic Study of Atherosclerosis (MESA). We determined the association among these 3 variants and incident HF in MESA. We separately evaluated significant associations in the Atherosclerosis Risk in Communities (ARIC) study. Of the 3 missense variants, rs5491 was common in Black participants (minor allele frequency [MAF] > 20%) and rare in other race/ethnic groups (MAF < 5%). In Black participants, the presence of rs5491 was associated with higher levels of circulating ICAM-1 at 2 timepoints separated by 8 years. Among Black participants in MESA (n = 1600), the presence of rs5491 was associated with an increased risk of incident HF with preserved ejection fraction (HFpEF; HR = 2.30; [95% CI 1.25-4.21; P = 0.007]). The other ICAM1 missense variants (rs5498 and rs1799969) were associated with ICAM-1 levels, but there were no associations with HF. In ARIC, rs5491 was significantly associated with incident HF (HR = 1.24 [95% CI 1.02 - 1.51]; P = 0.03), with a similar direction of effect for HFpEF that was not statistically significant., Conclusions: A common ICAM1 missense variant among Black individuals may be associated with increased risk of HF, which may be HFpEF-specific., (Copyright © 2023 Elsevier Inc. All rights reserved.)