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Background: Metabolic dysfunction associated steatotic liver disease (MASLD) has been linked to heart failure with preserved ejection fraction (HFpEF). We sought to understand association between individuals with amounts of liver adiposity greater than would be predicted by their body mass index (BMI) in order to understand whether this disproportionate liver fat (DLF) represents a proxy of metabolic risk shared between liver and heart disease., Methods: We studied 2,932 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) who received computed tomography (CT) measurements of hepatic attenuation. Quartiles of DLF were compared and multivariable linear regression was performed to evaluate the association of DLF with clinical, echocardiographic, and quality of life metrics., Results: Compared to the lowest quartile of DLF, individuals in the highest quartile of DLF were more likely to be male (52.0% vs 47.1%, P < .001), less likely to be Black or African American (14.8 % vs 38.1% P < .001), have higher rates of dysglycemia (31.9% vs 16.6%, P < .001) and triglycerides (140 [98.0, 199.0] vs 99.0 [72.0, 144.0] mg/dL, P > .001). These individuals had lower global longitudinal strain (-0.13 [-0.25, -0.02], P = .02), stroke volumes (-1.05 [-1.76, -0.33], P < .01), lateral e' velocity (-0.10 [-0.18, -0.02], P = .02), and 6-minute walk distances (-4.25 [-7.62 to -0.88], P = .01)., Conclusion: DLF is associated with abnormal metabolic profiles and ventricular functional changes known to be associated with HFpEF and may serve as an early metric to assess for those that may progress to clinical HFpEF., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Exposure to fine particulate matter (<2.5 um, particulate matter with an aerodynamic diameter <2.5 microns [PM 2.5 ]) has been implicated in atherogenesis. Limited data in animal studies suggest that PM 2.5 exposure leads to myocardial fibrosis and increased incidence of heart failure (HF). Whether PM 2.5 is associated with adverse outcomes in patients with preexisting HF has not been widely studied., Methods and Results: In this retrospective cohort study, Medicare patients hospitalized with first HF between 2013 and 2020 were identified from the Medicare Provider Analysis and Review Part A 100% files. Patients were linked with integrated estimates of ambient PM 2.5 obtained at 1×1 km using the zip code of participants' residence. The study outcomes were all-cause death, HF, and all-cause readmissions burden. A total of 2 599 525 patients were included in this study, with 6 321 731 person-years of follow-up. Mean PM 2.5 was 7.3±1.7 μg/m 3 . Each interquartile range of PM 2.5 was associated with 0.9% increased hazard of all-cause death, 4.5% increased hazard of first HF readmission, 3.1% increased risk of HF hospitalization burden, and 5.2% increase in all-cause readmission burden, after adjusting for 11 sociodemographic and medical factors. Subgroup analyses showed that the effects were more pronounced at levels <7 μg/m 3 and in patients aged <75 years, Asians, and those residing in rural areas., Conclusions: Ambient air pollution is associated with higher risk of adverse events in Medicare beneficiaries with established HF. These associations persist below the National Air Quality Standards (12 μg/m 3 ), supporting that no threshold effect exists for health effects of air pollution exposure.

Background: Increased hsCRP (high-sensitivity C-reactive protein), a marker of inflammation, is associated with incident cardiovascular events. We aim to determine whether the baseline or trajectory of hsCRP levels over time predicts incident heart failure (HF) hospitalization., Methods: JHS (Jackson Heart Study) participants' (n=3920 Black adults) hsCRP levels were measured over 3 visits (from 2000 to 2013). We assessed the association of hsCRP at baseline (visit 1) with incident HF hospitalization using Cox proportional hazards models. Furthermore, we assessed the association of the trajectory of hsCRP over repeated measurements (visits 1-3) with incident HF using joint models. Hazard ratios are reflective of an increase in hsCRP by 1 SD on a log2 scale. We also assessed the association of change in hsCRP between visit 1 and visit 3 with Cox proportional hazards models by grouping patients by low (<2 mg/L) and high (≥2 mg/L) hsCRP levels. The 4 groups were low-to-low (referent), low-to-high, high-to-low, and high-to-high., Results: Mean baseline age of participants was 54±13 years, and 63.8% were women. Over a median follow-up of 12 years, 308 (7.9%) participants were hospitalized with incident HF. Baseline hsCRP was not associated with incident HF (adjusted hazard ratio, 1.08 [95% CI, 0.96-1.22]). However, increasing hsCRP levels over repeated measures were associated with a higher risk of incident HF overall (adjusted hazard ratio, 1.22 [95% CI, 1.03-1.44]) and HF with preserved ejection fraction (adjusted hazard ratio, 1.30 [95% CI, 1.02-1.65]) but not HF with reduced ejection fraction ( P >0.05). Furthermore, changes in hsCRP from low-to-high and high-to-low levels were associated with incident HF ( P <0.05)., Conclusions: While baseline hsCRP was not associated with incident HF, an increasing trajectory of hsCRP over time was associated with increased risk for incident HF (particularly HF with preserved ejection fraction). Temporal change in hsCRP may be an important marker of risk for incident HF with preserved ejection fraction in Black adults., Competing Interests: Dr Mentz received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. Dr Shah reports research support not related to this study from Novartis and Philips Ultrasound and consulting fees from Philips Ultrasound. Dr Virani receives research support from the Department of Veterans Affairs, the National Institutes of Health, and Tahir and Jooma Family. Dr Virani also received an honorarium from the American College of Cardiology in his role as an Associate Editor for Innovations, acc.org. Dr Butler reported personal fees from Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, V-Wave Ltd, and Vifor outside the submitted work. The other authors report no conflicts. The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, the US Department of Health and Human Services, or the Department of Veterans Affairs.

Background and Aims: Peripheral artery disease (PAD) has not only been associated with recurrent hospitalization for acute decompensated heart failure (ADHF) but is also associated with chronic kidney disease (CKD), a known risk factor for worse heart failure outcomes. The interaction of CKD with PAD in post-discharge ADHF outcomes is not well known., Methods: Since 2005, hospitalizations for ADHF were sampled from 4 US regions by the Atherosclerosis Risk in Communities (ARIC) study and classified by physician review. We examined the adjusted association of PAD with 1-year ADHF readmissions, in patients with and without CKD (defined by glomerular filtration rate [GFR] ≤60 mL/min/1.73 m 2 [stage 3a or worse])., Results: From 2005 to 2018, there were 1049 index hospitalizations for patients with ADHF (mean age 77 years, 66 % white) with creatinine data, who were discharged alive. Of these, 155 (15 %) had PAD and 66 % had CKD. In comparison to those without PAD, patients with PAD had more comorbid conditions and higher 1-year ADHF readmission rates, irrespective of CKD status. After adjustment, PAD was associated with a greater risk of 1-year ADHF readmissions, both for patients with concomitant CKD (HR, 1.70; 95 % CI: 1.29-2.24) and those without CKD (HR, 1.97; 95 % CI: 1.14-3.40); p-interaction = 0.8., Conclusion: Among patients hospitalized with ADHF, those with concurrent PAD have more prevalent cardiovascular comorbidities and higher likelihood of 1-year ADHF readmission, irrespective of CKD status. Integrating a more holistic approach in management of patients with concomitant heart failure, PAD and CKD may be an important strategy to improve the prognosis in this vulnerable population., Competing Interests: Declaration of competing interest Dr. Bhatt discloses the following relationships - Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); Consultant: Broadview Ventures, Hims, SFJ, Youngene; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo.Dr. Robert J. Mentz received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Respicardia, Roche, Rocket Pharmaceuticals, Sanofi, Verily, Vifor, Windtree Therapeutics, and Zoll. Dr. Grodin reports consulting fees from Pfizer, Eidos/BridgeBio, Alnylam, Alexion, Intellia, and Astra-Zeneca. Dr. Matsushita received research funding from NHLBI (R01HL146132) and Resolve to Save Lives and personal fee from Fukuda Denshi, Kowa Company, and RhythmX AI outside of the submitted work. Dr. Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, 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. The other authors report no disclosures., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: High-density lipoprotein (HDL) is commonly characterized by its cholesterol concentration (HDL-C) and inverse association with atherosclerotic cardiovascular disease., Objectives: The authors sought to evaluate the association of HDL particle concentration (HDL-P), HDL particle size (HDL-size), HDL-C, and cholesterol content per particle (HDL-C/HDL-P) with risk of overall heart failure (HF) and subtypes., Methods: Participants from the Atherosclerosis Risk In Communities Study, Dallas Heart Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-stage Disease studies without HF history were included. Associations of HDL-P, HDL-size, HDL-C, and HDL-C/HDL-P with risk of overall HF, HF with reduced and preserved ejection fraction were assessed using adjusted Cox models., Results: Among 16,925 participants (53.5% women; 21.8% Black), there were 612 incident HF events (3.6%) (HF with reduced ejection fraction, 309 [50.5%]; HF preserved ejection fraction, 303 [49.5%]) over median follow-up of 11.4 years. In adjusted models, higher HDL-P was significantly associated with lower HF risk (HR of highest vs lowest tertile of HDL-P: 0.76 [95% CI: 0.62-0.93]). Larger HDL-size was significantly associated with higher overall HF risk (HR of largest vs smallest tertile of HDL-size: 1.27 [95% CI: 1.03-1.58]). HF risk associated with HDL-P and HDL-size was similar for HF subtypes. In adjusted analyses, there was no significant association between HDL-C and HF risk. Higher HDL-C/HDL-P was significantly associated with higher overall HF risk (HR of highest vs lowest tertile of HDL-C/HDL-P: 1.29 [95% CI: 1.04-1.60])., Conclusions: Higher HDL-P was associated with a lower risk of HF. In contrast, larger HDL-size was associated with higher risk of HF and there was no significant association observed between HDL-C and HF risk after accounting for cardiovascular risk factors., Competing Interests: Funding Support and Author Disclosures The ARIC study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under contracts HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, and HHSN268201700004I. The Dallas Heart Study was funded by a grant from the Donald W. Reynolds Foundation. The Multi-Ethnic Study of Atherosclerosis was supported by the National Heart, Lung, and Blood Institute (R01 HL071739 and contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, and N01-C-95169). The PREVEND cohort study was supported by The Dutch Kidney Foundation which supported the infrastructure of the PREVEND program from 1997 to 2003 (Grant E.033). The University Medical Center Groningen supported the infrastructure from 2003 to 2006. Dr Pandey is supported by the Texas Health Resources Clinical Scholarship, the Gilead Sciences Research Scholar Program, the National Institute of Aging GEMSSTAR Grant (1R03AG067960-01), and Applied Therapeutics; has served on the advisory board for Roche Diagnostics; and has received nonfinancial support from Pfizer and Merck. Dr Patel has served as a consultant to Novo Nordisk. Dr Segar has received speaker fees from Merck and is on the advisory board of descendantsDNA. Dr Shapiro has received grants from Amgen, Boehringer Ingelheim, 89Bio, Esperion, Novartis, Ionis, Merck, and New Amsterdam; has served on scientific advisory boards for Amgen, Agepha, Ionis, Novartis, Precision BioScience, New Amsterdam, and Merck; and has served as a consultant to Ionis, Novartis, Regeneron, Aidoc, Shanghai Pharma Biotherapeutics, Kaneka, and Novo Nordisk. Dr Connelly is an employee of Labcorp. Dr Rohatgi has received a research grant from CSL Behring; has served as a collaborator to Quest; has served as a consultant to HDL Diagnostics, JP Morgan, Johnson and Johnson, and Raydel. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Purpose of Review: To review ongoing and planned clinical trials of weight loss among individuals with or at high risk of heart failure., Recent Findings: Intentional weight loss via semaglutide among persons with heart failure and preserved ejection fraction and obesity significantly improves weight loss and health status as assessed by the KCCQ-CSS score and is associated with improvements in 6-min walk test. Ongoing and planned trials will explore the role of intentional weight loss with treatments such as semaglutide or tirzepatide for individuals with heart failure across the entire ejection fraction spectrum., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Patterns and disparities in guideline-directed medical therapy (GDMT) uptake for heart failure with reduced ejection fraction (HFrEF) across rural vs urban regions are not well described., Objectives: This study aims to evaluate patterns, prognostic implications, and rural-urban differences in GDMT use among Medicare beneficiaries following new-onset HFrEF., Methods: Patients with a diagnosis of new-onset HFrEF in a 5% Medicare sample with available data for Part D medication use were identified from January 2015 through December 2020. The primary exposure was residence in rural vs urban zip codes. Optimal triple GDMT was defined as ≥50% of the target daily dose of beta-blockers, ≥50% of the target daily dose of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker or any dose of sacubitril/valsartan, and any dose of mineralocorticoid receptor antagonist. The association between the achievement of optimal GDMT over time following new-onset HFrEF diagnosis and risk of all-cause mortality and subsequent HF hospitalization was also evaluated using adjusted Cox models. The association between living in rural vs urban location and time to optimal GDMT achievement over a 12-month follow-up was assessed using cumulative incidence curves and adjusted Fine-Gray subdistribution hazard models., Results: A total of 41,296 patients (age: 76.7 years; 15.0% Black; 27.6% rural) were included. Optimal GDMT use over the 12-month follow-up was low, with 22.5% initiated on any dose of triple GDMT and 9.1% on optimal GDMT doses. Optimal GDMT on follow-up was significantly associated with a lower risk of death (HR: 0.89 [95% CI: 0.85-0.94]; P < 0.001) and subsequent HF hospitalization (HR: 0.93 [95% CI: 0.87-0.98]; P = 0.02). Optimal GDMT use at 12 months was significantly lower among patients living in rural (vs urban) areas (8.4% vs 9.3%; P = 0.02). In adjusted analysis, living in rural (vs urban) locations was associated with a significantly lower probability of achieving optimal GDMT (HR: 0.92 [95% CI: 0.86-0.98]; P = 0.01 Differences in optimal GDMT use following HFrEF diagnosis accounted for 16% of excess mortality risk among patients living in rural (vs urban) areas., Conclusions: Use of optimal GDMT following new-onset HFrEF diagnosis is low, with substantially lower use noted among patients living in rural vs urban locations. Suboptimal GDMT use following new-onset HFrEF was associated with an increased risk of mortality and subsequent HF hospitalization., Competing Interests: Funding Support and Author Disclosures This study is supported by a National Institute of Minority Health and Disparities R01 grant (R01MD017529) and an American Heart Association grant (23DSG1154425) to Dr Pandey. Dr Keshvani has received grants from the National Heart, Lung, and Blood Institute (5T32HL125247-08) and consulting fees from Heart Test Laboratories and Tricog Health. Dr Khan has received consulting fees from Bayer. Dr Hsich is supported by grants from the National Heart, Lung, and Blood Institute (R01HL164405). Dr Fonarow has done consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Eli Lilly, Janssen, Medtronic, Merck, Novartis, and Pfizer. Dr Pandey has received research funding from the Texas Health Resources Clinical Scholarship, Gilead Sciences Research Scholar Program, Applied Therapeutics (investigator-initiated grant), and National Institute of Aging (GEMSSTAR grant 1R03AG067960-01); serves on the Advisory Board of Roche Diagnostics; has received grants from the National Institute on Aging (1R03AG067960-01), the National Institute on Minority Health and Disparities (R01MD017529), Applied Therapeutics, Gilead Sciences Research, and Myovista Research; has received consultant fees from Roche Diagnostics, Tricog Health, Pieces Technologies, Rivus, Palomarin Inc, Emmi Solutions; has received nonfinancial support from Pfizer and Merck; and has received Advisory Board fees from Lilly Inc, Cytokinetics, Alleviant Medical, Axon Therapies, and Bayer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The Biomarkers for the Diagnosis of Heart Failure in Diabetes webinar was hosted by Diabetes Technology Society on September 20, 2023, with the objective to review current evidence and management practices of biomarker screening for heart failure in people with diabetes. The webinar discussed (1) the four stages of heart failure, (2) diabetes and heart failure, (3) natriuretic peptide and troponin for diagnosing heart failure in diabetes, (4) emerging composite and investigational biomarkers for diagnosing heart failure, and (5) prevention of heart failure progression. Experts in heart failure from the fields of clinical chemistry, cardiology, and diabetology presented data about the importance of screening for heart failure as an often-unnoticed complication of people with type 1 and type 2 diabetes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: GAF is the Executive Chairman of Kinexum, which advises multiple health product companies, including multiple insulin manufacturers. Relevant device companies advised include Abbott, Biolinq, CMC Magnetics, Diabeloop, Hagar, Know Labs, Modular Medical, SFC Fluidics, and Surf Bio. He was formerly the Group Leader of the Division of Metabolism and Endocrine Drug Products at the US Food and Drug Administration. DBS receives research support from the Intramural Research Program at the National Institutes of Health. JLJ receives grant support from Novartis Pharmaceuticals, Applied Therapeutics, and Innolife; receives consulting income from Abbott Diagnostics, Jana Care, Janssen, Novartis, Prevencio, Quidel, and Roche Diagnostics; and belongs to clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda. JLJ is also a trustee of the American College of Cardiology. AP has received grant funding (to the institution) from Applied Therapeutics, Gilead Sciences, Ultromics, Myovista, and Roche; has served as a consultant for and/or received honoraria outside of this study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Roche Diagnostics, Sarfez Therapeutics, Edwards Lifesciences, Merck, Bayer, Novo Nordisk, Alleviant, Axon Therapies; and has received nonfinancial support from Pfizer and Merck. AP is also a consultant for Palomarin Inc with stocks compensation and has received research support from the National Institute on Aging GEMSSTAR Grant (1R03AG067960-01), the National Institute on Minority Health and Disparities (R01MD017529), and the National Institute of Heart, Lung, and Blood Institute (R21HL169708). RP-B receives grant support from Novo Nordisk, Lexicon Pharmaceuticals, and Medtronic and received consulting fee from Bayer, Lexicon Pharmaceuticals, Novo Nordisk, Roche. DCK is a consultant for Afon, Better Therapeutics, Integrity, Lifecare, Nevro, Novo, and Thirdwayv. REA, TT, AHBW, and IAH have no disclosures.

Patients with heart failure with preserved ejection fraction (HFpEF) often receive β-blocker (BB) therapy for management of co-morbidities. However, the association of BB therapy with exercise capacity and health-related quality of life (HRQL) in HFpEF is not well-studied. In this post hoc analysis of the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF (RELAX) trial, which included patients with chronic stable HFpEF with peak exercise capacity assessment at baseline and at 12 and 24 weeks of follow-up, we evaluated the association of BB use with the measures of exercise capacity (peak exercise oxygen uptake), anaerobic threshold, and HRQL (Minnesota living with heart failure questionnaire). Separate linear mixed-effect models were constructed for each outcome with adjustment for treatment arm, demographics, medical history, left ventricular ejection fraction, and duration of heart failure. Of the 216 study participants (median age 69 years, 48.2% women), 76% reported BB use at baseline. Participants with (vs without) BB therapy were older (70 vs 63.5 years, p = 0.001) and had a higher prevalence of ischemic heart disease (44% vs 23%, p = 0.01). In the adjusted linear mixed model, BB use over time was not associated with peak exercise oxygen uptake (β 95% confidence interval [CI] 0.2 (-0.31 to 0.7), p = 0.5) and 6-minute walk distance (β 95% CI 14.69 [-14.25 to 43.63], p = 0.3). However, BB use was associated with a higher anaerobic threshold (β 95% CI 0.32 (0.02 to 0.62), p = 0.036) and better HRQL (lower quality of life as assessed by Minnesota living with heart failure questionnaire score) (β 95% CI -6.68 [-10.96 to -2.4], p = 0.002). Future trials are needed to better evaluate the effects of BB on exercise capacity in patients with chronic stable HFpEF., Competing Interests: Declaration of competing interest Dr. Chandra has received grant funding outside the present study from August Health. Dr. Pandey has received grant funding outside the present study from Applied Therapeutics and Gilead Sciences; has received honoraria outside the present study as an advisor/consultant for Tricog Health Inc and Lilly, Rivus, and Roche Diagnostics; and has received nonfinancial support from Pfizer and Merck. Dr. Segar reports speaker fees from Merck & Co and grant support from the American Heart Association outside the present study. The remaining authors have no competing interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Implantable cardioverter-defibrillator (ICD) therapy is recommended to reduce mortality risk in patients with heart failure with reduced ejection fraction (HFrEF). Frailty is common among patients with HFrEF and is associated with increased mortality risk. Whether the therapeutic efficacy of ICD is consistent among frail and nonfrail patients with HFrEF remains unclear., Objectives: The aim of this study was to evaluate the effect modification of baseline frailty burden on ICD efficacy for primary prevention among participants of the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial)., Methods: Participants in SCD-HeFT with HFrEF randomized to ICD vs placebo were included. Baseline frailty was estimated using the Rockwood Frailty Index (FI), and participants were stratified into high (FI > median) vs low (FI ≤ median) frailty burden groups. Multivariable Cox models with multiplicative interaction terms (frailty × treatment arm) were constructed to evaluate whether baseline frailty status modified the treatment effect of ICD for all-cause mortality., Results: The study included 1,676 participants (mean age: 59 ± 12 years, 23% women) with a median FI of 0.30 (IQR: 0.23-0.37) in the low frailty group and 0.54 (IQR: 0.47-0.60) in the high frailty group. In adjusted Cox models, baseline frailty status significantly modified the treatment effect of ICD therapy (P interaction  = 0.047). In separate stratified analysis by frailty status, ICD therapy was associated with a lower risk of all-cause mortality among participants with low frailty burden (HR: 0.56; 95% CI: 0.40-0.78) but not among those with high frailty burden (HR: 0.86; 95% CI: 0.68-1.09)., Conclusions: Baseline frailty modified the efficacy of ICD therapy with a significant mortality benefit observed among participants with HFrEF and a low frailty burden but not among those with a high frailty burden., Competing Interests: Funding Support and Author Disclosures Dr Pandey is supported in part by the National Institute on Aging GEMSSTAR Grant (1R03AG067960-01) and the National Institute on Minority Health and Disparities (R01MD017529). Dr Kitzman has received honoraria outside the present study as a consultant for Boehringer-Ingelheim, NovoNordisk, AstraZeneca, Rivus, Keyto, Pfizer, and Novartis; has received grant funding outside the present study from Novartis, Bayer, NovoNordisk, Pfizer, and AstraZeneca; and has stock ownership in Gilead Sciences. Dr Pandey has received grant funding outside the present study from Applied Therapeutics and Gilead Sciences; has received honoraria outside the present study as an advisor/consultant for Tricog Health Inc and Lilly, USA, Rivus, and Roche Diagnostics; and has received nonfinancial support from Pfizer and Merck. The other authors report no conflicts. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Background: Individuals with acute decompensated heart failure (ADHF) have a varying response to diuretic therapy. Strategies for the early identification of low diuretic efficiency to inform decongestion therapies are lacking., Objectives: The authors sought to develop and externally validate a machine learning-based phenomapping approach and integer-based diuresis score to identify patients with low diuretic efficiency., Methods: Participants with ADHF from ROSE-AHF, CARRESS-HF, and ATHENA-HF were pooled in the derivation cohort (n = 794). Multivariable finite-mixture model-based phenomapping was performed to identify phenogroups based on diuretic efficiency (urine output over the first 72 hours per total intravenous furosemide equivalent loop diuretic dose). Phenogroups were externally validated in other pooled ADHF trials (DOSE/ESCAPE). An integer-based diuresis score (BAN-ADHF score: blood urea nitrogen, creatinine, natriuretic peptide levels, atrial fibrillation, diastolic blood pressure, hypertension and home diuretic, and heart failure hospitalization) was developed and validated based on predictors of the diuretic efficiency phenogroups to estimate the probability of low diuretic efficiency using the pooled ADHF trials described earlier. The associations of the BAN-ADHF score with markers and symptoms of congestion, length of stay, in-hospital mortality, and global well-being were assessed using adjusted regression models., Results: Clustering identified 3 phenogroups based on diuretic efficiency: phenogroup 1 (n = 370; 47%) had lower diuretic efficiency (median: 13.1 mL/mg; Q1-Q3: 7.7-19.4 mL/mg) than phenogroups 2 (n = 290; 37%) and 3 (n = 134; 17%) (median: 17.8 mL/mg; Q1-Q3: 10.8-26.1 mL/mg and median: 35.3 mL/mg; Q1-Q3: 17.5-49.0 mL/mg, respectively) (P < 0.001). The median urine output difference in response to 80 mg intravenous twice-daily furosemide between the lowest and highest diuretic efficiency group (phenogroup 1 vs 3) was 3,520 mL/d. The BAN-ADHF score demonstrated good model performance for predicting the lowest diuretic efficiency phenogroup membership (C-index: 0.92 in DOSE/ESCAPE validation cohort) that was superior to measures of kidney function (creatinine or blood urea nitrogen), natriuretic peptide levels, or home diuretic dose (DeLong P < 0.001 for all). Net urine output in response to 80 mg intravenous twice-daily furosemide among patients with a low vs high (5 vs 20) BAN-ADHF score was 2,650 vs 660 mL per 24 hours, respectively. Participants with higher BAN-ADHF scores had significantly lower global well-being, higher natriuretic peptide levels on discharge, a longer in-hospital stay, and a higher risk of in-hospital mortality in both derivation and validation cohorts., Conclusions: The authors developed and validated a phenomapping strategy and diuresis score for individuals with ADHF and differential response to diuretic therapy, which was associated with length of stay and mortality., Competing Interests: Funding Support and Author Disclosures Dr Pandey has received research support from the National Institute of Health (5R01MD017529, R21HL169708) and grant funding from Applied Therapeutics and Gilead Sciences; has received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Roche Diagnostics, Axon Therapies, Medtronic, Edward Lifesciences, Science37, Novo Nordisk, Bayer, Merck, Sarfez Pharmaceuticals, and Emmi Solutions; has received nonfinancial support from Pfizer and Merck; and is also a consultant for Palomarin Inc with stock compensation. Dr Segar has received honoraria from Merck. Dr Patel has served as a consultant to Novo Nordisk. Dr Fonarow has done consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Janssen, Medtronic, Merck, and Novartis. Dr Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. Dr Allen reports grant funding from American Heart Association, National Institutes of Health, and PCORI; and consulting fees from Amgen, Boston Scientific, Cytokinetics, Novartis, and WCG ACI Clinical. Dr Pandey has received grant funding from Applied Therapeutics and Gilead Sciences; has received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Bayer, Edwards Lifesciences, Medtronic, Sarfez Pharmacuticals, Novo Nordisk, and Roche Diagnostics; has received support from Pfizer and Merck; and is a consultant for Palomarin Inc with stock compensation. Dr Khan serves as an advisory board member for Bayer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Guideline-directed medical therapies (GDMTs) are the mainstay of treatment for heart failure with reduced ejection fraction (HFrEF), but they are underused. Whether sex differences exist in the initiation and intensification of GDMT for newly diagnosed HFrEF is not well established., Methods: Patients with incident HFrEF were identified from the 2016 to 2020 Optum deidentified Clinformatics Data Mart Database, which is derived from a database of administrative health claims for members of large commercial and Medicare Advantage health plans. The primary outcome was the use of optimal GDMT within 12 months of HFrEF diagnosis. Consistent with the guideline recommendations during the time period of the study, optimal GDMT was defined as ≥50% of the target dose of evidence-based beta-blocker plus ≥50% of the target dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, or any dose of angiotensin receptor neprilysin inhibitor plus any dose of mineralocorticoid receptor antagonist. The probability of achieving optimal GDMT on follow-up and predictors of optimal GDMT were evaluated with time-to-event analysis with adjusted Cox proportional hazard models., Results: The study cohort included 63 759 patients (mean age, 71.3 years; 15.2% non-Hispanic Black race; 56.6% male). Optimal GDMT use was achieved by 6.2% of patients at 12 months after diagnosis. Female (compared with male) patients with HFrEF had lower use across every GDMT class and lower use of optimal GDMT at each time point at follow-up. In an adjusted Cox model, female sex was associated with a 23% lower probability of achieving optimal GDMT after diagnosis (hazard ratio [HR], 0.77 [95% CI, 0.71-0.83]; P <0.001). The sex disparities in GDMT use after HFrEF diagnosis were most pronounced among patients with commercial insurance (females compared with males; HR, 0.66 [95% CI, 0.58-0.76]) compared with Medicare (HR, 0.85 [95% CI, 0.77-0.92]); P interaction sex×insurance status=0.005) and for younger patients (age <65 years: HR, 0.65 [95% CI, 0.58-0.74]) compared with older patients (age ≥65 years: HR, 87 [95% CI, 80-96]) P interaction sex×age=0.009)., Conclusions: Overall use of optimal GDMT after HFrEF diagnosis was low, with significantly lower use among female (compared with male) patients. These findings highlight the need for implementation efforts directed at improving GDMT initiation and titration., Competing Interests: Disclosures Dr Keshvani reports consulting fees from Heart Test Laboratories and Tricog Health. Dr Fonarow reports consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Eli Lilly, Janssen, Medtronic, Merck, Novartis, and Pfizer. Dr Pandey has received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Roche Diagnostics, Axon Therapies, Medtronic, Edward Lifesciences, Science37, Novo Nordisk, Bayer, Merck, Sarfez Pharmaceuticals, and Emmi Solutions, as well as nonfinancial support from Pfizer and Merck. Dr Pandey is also a consultant for Palomarin Inc with stock compensation. The other authors report no conflicts.

Background: Utilization patterns of bariatric surgery among older patients with heart failure (HF), and the associations with cardiovascular outcomes, are not well known., Methods: Medicare beneficiaries with HF and at least class II obesity from 2013 to 2020 were identified with Medicare Provider Analysis and Review 100% inpatient files and Medicare 5% outpatient files. Patients who underwent bariatric surgery were matched to controls in a 1:2 ratio (matched on exact age, sex, race, body mass index, HF encounter year, and HF hospitalization rate pre-surgery/matched period). In an exploratory analysis, patients prescribed pharmacotherapies with weight loss effects (semaglutide, liraglutide, naltrexone-bupropion, or orlistat) were identified and matched to controls with a similar strategy in addition to HF medical therapy data. Cox models evaluated associations between weight loss therapies (as a time-varying covariate) and mortality risk and HF hospitalization rate (calculated as the rate of HF hospitalizations following index HF encounter per 100 person-months) during follow-up., Results: Of 298 101 patients with HF and body mass index ≥35 kg/m 2 , 2594 (0.9%) underwent bariatric surgery (45% men; mean age, 56.2 years; mean body mass index, 51.5 kg/m 2 ). In propensity-matched analyses over a median follow-up of 4.7 years, bariatric surgery was associated with lower risk of all-cause mortality (HR, 0.55 [95% CI, 0.49-0.63]; P <0.001), greater reduction in HF hospitalization rate (rate ratio, 0.72 [95% CI, 0.67-0.77]; P <0.001), and lower atrial fibrillation risk (HR, 0.78 [95% CI, 0.65-0.93]; P =0.006). Use of pharmacotherapies with weight loss effects was low (4.8%), with 96.3% prescribed GLP-1 (glucagon-like peptide-1) agonists (semaglutide, 23.6%; liraglutide, 72.7%). In propensity-matched analysis over a median follow-up of 2.8 years, patients receiving pharmacotherapies with weight loss effects (versus matched controls) had a lower risk of all-cause mortality (HR, 0.82 [95% CI, 0.71-0.95]; P =0.007) and HF hospitalization rate (rate ratio, 0.87 [95% CI, 0.77-0.99]; P =0.04)., Conclusions: Bariatric surgery and pharmacotherapies with weight loss effects are associated with a lower risk of adverse outcomes among older patients with HF and obesity; however, overall utilization remains low., Competing Interests: Disclosures Dr Desai is a consultant at Medtronic, Cytokinetics, Tenaya, and Bristol Myers Squibb. Dr Patel has served as a consultant at Novo Nordisk. Dr Aminian received research support and honorarium from Medtronic and Ethicon. He is on the executive steering committee of a trial sponsored by Eli Lilly. Dr Keshvani has served as a consultant for HeartSciences and Tricog Inc. Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery and 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. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr Lincoff has received honoraria or served as a consultant for Novo Nordisk, Eli Lilly, Akebia, Alnylam, Ardelyx, Becton Dickinson, Brainstorm Cell, Cadrenal, Endologix, Fibrogen, GlaxoSmithKline, Intarcia, Medtronic, Neovasc, Provention Bio, and ReCor and has received research funding to his institution from AbbVie, AstraZeneca, CSL Behring, Eli Lilly, Esperion, and Novartis. Dr Van Spall receives research funding from the Canadian Institutes of Health Research and education program funding from Boehringer Ingelheim and Novartis. Dr Lam 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, 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, and Siemens Healthcare Diagnosticsand Us2.ai; and serves as cofounder and non-executive director of Us2.ai. Dr Butler has served as a consultant for Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Daxor Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Roche, Secretome, Sequana, SQ Innovation, Tenex, and Vifor. Dr Nissen reports that the Cleveland Clinic Center for Clinical Research has received funding to perform clinical trials from Abbvie, AstraZeneca, Amgen, Arrowhead, Bristol Myers Squibb, Eli Lilly, Esperion, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, Pfizer, and Silence Therapeutics. Dr Nissen is involved in these clinical trials but receives no personal remuneration for his participation. Dr Pandey has received research support from the National Institute of Health. Dr Pandey has received grant funding from Applied Therapeutics and Gilead Sciences; has received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Roche Diagnostics, Axon Therapies, Medtronic, Edward Lifesciences, Science37, Novo Nordisk, Bayer, Merck, Sarfez Pharmaceuticals, and Emmi Solutions; and has received nonfinancial support from Pfizer and Merck. Dr Pandey is also a consultant for Palomarin Inc with stock compensation. The other authors report no conflicts.

Aim: Left ventricular (LV) global longitudinal strain (GLS) may detect subtle abnormalities in myocardial contractility among individuals with normal LV ejection fraction (LVEF). However, the prognostic implications of GLS among healthy, community-dwelling adults is not well-established., Methods and Results: Overall, 2234 community-dwelling adults (56% women, 47% Black) with LVEF ≥50% without a history of cardiovascular disease (CVD) from the Dallas Heart Study who underwent cardiac magnetic resonance (CMR) with GLS assessed by feature tracking CMR (FT-CMR) were included. The association of GLS with the risk of incident major adverse cardiovascular events (MACE; composite of incident myocardial infarction, incident heart failure [HF], hospitalization for atrial fibrillation, coronary revascularization, and all-cause death), and incident HF or death were assessed with adjusted Cox proportional hazards models. A total of 309 participants (13.8%) had MACE during a median follow-up duration of 17 years. Participants with the worst GLS (Q4) were more likely male and of the Black race with a history of tobacco use and diabetes with lower LVEF, higher LV end-diastolic volume, and higher LV mass index. Cumulative incidence of MACE was higher among participants with worse (Q4 vs. Q1) GLS (20.4% vs. 9.0%). In multivariable-adjusted Cox models that included clinical characteristics, cardiac biomarkers and baseline LVEF, worse GLS (Q4 vs. Q1) was associated with a significantly higher risk of MACE (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.07-2.24, p = 0.02) and incident HF or death (HR 1.57, 95% CI 1.03-2.38, p = 0.04)., Conclusions: Impaired LV GLS assessed by FT-CMR among adults free of cardiovascular disease is associated with a higher risk of incident MACE and incident HF or death independent of cardiovascular risk factors, cardiac biomarkers and LVEF., (© 2024 European Society of Cardiology.)

Background: The optimal approach to identify individuals with diabetes who are at a high risk for developing heart failure (HF) to inform implementation of preventive therapies is unknown, especially in those without atherosclerotic cardiovascular disease (ASCVD)., Methods: Adults with diabetes and no HF at baseline from 7 community-based cohorts were included. Participants without ASCVD who were at high risk for developing HF were identified using 1-step screening strategies: risk score (WATCH-DM [Weight, Age, Hypertension, Creatinine, HDL-C, Diabetes Control, QRS Duration, MI, and CABG] ≥12), NT-proBNP (N-terminal pro-B-type natriuretic peptide ≥125 pg/mL), hs-cTn (high-sensitivity cardiac troponin T ≥14 ng/L; hs-cTnI ≥31 ng/L), and echocardiography-based diabetic cardiomyopathy (echo-DbCM; left atrial enlargement, left ventricular hypertrophy, or diastolic dysfunction). High-risk participants were also identified using 2-step screening strategies with a second test to identify residual risk among those deemed low risk by the first test: WATCH-DM/NT-proBNP, NT-proBNP/hs-cTn, NT-proBNP/echo-DbCM. Across screening strategies, the proportion of HF events identified, 5-year number needed to treat and number needed to screen to prevent 1 HF event with an SGLT2i (sodium-glucose cotransporter 2 inhibitor) among high-risk participants, and cost of screening were estimated., Results: The initial study cohort included 6293 participants (48.2% women), of whom 77.7% without prevalent ASCVD were evaluated with different HF screening strategies. At 5-year follow-up, 6.2% of participants without ASCVD developed incident HF. The 5-year number needed to treat to prevent 1 HF event with an SGLT2i among participants without ASCVD was 43 (95% CI, 29-72). In the cohort without ASCVD, high-risk participants identified using 1-step screening strategies had a low 5-year number needed to treat (22 for NT-proBNP to 37 for echo-DbCM). However, a substantial proportion of HF events occurred among participants identified as low risk using 1-step screening approaches (29% for echo-DbCM to 47% for hs-cTn). Two-step screening strategies captured most HF events (75-89%) in the high-risk subgroup with a comparable 5-year number needed to treat as the 1-step screening approaches (30-32). The 5-year number needed to screen to prevent 1 HF event was similar across 2-step screening strategies (45-61). However, the number of tests and associated costs were lowest for WATCH-DM/NT-proBNP ($1061) compared with other 2-step screening strategies (NT-proBNP/hs-cTn: $2894; NT-proBNP/echo-DbCM: $16 358)., Conclusions: Selective NT-proBNP testing based on the WATCH-DM score efficiently identified a high-risk primary prevention population with diabetes expected to derive marked absolute benefits from SGLT2i to prevent HF., Competing Interests: Disclosures Dr Patel has served as a consultant to Novo Nordisk. Dr Segar has received honoraria from Merck. Dr Klonoff has served as a consultant for Afon, Atropos Health, Better Therapeutics, Glucotrack, Lifecare, Novo, Samsung, and Thirdwayv. Dr Khan has received personal fees from Merck. Dr Lam has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as a consultant or on advisory boards/steering committees/executive committees for Actelion, Alleviant Medical, Allysta, Amgen, ANaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma, EchoNous, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and Development, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, Us2.ai, and WebMD Global; and has served as cofounder and nonexecutive director of Us2.ai. Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; has received research grants and honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, PhaseBio, and Pfizer; has received honoraria from Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; is a member of the scientific excellence committee of the EMPEROR-Reduced trial (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure With Reduced Ejection Fraction); has served as a national lead investigator of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and EMPEROR-Reduced trials; and is the president of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr Nasir is on the advisory board of Amgen, Novartis, and Novo Nordisk, and his research is partly supported by the Jerold B. Katz Academy of Translational Research. Dr Butler has served as a consultant for Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Daxor Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Roche, Secretome, Sequana, SQ Innovation, Tenex, and Vifor. Dr Vaduganathan is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (National Institutes of Health/National Center for Advancing Translational Sciences Award UL 1TR002541) and has served on advisory boards or has received research grant support from American Regent, Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, and Relypsa. Dr Pandey has received research support from the National Institute on Aging GEMSSTAR Grant (1R03AG067960-01) and the National Institute on Minority Health and Disparities (R01MD017529). Dr Pandey has received grant funding (to the institution) from Applied Therapeutics, Gilead Sciences, Ultromics, Myovista, and Roche; has served as a consultant for and/or has received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Roche Diagnostics, Sarfez Therapeutics, Edwards Lifesciences, Merck, Bayer, Novo Nordisk, Alleviant, Axon Therapies; and has received nonfinancial support from Pfizer and Merck. Dr Pandey is also a consultant for Palomarin Inc with stocks compensation. The other authors report no conflicts.

Heart failure (HF) is a common cause of hospitalization and death, and the hallmark symptoms of HF, including dyspnea, fatigue, and exercise intolerance, contribute to poor patient quality of life (QoL). Cardiac rehabilitation (CR) is a comprehensive disease management program incorporating exercise training, cardiovascular risk factor management, and psychosocial support. CR has been demonstrated to effectively improve patient functional status and QoL among patients with HF. However, CR participation among patients with HF is poor. This review details the mechanisms of dyspnea and exercise intolerance among patients with HF, the physiologic and clinical improvements observed with CR, and the key components of a CR program for patients with HF. Furthermore, unmet needs and future strategies to improve patient participation and engagement in CR for HF are reviewed., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: This study compared the predictive value of the race-independent creatinine- and cystatin C-based estimated glomerular filtration rate (eGFR cr-cys ) and the race-dependent creatinine-based eGFR (eGFR cr ) for incident heart failure (HF)., Methods: This study combined the participant-level data from ARIC (Atherosclerosis Risk in Communities) (visit 4) and MESA (Multi-Ethnic Study of Atherosclerosis) (visit 1) to calculate eGFR cr-cys and eGFR cr . The primary outcome of the study was adjudicated incident HF over a follow-up period of 10 years. Multivariable Cox models were used to assess the risk of incident HF with the quartiles of eGFR cr-cys and eGFR cr ., Results: Among 15,615 individuals (median age: 62 [57-68] years; 55.0% females; 23.9% Black), the median eGFR cr-cys and eGFR cr were 91.4 (79.4, 102.0) mL/min/1.73m 2 and 84.7 (72.0, 94.7) mL/min/1.73m 2 , respectively. Compared with the fourth quartile of eGFR cr-cys , the hazard ratio for incident HF was 1.02 (95% CI:0.80-1.30) in the third quartile, 1.02 (95% CI:0.80-1.30) in the second quartile, and 1.47 (95% CI:1.16-1.86) in the first quartile. Compared with the 4th quartile of the eGFR cr, the risk of incident HF was similar in the 3rd (HR adj :0.90 [95% CI:0.73-1.12]), 2nd (HR adj : 0.96 [95% CI:0.77-1.20]), and 1st (HR adj :1.15 [95% CI:0.93-1.44]) quartiles. C-statistics were similar for the multivariable-adjusted Cox models for incident HF using eGFR cr (0.80 [0.79-0.81]) and eGFR cr-cys (0.80 [0.79-0.82])., Conclusion: The eGFR cr and eGFR cr-cys had comparable predictive values for incident HF., Competing Interests: Disclosures None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Obesity is associated with incident heart failure (HF), independent of other cardiovascular risk factors. Despite rising rates of both obesity and incident HF, the associations remain poorly understood between: 1) obesity and HF outcomes; and 2) weight loss and HF outcomes. Evidence shows that patients with HF and obesity have high symptom burdens, lower exercise capacity, and higher rates of hospitalization for HF when compared with patients with HF without obesity. However, the impact of weight loss on these outcomes for patients with HF and obesity remains unclear. Recent advances in medical therapies for weight loss have offered a new opportunity for significant and sustained weight loss. Ongoing and recently concluded cardiovascular outcomes trials will offer new insights into the role of weight loss through these therapies in preventing HF and mitigating HF outcomes and symptom burdens among patients with established HF, particularly HF with preserved ejection fraction., Competing Interests: Funding Support and Author Disclosures Dr Felker has received research grants from the National Heart, Lung and Blood Institute, the American Heart Association, Amgen, Bayer, Bristol-Myers Squibb, Merck, Cytokinetics, and CSL Behring; has acted as a consultant to Novartis, Amgen, Bristol-Myers Squibb, Cytokinetics, Medtronic, Cardionomic, Boehringer Ingelheim, American Regent, Abbott, AstraZeneca, Reprieve, Myovant, Sequana, Windtree Therapeutics, and Whiteswell; and has served on clinical endpoint committees or data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. Dr Lingvay has received research funding (paid to institution) from Novo Nordisk, Sanofi, Merck, Pfizer, Mylan, and Boehringer Ingelheim; has received advisory or consulting fees and/or other support from Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca, Boehringer Ingelheim, Johnson and Johnson, Intercept, TARGET Pharma, Merck, Pfizer, Valeritas, Zealand Pharma, Shionogi, Carmot Therapeutics, Structure Therapeutics, Bayer, Translational Medical Academy, Mediflix, Biomea, The Comm Group, and WebMD; and has served on the data safety monitoring board for JAEB. Dr Pagidipati has received research support from Amgen, Boehringer Ingelheim, Eggland’s Best, Eli Lilly, Novartis, Novo Nordisk, and Verily Life Sciences; has served as a consultant or on an advisory panel for Bayer, Boehringer Ingelheim, CRISPR Therapeutics, Eli Lilly, Esperion, AstraZeneca, Merck, Novartis, and Novo Nordisk; has served as an executive committee member for trials sponsored by Novo Nordisk and Amgen; and has served on data safety monitoring boards for trials sponsored by Janssen and Novartis. Dr McGuire has received personal fees from Boehringer Ingelheim, Sanofi US, Merck and Co, Merck Sharp and Dohme Corp, Eli Lilly USA, Novo Nordisk, AstraZeneca, Lexicon Pharmaceuticals, Eisai, Pfizer, Metavant, Applied Therapeutics, Afimmune, Bayer, CSL Behring, and Esperion; has received research support for clinical trials leadership from Boehringer Ingelheim, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Eli Lilly USA, and CSL Behring; and has received honoraria for consultancy from Eli Lilly USA, Pfizer, Boehringer Ingelheim, Lexicon, Novo Nordisk, Applied Therapeutics, Altimmune, CSL Behring, Bayer, Intercept, and New Amsterdam. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Polypharmacy is common among patients with heart failure with reduced ejection fraction (HFrEF). However, its impact on the use of optimal guideline-directed medical therapy (GDMT) is not well established., Objectives: This study sought to evaluate the association between polypharmacy and odds of receiving optimal GDMT over time among patients with HFrEF., Methods: The authors conducted a post hoc analysis of the GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment) trial. Polypharmacy was defined as receiving ≥5 medications (excluding HFrEF GDMT) at baseline. The outcome of interest was optimal triple therapy GDMT (concurrent administration of a renin-angiotensin-aldosterone blocker and beta-blocker at 50% of the target dose and a mineralocorticoid receptor antagonist at any dose) achieved over the 12-month follow-up. Multivariable adjusted mixed-effect logistic regression models with multiplicative interaction terms (time × polypharmacy) were constructed to evaluate how polypharmacy at baseline modified the odds of achieving optimal GDMT on follow-up., Results: The study included 891 participants with HFrEF. The median number of non-GDMT medications at baseline was 4 (IQR: 3-6), with 414 (46.5%) prescribed ≥5 and identified as being on polypharmacy. The proportion of participants who achieved optimal GDMT at the end of the 12-month follow-up was lower with vs without polypharmacy at baseline (15% vs 19%, respectively). In adjusted mixed models, the odds of achieving optimal GDMT over time were modified by baseline polypharmacy status (P for interaction < 0.001). Patients without polypharmacy at baseline had increased odds of achieving GDMT (OR: 1.16 [95% CI: 1.12-1.21] per 1-month increase; P < 0.001) but not patients with polypharmacy (OR: 1.01 [95% CI: 0.96-1.06)] per 1-month increase)., Conclusions: Patients with HFrEF who are on non-GDMT polypharmacy have lower odds of achieving optimal GDMT on follow-up., Competing Interests: Funding Support and Author Disclosures Dr Pandey has received research support from the National Institute on Aging GEMSSTAR grant (1R03AG067960-01) and the National Institute on Minority Health and Disparities (R01MD017529); grant funding from Applied Therapeutics and Gilead Sciences; honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, and Roche Diagnostics; nonfinancial support from Pfizer and Merck; and is a consultant for Palomarin Inc with stock compensation. Dr Segar has received speaker fees from Merck and Co outside the present study. Dr Butler is a consultant for 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 Fonarow has done consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Eli Lilly, Johnson & Johnson, Medtronic, Merck, Novartis, and Pfizer. 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.)

Heart failure with preserved ejection fraction (HFpEF) has become the leading form of heart failure worldwide, particularly among elderly patient populations. HFpEF is associated with significant morbidity and mortality that may benefit from incorporation of palliative care (PC). Patients with HFpEF have similarly high mortality rates to patients with heart failure with reduced ejection fraction. PC trials for heart failure have shown improvement in quality of life, quality of death, and health care utilization, although most trials defined heart failure clinically without differentiating between HFpEF and heart failure with reduced ejection fraction. As such, the timing and role of PC for HFpEF care remains uncertain, and PC referral rates for HFpEF are very low despite potential improvements in important patient-centered outcomes. Specific barriers to referral include limited data, prognostic uncertainty, provider misconceptions about PC, inadequate specialty PC workforce, complexities of treating multimorbidity, and limited home care options for patients with heart failure. While there are many barriers to integration of PC into HFpEF care, there are multiple potential benefits to patients with HFpEF throughout their disease course. As this population continues to grow, targeted efforts to study and implement PC interventions are needed to improve patient quality of life and death., Competing Interests: Disclosures None.

Aims: Heart failure with reduced ejection fraction (HFrEF) is treatable but guideline-directed medical therapy (GDMT) may not be affordable or accessible to people living with the disease., Methods and Results: In this cross-sectional survey, we investigated the price, affordability, and accessibility of four pivotal classes of HFrEF GDMT: angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB) or angiotensin-neprilysin inhibitors (ARNI); beta-blockers; mineralocorticoid receptor antagonists (MRA); and sodium glucose co-transporter 2 inhibitors (SGLT2i). We sampled online or community pharmacies in 10 countries across a range of World Bank income groups, assessing mean 30 day retail prescription prices, affordability relative to gross national income per capita per month, and accessibility. We reported median price ratios relative to the International Reference Standard. We performed a literature review to evaluate accessibility to GDMT classes through publicly funded drug programmes in each country. HFrEF GDMT prices, both absolute and relative to the international reference, were highest in the United States and lowest in Pakistan and Bangladesh. The most expensive drug was the ARNI, sacubitril/valsartan, with a mean (standard deviation, SD) 30 day price ranging from $11.06 (0.81) in Pakistan to $611.50 (3.54) in United States. The least expensive drug was the MRA, spironolactone, with a mean (SD) 30 day price ranging from $0.18 (0.00) in Pakistan to $12.32 (0.00) in England. Affordability (SD) of quadruple therapy-ARNI, beta-blockers, MRA, and SGLT2i-was best in high-income and worst in low-income countries, ranging from 1.49 (0.00)% of gross national income per capita per month in England to 232.47 (31.47)% in Uganda. Publicly funded drug programmes offset costs for eligible patients, but ARNI and SGLT2i were inaccessible through these programmes in low- and middle-income countries. Price, affordability, and access were substantially improved in all countries by substituting ARNI for ACEi/ARB., Conclusions: There was marked variation between countries in the retail price of HFrEF GDMT. Despite higher prices in high-income countries, GDMT was more accessible and affordable than in low- and middle-income countries. Publicly funded drug programmes in lower income countries increased affordability but limited access to newer HFrEF GDMT classes. Pharmaco-disparities must be addressed to improve HFrEF outcomes globally., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to reduce the composite of heart failure hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials. While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents. The SGLT2 inhibitors have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and autophagic flux in addition to altering iron homeostasis, which may contribute to improved cardiac energetics and function. These agents also reduce epicardial adipose tissue and alter adipokine signalling, which may play a role in the reductions in inflammation and oxidative stress observed with SGLT2 inhibition. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized. Finally, SGLT2 inhibitors have been shown to reduce myofilament stiffness as well as extracellular matrix remodelling/fibrosis in the heart, improving diastolic function. The SGLT2 inhibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will likely become foundational in the therapy of HFpEF., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Source Citation: Gupta K, Spertus JA, Birmingham M, et al. Racial differences in quality of life in patients with heart failure treated with sodium-glucose cotransporter 2 inhibitors: a patient-level meta-analysis of the CHIEF-HF, DEFINE-HF, and PRESERVED-HF trials. Circulation. 2023;148:220-228. 37191040., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=J23-0071.

Heart failure (HF) is a heterogeneous syndrome affecting more than 60 million individuals globally. Despite recent advancements in understanding of the pathophysiology of HF, many issues remain including residual risk despite therapy, understanding the pathophysiology and phenotypes of patients with HF and preserved ejection fraction, and the challenges related to integrating a large amount of disparate information available for risk stratification and management of these patients. Risk prediction algorithms based on artificial intelligence (AI) may have superior predictive ability compared to traditional methods in certain instances. AI algorithms can play a pivotal role in the evolution of HF care by facilitating clinical decision making to overcome various challenges such as allocation of treatment to patients who are at highest risk or are more likely to benefit from therapies, prediction of adverse outcomes, and early identification of patients with subclinical disease or worsening HF. With the ability to integrate and synthesize large amounts of data with multidimensional interactions, AI algorithms can supply information with which physicians can improve their ability to make timely and better decisions. In this review, we provide an overview of the AI algorithms that have been developed for establishing early diagnosis of HF, phenotyping HF with preserved ejection fraction, and stratifying HF disease severity. This review also discusses the challenges in clinical deployment of AI algorithms in HF, and the potential path forward for developing future novel learning-based algorithms to improve HF care., (© 2023 European Society of Cardiology.)

Aims: Sex differences in long-term outcomes following hospitalization for heart failure (HF) across ejection fraction (EF) subtypes are not well described. In this study, we evaluated the risk of mortality and rehospitalization among males and females across the spectrum of EF over 5 years of follow-up following an index HF hospitalization event., Methods and Results: Patients hospitalized with HF between 1 January 2006 and 31 December 2014 from the American Heart Association's Get With The Guidelines-Heart Failure registry with available 5-year follow-up using Medicare Part A claims data were included. The association between sex and risk of mortality and readmission over a 5-year follow-up period for each HF subtype (HF with reduced EF [HFrEF, EF ≤40%], HF with mildly reduced EF [HFmrEF, EF 41-49%], and HF with preserved EF [HFpEF, EF >50%]) was assessed using adjusted Cox models. The effect modification by the HF subtype for the association between sex and outcomes was assessed by including multiplicative interaction terms in the models. A total of 155 670 patients (median age: 81 years, 53.4% female) were included. Over 5-year follow-up, males and females had comparably poor survival post-discharge; however, females (vs. males) had greater years of survival lost to HF compared with the median age- and sex-matched US population (HFpEF: 17.0 vs. 14.6 years; HFrEF: 17.3 vs. 15.1 years; HFmrEF: 17.7 vs. 14.6 years for age group 65-69 years). In adjusted analysis, females (vs. males) had a lower risk of 5-year mortality (adjusted hazard ratio [aHR] 0.89, 95% confidence interval [CI] 0.87-0.90, p < 0.0001), and the risk difference was most pronounced among patients with HFrEF (aHR 0.87, 95% CI 0.85-0.89; p interaction [sex*HF subtype] = 0.04). Females (vs. males) had a higher adjusted risk of HF readmission over 5-year follow-up (aHR 1.06, 95% CI 1.04-1.08, p < 0.0001), with the risk difference most pronounced among patients with HFpEF (aHR 1.11, 95% CI 1.07-1.14; p interaction [sex*HF subtype] = 0.001)., Conclusions: While females (vs. males) had lower adjusted mortality, females experienced a significantly greater loss in survival time than the median age- and sex-matched US population and had a greater risk of rehospitalization over 5 years following HF hospitalization., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The prognostic utility of the oxygen uptake efficiency slope (OUES) in heart failure with reduced ejection fraction is uncertain. In this post hoc analysis of the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial (n = 2,074), we tested for associations of OUES and peak oxygen uptake (VO 2 ) with heart failure hospitalization or cardiovascular death in multivariable Cox regression models, adjusting for minute ventilation/carbon dioxide production (VE/VCO 2 ) slope and other important confounders. Harrell's C-statistics assessed the discriminatory performance of OUES and peak VO 2 . Lower OUES was associated with increased risk of the outcome (quartile 1 vs 4: hazard ratio 2.1 [1.5 to 2.9, p <0.001]). Peak VO 2 had greater discrimination than OUES in comparable models (e.g., C-statistic = 0.73 vs 0.70, p <0.001, respectively). In the subgroup with respiratory exchange ratio <1 (n = 358), peak VO 2 was associated with the outcome (p <0.001) but OUES was not (p = 0.96). In conclusion, whereas OUES was associated with clinical outcomes independently of VE/VCO 2 slope, its prognostic utility was inferior to that of peak VO 2 , even when measured at submaximal effort., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Recent studies focusing on the prevalence, characteristics, and outcomes of primary heart failure (HF) with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF) in non-alcoholic fatty liver disease (NAFLD) are sparse. We sought to assess these using a nationally-representative population. We used the 2016-2018 National Inpatient Sample database to study the prevalence, characteristics, clinical risk profiles, morbidity, mortality, cost, and resource utilization among primary HFpEF and HFrEF hospitalizations with and without NAFLD. In the period from January 1, 2016, to December 31, 2018, there were 3,522,459 admissions of patients aged ≥18 years with a diagnosis of primary HF. Of these, 82,585 (2.3%) hospitalizations had secondary diagnosis of NAFLD. Admissions with NAFLD and HFrEF were associated with higher rates of in-hospital mortality (aOR 1.84, CI 1.66-2.04, P < 0.001) compared to admissions of HFrEF without NAFLD. Similarly, hospitalizations with HFpEF-NAFLD were associated with higher rates of in hospital mortality (aOR 1.65 CI 1.43-1.9, P < 0.001) compared to HFpEF admissions without NAFLD. Pressors use, cardiogenic shock, AKI with or without dialysis use, cardiac arrest, LOS and hospitalization cost were higher in admissions of HFrEF and HFpEF with NAFLD compared to those without NAFLD. In-hospital mortality, was higher in primary HFrEF and HFpEF admissions with NAFLD compared to without NAFLD. Physicians must be aware of the worse clinical outcomes of HFrEF and HFpEF in patients with NAFLD. Further clinical research is needed to address the knowledge gap and treatment options available for the patients with HF and NAFLD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The burden of heart failure among people with type 2 diabetes is increasing globally. People with comorbid type 2 diabetes and heart failure often have worse outcomes than those with only one of these conditions-eg, higher hospitalisation and mortality rates. Therefore, it is essential to implement optimal heart failure prevention strategies for people with type 2 diabetes. A detailed understanding of the pathophysiology underlying the occurrence of heart failure in type 2 diabetes can aid clinicians in identifying relevant risk factors and lead to early interventions that can help prevent heart failure. In this Review, we discuss the pathophysiology and risk factors of heart failure in type 2 diabetes. We also review the risk assessment tools for predicting heart failure incidence in people with type 2 diabetes as well as the data from clinical trials that have assessed the efficacy of lifestyle and pharmacological interventions. Finally, we discuss the potential challenges in implementing new management approaches and offer pragmatic recommendations to help overcome these challenges., Competing Interests: Declaration of interests AP has received research support from the National Institute on Aging (GEMSSTAR grant: 1R03AG067960-01) and the National Institute on Minority Health and Disparities (R01MD017529); grant funding from Applied Therapeutics and Gilead Sciences; has received honoraria outside of the present study as an advisor or consultant for Tricog Health, Eli Lilly, Rivus, Cytokinetics, and Roche Diagnostics; has received non-financial support from Pfizer and Merck; and is also a consultant for Palomarin with stocks compensation. KVP has served as a consultant to Novo Nordisk. DLB sits on the advisory board of Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; and on the board of directors of Angiowave (with stock options), Boston VA Research Institute, Bristol Myers Squibb (with stock), DRS.LINQ (with stock options), High Enroll (with stock), Society of Cardiovascular Patient Care, and TobeSoft. DLB was the inaugural chair of the American Heart Association Quality Oversight Committee. DLB is a consultant for Broadview Ventures and Hims; and sits on data monitoring committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute) for the PORTICO trial funded by St Jude Medical (now Abbott), Boston Scientific (chair for PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (chair for PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine for the ENVISAGE trial funded by Daiichi Sankyo and for the ABILITY-DM trial funded by Concept Medical, Novartis, Population Health Research Institute, and Rutgers University for the National Institutes of Health-funded MINT Trial. DLB reports honoraria from the American College of Cardiology as Senior Associate Editor of Clinical Trials and News and chair of American College of Cardiology Accreditation Oversight Committee; Arnold and Porter law firm for work related to Sanofi–Bristol Myers Squibb clopidogrel litigation; Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute) for the RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim and AEGIS-II executive committee funded by CSL Behring; Belvoir Publications as Editor in Chief of Harvard Heart Letter; Canadian Medical and Surgical Knowledge Translation Research Group for clinical trial steering committees; Cowen and Company; Duke Clinical Research Institute for clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals; HMP Global as Editor in Chief of the Journal of Invasive Cardiology; Journal of the American College of Cardiology as Guest Editor and Associate Editor; K2P as co-chair of interdisciplinary curriculum; Level Ex; Medtelligence–ReachMD for continuing medical education steering committees; MJH Life Sciences; Oakstone CME as Course Director of the Comprehensive Review of Interventional Cardiology; Piper Sandler; Population Health Research Institute for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer; Slack Publications as Chief Medical Editor of Cardiology Intervention Today; Society of Cardiovascular Patient Care as secretary and treasurer; WebMD for continuing medical education steering committees; Wiley for steering committee. DLB reports non-financial relationships as Deputy Editor of Clinical Cardiology; as chair of the National Cardiovascular Data Registry–Acute Coronary Intervention and Outcomes Network Registry steering committee; as chair of the Veterans Affairs Cardiovascular Assessment, Reporting, and Tracking Research and publications committee. DLB reports a patent for sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; however, neither DLB or Brigham and Women's Hospital receive any income from this patent). DLB reports research funding for Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Eli Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio. DLB reports royalties from Elsevier as Editor of Braunwald's Heart Disease; as site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; as trustee for the American College of Cardiology; and for unfunded research of FlowCo and Takeda. SV holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving research grants 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, and Sanofi. SV is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organisation. MSK declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Coverage for cardiac rehabilitation (CR) for patients with heart failure with reduced ejection fraction was expanded in 2014, but contemporary referral and participation rates remain unknown., Methods: Patients hospitalized for heart failure with reduced ejection fraction (≤35%) in the American Heart Association Get With The Guidelines-Heart Failure registry from 2010 to 2020 were included, and CR referral status was described as yes, no, or not captured. Temporal trends in CR referral were assessed in the overall cohort. Patient and hospital-level predictors of CR referral were assessed using multivariable-adjusted logistic regression models. Additionally, CR referral and proportional utilization of CR within 1-year of referral were evaluated among patients aged >65 years with available Medicare administrative claims data who were clinically stable for 6-weeks postdischarge. Finally, the association of CR referral with the risk of 1-year death and readmission was evaluated using multivariable-adjusted Cox models., Results: Of 69,441 patients with heart failure with reduced ejection fraction who were eligible for CR (median age 67 years; 33% women; 30% Black), 17,076 (24.6%) were referred to CR, and referral rates increased from 8.1% in 2010 to 24.1% in 2020 ( P <0.001). Of 8310 patients with Medicare who remained clinically stable 6-weeks after discharge, the CR referral rate was 25.8%, and utilization of CR among referred patients was 4.1% (mean sessions attended: 6.7). Patients not referred were more likely to be older, of Black race, and with a higher burden of comorbidities. In adjusted analysis, eligible patients with heart failure with reduced ejection fraction who were referred to CR (versus not referred) had a lower risk of 1-year death (hazard ratio, 0.84 [95% CI, 0.70-1.00]; trend <0.001). Of 8310 patients with Medicare who remained clinically stable 6-weeks after discharge, the CR referral rate was 25.8%, and utilization of CR among referred patients was 4.1% (mean sessions attended: 6.7). Patients not referred were more likely to be older, of Black race, and with a higher burden of comorbidities. In adjusted analysis, eligible patients with heart failure with reduced ejection fraction who were referred to CR (versus not referred) had a lower risk of 1-year death (hazard ratio, 0.84 [95% CI, 0.70-1.00]; P =0.049) without significant differences in 1-year readmission., Conclusions: CR referral rates have increased from 2010 to 2020. However, only 1 in 4 patients are referred to CR. Among eligible patients who received CR referral, participation was low, with <1 of 20 participating in CR., Competing Interests: Disclosures Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association ([AHA] 929502), National Heart, Lung, and Blood Institute (NHLBI), Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck & Co Inc, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim/Lilly, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, and Sanofi; serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Merck & Co Inc, PhamaIN, Roche Diagnostics, Sanofi, Tricog Health, Urovant Pharmaceuticals, and Vifor; and has received speaker fees from Boehringer Ingelheim. Dr DeVore reports research funding through his institution from the AHA, Biofourmis, Bodyport, Cytokinetics, American Regent Inc, the NHLBI, Novartis, and Story Health. He also provides consulting services for and/or receives honoraria from Abiomed, AstraZeneca, Cardionomic, InnaMed, LivaNova, Natera, Novartis, Procyrion, Story Health, Vifor, and Zoll. He has also received nonfinancial support from Abbott for educational and research activities. Dr Allen has received grant funding from National Institutes of Health, Patient Centered Outcomes Research Institute, Agency for Health Resource and Quality, and AHA; and consultant fees from ACI Clinical, Boston Scientific, Cytokinetics, and Novartis. Dr Fonarow reports consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Edwards, Eli Lilly, Janssen, Medtronic, Merck, and Novartis. Dr Pandey has received research funding from the Texas Health Resources Clinical Scholarship, Gilead Sciences Research Scholar Program, Applied Therapeutics (investigator-initiated grant), and National Institute of Aging (GEMSSTAR grant 1R03AG067960-01); and serves on the advisory board of Roche Diagnostics. The other authors report no conflicts.

Background: The association of historical redlining policies, a marker of structural racism, with contemporary heart failure (HF) risk among White and Black individuals is not well established., Methods: We aimed to evaluate the association of redlining with the risk of HF among White and Black Medicare beneficiaries. Zip code-level redlining was determined by the proportion of historically redlined areas using the Mapping Inequality Project within each zip code. The association between higher zip code redlining proportion (quartile 4 versus quartiles 1-3) and HF risk were assessed separately among White and Black Medicare beneficiaries using generalized linear mixed models adjusted for potential confounders, including measures of the zip code-level Social Deprivation Index., Results: A total of 2 388 955 Medicare beneficiaries (Black n=801 452; White n=1 587 503; mean age, 71 years; men, 44.6%) were included. Among Black beneficiaries, living in zip codes with higher redlining proportion (quartile 4 versus quartiles 1-3) was associated with increased risk of HF after adjusting for age, sex, and comorbidities (risk ratio, 1.08 [95% CI, 1.04-1.12]; P <0.001). This association remained significant after further adjustment for area-level Social Deprivation Index (risk ratio, 1.04 [95% CI, 1.002-1.08]; P =0.04). A significant interaction was observed between redlining proportion and Social Deprivation Index ( P interaction <0.01) such that higher redlining proportion was significantly associated with HF risk only among socioeconomically distressed regions (above the median Social Deprivation Index). Among White beneficiaries, redlining was associated with a lower risk of HF after adjustment for age, sex, and comorbidities (risk ratio, 0.94 [95% CI, 0.89-0.99]; P =0.02)., Conclusions: Historical redlining is associated with an increased risk of HF among Black patients. Contemporary zip code-level social determinants of health modify the relationship between redlining and HF risk, with the strongest relationship between redlining and HF observed in the most socioeconomically disadvantaged communities., Competing Interests: Disclosures Dr Desai is a consultant for Medtronic and Bristol Myers Squibb. He is on the executive steering committee of a trial sponsored by Bristol Myers Squibb. Dr Pandey has received grant funding outside the present study from Applied Therapeutics and Gilead Sciences; has received honoraria outside the present study as an advisor/consultant for Tricog Health Inc and Lilly, USA, Rivus, and Roche Diagnostics, and has received nonfinancial support from Pfizer and Merck. The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institute on Minority Health and Health Disparities; the National Institutes of Health; or the US Department of Health and Human Services. The remaining authors have nothing to disclose.

Background: In the CANVAS (Canagliflozin Cardiovascular Assessment Study) program, canagliflozin reduced the risk of heart failure (HF) hospitalization among individuals with type 2 diabetes mellitus (T2DM)., Objectives: The purpose of this study was to evaluate heterogeneity in absolute and relative treatment effects of canagliflozin on HF hospitalization according to baseline HF risk as assessed by diabetes-specific HF risk scores (WATCH-DM [Weight (body mass index), Age, hyperTension, Creatinine, HDL-C, Diabetes control (fasting plasma glucose) and QRS Duration, MI and CABG] and TRS-HF DM [TIMI Risk Score for HF in Diabetes])., Methods: Participants in the CANVAS trial were categorized into low, medium, and high risk for HF using the WATCH-DM score (for participants without prevalent HF) and the TRS-HF DM score (for all participants). The outcome of interest was time to first HF hospitalization. The treatment effect of canagliflozin vs placebo for HF hospitalization was compared across risk strata., Results: Among 10,137 participants with available HF data, 1,446 (14.3%) had HF at baseline. Among participants without baseline HF, WATCH-DM risk category did not modify the treatment effect of canagliflozin (vs placebo) on HF hospitalization (P interaction = 0.56). However, the absolute and relative risk reduction with canagliflozin was numerically greater in the high-risk group (cumulative incidence, canagliflozin vs placebo: 8.1% vs 12.7%; HR: 0.62 [95% CI: 0.37-0.93]; P = 0.03; number needed to treat: 22) than in the low- and intermediate-risk groups. When overall study participants were categorized according to the TRS-HF DM score, a statistically significant difference in the treatment effect of canagliflozin across risk strata was observed (P interaction = 0.04). Canagliflozin significantly reduced the risk of HF hospitalization by 39% in the high-risk group (HR: 0.61 [95% CI: 0.48-0.78]; P < 0.001; number needed to treat: 20) but not in the intermediate- or low-risk groups., Conclusions: Among participants with T2DM, the WATCH-DM and TRS-HF DM can reliably identify those at high risk for HF hospitalization and most likely to benefit from canagliflozin., Competing Interests: Funding Support and Author Disclosures This study, carried out under YODA Project # 2020-4213, used data obtained from the Yale University Open Data Access Project, which has an agreement with Janssen Research and Development, LLC. The interpretation and reporting of research using this data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or Janssen Research and Development, LLC. Dr Khan has received personal fees from Merck. Dr Patel has served as a consultant to Novo Nordisk. Dr DeVore has received research funding through his institution from the American Heart Association, Biofourmis, Bodyport, Cytokinetics, American Regent Inc, the National Heart, Lung, and Blood Institute, Novartis, and Story Health; has provided consulting services for and/or received honoraria from Abiomed, AstraZeneca, Cardionomic, InnaMed, LivaNova, Natera, Novartis, Procyrion, Story Health, Vifor, and Zoll; and has received nonfinancial support from Abbott for educational and research activities. Dr Vaduganathan is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (National Institutes of Health/National Center for Advancing Translational Sciences Award UL 1TR002541); and has served on advisory boards or has received research grant support from American Regent, Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, and Relypsa. Dr Lam has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as a consultant or on advisory boards/steering committees/executive committees for Actelion, Alleviant Medical, Allysta, Amgen, ANaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma, EchoNous, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and Development, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, Us2.ai and WebMD Global; and has served as cofounder and non-executive director of Us2.ai. Dr Zannad has received personal fees from Boehringer Ingelheim during the conduct of the study; has received personal fees from Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, Bayer, and Cellprothera outside of the submitted work; and has received other support from cardiovascular clinical trialists and Cardiorenal outside of the submitted work. Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; has received research grants and honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, PhaseBio, and Pfizer; has received honoraria from Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; is a member of the scientific excellence committee of the EMPEROR-Reduced trial (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure With Reduced Ejection Fraction); has served as a national lead investigator of the DAPA-HF and EMPEROR-Reduced trials; and is the president of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr Butler has received consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd, and Vifor. Dr Pandey has received grant funding outside the present study from Applied Therapeutics; has received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly, USA, Rivus, and Roche Diagnostics; has received nonfinancial support from Pfizer and Merck; is supported by the Texas Health Resources Clinical Scholarship, Gilead Sciences Research Scholar Program, and the National Institute of Aging GEMSSTAR Grant (1R03AG067960-01); and has received grant support from Applied 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.)

Diabetes Technology Society assembled a panel of clinician experts in diabetology, cardiology, clinical chemistry, nephrology, and primary care to review the current evidence on biomarker screening of people with diabetes (PWD) for heart failure (HF), who are, by definition, at risk for HF (Stage A HF). This consensus report reviews features of HF in PWD from the perspectives of 1) epidemiology, 2) classification of stages, 3) pathophysiology, 4) biomarkers for diagnosing, 5) biomarker assays, 6) diagnostic accuracy of biomarkers, 7) benefits of biomarker screening, 8) consensus recommendations for biomarker screening, 9) stratification of Stage B HF, 10) echocardiographic screening, 11) management of Stage A and Stage B HF, and 12) future directions. The Diabetes Technology Society panel recommends 1) biomarker screening with one of two circulating natriuretic peptides (B-type natriuretic peptide or N-terminal prohormone of B-type natriuretic peptide), 2) beginning screening five years following diagnosis of type 1 diabetes (T1D) and at the diagnosis of type 2 diabetes (T2D), 3) beginning routine screening no earlier than at age 30 years for T1D (irrespective of age of diagnosis) and at any age for T2D, 4) screening annually, and 5) testing any time of day. The panel also recommends that an abnormal biomarker test defines asymptomatic preclinical HF (Stage B HF). This diagnosis requires follow-up using transthoracic echocardiography for classification into one of four subcategories of Stage B HF, corresponding to risk of progression to symptomatic clinical HF (Stage C HF). These recommendations will allow identification and management of Stage A and Stage B HF in PWD to prevent progression to Stage C HF or advanced HF (Stage D HF)., Competing Interests: Declaration of Competing Interests APandey has received research support from the National Institute on Aging GEMSSTAR Grant (1R03AG067960-01), and the National Institute on Minority Health and Disparities (R01MD017529). APandey has received grant funding from Applied Therapeutics and Gilead Sciences; has received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc., Lilly USA, Rivus, Cytokinetics, Pieces Technologies, and Roche Diagnostics, and has received nonfinancial support from Pfizer and Merck. APandey is also a consultant for Palomarin Inc. with stock compensation. CMR has received funding from AstraZeneca, Dexcom Inc., Fresenius, Nutricia, and Recor. VNS' employer, University of Colorado, receives research support from Sanofi, NovoNordisk, Insulet, Dexcom, Tandem Diabetes Care, JDRF and NIH, and received honorarium from Dexcom, Insulet, NovoNordisk, Medscape, Lifescan and Tandem Diabetes Care for speaking or advisory role. ABG has received honoraria for lectures/ advisory boards from Abbott, AstraZeneca, Boehirnger Ingelheim, Roche Diagnostics, and Vifor. JB is a consultant for Abbott, Adrenomed, Amgen, Applied Therapeutics, American Regent, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Medtronic, Merck, Novartis, NovoNordisk, Occlutech, Relypsa, Roche, Sequana, and Vifor. RMB has received research support, has acted as a consultant, or has been on the scientific advisory board for Abbott Diabetes Care, Ascensia, Bigfoot Biomedical, Inc., CeQur, DexCom, Eli Lilly, Hygieia, Insulet, Medtronic, Novo Nordisk, Onduo, Roche Diabetes Care, Sanofi, United Healthcare, Vertex Pharmaceuticals and Zealand Pharma. RMB's employer, non-profit HealthPartners Institute, contracts for his services for which he receives no personal income. SJG has received research support from the Duke University Department of Medicine Chair's Research Award, American Heart Association (#929502), Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim/Lilly, Cytokinetics, Roche Diagnostics, scPharmaceuticals, and Sanofi; has received speaker fees from Boehringer Ingelheim and Cytokinetics; and serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Corteria Pharmaceuticals, CSL Vifor, Merck, PharmaIN, Roche Diagnostics, Sanofi, Tricog Health, and Urovant Pharmaceuticals. MNK is a consultant or on the advisory board for Alnylam, Amgen, Applied Therapeutics, Astra Zeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, Vifor Pharma, and Youngene. MNK received other research support from Astra Zeneca. MNK received honorariums from Astra Zeneca, Boehringer Ingelheim, and Novo Nordisk. LAL has received research funding from, has provided CME on behalf of and/or has acted as an advisor to Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion, HLS, Kowa, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi and Servier and is on a DSMB for Applied Therapeutics. BM was speaker honorarium and member of advisory board of Astra Zeneca, Boehringer Ingelheim, Novo Nordisk. CM serves or has served on the advisory panel for Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Imcyse, Insulet, Zealand Pharma, Avotres, Mannkind, Sandoz and Vertex. Financial compensation for these activities has been received by KU Leuven; KU Leuven has received research support for CM from Medtronic, Imcyse, Novo Nordisk, Sanofi and ActoBio Therapeutics; CM serves or has served on the speakers bureau for Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, Astra Zeneca and Novartis. Financial compensation for these activities has been received by KU Leuven. TWM provides research support and speaking support for Abbott Diabetes Care, Dexcom, Medtronic, Novo Nordisk, Lilly Diabetes, and Sanofi; research support for Insulet Corporation and Novo Nordisk; and is on the advisory panel for Dexcom and Medscape. All funds from all activities are managed by his employer, non-profit HealthPartners Institute dba International Diabetes Center and TWM receives no personal income from these activities. VM has acted as consultant and speaker, received research or educational grants from Sanofi, Novo Nordisk, MSD, Eli Lilly, Novartis, Boehringer Ingelheim, Lifescan J & J, Roche Diagnostics, Abbott, USV, Dr. Reddy’s Laboratories, Sun Pharma and from several Indian pharmaceutical companies. KVP has served as a consultant to Novo Nordisk. APeters received research support from Abbott, Dexcom, and Insulet; was on the advisory board for Zealand, Vertez, and Medscape; and has stock options in Omada/Teladoc. YS was on the advisory board for Roche Diagnostics and Abbott Diagnostics and was a a speaker for Roche Diagnostics. YS has a patent: 20210401347. JJS is faculty at Lifescan Diabetes Institute. GU has received research grant support from Dexcom and Abbott. GU's employer, Emory University, has received funding from Bayer. DCK is a consultant for EOFlow, Integrity, Lifecare, Rockley Photonics, and Thirdwayv. AMY, JH, DK, RP-B, LB, YMB, GAF, GG, ER, GMCR, DBS, KW, EEW, and AHBW have nothing relevant to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Sex-associated differences in clinical outcomes among left ventricular assist device recipients in the United States have been recognized. However, an investigation of the social and clinical determinants of sex-associated differences is lacking., Methods: Left ventricular assist device receiving patients enrolled in Interagency Registry for Mechanically Assisted Circulatory Support between 2005 and 2017 were included. The primary outcome was all-cause mortality. Secondary outcomes included heart transplantation and postimplantation adverse event rates. The cohort was stratified by the social subgroup of race and ethnicity (non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, and Hispanic), and clinical subgroups of device strategy (destination therapy, bridge to transplant, and bridge to candidacy), and implantation center volume (low [≤20 implants/y], medium [21-30 implants/y], and high [>30 implants/y]). A multivariable-adjusted Cox proportional hazard model was used to assess the risk of death and heart transplantation with prespecified interaction testing. Poisson regression was used to estimate adverse events by sex across the various subgroups., Results: Among 18 525 patients, there were 3968 (21.4%) females. Compared with their male counterparts, Hispanic (adjusted hazard ratio [HR adj ], 1.75 [1.23-2.47]) females had the highest risk of death followed by non-Hispanic White females (HR adj , 1.15 [1.07-1.25]; P interaction =0.02). Hispanic (HR adj , 0.60 [0.40-0.89]) females had the lowest cumulative incidence of heart transplantation followed by non-Hispanic Black females (HR adj , 0.76 [0.67-0.86]), and non-Hispanic White females (HR adj , 0.88 [0.80-0.96]) compared with their male counterparts ( P interaction <0.001). Compared with their male counterparts, females on the bridge to candidacy strategy (HR adj , 1.32 [1.18-1.48]) had the highest risk of death ( P interaction =0.01). The risk of death ( P interaction =0.44) and cumulative incidence of heart transplantation ( P interaction =0.40) did not vary by sex in the center volume subgroup. A higher incidence rate of adverse events after left ventricular assist device implantation was also seen in females compared with the males, overall, and across all subgroups., Conclusions: Among left ventricular assist device recipients, the risk of death, the cumulative incidence of heart transplantation, and adverse events differ by sex across the social and clinical subgroups., Competing Interests: Disclosures None.

Aims: Ketone bodies (KB) are an important alternative metabolic fuel source for the myocardium. Experimental and human investigations suggest that KB may have protective effects in patients with heart failure. This study aimed to examine the association between KB and cardiovascular outcomes and mortality in an ethnically diverse population free from cardiovascular disease (CVD)., Methods and Results: This analysis included 6796 participants (mean age 62 ± 10 years, 53% women) from the Multi-Ethnic Study of Atherosclerosis. Total KB was measured by nuclear magnetic resonance spectroscopy. Multivariable-adjusted Cox proportional hazard models were used to examine the association of total KB with cardiovascular outcomes. At a mean follow-up of 13.6 years, after adjusting for traditional CVD risk factors, increasing total KB was associated with a higher rate of hard CVD, defined as a composite of myocardial infarction, resuscitated cardiac arrest, stroke, and cardiovascular death, and all CVD (additionally included adjudicated angina) [hazard ratio, HR (95% confidence interval, CI): 1.54 (1.12-2.12) and 1.37 (1.04-1.80) per 10-fold increase in total KB, respectively]. Participants also experienced an 87% (95% CI: 1.17-2.97) increased rate of CVD mortality and an 81% (1.45-2.23) increased rate of all-cause mortality per 10-fold increase in total KB. Moreover, a higher rate of incident heart failure was observed with increasing total KB [1.68 (1.07-2.65), per 10-fold increase in total KB]., Conclusion: The study found that elevated endogenous KB in a healthy community-based population is associated with a higher rate of CVD and mortality. Ketone bodies could serve as a potential biomarker for cardiovascular risk assessment., Competing Interests: Conflict of interest statement F.R. reported receiving funding support from the National Heart, Lung, and Blood Institute, National Institutes of Health (1K01HL144607), Doris Duke Charitable Foundation, and the American Heart Association/Robert Wood Johnson Harold Amos Medical Faculty Development Program and consulting fees from Novartis, NovoNordisk, Amgen, and HealthPals. C.d.F. has received consulting fees from Abbott Diagnostics, FujiRebio, Ortho Diagnostics, Quidell, Roche Diagnostics, Siemens Healthineers, and a patent entitled ‘Methods for assessing differential risk for developing heart failure’ (patent number: PCT/US2015/029838). M.B. reported receiving funding support from the National Institutes of Health, the American Heart Association, the Food and Drug Administration, and NovoNordisk and consulting fees from Kowa. A.P. reported receiving funding support from the National Institute on Minority Health and Disparities (R01MD017529), National Institute on Aging GEMSSTAR Grant (1R03AG067960–01), Gilead Sciences, and has received consulting fees from Tricog Health Inc and Cytokinetics. M.V. has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, and Sanofi, speaker engagements with Novartis and Roche Diagnostics, and participates on clinical trial committees for studies sponsored by Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. M.D.S. reported receiving funding support from the National Institute Health, Amgen, Novartis, Regeneron and served on scientific advisory boards for Amgen, Novartis, Novo Nordisk, Esperion, Regeneron, Ionis. All other authors declare that they have no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Natriuretic peptides, brain (B-type) natriuretic peptide (BNP) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are globally and most often used for the diagnosis of heart failure (HF). In addition, they can have an important complementary role in the risk stratification of its prognosis. Since the development of angiotensin receptor-neprilysin inhibitors (ARNIs), the use of natriuretic peptides as therapeutic agents has grown in importance. The present document is the result of the Trilateral Cooperation Project among the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America and the Japanese Heart Failure Society. It represents an expert consensus that aims to provide a comprehensive, up-to-date perspective on natriuretic peptides in the diagnosis and management of HF, with a focus on the following main issues: (1) history and basic research: discovery, production and cardiovascular protection; (2) diagnostic and prognostic biomarkers: acute HF, chronic HF, inclusion/endpoint in clinical trials, and natriuretic peptide-guided therapy; (3) therapeutic use: nesiritide (BNP), carperitide (ANP) and ARNIs; and (4) gaps in knowledge and future directions., (© 2023 Elsevier Inc and European Society of Cardiology. Published by Elsevier Inc and Wiley. All rights reserved.)

Background: The contemporary measures of hospital performance for heart failure hospitalization and 30-day risk-standardized readmission rate (RSRR) and risk-standardized mortality rate (RSMR) are estimated using the same risk adjustment model and overall event rate for all patients. Thus, these measures are mainly driven by the care quality and outcomes for the majority racial and ethnic group, and may not adequately represent the hospital performance for patients of Black and other races., Methods: Fee-for-service Medicare beneficiaries from January 2014 to December 2019 hospitalized with heart failure were identified. Hospital-level 30-day RSRR and RSMR were estimated using the traditional race-agnostic models and the race-specific approach. The composite race-specific performance metric was calculated as the average of the RSRR/RMSR measures derived separately for each race and ethnicity group. Correlation and concordance in hospital performance for all patients and patients of Black and other races were assessed using the composite race-specific and race-agnostic metrics., Results: The study included 1 903 232 patients (75.7% White [n=1 439 958]; 14.5% Black [n=276 684]; and 9.8% other races [n=186 590]) with heart failure from 1860 hospitals. There was a modest correlation between hospital-level 30-day performance metrics for patients of White versus Black race (Pearson correlation coefficient: RSRR=0.42; RSMR=0.26). Compared with the race-agnostic RSRR and RSMR, composite race-specific metrics for all patients demonstrated stronger correlation with RSRR (correlation coefficient: 0.60 versus 0.74) and RSMR (correlation coefficient: 0.44 versus 0.51) for Black patients. Concordance in hospital performance for all patients and patients of Black race was also higher with race-specific (versus race-agnostic) metrics (RSRR=64% versus 53% concordantly high-performing; 61% versus 51% concordantly low-performing). Race-specific RSRR and RSMR metrics (versus race-agnostic) led to reclassification in performance ranking of 35.8% and 39.2% of hospitals, respectively, with better 30-day and 1-year outcomes for patients of all race groups at hospitals reclassified as high-performing., Conclusions: Among patients hospitalized with heart failure, race-specific 30-day RSMR and RSRR are more equitable in representing hospital performance for patients of Black and other races.

Background: Randomized controlled trials (RCTs) may report outcomes different from those prespecified on trial-registration websites, protocols and statistical analysis plans (SAPs). This study sought to investigate the prevalence and characteristics of heart failure (HF) RCTs that report outcomes different from those prespecified., Methods and Results: MEDLINE via PubMed was searched to include phase II-IV HF RCTs in 9 high-impact journals from 2010 to 2020. Outcomes reported in trial publications were compared with prespecified outcomes in protocols, registration websites and SAPs. We used the χ 2 or Fisher exact test to analyze correlations between trial characteristics and inconsistencies. Among 216 trials, 32 inconsistencies were observed in 28 trials (13.0%). Among 32 inconsistencies, 2 (6.3%) pertained to omission of prespecified primary outcomes, 4 (12.5%) to omission of prespecified secondary outcomes, 2 (6.3%) to changing prespecified primary outcomes to secondary outcomes, and 2 (6.3%) to changing prespecified secondary outcomes to primary outcomes. Of the inconsistencies, 3 (9.4%) pertained to addition of new primary outcomes, 17 (53.1%) to addition of new secondary outcomes, and 2 (6.3%,) to changes in the timing of assessment of primary outcomes. The majority of the inconsistencies favored statistically significant findings; 78 (36.1%) were registered retrospectively. Single-center recruitment was associated with outcome inconsistencies (β = -0.14; 95% CI, -0.22 - -0.01; P = 0.035)., Conclusions: More than 1 in 10 trials reported outcomes inconsistent with those specified in trial registration websites, SAPs and protocols. An action plan is warranted to minimize selective reporting and improve transparency., Competing Interests: Disclosures SJG has received research support from the American Heart Association, Amgen, AstraZeneca, Bristol-Myers Squibb, Cytokinetics, Merck, Novartis, and Pfizer; has served on advisory boards for Amgen, AstraZeneca, and Cytokinetics; and has served as a consultant for Amgen, Bayer, Merck and Vifor. AP is supported by the Texas Health Resources Clinical Scholarship, the Gilead Sciences Research Scholar Program, the National Institute of Aging GEMSSTAR Grant (1R03AG067960-01), and Applied Therapeutics; has served on the advisory board for Roche Diagnostics; and has received nonfinancial support from Pfizer and Merck. MV has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Relypsa, and Roche Diagnostics, performs speaker engagements with Novartis and Roche Diagnostics, and participates on clinical endpoint committees for studies sponsored by Galmed and Novartis. HGCVS is funded by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada. RJM has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Medtronic, Merck, Novartis, Roche, Sanofi, and Vifor. GCF reports research funding from the NIH and serving as a consultant for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Edwards, Janssen, Medtronic, Merck, and Novartis. All other authors declare no disclosures., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Few studies characterize the epidemiology and outcomes of aortic stenosis (AS) in acute decompensated heart failure (ADHF). This study investigates the significance of AS in contemporary patients who have experienced an ADHF hospitalization., Methods: The ARIC study (Atherosclerosis Risk in Communities) surveilled ADHF hospitalizations for residents ≥55 years of age in 4 US communities. ADHF cases were stratified by left ventricular ejection fraction (LVEF). Demographic differences in AS burden and the association of varying AS severities with mortality were estimated using multivariable logistic regression., Results: From 2005 through 2014, there were 3597 (weighted n=16 692) ADHF hospitalizations of which 48.6% had an LVEF <50% and 51.4% an LVEF ≥50%. AS prevalence was 12.1% and 18.7% in those with an LVEF <50% and ≥50%, respectively. AS was less likely in Black than White patients regardless of LVEF: LVEF <50% (odds ratio [OR], 0.34 [95% CI, 0.28-0.42]); LVEF ≥50% (OR, 0.51 [95% CI, 0.44-0.59]). Higher AS severity was independently associated with 1-year mortality in both LVEF subgroups: LVEF <50% (OR, 1.16 [95% CI, 1.04-1.28]); LVEF ≥50% (OR, 1.40 [95% CI, 1.28-1.54]). Sensitivity analyses excluding severe AS patients detected that mild/moderate AS was independently associated with 1-year mortality in both LVEF subgroups: LVEF <50% (OR, 1.23 [95% CI, 1.02-1.47]); LVEF ≥50% (OR, 1.31 [95% CI, 1.14-1.51])., Conclusions: Among patients who have experienced an ADHF hospitalization, AS is prevalent and portends poor mortality outcomes. Notably, mild/moderate AS is independently associated with 1-year mortality in this high-risk population.