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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.)

Digital health technologies can generate data that can be used to train artificial intelligence (AI) algorithms, which have been particularly transformative in cardiovascular health-care delivery. However, digital and health-care data repositories that are used to train AI algorithms can introduce bias when data are homogeneous and health-care processes are inequitable. AI bias can also be introduced during algorithm development, testing, implementation, and post-implementation processes. The consequences of AI algorithmic bias can be considerable, including missed diagnoses, misclassification of disease, incorrect risk prediction, and inappropriate treatment recommendations. This bias can disproportionately affect marginalised demographic groups. In this Series paper, we provide a brief overview of AI applications in cardiovascular health care, discuss stages of algorithm development and associated sources of bias, and provide examples of harm from biased algorithms. We propose strategies that can be applied during the training, testing, and implementation of AI algorithms to mitigate bias so that all those at risk for or living with cardiovascular disease might benefit equally from AI., Competing Interests: Declaration of interests AP has received research support from the National Institutes of Health; received grant funding from Applied Therapeutics and Gilead Sciences; received consulting fees for Tricog, Novo Nordisk, Bayer, Medtronic, Edward Lifesciences, Cytokinetics, Roche, Sarfez Pharma, Science37, Rivus, Axon Therapies, Alleviant, and Lilly; received non-financial support from Pfizer and Merck; participated on data and safety monitoring boards for Bayer, Cytokinetics, Novo Nordisk, and Medtronic; and is a consultant for Palomarin with stocks compensation. HCGV and AM declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. 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.)

Heart failure (HF) is a leading cause of hospitalization in older adults. Patients are at high risk of readmission and death following hospitalization for HF. There is no standard approach of health care delivery during the hospital-to-home transition period, leaving missed opportunities in care optimization. In this review, we discuss contemporary randomized clinical trials that tested decongestion strategies, disease-modifying therapies, and health care services that inform the care of patients with worsening HF. We provide evidence-informed recommendations for optimizing therapies and improving outcomes during and following hospitalization for HF. These include adequate decongestion with loop diuretics and select sequential nephron blockade strategies based on early evaluation of diuretic response; initiation of disease-modifying pharmacotherapies prior to hospital discharge with close follow-up and optimization after discharge; cardiac rehabilitation; and transitional or palliative care referral post-hospitalization. Evidence-based implementation strategies to facilitate broad uptake include digital health tools and algorithm-driven optimization of pharmacotherapies., Competing Interests: Dr Sauer has received research funding from 10.13039/100000046Abbott, 10.13039/100008497Boston Scientific, and 10.13039/100006520Edwards Lifesciences; and speaking and advising compensation from Acorai, Story Health, Boston Scientific, General Prognostics, Abbott, Impulse Dynamics, Bayer, and Biotronik. Dr Greene has received research support from the 10.13039/100005572Duke 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 or as consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Lilly, Bristol Myers Squibb, Corteria, CSL Vifor, Cytokinetics, Lexicon, Roche Diagnostics, Merck, PharmaIN, Sanofi, scPharmaceuticals, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Bayer, Boehringer Ingelheim, Cytokinetics, Lexicon, and Roche Diagnostics. Dr Albert received research funding from 10.13039/100004325AstraZeneca and 10.13039/100008272Novartis within the last 2 years and is a consultant to American Regent, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Merck, and Roche. Dr Spall is funded by the 10.13039/501100000024Canadian Institutes of Health Research and has research support from Medtronic and educational grants from 10.13039/100008272Novartis and 10.13039/100001003Boehringer Ingelheim. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Results from the COORDINATE-Diabetes trial (Coordinating Cardiology Clinics Randomized Trial of Interventions to Improve Outcomes - Diabetes) demonstrated that a multifaceted, clinic-based intervention increased prescription of evidence-based medical therapies to participants with type 2 diabetes and atherosclerotic cardiovascular disease. This secondary analysis assessed whether intervention success was consistent across sex, race, and ethnicity., Methods: COORDINATE-Diabetes, a cluster randomized trial, recruited participants from 43 US cardiology clinics (20 randomized to intervention and 23 randomized to usual care). The primary outcome was the proportion of participants prescribed all 3 groups of evidence-based therapy (high-intensity statin, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and sodium-glucose cotransporter-2 inhibitor or glucagon-like peptide 1 receptor agonist) at last trial assessment (6 to 12 months). In this prespecified analysis, mixed-effects logistic regression models were used to assess the outcome by self-reported sex, race, and ethnicity in the intervention and usual care groups, with adjustment for baseline characteristics, medications, comorbidities, and site location., Results: Among 1045 participants with type 2 diabetes and atherosclerotic cardiovascular disease, the median age was 70 years, 32% were female, 16% were Black, and 9% were Hispanic. At the last trial assessment, there was an absolute increase in the proportion of participants prescribed all 3 groups of evidence-based therapy in women (36% versus 15%), Black participants (41% versus 18%), and Hispanic participants (46% versus 18%) with the intervention compared with usual care, with consistent benefit across sex (male versus female; P interaction =0.44), race (Black versus White; P interaction =0.59), and ethnicity (Hispanic versus Non-Hispanic; P interaction = 0.78)., Conclusions: The COORDINATE-Diabetes intervention successfully improved delivery of evidence-based care, regardless of sex, race, or ethnicity. Widespread dissemination of this intervention could improve equitable health care quality, particularly among women and minority communities who are frequently underrepresented in clinical trials., Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03936660., Competing Interests: Dr Tannu has received funding from the National Institutes of Health (T32HL069749). Dr Pagidipati reported receiving personal fees from Boehringer Ingelheim, Lilly, AstraZeneca, Novartis, Novo Nordisk, Merck, and CRISPR Therapeutics and receiving grants from Amgen, Novartis, Novo Nordisk, and Eggland’s Best. Dr Nelson reported receiving personal fees from Boehringer Ingelheim, AstraZeneca, Amgen, Novartis, and Sanofi. Dr McGuire reported receiving personal fees from Duke Clinical Research Institute, AstraZeneca, Novo Nordisk, Esperion Therapeutics, Lilly, CSL Behring, Afimmune, Boehringer Ingelheim, Merck, Pfizer, Bayer, Lexicon Pharmaceuticals, Altimmune, Intercept Pharmaceuticals, and Applied Therapeutics. Dr Pop-Busui reported receiving personal fees from Boehringer Ingelheim, Roche, Procter & Gamble, and Lexicon Pharmaceuticals; receiving grants from JDRF (formerly the Juvenile Diabetes Research Foundation), Novo Nordisk, and Medtronic; and being on the board of directors and president of medicine and science for the American Diabetes Association. Dr Cavender reported receiving personal fees from Duke Clinical Research Institute, Novo Nordisk, Bayer, Medtronic, Boehringer Ingleheim, Zoll, Merck, Amgen, and Edwards Lifesciences and receiving grants from AstraZeneca, Novartis, Amgen, CSL Behring, and Boehringer-Ingelheim. Dr Aroda reported receiving personal fees from Duke Clinical Research Institute, Applied Therapeutics, Pfizer, Fractyl Health, Lilly, Novo Nordisk, and Sanofi and that her spouse is an employee of Janssen Pharmaceuticals and receives salary and employee benefits. Dr Richardson reported receiving grants from Blue Cross Blue Shield of Michigan and the Nielsen Foundation and receiving personal fees from the Annals of Family Medicine for serving as a diabetes editor. Dr Lingvay reported receiving grants from Novo Nordisk, Boehringer Ingelheim, Sanofi, Structure Therapeutics, Merck, Pfizer, and Mylan and receiving personal fees from Novo Nordisk, Boehringer Ingelheim, Lilly, Sanofi, Zealand Pharma, Target RWE, Shionogi & Co, Pfizer, Johnson & Johnson, Carmot Therapeutics, Altimmune, Merck, Valeritas, Intercept Pharmaceuticals, and Bayer. Dr Al-Khalidi reported receiving personal fees from Medpace Holdings Inc and CSL Behring. T. Gaynor reported being an employee of Boehringer Ingelheim Pharmaceuticals, Inc. Dr Pak reported being an employee of Eli Lilly and Co. Dr Lopes reported receiving personal fees from Bayer, Boehringer Ingleheim, Bristol Myers Squibb, Daiichi Sankyo, GSK (formerly GlaxoSmithKline), Medtronic, Merck, Pfizer, Portola Pharmaceuticals, and Sanofi and receiving grants from Bristol Myers Squibb, GSK, Medtronic, Pfizer, and Sanofi. Dr Green reported receiving personal fees from Boehringer Ingelheim, Lilly, Bayer, Novo Nordisk, Pfizer, AstraZeneca, Sanofi, Hawthorne Effect, Omada Health, Vertex Pharmaceuticals, Valo Therapeutics, and Anji Pharmaceuticals and receiving grants from Merck, Roche, Sanofi, and Lexicon Pharmaceuticals. Dr Granger reported receiving personal fees from AbbVie, Abiomed, Alnylam Pharmaceuticals, Anthos Therapeutics, Bayer, Boston Scientific, Bristol Myers Squibb, Cardionomic, CeleCor Therapeutics, Cadrenal Therapeutics, Janssen Pharmaceuticals, Medscape, Medtronic, Merck, Novo Nordisk, Novartis, PLx Pharma, Pfizer, Philips, Reata Pharmaceuticals, and NephroSynergy; receiving grants from Bristol Myers Squibb, Janssen Pharmaceuticals, Novartis, Pfizer, and Philips; and having equity in Tenac.io. The other authors reported no conflicts. This research was made possible in part by a collaborative grant with Boehringer Ingelheim Pharmaceuticals, Inc and Lilly USA, LLC, which provided financial support for the study. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors and were fully responsible for all aspects of the trial and publication development.

Background: Elevated interleukin (IL)-6 levels have been linked to adverse outcomes in patients with and without baseline cardiovascular disease (CVD)., Objectives: The purpose of this study was to examine the association between circulating IL-6 levels and CVD events without baseline CVD across racial and ethnic groups., Methods: We conducted an observational analysis utilizing the MESA (Multi-Ethnic Study of Atherosclerosis), a multicenter, prospective community-based study of CVD at baseline from four racial and ethnic groups. IL-6 levels were measured at the time of enrollment (visit 1) and were divided into 3 terciles. Patient baseline characteristics and outcomes, including all-cause mortality, CV mortality, heart failure, and non-CV mortality, were included. Cox proportional hazard regression models were used to assess associations between IL-6 levels and study outcomes with IL-6 tercile 1 as reference., Results: Of 6,622 individuals, over half were women (53%) with a median age of 62 (IQR: 53-70) years. Racial and ethnic composition was non-Hispanic White (39%) followed by African American (27%), Hispanic (22%), and Chinese American (12%). Compared to tercile 1, participants with IL-6 tercile 3 had a higher adjusted risk of and all-cause mortality (HR: 1.98 [95% CI: 1.67-2.36]), CV mortality (HR: 1.55 [95% CI: 1.05-2.30]), non-CV mortality (HR: 2.05 [95% CI: 1.65-2.56]), and heart failure (HR: 1.48 [95% CI: 0.99-2.19]). When tested as a continuous variable, higher levels of IL-6 were associated with an increased risk of all individual outcomes. Compared to non-Hispanic White participants, the unadjusted and adjusted risk of all outcomes across all races and ethnicities was similar across all IL-6 terciles., Conclusions: High levels of circulating IL-6 are associated with worse CV outcomes and increased all-cause mortality consistently across all racial and ethnic groups., Competing Interests: Dr Rymer has received research grant support from 10.13039/100007560Chiesi Pharmaceuticals, 10.13039/501100016198Idorsia Pharmaceuticals, and the 10.13039/100000968American Heart Association; and personal fees from Chiesi Pharmaceuticals outside the submitted work. Dr Borlaug has received research support from the 10.13039/100000002National Institutes of Health (R01 HL128526, R01 HL162828, and U01 HL160226) and the 10.13039/100000005United States Department of Defense (W81XWH2210245); has received research grant funding from 10.13039/100004325AstraZeneca, Axon, 10.13039/100004330GlaxoSmithKline, 10.13039/100004374Medtronic, Mesoblast, 10.13039/100015758Novo Nordisk, and 10.13039/100016949Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Janssen, Merck, and Novo Nordisk; and is a named inventor (US Patent no. 10307179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Cikes has received research grants and clinical study contracts to institution from 10.13039/100004336Novartis, 10.13039/100000046Abbott, 10.13039/100004319Pfizer, and CorVia; and personal fees and nonfinancial support from 10.13039/100004319Pfizer, 10.13039/100004326Bayer, 10.13039/100001003Boehringer Ingelheim, 10.13039/100004325AstraZeneca, 10.13039/100004336Novartis, Swixx, 10.13039/100020297Abiomed, 10.13039/100015362Amicus, 10.13039/100002429Amgen, 10.13039/100015758Novo Nordisk, 10.13039/100004374Medtronic, 10.13039/100006775GE Healthcare, 10.13039/100006259Teva Pharmaceutical Industries, and Krka Pharma. Dr Docherty reports that his employer, the University of Glasgow, has been remunerated by AstraZeneca for work relating to clinical trials; he has received speaker honoraria from AstraZeneca, Pharmacosmos, and Radcliffe Cardiology; has served on an advisory board for Us2.ai and Bayer AG; has served on a clinical end point committee for Bayer AG; and has received grant support from 10.13039/100001003Boehringer Ingelheim, 10.13039/100016545Roche Diagnostics, and 10.13039/100004325AstraZeneca (paid to his institution). Dr Pandey is supported by the Texas Health Resources Clinical Scholarship, the 10.13039/100005564Gilead Sciences Research Scholars Program, the 10.13039/100000049National Institute on Aging GEMSSTAR Grant (1R03AG067960-01) and Applied Therapeutics; has served on the advisory board for Roche Diagnostics; and has received nonfinancial support from 10.13039/100004319Pfizer and 10.13039/100004334Merck. Dr Kahles has served as a consultant to Bayer and Novo Nordisk and has served as a speaker for Novo Nordisk. Dr Lam is supported by a Clinician Scientist Award from the 10.13039/501100001349National Medical Research Council of Singapore; has received research support from 10.13039/100004326Bayer and 10.13039/100016545Roche Diagnostics; has served as consultant or on the Advisory Board, Steering Committee, or Executive Committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and has served as cofounder and non–executive director of Us2.ai. The employer of AAV has received consultancy fees and research support from AnaCardio, 10.13039/100004325AstraZeneca, 10.13039/100002491BMS, 10.13039/100004326Bayer, 10.13039/100001003Boehringer Ingelheim, Corteria, EliLilly, 10.13039/100004334Merck, 10.13039/100019533Moderna, 10.13039/100004336Novartis, 10.13039/100015758Novo Nordisk, 10.13039/100016545Roche Diagnostics. Dr Hernandez has received grants from Intellia Therapeutics; compensation from Prolaio for consultant services; grants from 10.13039/100004326Bayer; compensation from Eli Lilly and Company for consultant services; compensation from Novo Nordisk for consultant services; employment by Duke Clinical Research Institute; compensation from Intercept Pharmaceuticals, Inc, for data and safety monitoring services; grants from 10.13039/100001003Boehringer Ingelheim; compensation from CSL Behring for consultant services; compensation from Boehringer Ingelheim for consultant services; compensation from Amgen for consultant services; compensation from Novartis for consultant services; grants from 10.13039/100018044Verily; compensation from Merck for consultant services; grants from 10.13039/100016473American Regent; compensation from AstraZeneca for consultant services; compensation from Eidos for data and safety monitoring services; compensation from Cytokinetics for consultant services; grants from 10.13039/100015758Novo Nordisk Inc, 10.13039/100004336Novartis, AstraZeneca, and 10.13039/100001238Merck; compensation from Bayer for consultant services; and compensation from Boston Scientific Corporation and Intellia Therapeutics for consultant services. Dr Lincoff has received Esperion research funding for this trial; grants from Eli Lilly, 10.13039/100006483AbbVie, 10.13039/100008322CSL, 10.13039/100004325AstraZeneca, and 10.13039/100004336Novartis; and personal fees from Novo Nordisk, Glaxo, Akebia, Endologix, Fibrogen, Provention, and Becton Dickson. Dr Petrie has received grants from 10.13039/100001003Boehringer Ingelheim, 10.13039/100004337Roche, SQ Innovations, Astra Zeneca, 10.13039/100004336Novartis, 10.13039/100015758Novo Nordisk, 10.13039/100004374Medtronic, 10.13039/100008497Boston Scientific, Horizon, Pharmacosmos; consulting fees from Boehringer Ingelheim, Novartis, AstraZeneca, Novo Nordisk, Abbvie, Bayer, Takeda, Corvia, Cardiorentis, Pharmacosmos, Siemens, and Vifor; lecture fees from Boehringer Ingelheim, Novartis, Astra Zeneca, Novo Nordisk, Abbvie, Bayer, Takeda, Corvia, Cardiorentis, Pharmacosmos, Siemens, and Vifor; board participation for Teikoku and Astra Zeneca; and is the Director of Global Clinical Trial Partners Ltd. Dr Ridker has received institutional research grant support from the 10.13039/100000050NHLBI, 10.13039/100004336Novartis, and 10.13039/100015758Novo Nordisk (to evaluate the role of anti-inflammatory agents including methotrexate, interleukin-1 inhibitors, and interleukin-6 inhibitors) as well as Kowa, Amarin, Pfizer, and Esperion; has served as a consultant to Novartis, Novo Nordisk, Janssen, Flame, Agepha, Ardelyx, Zomagen, Horizon Therapeutics, CSL Behring, and Cardio Therapeutics (entities developing anti-inflammatory therapies including as examples colchicine, interleukin-1 inhibitors, interleukin-6 inhibitors, and agents that potentially target or interact with the NLRP3 inflammasome); has additionally served as a consultant to AstraZeneca, Civi Biopharm, Glaxo Smith Kline, SOCAR, Health Outlook, Montai Health, Eli Lilly, New Amsterdam, Boehringer-Ingelheim, RTI, and Cytokinetics; has minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; and has received compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute (Boston, MA). Dr Fudim was supported by the 10.13039/100000968American Heart Association (20IPA35310955), Doris Duke, 10.13039/100004326Bayer, Bodyport and Verily; has received consulting fees from Abbott, Ajax, Alio Health, Alleviant, Audicor, Axon Therapies, Bayer, BodyGuide, Bodyport, Boston Scientific, Broadview, Cadence, Cardionomics, Coridea, CVRx, Daxor, Deerfield Catalyst, Edwards Lifesciences, EKO, Feldschuh Foundation, FIRE1, Gradient, Hatteras, Impulse Dynamics, InterShunt, Medtronic, NI Medical, NXT Biomedical, Pharmacosmos, PreHealth, ReCor, Shifamed, Splendo, Summacor, SyMap, Verily, Vironix, VisCardia and Zoll outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

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.)

Steatotic liver disease (SLD) is a worldwide public health problem, causing considerable morbidity and mortality. Patients with SLD are at increased risk for major adverse cardiovascular (CV) events, type 2 diabetes mellitus and chronic kidney disease. Conversely, patients with cardiometabolic conditions have a high prevalence of SLD. In addition to epidemiological evidence linking many of these conditions, there is evidence of shared pathophysiological processes. In December 2022, a unique multi-stakeholder, multi-specialty meeting, called MOSAIC (Metabolic multi Organ Science Accelerating Innovation in Clinical Trials) was convened to foster collaboration across metabolic, hepatology, nephrology and CV disorders. One of the goals of the meeting was to consider approaches to drug development that would speed regulatory approval of treatments for multiple disorders by combining liver and cardiorenal endpoints within a single study. Non-invasive tests, including biomarkers and imaging, are needed in hepatic and cardiorenal trials. They can be used as trial endpoints, to enrich trial populations, to diagnose and risk stratify patients and to assess treatment efficacy and safety. Although they are used in proof of concept and phase 2 trials, they are often not acceptable for regulatory approval of therapies. The challenge is defining the optimal combination of biomarkers, imaging and morbidity/mortality outcomes and ensuring that they are included in future trials while minimizing the burden on patients, trialists and trial sponsors. This paper provides an overview of some of the wide array of CV, liver and kidney measurements that were discussed at the MOSAIC meeting., (© 2024 The Association for the Publication of the Journal of Internal Medicine.)

Aims: Compared with those without obesity, patients with obesity-related heart failure with preserved ejection fraction (HFpEF) have worse symptoms, haemodynamics, and outcomes. Current weight loss strategies (diet, drug, and surgical) work through decreased energy intake rather than increased expenditure and cause significant loss of skeletal muscle mass in addition to adipose tissue. This may have adverse implications for patients with HFpEF, who already have reduced skeletal muscle mass and function and high rates of physical frailty. Mitochondrial uncoupling agents may have unique beneficial effects by producing weight loss via increased catabolism rather than reduced caloric intake, thereby causing loss of adipose tissue while sparing skeletal muscle. HU6 is a controlled metabolic accelerator that is metabolized to the mitochondrial uncoupling agent 2,4-dinotrophenol. HU6 selectively increases carbon oxidation from fat and glucose while also decreasing toxic reactive oxygen species (ROS) production. In addition to sparing skeletal muscle loss, HU6 may have other benefits relevant to obesity-related HFpEF, including reduced specific tissue depots contributing to HFpEF; improved glucose utilization; and reduction in systemic inflammation via both decreased ROS production from mitochondria and decreased cytokine elaboration from excess, dysfunctional adipose., Methods: We describe the rationale and design of HuMAIN-HFpEF, a Phase 2a randomized, double-blind, placebo-controlled, dose-titration, parallel-group trial in patients with obesity-related HFpEF to evaluate the effects of HU6 on weight loss, body composition, exercise capacity, cardiac structure and function, metabolism, and inflammation, and identify optimal dosage for future Phase 3 trials., Conclusions: HuMAIN will test a promising novel agent for obesity-related HFpEF., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Cardiogenic shock after acute myocardial infarction (AMI-CS) carries significant mortality despite advances in revascularization and mechanical circulatory support. We sought to identify the process-based and structural characteristics of centers with lower mortality in AMI-CS. We analyzed 16,337 AMI-CS cases across 440 centers enrolled in the National Cardiovascular Data Registry's Chest Pain-MI Registry, a retrospective cohort database, between January 1, 2015, and December 31, 2018. Centers were stratified across tertiles of risk-adjusted in-hospital mortality rate (RAMR) for comparison. Risk-adjusted multivariable logistic regression was also performed to identify hospital-level characteristics associated with decreased mortality. The median participant age was 66 (interquartile range 57 to 75) years, and 33.0% (n = 5,390) were women. The median RAMR was 33.4% (interquartile range 26.0% to 40.0%) and ranged from 26.9% to 50.2% across tertiles. Even after risk adjustment, lower-RAMR centers saw patients with fewer co-morbidities. Lower-RAMR centers performed more revascularization (92.8% vs 90.6% vs 85.9%, p <0.001) and demonstrated better adherence to associated process measures. Left ventricular assist device capability (odds ratio [OR] 0.78 [0.67 to 0.92], p = 0.002), more frequent revascularization (OR 0.93 [0.88 to 0.98], p = 0.006), and higher AMI-CS volume (OR 0.95 [0.91 to 0.99], p = 0.009) were associated with lower in-hospital mortality. However, several such characteristics were not more frequently observed at low-RAMR centers, despite potentially reflecting greater institutional experience or resources. This may reflect the heterogeneity of AMI-CS even after risk adjustment. In conclusion, low-RAMR centers do not necessarily exhibit factors associated with decreased mortality in AMI-CS, which may reflect the challenges in performing outcomes research in this complex 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-Meyers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); Consultant: Broadview Ventures, GlaxoSmithKline, 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 Accrediation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Meyers 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-Meyers 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. oooo Dr. Fonarow reports consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Edwards, Janssen, Medtronic, Merck, and Novartis. Dr. Grodin reports consulting for Alnylam, Eidos, Sarepta, and Pfizer. Dr. Khera is a coinventor of US Pending Patent Applications. 63/177,117 and 63/346,610, unrelated to the present study; also a founder of Evidence2Health and Ensight-AI; received support from the National Heart, Lung, and Blood Institute of the National Institutes of Health (R01HL167858 and K23HL153775) and the Doris Duke Charitable Foundation (2,022,060); and receives research support from Bristol-Myers Squibb, Novo Nordisk, and BridgeBio, through Yale. The remaining authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.)

Obesity is a worsening public health epidemic that remains challenging to manage. Obesity substantially increases the risk of cardiovascular diseases and presents a significant financial burden on the healthcare system. Digital health interventions, specifically telemedicine, may offer an attractive and viable solution for managing obesity. During the COVID-19 pandemic, the need for a safer alternative to in-person visits led to the increased popularity of telemedicine. Multiple studies have tested the efficacy of telemedicine modalities, including digital coaching via videoconferencing sessions, e-health monitoring using wearable devices, and asynchronous forms of communication such as online chatrooms with counselors. In this review, we discuss the available evidence for telemedicine interventions in managing obesity, review current challenges and barriers to using telemedicine, and outline future directions to optimize the management of patients with obesity using telemedicine., (© 2024 World Obesity Federation.)

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.)

Background: Excess muscle fat is observed in obesity and associated with greater burden of cardiovascular risk factors and higher risk of mortality. Liraglutide reduces total body weight and visceral fat but its effect on muscle fat and adverse muscle composition is unknown., Methods: This is a pre-specified secondary analysis of a randomized, double-blind, placebo-controlled trial that examined the effects of liraglutide plus a lifestyle intervention on visceral adipose tissue and ectopic fat among adults without diabetes with body mass index ≥30 kg/m 2 or ≥27 kg/m 2 and metabolic syndrome. Participants were randomly assigned to a once-daily subcutaneous injection of liraglutide (target dose 3.0 mg) or matching placebo for 40 weeks. Body fat distribution and muscle composition was assessed by magnetic resonance imaging at baseline and 40-week follow-up. Muscle composition was described by the combination of thigh muscle fat and muscle volume. Treatment difference (95% confidence intervals [CI]) was calculated by least-square means adjusted for baseline thigh muscle fat. The association between changes in thigh muscle fat and changes in body weight were assessed using Spearman correlation coefficients. The effect of liraglutide versus placebo on adverse muscle composition, denoted by high thigh muscle fat and low thigh muscle volume, was explored., Results: Among the 128 participants with follow-up imaging (92.2% women, 36.7% Black), median muscle fat at baseline was 7.8%. The mean percent change in thigh muscle fat over median follow-up of 36 weeks was -2.87% among participants randomized to liraglutide (n = 73) and 0.05% in the placebo group (absolute change: -0.23% vs. 0.01%). The estimated treatment difference adjusted for baseline thigh muscle fat was -0.24% (95% CI, -0.41 to -0.06, P-value 0.009). Longitudinal change in thigh muscle fat was significantly associated with change in body weight in the placebo group but not the liraglutide group. The proportion of participants with adverse muscle composition decreased from 11.0% to 8.2% over follow-up with liraglutide, but there was no change with placebo., Conclusions: In a cohort of predominantly women with overweight or obesity in the absence of diabetes, once-daily subcutaneous liraglutide was associated with a reduction in thigh muscle fat and adverse muscle composition compared with placebo. The contribution of muscle fat improvement to the cardiometabolic benefits of liraglutide requires further study., (© 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

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.

Objective: Current guidelines for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) recommend targeting a low-density lipoprotein cholesterol (LDL-C) of < 70 mg/dL. However, temporal trends and racial/ethnic- and sex-differences in achievement of LDL-C targets are not well described. We assessed trends and racial/ethnic- and sex-differences in achievement of LDL-C < 70 mg/dL using data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2008 to 2017-March 2020., Methods: We combined NHANES cycles into 4 periods: 2005-2008, 2009-2012, 2013-2016, and 2017-March 2020 and included participants ≥ 40 years with self-reported ASCVD. We estimated LDL-C < 70 mg/dL prevalence over time and further stratified by sex and race/ethnicity. We used multivariable logistic regression adjusted for social determinants of health and clinical covariates to model LDL-C target attainment., Results: Among 1,826 NHANES participants representing 7,161,221 US adults with self-reported ASCVD (59.6% ≥ 65 years, 56.4% male, 74.8% White), LDL-C target attainment increased from 19.0% (95% CI, 15.3%-23.3%) in 2005-2008 to 26.3% (95% CI, 20.4%-33.1%) in 2017-March 2020 ( P = 0.012 for trend). Achievement of LDL-C < 70 mg/dL significantly rose among men from19.5% (95% CI, 15.1%-24.8%) to 29.4% (95% CI, 20.7%-29.9%) without significant change in women (from 18.3% [95% CI, 13.6%-24.2%] to 22.5% [95% CI, 13.0%-35.9%]; P = 0.241 for trend). Improvement in LDL-C target attainment was similar among White, Black, and Hispanic individuals (∼5-7% increase) and was greatest among individuals of other (non-White, Hispanic, or Black) race/ethnicity (23.1% increase). In our multivariable analysis, comorbid diabetes and ages 65-75 and > 75 years were associated with LDL-C target attainment., Conclusion: LDL-C control modestly improved between 2005 and 2008 and 2017-March 2020; however, only ∼1/4 of individuals met guideline-directed LDL-C treatment targets by 2017-March 2020. Women had lower LDL-C control and lesser magnitude of improvement in LDL-C control than men, highlighting a need for targeted interventions to improve lipid-lowering therapy utilization in this population., Competing Interests: We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (© 2024 The Authors. Published by Elsevier B.V.)

Aims: Adults with heart failure with preserved ejection fraction (HFpEF) responded more favorably to an exercise intervention compared to those with reduced ejection fraction. This study explores factors that contributed to this response focusing on the qualitative perceptions of adults with HFpEF enrolled in an exercise intervention., Methods and Results: This qualitative descriptive study is a secondary analysis of longitudinal interviews collected at 3, 6, 12, and 18-months from participants with HFpEF enrolled in a randomized controlled trial testing an intervention to promote adherence to exercise. We included participants with at least 2 interviews. Interviews were examined across and within participants and time points using thematic analysis. Analyses included 67 interviews from 21 adults with HFpEF enrolled in the intervention arm. The sample was 52% (11/21) male and over 47% (10/21) non-White. Mean age at enrollment was 63.7 ± 9.9 years. We identified 4 major themes: 1. Overcoming negative attitudes, barriers, and injury, 2. Motivations to exercise, 3. Exercise - the panacea for HFpEF symptoms and quality of life, and 4. Advice for others with HFpEF., Conclusions: Our findings suggest that for many adults with HFpEF, initial hesitancy, fear, and negative attitudes about exercise can be overcome. Exercise coaching using social cognitive constructs, medical fitness center memberships, and heart rate self-monitoring are successful strategies of engaging adults with HFpEF in long-term unsupervised exercise training., Registration: This study is registered at ClinicalTrials.gov, NCT01658670., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Highly bioavailable inorganic phosphate (Pi) is present in large quantities in the typical Western diet and represents a large fraction of total phosphate intake. Dietary Pi excess induces exercise intolerance and skeletal muscle mitochondrial dysfunction in normal mice. However, the relevance of this to humans remains unknown. The study was conducted on 13 individuals without a history of cardiopulmonary disease (46% female, 15% Black participants) enrolled in the pilot-phase of the Dallas Heart and Mind Study. Total dietary phosphate was estimated from 24-h dietary recall (ASA24). Muscle ATP synthesis was measured at rest, and phosphocreatinine (PCr) dynamics was measured during plantar flexion exercise using 7-T 31 P magnetic resonance (MR) spectroscopy in the calf muscle. Correlation was assessed between dietary phosphate intake normalized to total caloric intake, resting ATP synthesis, and PCr depletion during exercise. Higher dietary phosphate intake was associated with lower resting ATP synthesis ( r = -0.62, P = 0.03), and with higher levels of PCr depletion during plantar flexion exercise relative to the resting period ( r = -0.72; P = 0.004). These associations remain significant after adjustment for age and estimated glomerular filtration rate (both P < 0.05). High dietary phosphate intake was also associated with lower serum Klotho levels, and Klotho levels are in turn associated with PCr depletion and higher ADP accumulation post exercise. Our study suggests that higher dietary phosphate is associated with reduced skeletal muscle mitochondrial function at rest and exercise in humans providing new insight into potential mechanisms linking the Western diet to impaired energy metabolism. NEW & NOTEWORTHY This is the first translational research study directly demonstrating the adverse effects of dietary phosphate on muscle energy metabolism in humans. Importantly, our data show that dietary phosphate is associated with impaired muscle ATP synthesis at rest and during exercise, independent of age and renal function. This is a new biologic paradigm with significant clinical dietary implications.

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.)

Introduction/purpose: Lower cardiorespiratory fitness and obesity may accelerate aging processes. The degree to which changes in fitness and body mass index (BMI) may alter the rate of aging may be important for planning treatment. We assessed cross-sectional and longitudinal associations that cardiorespiratory fitness and BMI had with a deficit accumulation frailty index (FI)., Methods: Fitness, based on standardized graded exercise tests, and weight to calculate BMI at baseline and year 4 were collected from 3944 participants aged 45-76 yr in the Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial. A validated 38-item deficit accumulation FI was used as a marker of aging. Associations between baseline and changes in fitness and BMI with changes in FI were assessed using linear models., Results: Both baseline and 4-yr changes in fitness and BMI were independently associated with 4-yr changes in frailty (all P < 0.001). Mean (95% confidence interval) changes in FI ranged from -0.019 (-0.024, -0.013) for participants in the group with the greatest fitness increase and BMI loss to 0.029 (0.024, 0.034) for participants in the group with the greatest fitness loss and BMI gain. Associations of 4-yr changes in fitness and BMI with FI changes were similar across subgroups based on age, sex, baseline BMI, diabetes duration, and cardiovascular disease history. Increased fitness across 4 yr was associated with less FI accumulation independent of baseline fitness., Conclusions: Adults with type 2 diabetes and overweight or obesity may slow aging processes captured by an FI by increasing their cardiorespiratory fitness and losing weight., (Copyright © 2023 by the American College of Sports Medicine.)

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.)

This article examines the importance of advanced glycation endproducts (AGEs) and summarizes the structure of AGEs, pathological changes associated with AGEs, the contribution of AGEs to metabolic memory, and the value of AGEs as a predictor of diabetic complications and cardiovascular disease in people with and without diabetes. As a practical focus, skin autofluorescence (SAF) is examined as an attractive approach for estimating AGE burden. The measurement of AGEs may be of significant value to specific individuals and groups, including Black and Hispanic/Latino Americans, as they appear to have higher concentrations of hemoglobin A 1c (HbA 1c ) than would be predicted by other metrics of mean glycemia. We hypothesize that if the amount of glycation of HbA 1c is greater than expected from measured glucose levels, and if AGEs are accumulating, then this accumulation of AGEs might account for the increased rate of complications of diabetes in populations with high rates of vascular disease and other complications. Thus, identifying and modifying the burden of AGEs based on measurement of AGEs by SAF may turn out to be a worthwhile metric to determine individuals who are at high risk for the complications of diabetes as well as others without diabetes at risk of vascular disease. We conclude that available evidence supports SAF as both a clinical measurement and as a means of evaluating interventions aimed at reducing the risks of vascular disease and diabetic complications., 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: DCK is a consultant for Afon, Better Therapeutics, Integrity, Lifecare, Nevro, Novo, Samsung, and Thirdwayv. 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 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. 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). CR has received honoraria and/or grant support from AstraZeneca, Dexcom, Fresenius, and Vifor. GAF is an advisor for 180 Life Sciences, 89bio, Adocia, Abbott, AdipoPharma, Aerami, Amolyt, Carthera, Catalyst, Cohen Global, CMC Magnetics, Diasome, Eleos, Entera Bio, Enterin, Glyscend, Hagar, Hogan Lovells, IM Therapeutics, Innoneo, Intarcia, Levicure, Lilly Asia Ventures, Lumos, Mars Symbioscience, Melior, metaLead Therapeutics, Microbiotix, MMD, Modular Medical, New Amsterdam, Northwestern, NuSirt, NuVox, Oramed, Pano, Pasithea, PhylloPharma, Pleiogenix, Recordati, Regor, Remodeless, Renaissance, RenovoRx, Rivus, RxMP, Sera Biopharma, Seraxis, Serpin, SFC Fluidics, Skinject, SROne, Stalicla, Surf Bio, TIXiMED, Veroscience, Verthermia, WaveBreak, Zealand Pharma, and Zucara. DBS receives research support from the Intramural Research Program of the National Institutes of Health. RP-B receives grant support from Novo Nordisk, Lexicon Pharmaceuticals, and Medtronic and received consulting fee from Bayer, Lexicon Pharmaceuticals, Novo Nordisk, and Roche. DK has received research support from Abbott Diabetes Care and has been a Consultant to Sanofi, Better Therapeutics, and Abbott Diagnostics.

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: A single, multitiered valve center designation has been proposed to publicly identify centers with expertise for all valve therapies. The correlation between transcatheter aortic valve replacement (TAVR) and mitral transcatheter edge-to-edge repair (MTEER) procedures is unknown., Objectives: The authors sought to examine the relationship between site-level volumes and outcomes for TAVR and MTEER. We further explored variability between sites for MTEER outcomes., Methods: Using the STS/ACC TVT (Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy) national registry, TAVR and MTEER procedures at sites offering both therapies from 2013 to 2022 were examined. Sites were ranked into deciles of adjusted in-hospital and 30-day outcomes separately for TAVR and MTEER and compared. Stepwise, hierarchical multivariable models were constructed for MTEER outcomes, and the median OR was calculated., Results: Between 2013 and 2022, 384,394 TAVRs and 53,274 MTEERs (median annualized volumes: 93.6 and 18.8, respectively) were performed across 453 U.S. sites. Annualized TAVR and MTEER volumes were moderately correlated (r = 0.48; P < 0.001). After adjustment, 14.3% of sites had the same decile rank for TAVR and MTEER 30-day composite outcome, 50.6% were within 2 decile ranks; 35% had more discordant outcomes for the 2 procedures (P = 0.0005). For MTEER procedures, the median OR for the 30-day composite outcome was 1.57 (95% CI: 1.51-1.64), indicating a 57% variability in outcome by site., Conclusions: There is modest correlation between hospital-level volumes for TAVR and MTEER but low interprocedural correlation of outcomes. For similar patients, site-level variability for mortality/morbidity following MTEER was high. Factors influencing outcomes and "centers of excellence" as a whole may differ for TAVR and MTEER., Competing Interests: Funding Support and Author Disclosures Dr Kumbhani has received honoraria from the American College of Cardiology and the American Heart Association. Dr Chhatriwalla has served on Speakers Bureau for Abbott Vascular, Edwards Lifesciences, and Medtronic Inc; has been a proctor for Edwards Lifesciences and Medtronic Inc; and has received research support from Boston Scientific. Dr Giri has received institutional research funds and served on advisory boards for Boston Scientific, Abiomed, Recor Medical, Inari Medical, AstraZeneca, and Abbott Vascular. Dr Mack served as Trial Co-PI for Edwards Lifesciences and Abbott and Study Chair for Medtronic. Dr Carroll has served as a local site investigator in multicenter clinical trials sponsored by Medtronic, Abbott, and Edwards Lifesciences; and has served as a consultant and on advisory boards, and received honoraria from Edwards Lifesciences and Abbott. Dr Vemulapalli has received grants/contracts from the American College of Cardiology, Society of Thoracic Surgeons, Abbott Vascular, Cytokinetics, and the National Institutes of Health; and has served as a consultant and on advisory boards, and received honoraria from Medtronic, Edwards Lifesciences, and the American College of Physicians. 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.

The oblique random survival forest (RSF) is an ensemble supervised learning method for right-censored outcomes. Trees in the oblique RSF are grown using linear combinations of predictors, whereas in the standard RSF, a single predictor is used. Oblique RSF ensembles have high prediction accuracy, but assessing many linear combinations of predictors induces high computational overhead. In addition, few methods have been developed for estimation of variable importance (VI) with oblique RSFs. We introduce a method to increase computational efficiency of the oblique RSF and a method to estimate VI with the oblique RSF. Our computational approach uses Newton-Raphson scoring in each non-leaf node, We estimate VI by negating each coefficient used for a given predictor in linear combinations, and then computing the reduction in out-of-bag accuracy. In benchmarking experiments, we find our implementation of the oblique RSF is hundreds of times faster, with equivalent prediction accuracy, compared to existing software for oblique RSFs. We find in simulation studies that "negation VI" discriminates between relevant and irrelevant numeric predictors more accurately than permutation VI, Shapley VI, and a technique to measure VI using analysis of variance. All oblique RSF methods in the current study are available in the aorsf R package, and additional supplemental materials are available online., Competing Interests: Disclosure Statement No potential conflict of interest was reported by the authors.

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: Previous studies have linked cardiovascular risk factors during midlife to cognitive function in later life. However, few studies have looked at the association between cardiac function, brain structure, and cognitive function and even less have included diverse middle-aged populations., Objectives: The objective of this study was to determine associations between cardiac and brain structure and function in a multiethnic cohort of middle-aged adults., Methods: A cross-sectional study was conducted in participants of the Dallas Heart Study phase 2 (N = 1,919; 46% Black participants). Left ventricular (LV) mass, LV ejection fraction, LV concentricity, and peak systolic strain (LV E cc ) were assessed by cardiac magnetic resonance imaging. White matter hyperintensities (WMH) volume was measured by fluid attenuated inversion recovery magnetic resonance imaging. The Montreal Cognitive Assessment was used to measure cognitive functioning. Associations between cardiac and brain measures were determined using multivariable linear regression after adjusting for cardiovascular risk factors, education level, and physical activity., Results: LV ejection fraction was associated with total Montreal Cognitive Assessment score (β = 0.06 [95% CI: 0.003-0.12], P  = 0.042) and LV E cc was associated with WMH volume (β = 0.08 [95% CI: 0.01-0.14], P  = 0.025) in the overall cohort without significant interaction by race/ethnicity. Higher LV mass and concentricity were associated with larger WMH volume in the overall cohort (β = 0.13 [95% CI: 0.03-0.23], P  = 0.008 and 0.10 [95% CI: 0.03-0.17], P  = 0.005). These associations were more predominant in Black than White participants (β = 0.17 [95% CI: 0.04-0.30] vs β = -0.009 [95% CI: -0.16 to 0.14], P  = 0.036 and β = 0.22 [95% CI: 0.13-0.32] vs β = -0.11 [95% CI: -0.21 to -0.01], P  < 0.0001, for LV mass and concentricity, respectively)., Conclusions: Subclinical cardiac dysfunction indicated by LVEF was associated with lower cognitive function. Moreover, LV mass and concentric remodeling were associated with higher WMH burden, particularly among Black individuals., Competing Interests: The Dallas Heart Study was funded by the Donald W. Reynolds Foundation and was partially supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award Number UL1TR001105. Dr Vongpatanasin is supported by the 10.13039/100007914UT Southwestern O’Brien Kidney Center, the Charles and Jane Pak Center for Mineral Metabolism and Clinical Research: R01 AG057571. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.PERSPECTIVESCOMPETENCY IN MEDICAL KNOWLEDGE: Subclinical cardiac dysfunction was associated with lower cognitive function. Additionally, subclinical cardiac remodeling was associated with subclinical brain injury. These findings highlight the importance of maintaining optimal cardiovascular health to aid in maintaining brain health. TRANSLATIONAL OUTLOOK: Further studies are needed to determine if strategies to maintain normal cardiac structure and function during midlife offers protection against cognitive decline in late life., (© 2024 The Authors.)

Introduction: Diabetic cardiomyopathy (DbCM) is characterized by subclinical abnormalities in cardiac structure/function and is associated with a higher risk of overt heart failure (HF). However, there are limited data on optimal strategies to identify individuals with DbCM in contemporary health systems. The aim of this study was to evaluate the prevalence of DbCM in a health system using existing data from the electronic health record (EHR)., Methods: Adult patients with type 2 diabetes mellitus free of cardiovascular disease (CVD) with available data on HF risk in a single-center EHR were included. The presence of DbCM was defined using different definitions: (1) least restrictive: ≥1 echocardiographic abnormality (left atrial enlargement, left ventricle hypertrophy, diastolic dysfunction); (2) intermediate restrictive: ≥2 echocardiographic abnormalities; (3) most restrictive: 3 echocardiographic abnormalities. DbCM prevalence was compared across age, sex, race, and ethnicity-based subgroups, with differences assessed using the chi-squared test. Adjusted logistic regression models were constructed to evaluate significant predictors of DbCM., Results: Among 1921 individuals with type 2 diabetes mellitus, the prevalence of DbCM in the overall cohort was 8.7% and 64.4% in the most and least restrictive definitions, respectively. Across all definitions, older age and Hispanic ethnicity were associated with a higher proportion of DbCM. Females had a higher prevalence than males only in the most restrictive definition. In multivariable-adjusted logistic regression, higher systolic blood pressure, higher creatinine, and longer QRS duration were associated with a higher risk of DbCM across all definitions., Conclusions: In this single-center, EHR cohort, the prevalence of DbCM varies from 9% to 64%, with a higher prevalence with older age and Hispanic ethnicity., 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: MWS has received personal fees from Merck & Co. NK has received consultant fees from HeartSciences and Tricog Health. KP has served as a consultant to Novo Nordisk. AP has received research support from the National Institute of Health (5R01MD017529, R21HL169708), 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, Emmi Solutions; and has received nonfinancial support from Pfizer and Merck. Dr. Pandey is also a consultant for Palomarin Inc. with stock compensation. All other authors declare no competing interests.

Objective: Glucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2Is) lower adverse cardiac and kidney events among high-risk patients with diabetes mellitus (DM) and are now guideline-recommended as first-line therapy alongside metformin. However, the adoption of these new treatments from 2015 to 2020 among the highest-risk adults with DM remains unclear., Methods: We performed a cross-sectional analysis of the National Health and Nutrition Examination Surveys (NHANES) 2015-2020 to estimate the use of GLP1-RAs and SGLT2Is among adults with DM overall and by level of cardiovascular and kidney risk (CKR). We defined high CKR by history of atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), heart failure, or age ≥55 years with at least 2 ASCVD risk factors (i.e., obesity, hypertension, hyperlipidemia, or current smoker)., Results: Overall, 2,432 participants with DM (mean age 60.6 years, 46.8 % female, 58.8 % Non-Hispanic White) were included, of which 1,869 and 563 were with and without high CKR, respectively. Participants with vs. without high CKR were more likely to be older, have higher systolic blood pressure, lower estimated glomerular filtration rate, use oral antidiabetic agents, and have health insurance. Overall, the weighted prevalence of GLP1-RA or SGLT2I was 9.0 % (95 % confidence interval [CI] 6.9-11.0): 4.8 % (95 % CI 3.6-6.1) took GLP1-RAs, and 5.1 % (95 % CI 3.3-7.0) took SGLT2Is. Use of GLP1-RAs or SGLT2Is did not differ between participants with vs. without high CKR (adjusted prevalence ratio [aPR] 1.00; 95 % CI 0.98-1.02). Participants with ASCVD were more likely to be on a GLP1-RA or SGLT2I (aPR 1.28; 95 % CI 1.25-1.31), while adults with CKD were less likely (aPR 0.84; 95 % CI 0.82-0.86)., Conclusion: Among US adults with DM, GLP1-RA and SGLT2I use was low regardless of CKR. Data since 2020 analyzing the utilization of GLP1-RAs and SGLT2Is among high-CKR patients with DM is needed to identify implementation strategies for increased utilization., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Catherine G. Derington reports a relationship with Amarin Pharma Inc that includes: funding grants. Jordan B. King reports a relationship with National Heart Lung and Blood Institute that includes: funding grants. Adam P. Bress reports a relationship with National Heart Lung and Blood Institute that includes: funding grants. Adam P. Bress reports a relationship with Amarin Pharma Inc that includes: consulting or advisory and funding grants. Adam P. Bress reports a relationship with Amgen Inc that includes: funding grants. Ambarish Pandey reports a relationship with i) Gilead Sciences that includes: funding grants. ii) National Institute on Aging that includes: funding grants iii) Applied Therapeutics Inc that includes: funding grants iv) Tricog Health Inc. that includes: consulting or advisory v) Eli Lilly and Company that includes: consulting or advisory vi) Cytokinetics Inc that includes: consulting or advisory vii) Rivus that includes: consulting or advisory viii) Roche Diagnostics Corp that includes: consulting or advisory.ix) Pfizer Inc that includes: non-financial support x) Merck & Co Inc that includes: non-financial support., (© 2023 The Authors. Published by Elsevier B.V.)

Background High-density lipoprotein (HDL) particle concentration likely outperforms HDL cholesterol in predicting atherosclerotic cardiovascular events. Whether size-based HDL subspecies explain the atheroprotective associations of HDL particle concentration remains unknown. Our objective was to assess whether levels of specific size-based HDL subspecies associate with atherosclerotic cardiovascular disease in a multiethnic pooled cohort and improve risk prediction beyond traditional atherosclerotic cardiovascular disease risk factors. Methods and Results Seven HDL size-based subspecies were quantified by nuclear magnetic resonance (LP4 algorithm; H1=smallest; H7=largest) among participants without prior atherosclerotic cardiovascular disease in ARIC (Atherosclerosis Risk in Communities), MESA (Multi-Ethnic Study of Atherosclerosis), PREVEND (Prevention of Renal and Vascular Endstage Disease), and DHS (Dallas Heart Study) cohorts (n=15 371 people). Multivariable Cox proportional hazards models were used to evaluate the association between HDL subspecies and incident myocardial infarction (MI) or ischemic stroke at follow-up (average 8-10 years) adjusting for HDL cholesterol and risk factors. Improvement in risk prediction was assessed via discrimination and reclassification analysis. Within the pooled cohort (median age 57 years; female 54%; Black 22%) higher H1 (small) and H4 (medium) concentrations were inversely associated with incident MI (hazard ratio [HR]/SD, H1 0.88 [95% CI, 0.81-0.94]; H4 0.89 [95% CI, 0.82-0.97]). H4 but not H1 improved risk prediction indices for incident MI. Increasing H2 and H4 were inversely associated with improved risk prediction indices for composite end point of stroke, MI, and cardiovascular death (HR/SD, H2 0.94 [95% CI, 0.88-0.99]; H4 0.91 [95% CI, 0.85-0.98]). Levels of the large subspecies (H6 and H7) were not associated with any vascular end point. Conclusions Two of 7 HDL size-based subspecies modestly improved risk prediction for MI and composite vascular end points in a large multiethnic pooled cohort. These findings support assessment of precise HDL subspecies for future studies regarding clinical utility.

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.

Background: Some patients with heart failure (HF) have low natriuretic peptide (NP) levels. It is unclear whether specific populations are disproportionately excluded from participation in randomized clinical trials (RCT) with inclusion requirements for elevated NPs. We investigated factors associated with unexpectedly low NP levels in a cohort of patients hospitalized with HF, and the implications on racial diversity in a prototype HF RCT., Methods: We created a retrospective cohort of 31,704 patients (age 72 ± 16 years, 49% female, 52% Black) hospitalized with HF from 2010 to 2020 with B-type natriuretic peptide (BNP) measurements. Factors associated with unexpectedly low BNP levels (<50 pg/mL) were identified using multivariable logistic regression models. We simulated patient eligibility for a prototype HF trial using specific inclusion and exclusion criteria, and varying BNP cut-offs., Results: Unexpectedly low BNP levels were observed in 8.9% of the cohort. Factors associated with unexpectedly low BNP levels included HFpEF (aOR 3.76, 95% CI: 3.36, 4.20), obesity (aOR 1.96, 95% CI: 1.73, 2.21), self-identification as Black (aOR 1.53, 95% CI: 1.36, 1.71), and male gender (aOR 1.45, 95% CI: 1.31, 1.60). Applying limited clinical inclusion and exclusion criteria from PARAGLIDE-HF disproportionately excluded Black patients, with impairment in renal function having the greatest impact. Adding thresholds for BNP of ≥35, ≥50, ≥67, ≥100, and ≥150 pg/mL demonstrated the risk of exclusion was higher for Black compared to non-Black patients (RR = 2.03 [95% CI: 1.73, 2.39], 1.90 [95% CI: 1.68, 2.15], 1.63 [95% CI: 1.48, 1.81], 1.38 [95% CI: 1.28, 1.50], and 1.23 [95% CI: 1.15, 1.31], respectively)., Conclusions: Nearly 10% of patients hospitalized with HF have unexpectedly low BNP levels. Simulating inclusion into a prototype HFpEF RCT demonstrated that requiring increasingly elevated NP levels disproportionately excludes Black patients., Competing Interests: Disclosures AAM reports consulting fees from Abbott, Acorai, BI Lilly, Cytokinetics, Edwards Lifesciences, Ionis, and Merck., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Multidomain lifestyle interventions may slow aging as captured by deficit accumulation frailty indices; however, it is unknown whether benefits extend beyond intervention delivery., Methods: We developed a deficit accumulation frailty index (FI-E) to span the 10 years that the Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial delivered interventions (a multidomain lifestyle intervention focused on caloric restriction, increased physical activity, and diet compared to a control condition) and to extend across an additional 8 years post-delivery. The study cohort included 5 145 individuals, aged 45-76 years at enrollment, who had type 2 diabetes and either obesity or overweight., Results: Overall, FI-E scores were relatively lower among lifestyle participants throughout follow-up, averaging 0.0130 [95% confidence interval: 0.0104, 0.0156] (p < .001) less across the 18 years. During Years 1-8, the mean relative difference between control and lifestyle participants' FI-E scores was 0.0139 [0.0115, 0.0163], approximately 10% of the baseline level. During Years 9-18, this average difference was 0.0107 [0.0066, 0.0148]. Benefits were comparable for individuals grouped by baseline age and body mass index and sex but were not evident for those entering the trial with a history of cardiovascular disease., Conclusions: Multidomain lifestyle intervention may slow biological aging long term, as captured by an FI-E. Clinical Trials Registration Number: NCT00017953., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)