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Heart failure (HF) is a highly heterogeneous condition, and current methods struggle to synthesize extensive clinical data for personalized care. Using data from 343 HF patients, we developed mechanistic computational models of the cardiovascular system to create digital twins. These twins, consisting of optimized measurable and unmeasurable parameters alongside simulations of cardiovascular function, provided comprehensive representations of individual disease states. Unsupervised machine learning applied to digital twin-derived features identified interpretable phenogroups and mechanistic drivers of cardiovascular death risk. Incorporating these features into prognostic AI models improved performance, transferability, and interpretability compared to models using only clinical variables. This framework demonstrates potential to enhance prognosis and guide therapy, paving the way for more precise, individualized HF management., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The Great Lakes Restoration Initiative aims to protect and restore the nation's largest freshwater resource, in part, by furthering our understanding of the effects of contaminants of emerging concern (CECs) and chemical mixtures on aquatic and terrestrial organisms. To address this goal, an interagency team conducted field studies at sites along the Maumee River in Ohio, USA, in 2016-2017, monitoring CEC levels along with diverse in vitro and in vivo biological effects in ecologically relevant species (fathead minnows, tree swallows, and golden clams). The objective of the present work was to prioritize the CECs in these studies for further monitoring and assessment by determining if there are patterns in chemical-bioeffect relations across data sets, species, and response types that indicate relatively high or low hazard to aquatic life from CEC exposure. Of the 748 monitored chemicals, 425 were detected and were analyzed for covariance with bioeffects. All 748 chemicals were placed into 10 bins based on their frequencies of monitoring, detection, and covariance with bioeffects across studies and species. We describe how chemicals can be prioritized across bins to aid monitoring and assessment efforts. Our approach using effects-based monitoring data is especially useful for prioritizing chemicals with little or no traditional toxicity testing data. Similar evidence-based prioritizations will allow agencies to more efficiently allocate limited resources to improve the ability to protect aquatic and terrestrial organisms from adverse impacts due to contaminant exposure., (Published by Oxford University Press on behalf of the Society of Environmental Toxicology and Chemistry 2025.)

Patients with heart failure with preserved ejection fraction (HFpEF) are burdened by multiple diet-sensitive comorbidities, including obesity and malnutrition. Despite this, a low percentage of patients with HFpEF have been enrolled in dietary intervention trials in heart failure and few dietary interventions have been conducted in HFpEF exclusively. This scoping review will examine available evidence regarding dietary interventions in patients with HFpEF, highlight existing gaps in knowledge, and discuss emerging dietary therapies in this population., Competing Interests: Dr Billingsley was supported by T32 Training Grant 5T32AG062403-04. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Dietary interventions have potential to improve symptoms and outcomes in patients with heart failure (HF), but there are barriers to eating nutrient-dense diets. One strategy to address challenges is to provide medically tailored meals (MTMs), fully prepared meals that align with an individual's nutritional needs. In this systematic review, we examined clinical outcomes of studies that provided MTMs to patients with HF., Methods and Results: We searched CINAH, EBSCO/MEDLINE, EMBASE, PUBMED and the Cochrane Central Register of Controlled Trials to identify MTM interventions published between 2013 and 2023. We included six studies. Five studies involved sodium restriction. Four of these were randomized control trials and one was a matched cohort study. Sample sizes ranged from 31 to 641. Patient populations included individuals who had heart failure, acute decompensated heart failure and heart failure with preserved ejection fraction. One study involved energy restriction in patients with heart failure with preserved ejection fraction and obesity. This was a randomized controlled study with a sample size of 100. Sodium-restriction interventions, when aligned with Dietary Approaches to Stop Hypertension goals, reduced 90-day HF readmissions in one study and trended towards improving 30-day and 12-week HF readmissions in another. The energy-restriction intervention reduced diastolic blood pressure, weight, and inflammatory biomarkers, and improved quality of life (QoL) and cardiorespiratory fitness. Neither intervention had an impact on mortality., Conclusions: Provision of sodium-restricted MTMs to patients with HF may reduce the risk of rehospitalization. Provision of energy-restricted MTMs to patients with HF and obesity can improve symptoms, weight loss, QoL, and cardiorespiratory fitness. Adequately powered randomized controlled trials are needed to confirm these effects and investigate underlying mechanisms., (Published by Elsevier Inc.)

Background: There is a little evidence regarding long-term safety and efficacy for atrial shunt devices in heart failure (HF)., Methods: The REDUCE LAP-HF I (n = 44) and II (n = 621) trials (RCT-I and -II) were multicenter, randomized, sham-controlled trials of patients with HF and ejection fraction >40%. Outcome data were analyzed from RCT-I, a mechanistic trial with 5-year follow-up, and RCT-II, a pivotal trial identifying a responder group (n = 313) defined by exercise PVR <1.74 WU and no cardiac rhythm management device with 3-year follow-up., Results: At 5 years in RCT I, there were no differences in cardiovascular (CV) mortality, HF events, embolic stroke, or new-onset atrial fibrillation between groups. After 3 years in RCT II, there was no difference in the primary outcome (hierarchical composite of CV mortality, stroke, HF events, and KCCQ) between shunt and sham in the overall trial. Compared to sham, those with responder characteristics in RCT-II had a better outcome with shunt (win ratio 1.6 [95% CI 1.2-2.2], P = .006; 44% reduction in HF events [shunt 9 vs. control 16 per 100 patient-years], P = .005; and greater improvement in KCCQ overall summary score [+17.9 ± 20.0 vs. +7.6 ± 20.4], P < .001), while nonresponders had significantly more HF events. Shunt treatment at 3 years was associated with a higher rate of ischemic stroke (3.2% vs. 0%, 95% CI 2%-6.1%, P = .032) and lower incidence of worsening kidney dysfunction (10.7% vs. 19.3%, P = .041)., Conclusions: With up to 5 years of follow up, adverse events were low in patients receiving atrial shunts. In the responder group, atrial shunt treatment was associated with a significantly lower HF event rate and improved KCCQ compared to sham through 3 years of follow-up., Gov Registration: NCT02600234, NCT03088033., Competing Interests: Conflict of Interest None., (Published by Elsevier Inc.)

Importance: Greater splanchnic nerve ablation may improve hemodynamics in patients with heart failure and preserved ejection fraction (HFpEF)., Objective: To explore the feasibility and safety of endovascular right-sided splanchnic nerve ablation for volume management (SAVM)., Design, Setting, and Participants: This was a phase 2, double-blind, 1:1, sham-controlled, multicenter, randomized clinical trial conducted at 14 centers in the US and 1 center in the Republic of Georgia. Patients with HFpEF, left ventricular ejection fraction of 40% or greater, and invasively measured peak exercise pulmonary capillary wedge pressure (PCWP) of 25 mm Hg or greater were included. Study data were analyzed from May 2023 to June 2024., Intervention: SAVM vs sham control procedure., Main Outcomes and Measures: The primary efficacy end point was a reduction in legs-up and exercise PCWP at 1 month. The primary safety end point was serious device- or procedure-related adverse events at 1 month. Secondary efficacy end points included HF hospitalizations, changes in exercise function and health status through 12 months, and baseline to 1-month change in resting, legs-up, and 20-W exercise PCWP., Results: A total of 90 patients (median [range] age, 71 [47-90] years; 58 female [64.4%]) were randomized at 15 centers (44 SAVM vs 46 sham). There were no differences in adverse events between groups. The primary efficacy end point did not differ between SAVM or sham (mean between-group difference in PCWP, -0.03 mm Hg; 95% CI, -2.5 to 2.5 mm Hg; P = .95). There were also no differences in the secondary efficacy end points. There was no difference in the primary safety end point between the treatment (6.8% [3 of 44]) and sham (2.2% [1 of 46]) groups (difference, 4.6%; 95% CI, -6.1% to 15.4%; P = .36). There was no difference in the incidence of orthostatic hypotension between the treatment (11.4% [5 of 44]) and sham (6.5% [3 of 46]) groups (difference, 4.9%; 95% CI, -9.2% to 18.8%; P = .48)., Conclusions and Relevance: Results show that SAVM was safe and technically feasible, but it did not reduce exercise PCWP at 1 month or improve clinical outcomes at 12 months in a broad population of patients with HFpEF., Trial Registration: ClinicalTrials.gov Identifier: NCT04592445.

Introduction: Guideline-directed medical therapy (GDMT) has significantly improved outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, GDMT prescribing remains suboptimal. The purpose of this study was to survey cardiologists, internists, and pharmacists on their approach to GDMT prescribing., Methods: A survey containing 20 clinical vignettes of patients with HFrEF was answered by 127 cardiologists, 68 internists, and 89 pharmacists. Each vignette presented options for adjusting GDMT. Responses were dichotomized to the answer of interest. A mixed-effect model was used to calculate the odds of changing GDMT between pharmacists and physicians., Results: Pharmacists were more likely to make changes to GDMT compared with internists (92.1% vs 82%; odds ratio [OR] 3.02 [1.50-6.06]; p=0.002). In medically-naïve patients, pharmacists were more likely to initiate beta-blockers than internists (45.4% vs 32.0%; OR 2.19 [1.00-4.79], p=0.049). Pharmacists were more likely than both internists and cardiologists to initiate mineralocorticoid receptor antagonists (34.4% vs 11.5%; OR 4.95 [2.41-10.18]; p<0.001 and 34.4% vs 13.9%; OR 3.95 [2.16-7.21]; p<0.001). Pharmacists were more likely than both internists and cardiologists to titrate beta-blockers (30.9% vs 16.4%; OR 3.15 [1.92-5.19]; p<0.001 and 30.9% vs 22.0%; OR 1.88 [0.18-2.87]; p=0.0030). Pharmacists were more likely than internists to titrate angiotensin receptor-neprilysin inhibitors (ARNI) (61.8% vs 34.1%; OR 3.54 [1.50-8.39]; p=0.004)., Conclusions: The survey results show pharmacists were more likely to make any adjustments to GDMT than internists and cardiologists. Pharmacists prefer adding spironolactone and titrating beta-blockers compared with cardiologists and internists. Compared with only internists, pharmacists were more likely to initiate beta-blockers and titrate the dose of ARNI., Competing Interests: Conflict of Interest: The authors declare no conflicts of interest.

Objective: Splanchnic vasoconstriction augments transfer of blood volume from the abdomen into the thorax, which may increase filling pressures and hemodynamic congestion in patients with noncompliant hearts. Therapeutic interruption of splanchnic nerve activity holds promise to reduce hemodynamic congestion in patients with heart failure with preserved ejection fraction (HFpEF). Here we describe (1) the rationale and design of the first sham-controlled, randomized clinical trial of splanchnic nerve ablation for HFpEF and (2) the 12-month results of the lead-in (open-label) trial's participants., Methods: REBALANCE-HF is a prospective, multicenter, randomized, double-blinded, sham-controlled clinical trial of endovascular, transcatheter, right-sided greater splanchnic nerve ablation for volume management (SAVM) in patients with HFpEF. The primary objectives are to evaluate the safety and efficacy of SAVM and identify responder characteristics to inform future studies. The trial consists of an open-label lead-in phase followed by the randomized, sham-controlled phase. The primary efficacy endpoint is the reduction in pulmonary capillary wedge pressure (PCWP) at 1-month follow-up compared to baseline during passive leg raise and 20W exercise. Secondary and exploratory endpoints include health status (Kansas City Cardiomyopathy Questionnaire), 6-minute walk test distance, New York Heart Association class, and NTproBNP levels at 3, 6 and 12 months. The primary safety endpoint is device- or procedure-related serious adverse events at the 1-month follow-up., Results: The lead-in phase of the study, which enrolled 26 patients with HFpEF who underwent SAVM, demonstrated favorable safety outcomes and reduction in exercise PCWP at 1 month post-procedure and improvements in all secondary endpoints at 6 and 12 months of follow-up. The randomized phase of the trial (n = 44 SAVM; n = 46 sham) has completed enrollment, and follow-up is ongoing., Conclusion: REBALANCE-HF is the first sham-controlled randomized clinical trial of greater splanchnic nerve ablation in HFpEF. Initial 12-month open-label results are promising, and the results of the randomized portion of the trial will inform the design of a future pivotal clinical trial. SAVM may offer a promising therapeutic option for patients with HFpEF., Trial Registration: NCT04592445., Competing Interests: DISCLOSURES MF was supported by the NIH (1OT2HL156812-01) and Doris Duke, and he consults for or owns equity in Abbott, Ajax, Alio Health, Alleviant, Artha, Audicor, AxonTherapies, Bayer, Bodyguide, Bodyport, Boston Scientific, Broadview, Cadence, Cardioflow, Cardionomics, Coridea, CVRx, Daxor, Deerfield Catalyst, Edwards LifeSciences, Echosens, EKO, Feldschuh Foundation, Fire1, FutureCardia, Galvani, Gradient, Hatteras, HemodynamiQ, Impulse Dynamics, Intershunt, Medtronic, Merck, NIMedical, NovoNordisk, NucleusRx, NXT Biomedical, Orchestra, Pharmacosmos, PreHealth, Presidio, Procyreon, ReCor, Rockley, SCPharma, Shifamed, Splendo, Summacor, SyMap, Verily, Vironix, Viscardia, Zoll. SL reports research support from Axon, Corvia, V Wave, Astra Zeneca, Eli Lilly, and Rivus and has consulting relationships with Axon, Corvia, Eli Lilly, and Rivus. BAB receives research support from the National Institutes of Health and the United States Department of Defense as well as research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax Therapeutics and has served as a consultant for Actelion, Amgen, Aria, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Janssen, Merck, and Novo Nordisk. BAB and SJA are named inventors (U.S. Patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. RCM consults for Alleviant, Corvia and HemodynamiQ. MJP reports consulting honoraria, speaker's fees and proctoring fees from Abbott Vascular and Boston Scientific, consulting honoraria from W.L. Gore, Biotronik, and Philips Medical, consulting honoraria and speaker's fees from Medtronic, consulting honoraria from Shockwave and Innovheart and equity in InterShunt. PG has grant support from the NIH (K76AG064428, R21AG077092, R24AG064025), has received consulting fees from Sensorum Health and Axon Therapies and has received personal fees for expert testimony related to heart failure. RVP reports consulting fees from ICA. VYR reports serving as a consultant to and receiving stock options from Axon Therapies and, unrelated to this manuscript, VYR also serves as a consultant for and has equity in Ablacon, Acutus Medical, Affera-Medtronic, Apama Medical-Boston Scientific, Anumana, APN Health, Aquaheart, Atacor, Autonomix, Backbeat, BioSig, CardiaCare, CardioNXT/AFTx, Circa Scientific, CoRISMA, Corvia Medical, Dinova-Hangzhou DiNovA EP Technology, East End Medical, EPD-Philips, EP Frontiers, Epix Therapeutics-Medtronic, EpiEP, Eximo, Farapulse-Boston Scientific, Field Medical, Focused Therapeutics, HRT, Intershunt, Javelin, Kardium, Keystone Heart, LuxMed, Medlumics, Middlepeak, Neutrace, Nuvera-Biosense Webster, Oracle Health, Restore Medical, Sirona Medical, SoundCath, Valcare; and, unrelated to this work, has served as a consultant for Abbott, AtriAN, Biosense-Webster, BioTel Heart, Biotronik, Boston Scientific, Cairdac, Cardiofocus, Cardionomic, CoreMap, Fire1, Gore & Associates, Impulse Dynamics, Medtronic, Novartis, Philips, Pulse Biosciences and has equity in DRS Vascular, Manual Surgical Sciences, Newpace, Nyra Medical, Surecor, and Vizaramed. DB reports consulting fees and grant support from Axon Therapies. MRP is a consultant to Axon Therapies. SIS is an employee of Axon Therapies. SJS reports support from research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Pfizer and AstraZeneca and consulting fees from Abbott, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, Metabolic Flux, MyoKardia, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. All other authors have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Although the results of A Study to Evaluate the Corvia Medical Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF II) trial were neutral overall, atrial shunt therapy demonstrated potential efficacy in responders (no latent pulmonary vascular disease and no cardiac rhythm management device). Post hoc analyses were conducted to evaluate the effect of shunt vs sham stratified by responder status., Objective: To evaluate the effect of atrial shunt vs sham control on cardiac structure/function in the overall study and stratified by responder status., Design, Setting, and Participants: This was a sham-controlled randomized clinical trial of an atrial shunt device in heart failure with preserved ejection fraction (HFpEF)/HF with mildly reduced EF (HFmrEF). Trial participants with evaluable echocardiography scans were recruited from 89 international medical centers. Data were analyzed from April 2023 to January 2024., Interventions: Atrial shunt device or sham control., Main Outcome Measures: Changes in echocardiographic measures from baseline to 1, 6, 12, and 24 months after index procedure., Results: The modified intention-to-treat analysis of the REDUCE LAP-HF II trial included 621 randomized patients (median [IQR] age, 72.0 [66.0-77.0] years; 382 female [61.5%]; shunt arm, 309 [49.8%]; sham control arm, 312 [50.2%]). Through 24 months, 212 of 217 patients (98%) in the shunt arm with evaluable echocardiograms had patent shunts. In the overall trial population, the shunt reduced left ventricular (LV) end-diastolic volume (mean difference, -5.65 mL; P <.001), left atrial (LA) minimal volume (mean difference, -2.8 mL; P =.01), and improved LV systolic tissue Doppler velocity (mean difference, 0.69 cm/s; P <.001) and LA emptying fraction (mean difference, 1.88 percentage units; P =.02) compared with sham. Shunt treatment also increased right ventricular (RV; mean difference, 9.58 mL; P <.001) and right atrial (RA; mean difference, 9.71 mL; P <.001) volumes but had no effect on RV systolic function, pulmonary artery pressure, or RA pressure compared with sham. In the shunt arm, responders had smaller increases in RV end-diastolic volume (mean difference, 5.71 mL vs 15.18 mL; interaction P =.01), RV end-systolic volume (mean difference, 1.58 mL vs 7.89 mL; interaction P =.002), and RV/LV ratio (mean difference, 0.07 vs 0.20; interaction P <.001) and larger increases in transmitral A wave velocity (mean difference, 5.08 cm/s vs -1.97 cm/s; interaction P =.02) compared with nonresponders randomized to the shunt, suggesting greater ability to accommodate shunted blood through the pulmonary circulation enabling LA unloading., Conclusions and Relevance: In this post hoc analysis of the REDUCE LAP-HF II trial, over 2 years of follow-up, atrial shunting led to reverse remodeling of left-sided chambers and increases in volume of right-sided chambers consistent with the shunt flow but no change in RV systolic function compared with sham. Changes in cardiac structure/function were more favorable in responders compared with nonresponders treated with the shunt, supporting the previously identified responder group hypothesis and mechanism, although further evaluation with longer follow-up is needed., Trial Registration: ClinicalTrials.gov Identifier: NCT03088033.

Background: Despite the strong evidence supporting guideline-directed medical therapy (GDMT) in patients with heart failure with reduced ejection fraction (HFrEF), prescription rates in clinical practice are still lacking., Methods: A survey containing 20 clinical vignettes of patients with HFrEF was answered by a national sample of 127 cardiologists and 68 internal/family medicine physicians. Each vignette had 4-5 options for adjusting GDMT and the option to make no medication changes. Survey respondents could only select one option. For analysis, responses were dichotomized to the answer of interest., Results: Cardiologists were more likely to make GDMT changes than general medicine physicians (91.8% vs. 82.0%; OR 1.84 [1.07-3.19]; p = 0.020). Cardiologists were more likely to initiate beta-blockers (46.3% vs. 32.0%; OR 2.38 [1.18-4.81], p = 0.016), angiotensin receptor blocker/neprilysin inhibitor (ARNI) (63.8% vs. 48.1%; OR 1.76 [1.01-3.09], p = 0.047), and hydralazine and isosorbide dinitrate (HYD/ISDN) (38.2% vs. 23.7%; OR 2.47 [1.48-4.12], p < 0.001) compared to general medicine physicians. No differences were found in initiating angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARBs), initiating mineralocorticoid receptor antagonist (MRA), sodium-glucose transporter protein 2 (SGLT2) inhibitors, digoxin, or ivabradine., Conclusions: Our results demonstrate cardiologists were more likely to adjust GDMT than general medicine physicians. Future focus on improving GDMT prescribing should target providers other than cardiologists to improve care in patients with HFrEF., (© 2024. The Author(s).)

Freshwater mussels provide invaluable ecological services but are threatened by habitat alteration, poor water quality, invasive species, climate change, and contaminants, including contaminants of emerging concern (CECs). Contaminants of emerging concerns are well documented in aquatic environments, including the Great Lakes Basin, but limited information is available on how environmentally relevant mixtures affect freshwater mussel biology throughout their varied life stages. Our main goal was to assess mussels' reproductive output in response to exposure to agricultural and urban CEC mixtures during glochidial development through juvenile transformation and excystment focusing on how exposure duration and treatment affect: (1) the number of glochidia prematurely released by brooding females, (2) glochidial transformation through host-fish excystment, and (3) the number of fully metamorphosed juveniles able to continue the lifecycle. Mussels and host fish were exposed to either a control water (CW), control ethanol (CE), agriculture CEC mixture (AM), or urban CEC mixture (UM) for 40 and 100 days. We found no effect from treatment or exposure duration on the number of glochidia prematurely released. Fewer partially and fully metamorphosed AM juveniles were observed during the 100-day exposure, compared with the 40-day. During the 40-day exposure, CW produced more fully metamorphosed individuals compared with CE and UM, but during the 100-day exposure AM produced more fully metamorphosed individuals compared with the CW. There was reduction in fully metamorphosed juveniles compared with partially metamorphosed for CE and UM during the 40-day exposure, as well as in the CW during the 100-day exposure. These results will be important for understanding how mussel populations are affected by CEC exposure. The experiments also yielded many insights for laboratory toxicology exposure studies. Environ Toxicol Chem 2024;43:1112-1125. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA., (© 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Purpose: Acute heart failure (AHF) syndromes manifest increased inflammation and vascular dysfunction; however, mechanisms that integrate the two in AHF remain largely unknown. The glycocalyx (GAC) is a sugar-based shell that envelops all mammalian cells. Much GAC research has focused on its role in vascular responses, with comparatively little known about how the GAC regulates immune cell function., Methods: In this study, we sought to determine if GAC degradation products are elevated in AHF patients, how these degradation products relate to circulating inflammatory mediators, and whether the monocyte GAC (mGAC) itself modulates monocyte activation. Inflammatory markers and GAC degradation products were profiled using ELISAs. Flow cytometry was used to assess the mGAC and RNA-seq was employed to understand the role of the mGAC in regulating inflammatory activation programs., Results: In a cohort of hospitalized AHF patients (n = 17), we found that (1) the GAC degradation product heparan sulfate (HS) was elevated compared with age-matched controls (4396 and 2903 ng/mL; p = 0.01) and that (2) HS and soluble CD14 (a marker of monocyte activation) levels were closely related (Pearson's r = 0.65; p = 0.002). Mechanistically, Toll-like receptor (TLR) activation of human monocytes results in GAC remodeling and a decrease in the mGAC (71% compared with no treatment; p = 0.0007). Additionally, we found that ex vivo enzymatic removal of HS and disruption of the mGAC triggers human monocyte activation and amplifies monocyte inflammatory responses. Specifically, using RNA-seq, we found that enzymatic degradation of the mGAC increases transcription of inflammatory (IL6, CCL3) and vascular (tissue factor/F3) mediators., Conclusion: These studies indicate that the mGAC is dynamically remodeled during monocyte activation and that mGAC remodeling itself may contribute to the heightened inflammation associated with AHF., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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

Assessing the ecological risk of contaminants in the field typically involves consideration of a complex mixture of compounds which may or may not be detected via instrumental analyses. Further, there are insufficient data to predict the potential biological effects of many detected compounds, leading to their being characterized as contaminants of emerging concern (CECs). Over the past several years, advances in chemistry, toxicology, and bioinformatics have resulted in a variety of concepts and tools that can enhance the pragmatic assessment of the ecological risk of CECs. The present Focus article describes a 10+- year multiagency effort supported through the U.S. Great Lakes Restoration Initiative to assess the occurrence and implications of CECs in the North American Great Lakes. State-of-the-science methods and models were used to evaluate more than 700 sites in about approximately 200 tributaries across lakes Ontario, Erie, Huron, Michigan, and Superior, sometimes on multiple occasions. Studies featured measurement of up to 500 different target analytes in different environmental matrices, coupled with evaluation of biological effects in resident species, animals from in situ and laboratory exposures, and in vitro systems. Experimental taxa included birds, fish, and a variety of invertebrates, and measured endpoints ranged from molecular to apical responses. Data were integrated and evaluated using a diversity of curated knowledgebases and models with the goal of producing actionable insights for risk assessors and managers charged with evaluating and mitigating the effects of CECs in the Great Lakes. This overview is based on research and data captured in approximately about 90 peer-reviewed journal articles and reports, including approximately about 30 appearing in a virtual issue comprised of highlighted papers published in Environmental Toxicology and Chemistry or Integrated Environmental Assessment and Management. Environ Toxicol Chem 2023;42:2506-2518. © 2023 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA., (© 2023 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Malnutrition may be an important geriatric condition in adults with heart failure with preserved ejection fraction (HFpEF), but studies on its prevalence and associated clinical outcomes are limited. The aim of this study was to determine if malnutrition is associated with short-term morbidity and mortality in ambulatory patients with HFpEF., Methods: We examined 231 patients with a clinical diagnosis of HFpEF seen at two dedicated academic HFpEF programs (Weill Cornell Medicine and Michigan Medicine) from June 2018 to April 2022. Malnutrition was defined by Mini-Nutritional Assessment Short Form (MNA-SF) scores ≤11. The primary endpoint was a 6-month composite of all-cause mortality and all-cause hospitalization. A Cox proportional-hazard models was used to examine the association between malnutrition and the primary endpoint, adjusting for race, prior hospitalization history, and the validated Meta-Analysis Global Group in Chronic (MAGGIC) heart failure prognostic risk score., Results: The median age of the cohort was 73 years (interquartile range 64-81). The most common comorbid conditions included hypertension (prevalence 81%), atrial fibrillation (43%), and obesity (63%). The prevalence of malnutrition was 42% (n = 97), and MNA-SF scores did not significantly correlate with body mass index (R = -0.02, p = 0.71). At the 6-month follow-up, 62 patients (26.8%) were hospitalized and four patients died (1.7%). In a fully-adjusted analysis, malnutrition was independently associated with the composite outcome of all-cause mortality and all-cause hospitalization (HR 1.94 [95% CI: 1.17-3.20], p = 0.01)., Conclusion: Despite a high prevalence of obesity, two out of five ambulatory adults with HFpEF are malnourished. Malnutrition was independently associated with adverse outcomes at 6 months. Future work is necessary to develop interventions that can address malnutrition., (© 2023 The American Geriatrics Society.)

Competing Interests: Disclosures SLH has previously received research funding from PurFoods. His effort is supported by VA CSR&D Merit Award RDC-2017-1066, and NIH grants R01-AG062582 and R61-HL155498, and research funding from PurFoods. His efforts are supported by VA CSR&D Merit AwardRDC-2017-1066 and NIH grants R01-AG062582 and R61-HL155498.

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

We review a comprehensive risk assessment approach for percutaneous coronary interventions in older adults and highlight the relevance of geriatric syndromes within that broader perspective to optimize patient-centered outcomes in interventional cardiology practice. Reflecting the influence of geriatric principles in older adults undergoing percutaneous coronary interventions, we propose a "geriatric" heart team to incorporate the expertise of geriatric specialists in addition to the traditional heart team members, facilitate uptake of the geriatric risk assessment into the preprocedural risk assessment, and address ways to mitigate these geriatric risks. We also address goals of care in older adults, highlighting common priorities that can impact shared decision making among older patients, as well as frequently encountered pharmacotherapeutic considerations in the older adult population. Finally, we clarify gaps in current knowledge and describe crucial areas for future investigation.

As the population ages, older adults represent an increasing proportion of patients referred to the cardiac catheterization laboratory. Older adults are the highest-risk group for morbidity and mortality, particularly after complex, high-risk percutaneous coronary interventions. Structured risk assessment plays a key role in differentiating patients who are likely to derive net benefit vs those who have disproportionate risks for harm. Conventional risk assessment tools from national cardiovascular societies typically rely on 3 pillars: 1) cardiovascular risk; 2) physiologic and hemodynamic risk; and 3) anatomic and procedural risks. We propose adding a fourth pillar: geriatric syndromes, as geriatric domains can supersede all other aspects of risk.

Aims: Elevated left atrial (LA) pressure is a pathophysiologic hallmark of heart failure with preserved ejection fraction (HFpEF). Chronically elevated LA pressure leads to LA enlargement, which may impair LA function and increase pulmonary pressures. We sought to evaluate the relationship between LA volume and pulmonary arterial haemodynamics in patients with HFpEF., Methods and Results: Data from 85 patients (aged 69 ± 8 years) who underwent exercise right heart catheterization and echocardiography were retrospectively analysed. All had symptoms of heart failure, left ventricular ejection fraction ≥50% and haemodynamic features of HFpEF. Patients were divided into LA volume index-based tertiles (≤34 ml/m 2 , >34 to ≤45 ml/m 2 , >45 ml/m 2 ). A subgroup analysis was performed in patients with recorded LA global reservoir strain (n = 60), with reduced strain defined as ≤24%. Age, sex, body surface area and left ventricular ejection fraction were similar between volume groups. LA volume was associated with blunted increases in cardiac output with exercise (p adjusted  <0.001), higher resting mean pulmonary artery pressure (p adjusted  = 0.003), with similar wedge pressure (p adjusted  = 1). Pulmonary vascular resistance (PVR) increased with increasing LA volume (p adjusted  <0.001). Larger LA volumes featured reduced LA strain (p adjusted  <0.001), with reduced strain associated with reduced PVR-compliance time (0.34 [0.28-0.40] vs. 0.38 [0.33-0.43], p = 0.03)., Conclusion: Increasing LA volume may be associated with more advanced pulmonary vascular disease in HFpEF, featuring higher PVR and pulmonary pressures. Reduced LA function, worse at increasing LA volumes, is associated with a disrupted PVR-compliance relationship, further augmenting impaired pulmonary haemodynamics., (© 2023 European Society of Cardiology.)

Objective: The aims of this study were: 1) to assess relationships among insulin-mediated glucose uptake with standard clinical outcomes and deep-phenotyping measures (including fatty acid [FA] rate of appearance [FA Ra] into the systemic circulation); and 2) to examine the contribution of adipocyte size, fibrosis, and proteomic profile to FA Ra regulation., Methods: A total of 66 adults with obesity (BMI = 34 [SD 3] kg/m 2 ) were assessed for insulin sensitivity (hyperinsulinemic-euglycemic clamp), and stable isotope dilution methods quantified glucose, FA, and glycerol kinetics in vivo. Abdominal subcutaneous adipose tissue (aSAT) and skeletal muscle biopsies were collected, and magnetic resonance imaging quantified liver and visceral fat content., Results: Insulin-mediated FA Ra suppression associated with insulin-mediated glucose uptake (r = 0.51; p < 0.01) and negatively correlated with liver (r = -0.36; p < 0.01) and visceral fat (r = -0.42; p < 0.01). aSAT proteomics from subcohorts of participants with low FA Ra suppression (n = 8) versus high FA Ra suppression (n = 8) demonstrated greater extracellular matrix collagen protein in low versus high FA Ra suppression. Skeletal muscle lipidomics (n = 18) revealed inverse correlations of FA Ra suppression with acyl-chain length of acylcarnitine (r = -0.42; p = 0.02) and triacylglycerol (r = -0.51; p < 0.01), in addition to insulin-mediated glucose uptake (acylcarnitine: r = -0.49; p < 0.01, triacylglycerol: r = -0.40; p < 0.01)., Conclusions: Insulin's ability to suppress FA release from aSAT in obesity is related to enhanced insulin-mediated glucose uptake and metabolic health in peripheral tissues., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

β-blockers are commonly used in heart failure with preserved ejection fraction (HFpEF), even in the absence of a compelling indication and despite the potential to cause harm. Identifying reasons for β-blocker prescription in HFpEF could permit the development of strategies to reduce unnecessary use and potentially improve medication prescribing patterns in this vulnerable population. We administered an online survey regarding β-blocker prescribing behavior to physicians trained in internal medicine or geriatrics (noncardiology physicians) and to cardiologists at 2 large academic medical centers. The survey assessed the reasons for β-blocker initiation, agreement regarding initiation and/or continuation of β-blockers by another clinician, and deprescribing behavior. The response rate was 28.2% (n = 231). Among respondents, 68.2% reported initiating β-blockers in patients with HFpEF. The most common reason for initiating a β-blocker was for treatment of an atrial arrhythmia. Notably, 23.7% of physicians reported initiating a β-blocker without an evidence-based indication. When a β-blocker was considered not necessary, 40.1% of physicians reported they were rarely or never willing to deprescribe. The most common reason for not deprescribing a β-blocker when the physician felt that a β-blocker was unnecessary was the concern about interfering with another physicians' treatment plan (76.6%). In conclusion, a significant proportion of noncardiology physicians and cardiologists report prescribing β-blockers to patients with HFpEF, even when evidence-based indications are absent, and rarely deprescribe β-blockers in these scenarios., Competing Interests: Disclosures Dr. Goyal receives personal fees for medicolegal consulting related to heart failure and has received honoraria from Akcea Therapeutics Inc and Bionest Inc. Dr. Steinman receives honoraria from UpToDate and the American Geriatrics Society. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Guideline-directed medical therapy (GDMT) optimization can improve outcomes in heart failure with reduced ejection fraction., Objectives: The objective of this study was to determine if a novel computable algorithm appropriately recommended GDMT., Methods: Clinical trial data from the GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment in Heart Failure) and HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trials were evaluated with a computable medication optimization algorithm that outputs GDMT recommendations and a medication optimization score (MOS). Algorithm-based recommendations were compared to medication changes. A Cox proportional-hazards model was used to estimate the associations between MOS and the composite primary end point for both trials., Results: The algorithm recommended initiation of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blockers, and mineralocorticoid receptor antagonists in 52.8%, 34.9%, and 68.1% of GUIDE-IT visits, respectively, when not prescribed the drug. Initiation only occurred in 20.8%, 56.9%, and 15.8% of subsequent visits. The algorithm also identified dose titration in 48.8% of visits for angiotensin-converting enzyme inhibitor/angiotensin receptor blockers and 39.4% of visits for beta-blockers. Those increases only occurred in 24.3% and 36.8% of subsequent visits. A higher baseline MOS was associated with a lower risk of cardiovascular death or heart failure hospitalization (HR: 0.41; 95% CI: 0.21-0.80; P  = 0.009) in GUIDE-IT and all-cause death and hospitalization (HR: 0.61; 95% CI: 0.44-0.84; P  = 0.003) in HF-ACTION., Conclusions: The algorithm accurately identified patients for GDMT optimization. Even in a clinical trial with robust protocols, GDMT could have been further optimized in a meaningful number of visits. The algorithm-generated MOS was associated with a lower risk of clinical outcomes. Implementation into clinical care may identify and address suboptimal GDMT in patients with heart failure with reduced ejection fraction., Competing Interests: Dr Dorsch is supported by R18 HS026874 from the Agency for Health Research and Quality, R01 AG062582 and R61 HL155498 from the 10.13039/100000002National Institutes of Health, and the American Health Association Health IT Strategically Focused Research Network. Dr Hummel is supported by a grant from 10.13039/100000738Veterans Affairs CARA-009-16F9050 and R01 AG062582 and R61 HL155498 from the 10.13039/100000002National Institutes of Health. Dr Koelling is supported by R01 AG062582 from the 10.13039/100000002National Institutes of Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Purpose: Vascular and immune dysfunction are hallmarks of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections and coronavirus disease 2019 (COVID-19). Although our understanding of the pathogenesis of COVID-19 has rapidly evolved, much of the focus has been on the immune mechanisms underlying COVID-19. In addition to immune dysfunction, vascular injury is also associated with COVID-19 and is a major driver of clinical deterioration in SARS-CoV-2 infections. The glycocalyx (GAC), a sugar-based shell that surrounds all mammalian cells, is an important regulator of vascular and immune responses. In sepsis, vascular dysfunction contributes to acute respiratory distress syndrome (ARDS) by altering vessel integrity, promoting thrombosis, and accelerating inflammation, all of which are also present in COVID-19. Observational studies in sepsis have found an association between levels of circulating GAC degradation products with both organ dysfunction and mortality. Although vascular dysfunction is a hallmark of COVID-19, it remains unclear whether GAC disruption occurs in COVID-19 and if GAC disruption contributes to the clinical progression of COVID-19., Methods: In this prospective cohort study, we measured the GAC components syndecan-1 (SDC1) and hyaluronan (Hyal) along with inflammatory cytokines in 12 hospitalized COVID-19 patients and 8 healthy controls (HC)., Results: In agreement with other studies, we found that inflammatory cytokines are elevated in hospitalized COVID-19 patients compared with HC [median (IQR), all units picograms per milliliter: IL-6 4.65 (3.32-9.16) vs 0.69 (0.55-0.89), p < 0.001; TNFα 4.49 (1.87-8.03) vs 0.04 (0.04-0.84), p < 0.001]. Additionally, we found that the GAC components SDC1 and Hyal are also elevated in COVID-19 patients [median (IQR), all units picograms per milliliter: SDC1: 247.37 (101.43-458.26) vs 84.8 (52.88-123.59), p = 0.036; Hyal: 26.41 (16.4-35.1) vs 3.01 (1.66-4.61), p < 0.001]., Conclusion: We propose that GAC markers offer insights into the pathobiology of COVID-19, potentially guide therapeutic approaches, and could aid in early risk stratification that is particularly beneficial in phasic diseases such as COVID-19., (© 2021. The Author(s).)

What Is This Plain Language Summary About?: This summary presents the results from an ongoing, long-term extension study that followed an earlier study called ATTR-ACT. People who took part in this extension study and ATTR-ACT have a type of heart disease known as transthyretin amyloid cardiomyopathy (ATTR-CM for short), which causes heart failure and death. In ATTR-ACT, people took either a medicine called tafamidis or a placebo (a pill that looks like the study drug but does not contain any active ingredients) for up to 2½ years. So far, in the long-term extension study, people have continued taking tafamidis, or switched from taking a placebo to tafamidis, for another 2½ years. Researchers looked at how many people died in ATTR-ACT and the extension study. The long-term extension study is expected to end in 2027, so these are interim (not final) results., What Did Researchers Find Out?: In the extension study of ATTR-ACT, the risk of dying was lower in people who took tafamidis continuously throughout ATTR-ACT and the extension study than in people who took placebo in ATTR-ACT and switched to tafamidis in the extension study., What Do the Results Mean?: Taking tafamidis increases how long people with ATTR-CM live. People with ATTR-CM who take tafamidis early and continuously are more likely to live longer than those who do not. These results highlight the importance of early detection and treatment in people with ATTR-CM. Clinical Trial Registration : NCT01994889 (ClinicalTrials.gov) Clinical Trial Registration : NCT02791230 (ClinicalTrials.gov).

Background Descriptions of do not attempt resuscitation (DNAR) orders in heart failure (HF) are limited. We describe use of DNAR orders in HF hospitalizations relative to other common conditions, focusing on race. Methods and Results This was a retrospective study of all adult hospitalizations for HF, acute myocardial infarction (AMI), chronic obstructive pulmonary disease (COPD), and pneumonia from 2010 to 2016 using the California State Inpatient Dataset. Using a hierarchical multivariable logistic regression model with random effects for the hospital, we identified factors associated with DNAR orders for each condition. For racial variation, hospitals were divided into quintiles based on proportion of Black patients cared for. Our cohort comprised 399 816 HF, 190 802 AMI, 192 640 COPD, and 269 262 pneumonia hospitalizations. DNAR orders were most prevalent in HF (11.9%), followed by pneumonia (11.1%), COPD (7.9%), and AMI (7.1%). Prevalence of DNAR orders did not change from 2010 to 2016 for each condition. For all conditions, DNAR orders were more common in elderly people, women, and White people with significant site-level variation across 472 hospitals. For HF and COPD, hospitalizations at sites that cared for a higher proportion of Black patients were less likely associated with DNAR orders. For AMI and pneumonia, conditions such as dementia and malignancy were strongly associated with DNAR orders. Conclusions DNAR orders were present in 12% of HF hospitalizations, similar to pneumonia but higher than AMI and COPD. For HF, we noted significant variability across sites when stratified by proportion of Black patients cared for, suggesting geographic and racial differences in end-of-life care.

Background: Food environment factors contribute to cardiovascular disease, but their effect on population-level heart failure (HF) mortality is unclear., Methods: We utilized the National Vital Statistics System and USDA Food Environment Atlas to collect HF mortality rates (MR) and 2 county food environment indices: (1) food insecurity percentage (FI%) and (2) food environment index (FEI), a scaled index (0-10, 10 best) incorporating FI% and access to healthy food. We used linear regression to estimate the association between food environment and HF MR Results: Mean county FI% and FEI were 13% and 7.8 in 2956 included counties. Counties with FI% above the national median had significantly higher HF MR (30.7 versus 26.7 per 100 000; P <0.001) compared with FI% below the national median. Counties with HF MR above the national median had higher FI%, lower FEI, lower density of grocery stores, poorer access to stores among older adults, and lower Supplemental Nutrition Assistance Program participation rate ( P <0.001 for all). Lower county FI% (β=-1.3% per 1% decrease) and higher county FEI (β=-3.6% per 1-unit increase in FEI) were significantly associated with lower HF MR after adjustment for county demographic, socioeconomic, and health factors. This association was stronger for HF MR compared with non-HF cardiovascular disease MR and all-cause MR The relationship between food environment and HF MR was stronger in counties with the highest income inequity and poverty rate., Conclusions: Healthier food environment is significantly associated with lower HF mortality at the county level. This reinforces the role of food security on cardiovascular outcomes.

Competing Interests: Conflict of interest: S.L.H. serves/has served as a heart failure clinical trial site investigator for Pfizer, Novartis, Astra-Zeneca, Axon Therapeutics, and Corvia Medical. K.T.G. has no perceived or actual conflicts of interest. The authors have no other conflicts of interest.

Medical management of heart failure (HF) has evolved and has achieved significant survival benefits, resulting in highly complex medication regimens. Complex medication regimens create challenges for older adults, including nonadherence and increased adverse drug events, especially associated with cognitive impairment, physical limitations, or lack of social support. However, the association between medication complexity and patients' health outcomes among older adults with HF is unclear. The purpose of this review is to address how the complexity of HF medications has been assessed in the literature and what clinical outcomes are associated with medication regimen complexity in HF. Further, we aimed to explore how older adults were represented in those studies. The Medication Regimen Complexity Index was the most commonly used tool for assessment of medication regimen complexity. Rehospitalization was most frequently assessed as the clinical outcome, and other studies used medication adherence, quality of life, healthcare utilization, healthcare cost, or side effect. However, the studies showed inconsistent results in the association between the medication regimen complexity and clinical outcomes. We also identified an extremely small number of studies that focused on older adults. Notably, current medication regimen complexity tools did not consider a complicated clinical condition of an older adult with multimorbidity, therapeutic competition, drug interactions, or altered tolerance to the usual dose strength of the medications. Furthermore, the outcomes that studies assessed were rarely comprehensive or patient centered. More studies are required to fill the knowledge gap identifying more comprehensive and accurate medication regimen complexity tools and more patient-centered outcome assessment., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Lake sturgeon (Acipenser fulvescens) populations have significantly declined across their historic range, in large part due to anthropogenic impacts that have likely been exacerbated by the life-history traits of this slow-growing and long-lived species. We developed a population model to explore how Contaminants of Emerging Concern (CECs) impact lake sturgeon populations. We explored how different physiological modes of action (pMoAs) of CECs impacted population abundance and recovery and how different simulated management actions could enable recovery. We first estimated the impacts on population abundance and recovery by comparing the trajectory of an unexposed population to a population that had been exposed to a CEC with a specific pMoA after the end of the exposure. We then predicted how different management actions would impact population recovery by comparing the trajectories of an unexposed population to an exposed population for which a management action started at a fixed time without discontinuation of the exposure. Our results predicted that the individual-level pMoA of CECs has an important impact on population-level effects because different stressor's pMoA impacts the life-history traits of sturgeon differently. For example, the feeding and reproduction pMoAs caused the strongest and weakest population declines, respectively. For the same reason, pMoA also impacted recovery. For example, recovery was delayed when the pMoA was growth, maintenance, or feeding, but it was immediate when the pMoA was reproduction. We found that management actions that increased the egg survival rate or the stocking of fingerlings resulted in faster and stronger recovery than management actions that increased the juvenile or adult survival rate. This result occurred because the first two management actions immediately impacted recruitment, whereas the impact was delayed for the last two. Finally, there was greater potential for recovery when management action targeted eggs and fingerlings because these life stages have lower natural survival rates. Integr Environ Assess Manag 2022;18:1597-1608. © 2022 Society of Environmental Toxicology & Chemistry (SETAC). This article has been contributed to by US Government employees and their work is in the public domain in the USA., (© 2022 Society of Environmental Toxicology & Chemistry (SETAC). This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Diastolic dysfunction (DD) underlies heart failure with preserved ejection fraction (HFpEF), a clinical syndrome associated with aging that is becoming more prevalent. Despite extensive clinical studies, no effective treatment exists for HFpEF. Recent findings suggest that oxidative stress contributes to the pathophysiology of DD, but molecular mechanisms underpinning redox-sensitive cardiac remodeling in DD remain obscure. Using transgenic mice with mitochondria-targeted NOX4 overexpression (Nox4TG618) as a model, we demonstrate that NOX4-dependent mitochondrial oxidative stress induces DD in mice as measured by increased E/E', isovolumic relaxation time, Tau Glantz and reduced dP/dt min while EF is preserved. In Nox4TG618 mice, fragmentation of cardiomyocyte mitochondria, increased DRP1 phosphorylation, decreased expression of MFN2, and a higher percentage of apoptotic cells in the myocardium are associated with lower ATP-driven and maximal mitochondrial oxygen consumption rates, a decrease in respiratory reserve, and a decrease in citrate synthase and Complex I activities. Transgenic mice have an increased concentration of TGFβ and osteopontin in LV lysates, as well as MCP-1 in plasma, which correlates with a higher percentage of LV myocardial periostin- and ACTA2-positive cells compared with wild-type mice. Accordingly, the levels of ECM as measured by Picrosirius Red staining as well as interstitial deposition of collagen I are elevated in the myocardium of Nox4TG618 mice. The LV tissue of Nox4TG618 mice also exhibited increased I CaL current, calpain 2 expression, and altered/disrupted Z-disc structure. As it pertains to human pathology, similar changes were found in samples of LV from patients with DD. Finally, treatment with GKT137831, a specific NOX1 and NOX4 inhibitor, or overexpression of mCAT attenuated myocardial fibrosis and prevented DD in the Nox4TG618 mice. Together, our results indicate that mitochondrial oxidative stress contributes to DD by causing mitochondrial dysfunction, impaired mitochondrial dynamics, increased synthesis of pro-inflammatory and pro-fibrotic cytokines, activation of fibroblasts, and the accumulation of extracellular matrix, which leads to interstitial fibrosis and passive stiffness of the myocardium. Further, mitochondrial oxidative stress increases cardiomyocyte Ca 2+ influx, which worsens CM relaxation and raises the LV filling pressure in conjunction with structural proteolytic damage., Competing Interests: Conflict of interest Dr. Marschall Runge is a member of the Board of Directors at Eli Lilly and Company., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Heart failure with preserved ejection fraction (HFpEF) is common and increasing in prevalence. Despite this, HFpEF is challenging to diagnose due in part to its shared clinical features with other comorbid conditions. HFpEF is now understood as a systemic syndrome, often driven by pro-inflammatory comorbidities, rather than solely a cardiac disease. This review summarizes the epidemiology, diagnostic criteria, and pathophysiology of HFpEF and proposes a clinical approach for patients suspected of having or diagnosed with HFpEF., Competing Interests: Disclosure Dr. Hummel is supported by the National Institutes of Health (R01-AG062582, R01-HL139813) and the Department of Veterans Affairs (RDC-2017-1066). Otherwise regarding this publication and contents written, all authors have nothing to disclose., (Published by Elsevier Inc.)

Background & Aims: Dietary sodium restriction is recommended by current guidelines to reduce blood pressure and decrease the risk of cardiovascular disease. Current methods to assess sodium intake such as dietary questionnaires and 24-h urine collection are cumbersome, and the results are not readily available to patients. In this analysis, we evaluated using chloride and creatinine dipsticks as a convenient method to monitor sodium intake, in addition to patients' ability to practice this method independently., Methods: This is a post-hoc analysis of a previously published trial, LowSalt4Life, that measured change in sodium consumption over 8 weeks to evaluate the effect of a just-in-time adaptive mobile application intervention. Participants were instructed on how to complete and interpret Quantab® chloride and Multistix® PRO 10 LS creatinine dipstick measurements at home and upload a picture of their results. A pharmacy student interpreted the chloride dipsticks, and intraclass correlation coefficients (ICC) were calculated to assess interrater reliability between the participant and pharmacy student. Predicted 24-h sodium values were calculated by the Kawasaki and Mann methods and compared to actual 24-h sodium excretion., Results: There was a strong interobserver correlation between interpretations of the chloride dipsticks, with the ICC values 0.90, 0.97, 0.99, and 0.98 at weeks 2, 4, 6, and 8, respectively. There was a moderate correlation between the dipstick predicted 24-h sodium excretion and actual 24-h sodium excretion at baseline (r = 0.506; P < 0.001), and a weak correlation at week 8 (r = 0.187; P = 0.217). When corrected creatinine values were used, the dipstick predicted 24-h sodium excretion correlated with the actual 24-h sodium excretion at baseline and week 8 (r = 0.512; P < 0.001 and r = 0.451; P = 0.002)., Conclusions: Our analysis suggests that chloride and creatinine dipsticks have the potential to predict total daily excretion of sodium. This method provides patients with an easy, convenient, and accurate method to assess sodium excretion at home. Further research is needed to identify the optimal timing of performing the dipstick analysis as well as ways to improve the creatinine measurement of the urine samples., Trial Registration: ClinicalTrials.gov NCT03099343; https://clinicaltrials.gov/ct2/show/NCT03099343., Competing Interests: Declaration of competing interest The study was approved by the University of Michigan IRB. The data used for this analysis is not open to the public. Dr. Hummel is supported by a grant from Veterans Affairs, CARA-009-16F9050. Dr. Dorsch has received research funding from the Agency for Healthcare Research and Quality, National Institute of Health, and the American Heart Association in the past 2 years., (Copyright © 2022 European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases regulate production of reactive oxygen species (ROS) that cause oxidative damage to cellular components but also regulate redox signaling in many cell types with essential functions in the cardiovascular system. Research over the past couple of decades has uncovered mechanisms by which NADPH oxidase (NOX) enzymes regulate oxidative stress and compartmentalize intracellular signaling in endothelial cells, smooth muscle cells, macrophages, cardiomyocytes, fibroblasts, and other cell types. NOX2 and NOX4, for example, regulate distinct redox signaling mechanisms in cardiac myocytes pertinent to the onset and progression of cardiac hypertrophy and heart failure. Heart failure with preserved ejection fraction (HFpEF), which accounts for at least half of all heart failure cases and has few effective treatments to date, is classically associated with ventricular diastolic dysfunction, i.e., defects in ventricular relaxation and/or filling. However, HFpEF afflicts multiple organ systems and is associated with systemic pathologies including inflammation, oxidative stress, arterial stiffening, cardiac fibrosis, and renal, adipose tissue, and skeletal muscle dysfunction. Basic science studies and clinical data suggest a role for systemic and myocardial oxidative stress in HFpEF, and evidence from animal models demonstrates the critical functions of NOX enzymes in diastolic function and several HFpEF-associated comorbidities. Here, we discuss the roles of NOX enzymes in cardiovascular cells that are pertinent to the development and progression of diastolic dysfunction and HFpEF and outline potential clinical implications.

Background Current guidelines recommend use of sacubitril-valsartan in patients with heart failure with reduced ejection fraction (HFrEF). Early data suggested low uptake of sacubitril-valsartan, but contemporary data on real-world use and their associated cost are limited. Methods and Results This was a retrospective study of individuals enrolled in Optum Clinformatics, a national insurance claims data set from 2016 to 2018. We included all adult patients with HFrEF with 2 outpatient encounters or 1 inpatient encounter with an International Classification of Diseases, Tenth Revision ( ICD-10 ), diagnosis of HFrEF and 6 months of continuous enrollment, also receiving β-blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers within 6 months of HFrEF diagnosis. We included 70 245 patients with HFrEF, and 5217 patients (7.4%) received sacubitril-valsartan prescriptions. Patients receiving care through a cardiologist compared with a primary care physician alone were more likely to receive sacubitril-valsartan (odds ratio, 1.61 [95% CI, 1.52-1.71]). Monthly out-of-pocket (OOP) cost for sacubitril-valsartan, compared with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, was higher for both commercially insured patients (mean, $69 versus $6.74) and Medicare Advantage (mean, $62 versus $2.52). For patients with commercial insurance, OOP cost was lower in 2016 than in 2018. For patients with Medicare Advantage, there was a significant geographic variation in the OOP costs across the country, ranging from $31 to $68 per month across different regions, holding all other patient-related factors constant. Conclusions Sacubitril-valsartan use was infrequent among patients with HFrEF. Patients receiving care with a cardiologist were more likely to receive sacubitril-valsartan. OOP costs remain high, potentially limiting use. Significant geographic variation in OOP costs, unexplained by patient factors, was noted.

Contaminants of emerging concern (CECs; e.g., pharmaceuticals, flame retardants, pesticides, and industrial chemicals) are omnipresent throughout tributaries to the Great Lakes. Furthermore, CECs are often present at concentrations that are potentially hazardous to aquatic species. Since 2010, we characterized the presence of CECs at 309 sites within 47 Great Lakes tributaries and characterized responses of fathead minnow (Pimephales promelas) exposed to river water at a subset of 26 sites within four tributaries. Our work resulted in three independent lines of evidence related to the potential hazards of CEC exposure to fish. First, vulnerability (where vulnerability refers to likelihood) of surface waters to CEC presence was predicted using select watershed characteristics. Second, hazard to fish (where hazard means the potential for adverse biological responses) was predicted using screening values for a subset of CECs. Third, biological responses of fathead minnow exposed to river water in streamside exposures were measured. We assessed the congruence of these three lines of evidence for identifying sites with elevated hazards to CEC exposure. Predicted vulnerability and hazards agreed at 66% of all sites. Where the two indices did not agree, vulnerability often underestimated predicted hazard. When compared with measured biological responses from streamside exposures, predicted hazards agreed for 42% of samples. Furthermore, when predicted hazards for specific effect categories were compared with similar measured biomarkers, 26% and 46% of samples agreed for reproductive and physiological effect categories, respectively. Overall, vulnerability and hazard predictions tended to overestimate the measured biological responses, providing a protective estimate of the potential hazards of CEC exposure to fish. When used together, these three approaches can help resource managers prioritize management activities in minimizing hazards of CEC exposure and can be used by researchers to prioritize studies focused on understanding the hazards of CEC exposure to fish. Integr Environ Assess Manag 2022;18:1246-1259. © 2021 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). This article has been contributed to by US Government employees and their work is in the public domain in the USA., (© 2021 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Aims: In heart failure (HF) with preserved ejection fraction (HFpEF), excessive redistribution of blood volume into the central circulation leads to elevations of intracardiac pressures with exercise limitations. Splanchnic ablation for volume management (SAVM) has been proposed as a therapeutic intervention. Here we present preliminary safety and efficacy data from the initial roll-in cohort of the REBALANCE-HF trial., Methods and Results: The open-label (roll-in) arm of REBALANCE-HF will enrol up to 30 patients, followed by the randomized, sham-controlled portion of the trial (up to 80 additional patients). Patients with HF, left ventricular ejection fraction (LVEF) ≥50%, and invasive peak exercise pulmonary capillary wedge pressure (PCWP) ≥25 mmHg underwent SAVM. Baseline and follow-up assessments included resting and exercise PCWP, New York Heart Association (NYHA) class, Kansas City Cardiomyopathy Questionnaire (KCCQ), 6-min walk test, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Efficacy and safety were assessed at 1 and 3 months. Here we report on the first 18 patients with HFpEF that have been enrolled into the roll-in, open-label arm of the study across nine centres; 14 (78%) female; 16 (89%) in NYHA class III; and median (interquartile range) age 75.2 (68.4-81) years, LVEF 61.0 (56.0-63.2)%, and average (standard deviation) 20 W exercise PCWP 36.4 (±8.6) mmHg. All 18 patients were successfully treated. Three non-serious moderate device/procedure-related adverse events were reported. At 1-month, the mean PCWP at 20 W exercise decreased from 36.4 (±8.6) to 28.9 (±7.8) mmHg (p < 0.01), NYHA class improved by at least one class in 33% of patients (p = 0.02) and KCCQ score improved by 22.1 points (95% confidence interval 9.4-34.2) (p < 0.01)., Conclusion: The preliminary open-label results from the multicentre REBALANCE-HF roll-in cohort support the safety and efficacy of SAVM in HFpEF. The findings require confirmation in the ongoing randomized, sham-controlled portion of the trial., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Widespread occurrence of emerging contaminants in Great Lakes tributaries led to the development and publication of a vulnerability index (VI) to assess the potential exposure of aquatic communities to chemicals of emerging concern (CEC) in the Great Lakes basin. The robust nature of the VI was tested to evaluate the underlying statistical model and expand the spatial domain of the index. Data collected at 131 new sampling sites (Test 1) and published data from independent studies (Test 2) were used to test the model predictions. Test 1 water and sediment samples were analyzed for the same classes of CEC chemicals and compared to the predictions for the original VI. Concentrations and numbers of unique CECs detected in water and sediment samples were similar between the original data and the two test datasets, although CECs tended to have higher detection frequencies in the original dataset compared to the Test 1 and Test 2 datasets. For example, 69 CECs were detected in ≥30% of water samples in the original dataset compared with 17 CECs in the Test 1 data and 59 in the Test 2 data. Predicted vulnerability for test sites agreed with actual vulnerability 64% of the time for water and 71% of the time for sediment. Agreement percentage results were greater when individual sites were grouped by river, with 82% agreement between predictions and actual vulnerability for water and 78% agreement for sediment. For the entire dataset, the VI ranks correlated with an independent estimate of potential biological impact. Agreement percentage was the greatest for low or high vulnerability index values but highly variable for sites that are classified as having medium vulnerability. Despite the underlying variability, there is a significant correlation (R 2 = 0.26; p < 0.01) between the VI ranking of tributaries and the independent ranking of potential negative biological impact., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Background: In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit., Methods: REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance <3.5 Wood units who were randomized 1:1 to atrial shunt device or sham control. The primary outcome-a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status-was analyzed using the win ratio. Latent PVD was defined as pulmonary vascular resistance ≥1.74 Wood units (highest tertile) at peak exercise, measured before randomization., Results: Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86]; P =0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68]; P =0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313; 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00]; P =0.004)., Conclusions: In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.

Importance: Cardiovascular disease is the leading cause of death in the United States. Synthetic thyroid hormones are among the 3 most commonly prescribed medications, yet studies evaluating the association between the intensity of thyroid hormone treatment and cardiovascular mortality are scarce., Objective: To evaluate the association between thyroid hormone treatment intensity and cardiovascular mortality., Design, Setting, and Participants: This retrospective cohort study used data on 705 307 adults who received thyroid hormone treatment from the Veterans Health Administration Corporate Data Warehouse between January 1, 2004, and December 31, 2017, with a median follow-up of 4 years (IQR, 2-9 years). Two cohorts were studied: 701 929 adults aged 18 years or older who initiated thyroid hormone treatment with at least 2 thyrotropin measurements between treatment initiation and either death or the end of the study period, and, separately, 373 981 patients with at least 2 free thyroxine (FT4) measurements. Data were merged with the National Death Index for mortality ascertainment and cause of death, and analysis was conducted from March 25 to September 2, 2020., Exposures: Time-varying serum thyrotropin and FT4 levels (euthyroidism: thyrotropin level, 0.5-5.5 mIU/L; FT4 level, 0.7-1.9 ng/dL; exogenous hyperthyroidism: thyrotropin level, <0.5 mIU/L; FT4 level, >1.9 ng/dL; exogenous hypothyroidism: thyrotropin level, >5.5 mIU/L; FT4 level, <0.7 ng/dL)., Main Outcomes and Measures: Cardiovascular mortality (ie, death from cardiovascular causes, including myocardial infarction, heart failure, or stroke). Survival analyses were performed using Cox proportional hazards regression models using serum thyrotropin and FT4 levels as time-varying covariates., Results: Of the 705 307 patients in the study, 625 444 (88.7%) were men, and the median age was 67 years (IQR, 57-78 years; range, 18-110 years). Overall, 75 963 patients (10.8%) died of cardiovascular causes. After adjusting for age, sex, traditional cardiovascular risk factors (eg, hypertension, smoking, and previous cardiovascular disease or arrhythmia), patients with exogenous hyperthyroidism (eg, thyrotropin levels, <0.1 mIU/L: adjusted hazard ratio [AHR], 1.39; 95% CI, 1.32-1.47; FT4 levels, >1.9 ng/dL: AHR, 1.29; 95% CI, 1.20-1.40) and patients with exogenous hypothyroidism (eg, thyrotropin levels, >20 mIU/L: AHR, 2.67; 95% CI, 2.55-2.80; FT4 levels, <0.7 ng/dL: AHR, 1.56; 95% CI, 1.50-1.63) had increased risk of cardiovascular mortality compared with individuals with euthyroidism., Conclusions and Relevance: This study suggests that both exogenous hyperthyroidism and exogenous hypothyroidism were associated with increased risk of cardiovascular mortality. These findings emphasize the importance of maintaining euthyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.

Excessive adipose tissue mass underlies much of the metabolic health complications in obesity. Although exercise training is known to improve metabolic health in individuals with obesity, the effects of exercise training without weight loss on adipose tissue structure and metabolic function remain unclear. Thirty-six adults with obesity (body mass index = 33 ± 3 kg · m -2 ) were assigned to 12 weeks (4 days week -1 ) of either moderate-intensity continuous training (MICT; 70% maximal heart rate, 45 min; n = 17) or high-intensity interval training (HIIT; 90% maximal heart rate, 10 × 1 min; n = 19), maintaining their body weight throughout. Abdominal subcutaneous adipose tissue (aSAT) biopsy samples were collected once before and twice after training (1 day after last exercise and again 4 days later). Exercise training modified aSAT morphology (i.e. reduced fat cell size, increased collagen type 5a3, both P ≤ 0.05, increased capillary density, P = 0.05) and altered protein abundance of factors that regulate aSAT remodelling (i.e. reduced matrix metallopeptidase 9; P = 0.02; increased angiopoietin-2; P < 0.01). Exercise training also increased protein abundance of factors that regulate lipid metabolism (e.g. hormone sensitive lipase and fatty acid translocase; P ≤ 0.03) and key proteins involved in the mitogen-activated protein kinase pathway when measured the day after the last exercise session. However, most of these exercise-mediated changes were no longer significant 4 days after exercise. Importantly, MICT and HIIT induced remarkably similar adaptations in aSAT. Collectively, even in the absence of weight loss, 12 weeks of exercise training induced changes in aSAT structure, as well as factors that regulate metabolism and the inflammatory signal pathway in adults with obesity. KEY POINTS: Exercise training is well-known to improve metabolic health in obesity, although how exercise modifies the structure and metabolic function of adipose tissue, in the absence of weight loss, remains unclear. We report that both 12 weeks of moderate-intensity continuous training (MICT) and 12 weeks of high-intensity interval training (HIIT) induced modifications in adipose tissue structure and factors that regulate adipose tissue remodelling, metabolism and the inflammatory signal pathway in adults with obesity, even without weight loss (with no meaningful differences between MICT and HIIT). The modest modifications in adipose tissue structure in response to 12 weeks of MICT or HIIT did not lead to changes in the rate of fatty acid release from adipose tissue. These results expand our understanding about the effects of two commonly used exercise training prescriptions (MICT and HIIT) on adipose tissue remodelling that may lead to advanced strategies for improving metabolic health outcomes in adults with obesity., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Despite the high prevalence of nutrition disorders in patients with heart failure (HF), major HF guidelines lack specific nutrition recommendations. Because of the lack of standardized definitions and assessment tools to quantify nutritional status, nutrition disorders are often missed in patients with HF. Additionally, a wide range of dietary interventions and overall dietary patterns have been studied in this population. The resulting evidence of benefit is, however, conflicting, making it challenging to determine which strategies are the most beneficial. In this document, we review the available nutritional status assessment tools for patients with HF. In addition, we appraise the current evidence for dietary interventions in HF, including sodium restriction, obesity, malnutrition, dietary patterns, and specific macronutrient and micronutrient supplementation. Furthermore, we discuss the feasibility and challenges associated with the implementation of multimodal nutrition interventions and delineate potential solutions to facilitate addressing nutrition in patients with HF., Competing Interests: Funding Support and Author Disclosures Dr Gallagher has received grant support from National Institutes of Health (UG3 DK128302-01, P30 DK26687-41 and 5T32DK007559-31). Dr Karmally is a health advisor at Sesame Workshop; and is a member of Heali Diet Advisory Group and a member of the Abbott Diversity Council. Dr Maddox has received grant funding from the National Institutes of Health National Center for Advancing Translational Sciences (1U24TR002306-01: A National Center for Digital Health Informatics Innovation); has received honoraria and/or expense reimbursement in the past 3 years from the Henry Ford health system (March 2019), the University of California, San Diego (January 2020), the University of Chicago (January 2021), George Washington University (January 2021), Baylor College of Medicine (April 2021), and the New York Cardiological Society (May 2021); has received compensation and travel expense reimbursement for American College of Cardiology leadership roles and meetings; is currently employed as a cardiologist and vice president of digital products and innovation at BJC HealthCare/Washington University School of Medicine, and in this capacity is advising Myia Labs, for which his employer is receiving equity compensation in the company (he is receiving no individual compensation from the company); and is a compensated director for a New Mexico–based foundation, the J.F. Maddox Foundation. Dr Hummel has grant support from the National Institutes of Health (R01-HL39813, R01-AG062582, R61-HL155498), American Heart Association (20-SFRN35370008), and Veterans Affairs Clinical Science Research & Development (CARA-009-16F9050); has received previous grant support from PurFoods, LLC; and has institutional support in the form of clinical trial funding from Pfizer, Novartis, Corvia, and Axon Therapeutics. Dr Carbone is supported by a Career Development Award (19CDA34660318) from the American Heart Association and by the Clinical and Translational Science Awards Program (UL1TR002649) from the National Institutes of Health to Virginia Commonwealth University. Dr Maurer has grant support from the National Institutes of Health (R01HL139671, R21AG058348, and K24AG036778); has received consulting income from Eidos, Prothena, Akcea, Alnylam, Intellia, and GlaxoSmithKline; and has received institutional support in the form of clinical trial funding from Pfizer, Ionis, Eidos, and Alnylam. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Tafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial)., Methods: Patients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE., Results: Median follow-up was 58.5 months in the continuous tafamidis group (n=176) and 57.1 months in the placebo to tafamidis group (n=177). There were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (hazard ratio, 0.59 [95% CI, 0.44-0.79]; P <0.001). Mortality was also reduced in the continuous tafamidis (versus placebo to tafamidis) subgroups of: variant transthyretin amyloidosis (0.57 [0.33-0.99]; P =0.05) and wild-type transthyretin amyloidosis (0.61 [0.43-0.87]; P =0.006); and baseline New York Heart Association class I and II (0.56 [0.38-0.82]; P =0.003) and class III (0.65 [0.41-1.01]; P =0.06)., Conclusions: In the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01994889 and NCT02791230.