<div><h4>Impact of Female Sex on Cardiogenic Shock Outcomes: A Cardiogenic Shock Working Group Report.</h4><i>Ton VK, Kanwar MK, Li B, Blumer V, ... Burkhoff D, Kapur NK</i><br /><b>Background</b><br />Studies reporting cardiogenic shock (CS) outcomes in women are scarce.<br /><b>Objectives</b><br />The authors compared survival at discharge among women vs men with CS complicating acute myocardial infarction (AMI-CS) and heart failure (HF-CS).<br /><b>Methods</b><br />The authors analyzed 5,083 CS patients in the Cardiogenic Shock Working Group. Propensity score matching (PSM) was performed with the use of baseline characteristics. Logistic regression was performed for log odds of survival.<br /><b>Results</b><br />Among 5,083 patients, 1,522 were women (30%), whose mean age was 61.8 ± 15.8 years. There were 30% women and 29.1% men with AMI-CS (P = 0.03). More women presented with de novo HF-CS compared with men (26.2% vs 19.3%; P < 0.001). Before PSM, differences in baseline characteristics and sex-specific outcomes were seen in the HF-CS cohort, with worse survival at discharge (69.9% vs 74.4%; P = 0.009) and a higher rate of maximum Society for Cardiac Angiography and Interventions stage E (26% vs 21%; P = 0.04) in women than in men. Women were less likely to receive pulmonary artery catheterization (52.9% vs 54.6%; P < 0.001), heart transplantation (6.5% vs 10.3%; P < 0.001), or left ventricular assist device implantation (7.8% vs 10%; P = 0.01). Regardless of CS etiology, women had more vascular complications (8.8% vs 5.7%; P < 0.001), bleeding (7.1% vs 5.2%; P = 0.01), and limb ischemia (6.8% vs 4.5%; P = 0.001). More vascular complications persisted in women after PSM (10.4% women vs 7.4% men; P = 0.06).<br /><b>Conclusions</b><br />Women with HF-CS had worse outcomes and more vascular complications than men with HF-CS. More studies are needed to identify barriers to advanced therapies, decrease complications, and improve outcomes of women with CS.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 01 Nov 2023; epub ahead of print</small></div>

<div><h4>Health Status in Heart Failure and Cancer: Analysis of the Medicare Health Outcomes Survey 2016-2020.</h4><i>Shah KP, Khan SS, Baldridge AS, Grady KL, ... Lagu TC, Ahmad FS</i><br /><b>Background</b><br />People with heart failure (HF) and cancer experience impaired physical and mental health status. However, health-related quality of life (HRQOL) has not been directly compared between these conditions in a contemporary population of older people.<br /><b>Objectives</b><br />The authors sought to compare HRQOL in people with HF vs those with lung, colorectal, breast, and prostate cancers.<br /><b>Methods</b><br />The authors performed a pooled analysis of Medicare Health Outcomes Survey data from 2016 to 2020 in participants ≥65 years of age with a self-reported history of HF or active treatment for lung, colon, breast, or prostate cancer. They used the Veterans RAND-12 physical component score (PCS) and mental component score (MCS), which range from 0-100 with a mean score of 50 (based on the U.S. general population) and an SD of 10. The authors used pairwise Student\'s t-tests to evaluate for differences in PCS and MCS between groups.<br /><b>Results</b><br />Among participants with HF (n = 71,025; 54% female, 16% Black), mean PCS was 29.5 and mean MCS 47.9. Mean PCS was lower in people with HF compared with lung (31.2; n = 4,165), colorectal (35.6; n = 4,270), breast (37.7; n = 14,542), and prostate (39.6; n = 17,670) cancer (all P < 0.001). Participants with HF had a significantly lower mean MCS than those with lung (31.2), colon (50.0), breast (52.0), and prostate (53.0) cancer (all P < 0.001).<br /><b>Conclusions</b><br />People with HF experience worse HRQOL than those with cancer actively receiving treatment. The pervasiveness of low HRQOL in HF underscores the need to implement evidence-based interventions that target physical and mental health status and scale multidisciplinary clinics.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 30 Oct 2023; epub ahead of print</small></div>

<div><h4>Myocardial DNA Damage Predicts Heart Failure Outcome in Various Underlying Diseases.</h4><i>Dai Z, Ko T, Fujita K, Nomura S, ... Saito Y, Komuro I</i><br /><b>Background</b><br />Reliable predictors of treatment efficacy in heart failure have been long awaited. DNA damage has been implicated as a cause of heart failure.<br /><b>Objectives</b><br />The purpose of this study was to investigate the association of DNA damage in myocardial tissue with treatment response and prognosis of heart failure.<br /><b>Methods</b><br />The authors performed immunostaining of DNA damage markers poly(ADP-ribose) (PAR) and γ-H2A.X in endomyocardial biopsy specimens from 175 patients with heart failure with reduced ejection fraction (HFrEF) of various underlying etiologies. They calculated the percentage of nuclei positive for each DNA damage marker (%PAR and %γ-H2A.X). The primary outcome was left ventricular reverse remodeling (LVRR) at 1 year, and the secondary outcome was a composite of cardiovascular death, heart transplantation, and ventricular assist device implantation.<br /><b>Results</b><br />Patients who did not achieve LVRR after the optimization of medical therapies presented with significantly higher %PAR and %γ-H2A.X. The ROC analysis demonstrated good performance of both %PAR and %γ-H2A.X for predicting LVRR (AUCs: 0.867 and 0.855, respectively). There was a negative correlation between the mean proportion of DNA damage marker-positive nuclei and the probability of LVRR across different underlying diseases. In addition, patients with higher %PAR or %γ-H2A.X had more long-term clinical events (PAR HR: 1.63 [95% CI: 1.31-2.01; P < 0.001]; γ-H2A.X HR: 1.48 [95% CI: 1.27-1.72; P < 0.001]).<br /><b>Conclusions</b><br />DNA damage determines the consequences of human heart failure. Assessment of DNA damage is useful to predict treatment efficacy and prognosis of heart failure patients with various underlying etiologies.<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 28 Oct 2023; epub ahead of print</small></div>

<div><h4>Clinical Utility of Patient-Reported Outcome Instruments in the Management of Pulmonary Hypertension: A Systematic Review.</h4><i>Rose SW, Highland KB, Kelkar AA</i><br /><b>Background</b><br />Despite the greater sensitivity and specificity of disease-specific patient-reported outcome measures (PROM) to detect clinical change, only recently have such instruments been developed for pulmonary hypertension (PH), specifically pulmonary arterial hypertension (PAH) and chronic thromboembolic disease (CTEPH). Although these valuable tools are now being incorporated into clinical studies of PH, they have not yet reached widespread integration into routine clinical care.<br /><b>Objectives</b><br />In this systematic review, we assess the psychometric properties of PROM developed for PH, compare PROM with other clinical outcomes in PH, and address the utility of PROM in clinical care.<br /><b>Methods</b><br />The authors performed a systematic search of papers published between January 1, 2006, and October 1, 2022, using the MEDLINE database to identify PROM developed and validated for PH. The identified PROM were found to have been developed only in groups with PAH and CTEPH. The authors evaluated the identified instruments according to established psychometric criteria. An additional search was performed to identify randomized controlled trials (RCTs)∖utilizing these PROM for comparison with clinical outcomes.<br /><b>Results</b><br />From 527 papers retrieved, a total of 35 PROM were identified. Of these, 5 disease-specific instruments were included in the final analysis. While both Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) and XXX (emPHasis-10) performed well in patients with PAH and CTEPH with regard to their psychometric properties, emPHasis-10 demonstrated superior feasibility for use in clinical practice due to its concise format. The Pulmonary Arterial Hypertension-Symptoms and Impacts Questionnaire performed well in the authors\' analysis, though additional data is needed regarding interpretability and feasibility.<br /><b>Conclusions</b><br />EmPHasis-10 demonstrated strong psychometric properties and the greatest feasibility for clinical use. Further study assessing the integration of PROM into routine clinical care for PH is needed.<br /><br />Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 25 Oct 2023; epub ahead of print</small></div>

<div><h4>Combined Inhibition of Phosphodiesterases 5 and 9 in Experimental Heart Failure.</h4><i>Rademaker MT, Scott NJA, Charles CJ, Richards AM</i><br /><b>Background</b><br />Intracellular second messenger cyclic guanosine monophosphate (cGMP) mediates bioactivity of the natriuretic peptides and nitric oxide, and is key to circulatory homeostasis and protection against cardiovascular disease. Inhibition of cGMP-degrading phosphodiesterases (PDEs) PDE5 and PDE9 are emerging as pharmacological targets in heart failure (HF).<br /><b>Objectives</b><br />The present study investigated dual enhancement of cGMP in experimental HF by combining inhibition of PDE5 (P5-I) and PDE9 (P9-I).<br /><b>Methods</b><br />Eight sheep with pacing-induced HF received on separate days intravenous P5-I (sildenafil), P9-I (PF-04749982), P5-I+P9-I, and vehicle control, in counterbalanced order.<br /><b>Results</b><br />Compared with control, separate P5-I and P9-I significantly increased circulating cGMP concentrations in association with reductions in mean arterial pressure (MAP), left atrial pressure (LAP) and pulmonary arterial pressure (PAP), with effects of P5-I on cGMP, MAP and PAP greater than those of P9-I. Only P5-I decreased pulmonary vascular resistance. Combination P5-I+P9-I further reduced MAP, LAP, and PAP relative to inhibition of either phosphodiesterase alone. P9-I and, especially, P5-I elevated urinary cGMP levels relative to control. However, whereas inhibition of either enzyme increased urine creatinine excretion and clearance, only P9-I induced a significant diuresis and natriuresis. Combined P5-I+P9-I further elevated urine cGMP with concomitant increases in urine volume, sodium and creatinine excretion, and clearance similar to P9-I alone, despite the greater MAP reductions induced by combination treatment.<br /><b>Conclusions</b><br />Combined P5-I+P9-I amalgamated the superior renal effects of P9-I and pulmonary effects of P5-1, while concurrently further reducing cardiac preload and afterload. These findings support combination P5-I+P9-I as a therapeutic strategy in HF.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 16 Oct 2023; epub ahead of print</small></div>

<div><h4>Managing Obesity in Heart Failure: A Chance to Tip the Scales?</h4><i>Harrington J, Felker GM, Lingvay I, Pagidipati NJ, Pandey A, McGuire DK</i><br /><AbstractText>Obesity is associated with incident heart failure (HF), independent of other cardiovascular risk factors. Despite rising rates of both obesity and incident HF, the associations remain poorly understood between: 1) obesity and HF outcomes; and 2) weight loss and HF outcomes. Evidence shows that patients with HF and obesity have high symptom burdens, lower exercise capacity, and higher rates of hospitalization for HF when compared with patients with HF without obesity. However, the impact of weight loss on these outcomes for patients with HF and obesity remains unclear. Recent advances in medical therapies for weight loss have offered a new opportunity for significant and sustained weight loss. Ongoing and recently concluded cardiovascular outcomes trials will offer new insights into the role of weight loss through these therapies in preventing HF and mitigating HF outcomes and symptom burdens among patients with established HF, particularly HF with preserved ejection fraction.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 14 Oct 2023; epub ahead of print</small></div>

<div><h4>Differential Associations of A-/B-Type Natriuretic Peptides With Cardiac Structure, Function, and Prognosis in Heart Failure.</h4><i>Tan ESJ, Chan SP, Liew OW, Chong JPC, ... Lam CSP, Richards AM</i><br /><b>Background</b><br />Natriuretic peptide (NP) elevations are prognostic in heart failure (HF), but relative atrial NP deficiency in acute HF has been suggested.<br /><b>Objectives</b><br />The authors compared plasma concentrations and relative strength of associations of A- and B-type NPs with cardiac structure/function and clinical outcomes in HF.<br /><b>Methods</b><br />Midregional pro-atrial natriuretic peptide (MR-proANP), B-type natriuretic peptide (BNP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured in patients with compensated HF in a prospective, multicenter study. The primary outcome was a composite of HF-hospitalization or all-cause mortality. Secondary outcomes included individual primary outcome components and cardiovascular admission.<br /><b>Results</b><br />Among 1,278 patients (mean ± SD: age 60.1 ± 12.1 years, 82% men, left ventricular ejection fraction [LVEF] 34 ± 14%), median concentrations of MR-proANP were 990 pg/mL (Q1-Q3: 557-1,563 pg/mL), NT-proBNP 1,648 pg/mL (Q1-Q3: 652-3,960 pg/mL), and BNP 291 pg/mL (Q1-Q3: 103-777 pg/mL). No subpopulation with inappropriately low MR-proANP (relative to BNP/NT-proBNP) was observed. Clinical event rates were similar for biomarker tertiles. Increments in MR-proANP exhibited steeper associations with concurrent shifts in left ventricular size, diastolic indexes and LVEF than BNP/NT-proBNP at baseline and serially (P < 0.05), and lower odds of beneficial left ventricular reverse remodeling: OR: 0.35 (95% CI: 0.18-0.70). In single-biomarker models, MR-proANP(log<sub>10</sub>) was associated with the highest hazard (4 to 6 times) for each outcome. In multimarker models, independent associations were observed for the primary outcome (MR-proANP and NT-proBNP), HF-hospitalization and cardiovascular admission (MR-proANP only), and all-cause mortality (NT-proBNP only) (P < 0.05). The discriminative value of MR-proANP was superior to BNP/NT-proBNP (HF-hospitalization) and BNP (primary outcome) (P < 0.05).<br /><b>Conclusions</b><br />MR-proANP was not inappropriately low relative to concurrent BNP/NT-proBNP values. Proportional increments in MR-proANP were more pronounced than for B-peptides for given decrements in cardiac structure/function. MR-proANP offered greater independent predictive power overall.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 13 Oct 2023; epub ahead of print</small></div>

<div><h4>Mavacamten for Obstructive Hypertrophic Cardiomyopathy With or Without Hypertension: Post-Hoc Analysis of the EXPLORER-HCM Trial.</h4><i>Wang A, Spertus JA, Wojdyla DM, Abraham TP, ... Sehnert A, Lakdawala NK</i><br /><b>Background</b><br />Hypertension (HTN) is common in patients with hypertrophic cardiomyopathy (HCM), but its effect on the treatment of left ventricular outflow tract (LVOT) obstruction is undefined. Although elevated systolic blood pressure (SBP) may impact dynamic LVOT gradients, its response to cardiac myosin inhibition is unknown.<br /><b>Objectives</b><br />In a post hoc exploratory analysis of the EXPLORER-HCM trial (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy), the authors examined the characteristics of patients with obstructive HCM and HTN and the associations between HTN, SBP, and the response to mavacamten treatment of LVOT obstruction.<br /><b>Methods</b><br />Patients were stratified by baseline history of HTN and mean SBP during 30-week treatment with mavacamten or placebo. The study estimated treatment differences and evaluated HTN and SBP groups by treatment interaction. Analysis of covariance was used to model changes in continuous endpoints, and a generalized linear model was used for binary endpoints.<br /><b>Results</b><br />HTN was present in 119 of 251 patients (47.4%), including 60 receiving mavacamten and 59 receiving placebo. Patients with HTN vs no HTN were older (63.4 vs 54.0 years; P < 0.001), had higher SBP (134 ± 15.1 mm Hg vs 123 ± 13.8 mm Hg; P < 0.001), more comorbidities, and lower peak oxygen consumption (19 ± 3 vs 20 ± 4 mL/kg/min; P = 0.021). Patients with HTN had similar NYHA functional class (NYHA functional class II, 72% vs 73%), Valsalva LVOT gradients (72 ± 34 mm Hg vs 74 ± 30 mm Hg), Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores (70.6 ± 18.8 vs 68.9 ± 23.1), and NT pro-B-type natriuretic peptide levels (geometric mean 632 ± 129 pg/mL vs 745 ± 130 pg/mL). Mavacamten-treated patients had improvement in all primary, secondary, and exploratory endpoints regardless of HTN status or mean SBP.<br /><b>Conclusions</b><br />The clinical benefits of mavacamten in symptomatic, obstructive HCM were similar in patients with and without HTN, despite differences in baseline characteristics. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy [EXPLORER-HCM]; NCT03470545).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 12 Oct 2023; epub ahead of print</small></div>

<div><h4>SGLT2 Inhibitor Use and Risk of Clinical Events in Patients With Cancer Therapy-Related Cardiac Dysfunction.</h4><i>Avula V, Sharma G, Kosiborod MN, Vaduganathan M, ... Dani SS, Ganatra S</i><br /><b>Background</b><br />Certain antineoplastic therapies are associated with an increased risk of cardiomyopathy and heart failure (HF). Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in patients with HF.<br /><b>Objectives</b><br />This study aims to examine the efficacy of SGLT2 inhibitors in patients with cancer therapy-related cardiac dysfunction (CTRCD) or HF.<br /><b>Methods</b><br />The authors conducted a retrospective cohort analysis of deidentified, aggregate patient data from the TriNetX research network. Patients aged ≥18 years with a history of type 2 diabetes mellitus, cancer, and exposure to potentially cardiotoxic antineoplastic therapies, with a subsequent diagnosis of cardiomyopathy or HF between January 1, 2013, and April 30, 2020, were identified. Patients with ischemic heart disease were excluded. Patients receiving guideline-directed medical therapy were divided into 2 groups based on SGLT2 inhibitor use. After propensity score matching, odds ratios (ORs) and Cox proportional HRs were used to compare outcomes over a 2-year follow-up period.<br /><b>Results</b><br />The study cohort included 1,280 patients with CTRCD/HF (n = 640 per group; mean age: 67.6 years; 41.6% female; 68% White). Patients on SGLT2 inhibitors in addition to conventional guideline-directed medical therapy had a lower risk of acute HF exacerbation (OR: 0.483 [95% CI: 0.36-0.65]; P < 0.001) and all-cause mortality (OR: 0.296 [95% CI: 0.22-0.40]; P = 0.001). All-cause hospitalizations or emergency department visits (OR: 0.479; 95% CI: 0.383-0.599; P < 0.001), atrial fibrillation/flutter (OR: 0.397 [95% CI: 0.213-0.737]; P = 0.003), acute kidney injury (OR: 0.486 [95% CI: 0.382-0.619]; P < 0.001), and need for renal replacement therapy (OR: 0.398 [95% CI: 0.189-0.839]; P = 0.012) were also less frequent in patients on SGLT2 inhibitors.<br /><b>Conclusions</b><br />SGLT2 inhibitor use is associated with improved outcomes in patients with CTRCD/HF.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 12 Oct 2023; epub ahead of print</small></div>

<div><h4>Clinical Outcomes With a Fully Magnetically Levitated Left Ventricular Assist Device Among Women and Men.</h4><i>Ramu B, Cogswell R, Ravichandran AK, Cleveland J, ... Ahmed S, Yuzefpolskaya M</i><br /><b>Background</b><br />Left ventricular assist devices (LVADs) are underused among women with advanced heart failure, but reasons remain unclear. Outcomes in women compared with men with contemporary fully magnetically levitated LVADs remain uncertain.<br /><b>Objectives</b><br />The authors examined differences in characteristics, 2-year outcomes, and risk for key adverse events among women and men.<br /><b>Methods</b><br />In 2,200 HeartMate3 (HM3) (Abbott Cardiovascular) LVAD recipients in the MOMENTUM 3 study (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3), survival free of disabling stroke or reoperation to replace or remove a malfunctioning pump at 2 years was analyzed between women and men. Other outcomes included overall 2-year survival, adverse events, and functional measures.<br /><b>Results</b><br />Women comprised 20.4% (n = 448 of 2,200) of the study population and were younger, with nonischemic cardiomyopathy, and more often were Black persons compared with men. The primary endpoint (women 79.4% vs men 75.5% (adjusted [a]HR: 0.96 [95% CI: 0.75-1.24]; P = 0.66) or survival at 2 years (women 82.4% vs men 80.2%; aHR: 1.06 [95% CI: 0.81-1.40]; P = 0.66) was no different. Women had an increased rate of stroke (adjusted incidence rate ratio [aIRR]: 1.52 [95% CI: 1.09-2.11]; P = 0.012), major bleeding (aIRR: 1.28 [95% CI: 1.15-1.42]; P < 0.0001) and infection (aIRR 1.14 [95% CI: 1.03-1.55]; P = 0.01), but these differences were not seen among older (>65 years) patients. Both groups had similar gains in 6-minute walk distance and quality-of-life measurements.<br /><b>Conclusions</b><br />There were no differences in the primary composite endpoint or overall survival in women compared with men at 2 years of support. Reasons underlying increase in hemocompatibility-related events and infection-related morbidity in younger women deserves further study. (MOMENTUM 3 IDE Clinical Study Protocol [HM3] NCT02224755; and MOMENTUM 3 Continued Access Protocol [MOMENTUM 3 CAP] NCT02892955).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 02 Oct 2023; epub ahead of print</small></div>

<div><h4>Sex Differences in Heart Failure With Reduced Ejection Fraction in the GALACTIC-HF Trial.</h4><i>Pabon M, Cunningham J, Claggett B, Felker GM, ... Teerlink JR, GALACTIC-HF Investigators</i><br /><b>Background</b><br />Women with heart failure with reduced ejection fraction (HFrEF) receive less guideline-recommended therapy and experience worse quality of life than men.<br /><b>Objectives</b><br />The authors sought to assess differences in baseline characteristics, outcomes, efficacy, and safety of omecamtiv mecarbil between men and women enrolled in the GALACTIC-HF (Registrational Study With Omecamtiv Mecarbil [AMG 423] to Treat Chronic Heart Failure With Reduced Ejection Fraction) study.<br /><b>Methods</b><br />In GALACTIC-HF, patients with symptomatic heart failure with EF of 35% or less, recent heart failure event, and elevated natriuretic peptides were randomized to omecamtiv mecarbil or placebo. The current analysis investigated differences in baseline characteristics, clinical outcomes, and efficacy and safety of omecamtiv mecarbil between men and women.<br /><b>Results</b><br />Of 8,232 patients analyzed, 21.2% were women. Women more likely self-identified as being Black, had worse symptoms (lower Kansas City Cardiomyopathy Questionnaire Total Symptom Score; KCCQ-TSS), and were less likely to be treated with angiotensin receptor/neprilysin inhibitor and devices at baseline. Compared with men, women had lower rates of the primary endpoint (adjusted HR: 0.80, 95% CI: 0.73-0.88). Sex did not significantly modify omecamtiv mecarbil\'s treatment effect (P interaction = 0.68). Women also had 20% less risk of cardiovascular death, heart failure event, and all-cause death. Women participants had lower rates of serious adverse events.<br /><b>Conclusions</b><br />Women participants of the GALACTIC-HF trial had worse quality of life and were less likely to be treated with guideline-based therapies at baseline. Despite KCCQ-TSS being predictive of poor outcomes in this population, women had a 20% lower risk of an HF event or cardiovascular death compared with men. The beneficial effect of omecamtiv mecarbil did not significantly differ by sex. (Registrational Study With Omecamtiv Mecarbil [AMG 423] to Treat Chronic Heart Failure With Reduced Ejection Fraction [GALACTIC-HF]; NCT02929329).<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 25 Sep 2023; epub ahead of print</small></div>

<div><h4>Contemporary Use and Implications of Beta-blockers in Patients with HFmrEF or HFpEF: the DELIVER Trial.</h4><i>Peikert A, Bart BA, Vaduganathan M, Claggett BL, ... Solomon SD, Vardeny O</i><br /><b>Background</b><br />While beta-blockers are not recommended for the treatment of HFpEF according to the latest ESC and AHA/ACC/HFSA guidelines, these therapies remain commonly used for comorbidity management. There has been concern that beta-blockers might adversely influence clinical outcomes by limiting chronotropic response in HFpEF.<br /><b>Objectives</b><br />To examine the contemporary use and implications of beta-blockers in patients with HFmrEF or HFpEF.<br /><b>Methods</b><br />In the DELIVER trial, a total of 6,263 patients with symptomatic HF with LVEF >40% were randomized to dapagliflozin or placebo across 20 countries. In this prespecified analysis, efficacy and safety outcomes were examined according to beta-blocker use at randomization. The primary outcome was cardiovascular death or worsening HF.<br /><b>Results</b><br />Overall, beta-blockers were used in 5,177 patients (83%) with wide variation by geographic region. Beta-blocker use was associated with a lower risk of the primary outcome in covariate-adjusted models (HR 0.70 [95% CI 0.60-0.83]). Dapagliflozin consistently reduced the risk of the primary outcome in patients taking beta-blockers (HR 0.82 [95% CI 0.72-0.94]) and those not taking beta-blockers (HR 0.79 [95% CI 0.61-1.03]; P<sub>interaction</sub>=0.85), with similar findings for key secondary endpoints. Adverse events were balanced between patients randomized to dapagliflozin and placebo, regardless of background beta-blocker use.<br /><b>Conclusions</b><br />In patients with HFmrEF or HFpEF enrolled in DELIVER, 4 out of 5 participants were treated with a beta-blocker. Beta-blocker use was not associated with a higher risk of worsening HF or cardiovascular death. Dapagliflozin consistently and safely reduced clinical events, irrespective of background beta-blocker use.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 22 Sep 2023; epub ahead of print</small></div>

<div><h4>Safety and Performance of the Aortix Device in Acute Decompensated Heart Failure and Cardiorenal Syndrome.</h4><i>Cowger JA, Basir MB, Baran DA, Hayward CS, ... Shah P, Aortix CRS Pilot Study Investigators</i><br /><b>Background</b><br />Cardiorenal syndrome (CRS) complicates 33% of acute decompensated heart failure (ADHF) admissions, and patients with persistent congestion at discharge have high 30-day event rates.<br /><b>Objectives</b><br />The purpose of this study was to evaluate a novel catheter-deployed intra-aortic entrainment pump (IAEP) in patients with ADHF with CRS and persistent congestion.<br /><b>Methods</b><br />A multicenter (n = 14), nonrandomized, single-arm, safety and feasibility study of IAEP therapy was conducted. Within patient changes (post-pre IAEP therapy) in fluid loss, hemodynamics, patient-reported dyspnea, and serum biomarkers were assessed using Wilcoxon signed-rank testing.<br /><b>Results</b><br />Of 21 enrolled patients, 18 received Aortix therapy. Mean ± SD patient age was 60.3 ± 7.9 years. The median left ventricular ejection fraction was 22.5% (25th-75th percentile: 10.0%-53.5%); 27.8% had a left ventricular ejection fraction ≥50%. Pre-therapy, patients received 8.7 ± 4.1 days of loop diuretic agents and 44% were on inotropes. Pump therapy averaged 4.6 ± 1.6 days, yielding net fluid losses of 10.7 ± 6.5 L (P < 0.001) and significant (P < 0.01) reductions in central venous pressure (change from baseline: -8.5 mm Hg [25th-75th percentile: -3.5 to -10.0 mm Hg]), pulmonary capillary wedge pressure (-11.0 mm Hg [25th-75th percentile: -5.0 to -14.0 mm Hg]), and serum creatinine (-0.2 mg/dL [25th-75th percentile: -0.1 to -0.5 mg/dL]) with improved estimated glomerular filtration rate (+5.0 mL/min/1.73 m<sup>2</sup> [25th-75th percentile: 2.0-9.0 mL/min/1.73 m<sup>2</sup>]) and patient-reported dyspnea score (+16 [25th-75th percentile: 3-37]). Dyspnea scores, natriuretic peptides, and renal function improvements persisted through 30 days.<br /><b>Conclusions</b><br />This pilot study of patients with ADHF, persistent congestion, and worsening renal function due to CRS supports the potential for safely achieving decongestion using IAEP therapy. These initial promising results provide the basis for future randomized clinical trials of this novel pump. (An Evaluation of the Safety and Performance of the Aortix System for Intra-Aortic Mechanical Circulatory Support in Patients with Cardiorenal Syndrome [The Aortix CRS Pilot Study]; NCT04145635).<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 20 Sep 2023; epub ahead of print</small></div>

<div><h4>Proteomic Profiling in Patients With Peripartum Cardiomyopathy: A Biomarker Study of the ESC EORP PPCM Registry.</h4><i>Kodogo V, Viljoen C, Hoevelmann J, Chakafana G, ... Sliwa K, EURObservational Research Programme in conjunction with the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy</i><br /><b>Background</b><br />Peripartum cardiomyopathy (PPCM) remains an important cause of maternal morbidity and mortality globally. The pathophysiology remains incompletely understood, and the diagnosis is often missed or delayed.<br /><b>Objectives</b><br />This study explored the serum proteome profile of patients with newly diagnosed PPCM, as compared with matched healthy postpartum mothers, to unravel novel protein biomarkers that would further an understanding of the pathogenesis of PPCM and improve diagnostic precision.<br /><b>Methods</b><br />Study investigators performed untargeted serum proteome profiling using data-independent acquisition-based label-free quantitative liquid chromatography-tandem mass spectrometry on 84 patients with PPCM, as compared with 29 postpartum healthy control subjects (HCs). Significant changes in protein intensities were determined with nonpaired Student\'s t-tests and were further classified by using the Boruta algorithm. The proteins\' diagnostic performance was evaluated by area under the curve (AUC) and validated using the 10-fold cross-validation.<br /><b>Results</b><br />Patients with PPCM presented with a mean (± SD) left ventricular ejection fraction of 33.5 ± 9.3% vs 57.0 ± 8.8% in HCs (P < 0.001). Study investigators identified 15 differentially up-regulated and 14 down-regulated proteins in patients with PPCM compared with HCs. Seven of these proteins were recognized as significant by the Boruta algorithm. The combination of adiponectin, quiescin sulfhydryl oxidase 1, inter-α-trypsin inhibitor heavy chain, and N-terminal pro-B-type natriuretic peptide had the best diagnostic precision (AUC: 0.90; 95% CI: 0.84-0.96) to distinguish patients with PPCM from HCs.<br /><b>Conclusions</b><br />Salient biologic themes related to immune response proteins, inflammation, fibrosis, angiogenesis, apoptosis, and coagulation were predominant in patients with PPCM compared with HCs. These newly identified proteins warrant further evaluation to establish their role in the pathogenesis of PPCM and potential use as diagnostic markers.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 20 Sep 2023; epub ahead of print</small></div>

<div><h4>Maternal and Pregnancy Outcomes Following Heart Transplantation in the United States.</h4><i>Craig AM, Campbell A, Snow SC, Spates TN, ... Ward CC, Federspiel JJ</i><br /><b>Background</b><br />Improved survival following heart transplantation (HT) has led to more recipients contemplating pregnancy, but data on outcomes are limited.<br /><b>Objectives</b><br />The authors used a national data set to investigate and describe outcomes of pregnancies and deliveries in the United States in HT recipients.<br /><b>Methods</b><br />Diagnosis and procedure codes from the 2010-2020 Nationwide Readmissions Database identified delivery hospitalizations, history of HT, comorbid conditions, and outcomes. The authors compared rates of severe maternal morbidity (SMM), nontransfusion SMM, cardiovascular SMM (cSMM), and preterm birth from delivery hospitalization between HT recipients and No-HT recipients. The authors evaluated readmission to 330 days postpartum. Logistic and proportional hazard regressions were performed, adjusting for age, socioeconomic and facility characteristics, and clinical comorbidities.<br /><b>Results</b><br />Among 19,399,521 deliveries, 105 were HT recipients. Compared with No-HT, HT recipients were at higher risk for all SMM (24.8% vs 1.7%), nontransfusion SMM (20.8% vs 0.7%), cSMM (8.5% vs 0.12%), and preterm birth (44.3% vs 8.0%), all P < 0.001. In adjusted analyses, HT recipients had 15-fold greater odds of SMM, 28-fold greater odds of nontransfusion SMM, 38-fold greater odds of cSMM, and 7-fold greater odds of preterm birth. HT recipients had higher morbidity rates during delivery hospitalization and higher readmission rates within 1 year following delivery (26.9% vs 3.8%; adjusted HR: 6.03 [95% CI: 3.73-9.75]).<br /><b>Conclusions</b><br />Delivery with history of HT is associated with significantly increased rates of SMM, preterm birth, and hospital readmission. These results provide data regarding pregnancy outcomes for use when counseling patients with HT history who are considering pregnancy or who are pregnant.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 20 Sep 2023; epub ahead of print</small></div>

<div><h4>Value of Invasive Hemodynamic Assessments in Patients Supported by Continuous Flow Left Ventricular Assist Devices.</h4><i>Rodenas-Alesina E, Brahmbhatt DH, Mak S, Ross HJ, ... Rao V, Billia F</i><br /><AbstractText>Left ventricular assist devices (LVADs) are increasingly used in patients with end-stage heart failure (HF). There is a significant risk of HF admissions and hemocompatibility-related adverse events that can be minimized by optimizing the LVAD support. Invasive hemodynamic assessment, which is currently underutilized, allows personalization of care for patients with LVAD, and may decrease the need for recurrent hospitalizations. It also aids in triaging patients with persistent low-flow alarms, evaluating reversal of pulmonary vasculature remodeling, and assessing right ventricular function. In addition, it can assist in determining the precipitant for residual HF symptoms and physical limitation during exercise and is the cornerstone of the assessment of myocardial recovery. This review provides a comprehensive approach to the use of invasive hemodynamic assessments in patients supported with LVADs.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. All rights reserved.<br /><br /><small>JACC Heart Fail: 20 Sep 2023; epub ahead of print</small></div>

<div><h4>Age at Onset of Heart Failure and Subsequent Risk of Dementia: A Longitudinal Cohort Study.</h4><i>Zheng F, Liang J, Li C, Ma Q, ... Wang Y, Xie W</i><br /><b>Background</b><br />The average age at onset of heart failure (HF) shows a progressive decrease in recent years; however, the association between age at onset of HF and risk of subsequent dementia remains undetermined.<br /><b>Objectives</b><br />The study sought to examine whether younger onset age of HF is associated with a higher risk of incident dementia.<br /><b>Methods</b><br />Individual-level data from the UK Biobank cohort study were analyzed in the present study. Cox regression models and the propensity score matching method were used to analyze the associations of HF and its onset age with subsequent all-cause dementia, Alzheimer\'s disease (AD), and vascular dementia (VD).<br /><b>Results</b><br />Compared with 442,791 participants without HF, those with HF had a higher risk of all-cause dementia (HR: 1.14). Among 14,413 participants with HF, multivariable-adjusted HRs for all-cause dementia, AD, and VD were 1.18, 1.64, and 1.27, respectively, per 10-year decrease in age at HF onset. The propensity score matching analyses found that the strength of association between HF and all-cause dementia increased with decreasing onset age of HF (≥75 years, HR: 1.05; 65-74 years, HR: 1.10; <65 years, HR: 1.67) after multivariable adjustment. Similarly, participants with onset age of HF <65 years had the greatest HRs for incident AD and VD, compared with their matched control subjects.<br /><b>Conclusions</b><br />Younger age at HF onset was associated with increased risk of dementia. Individuals with an onset age of HF before 65 years of age may represent a particularly vulnerable population for dementia irrespective of subtypes and need careful monitoring and timely intervention to attenuate subsequent risk of incident dementia.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 14 Sep 2023; epub ahead of print</small></div>

<div><h4>Natriuretic Peptide Normative Levels and Deficiency: The National Health and Nutrition Examination Survey.</h4><i>Shetty NS, Patel N, Gaonkar M, Li P, Arora G, Arora P</i><br /><b>Background</b><br />Natriuretic peptides (NPs) are hormones with a range of key functions vital for cardiometabolic health. However, the reference ranges of NPs and the prevalence of NP deficiency in the healthy United States population remains poorly defined.<br /><b>Objective</b><br />This study aims to establish the reference range for N-terminal pro-B-type natriuretic peptide (NT-proBNP) values and to assess the prevalence of NP deficiency in a nationally representative healthy United States population.<br /><b>Methods</b><br />Healthy participants with NT-proBNP measurements from the 1999-2004 National Health and Nutrition Examination Survey were included. Weighted multivariable-adjusted linear regression models were used to assess the adjusted percentage difference of NT-proBNP concentrations by sex and race and ethnicity. NP deficiency was defined as concentrations <2.5th percentile in the study cohort.<br /><b>Results</b><br />Among 18,145 individuals (median age: 33.9 years [IQR: 17.1, 49.0 years], 49.8% males, and 68.5% non-Hispanic White individuals), females had similar NT-proBNP concentrations in the 1-10 years group (4.2% [95% CI: -3.3% to 12.2%]), and highest differences in the 20-30 years group (150.5% [95% CI: 123.5%-180.8%]) compared with males in their respective age groups. Compared with non-Hispanic White individuals, non-Hispanic Black individuals had lower NT-proBNP concentrations in the 1- to 10-years group (19.6% [95% CI: 10.7%-27.6%]), and these differences were most pronounced in the 30-40 years group (40.2% [95% CI: 33.7%-46.0%]). An estimated 9.1 million United States individuals had NP deficiency. NP deficiency was associated with a higher risk of cardiometabolic diseases such as hypertension, dyslipidemia, obesity, and insulin resistance.<br /><b>Conclusions</b><br />This study establishes the normative NP concentrations across the lifespan of a healthy United States population.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 12 Sep 2023; epub ahead of print</small></div>

<div><h4>Deactivation of Left Ventricular Assist Devices at the End of Life: Narrative Review and Ethical Framework.</h4><i>Zaidi D, Kirkpatrick JN, Fedson SE, Hull SC</i><br /><AbstractText>Left ventricular assist devices (LVADs) have become an increasingly common advanced therapy in patients with severe symptomatic heart failure. Their unique nature in prolonging life through incorporation into the circulatory system raises ethical questions regarding patient identity and values, device ontology, and treatment categorization; approaching requests for LVAD deactivation requires consideration of these factors, among others. To that end, clinicians would benefit from a deeper understanding of: 1) the history and nature of LVADs; 2) the wider context of device deactivation and associated ethical considerations; and 3) an introductory framework incorporating best practices in requests for LVAD deactivation (specifically in controversial situations without obvious medical or device-related complications). In such decisions, heart failure teams can safeguard patient preferences without compromising ethical practice through more explicit advance care planning before LVAD implantation, early integration of hospice and palliative medicine specialists (maintained throughout the disease process), and further research interrogating behaviors and attitudes related to LVAD deactivation.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 12 Sep 2023; epub ahead of print</small></div>

<div><h4>Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in UK Biobank.</h4><i>Asatryan B, Shah RA, Sharaf Dabbagh G, Landstrom AP, ... Chahal CAA, Genotype-First Approach Investigators</i><br /><b>Background</b><br />Inherited cardiomyopathies present with broad variation of phenotype. Data are limited regarding genetic screening strategies and outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the general population.<br /><b>Objectives</b><br />The authors aimed to determine the risk of mortality and composite cardiomyopathy-related outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the UK Biobank.<br /><b>Methods</b><br />Using whole exome sequencing data, variants in dilated, hypertrophic, and arrhythmogenic right ventricular cardiomyopathy-associated genes with at least moderate evidence of disease causality according to ClinGen Expert Panel curations were annotated using REVEL (≥0.65) and ANNOVAR (predicted loss-of-function) considering gene-disease mechanisms. Genotype-positive and genotype-negative groups were compared using time-to-event analyses for the primary (all-cause mortality) and secondary outcomes (diagnosis of cardiomyopathy; composite outcome of diagnosis of cardiomyopathy, heart failure, arrhythmia, stroke, and death).<br /><b>Results</b><br />Among 200,619 participants (age at recruitment 56.46 ± 8.1 years), 5,292 (2.64%) were found to host ≥1 predicted deleterious variants in cardiomyopathy-associated genes (CMP-G+). After adjusting for age and sex, CMP-G+ individuals had higher risk for all-cause mortality (HR: 1.13 [95% CI: 1.01-1.25]; P = 0.027), increased risk for being diagnosed with cardiomyopathy later in life (HR: 5.75 [95% CI: 4.58-7.23]; P < 0.0001), and elevated risk for composite outcome (HR: 1.29 [95% CI: 1.20-1.39]; P < 0.0001) than CMP-G- individuals. The higher risk for being diagnosed with cardiomyopathy and composite outcomes in the genotype-positive subjects remained consistent across all cardiomyopathy subgroups.<br /><b>Conclusions</b><br />Adults with predicted deleterious variants in cardiomyopathy-associated genes exhibited a slightly higher risk of mortality and a significantly increased risk of developing cardiomyopathy, and cardiomyopathy-related composite outcomes, in comparison with genotype-negative controls.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 02 Sep 2023; epub ahead of print</small></div>

<div><h4>Cardio-Obstetrics and Heart Failure: JACC: Heart Failure State-of-the-Art Review.</h4><i>DeFilippis EM, Bhagra C, Casale J, Ging P, ... Walsh MN, Kittleson MM</i><br /><AbstractText>Heart failure and cardiomyopathy are significant contributors to pregnancy-related deaths, as maternal morbidity and mortality have been increasing over time. In this setting, the role of the multidisciplinary cardio-obstetrics team is crucial to optimizing maternal, obstetrical and fetal outcomes. Although peripartum cardiomyopathy is the most common cardiomyopathy experienced by pregnant individuals, the hemodynamic changes of pregnancy may unmask a pre-existing cardiomyopathy leading to clinical decompensation. Additionally, there are unique management considerations for women with pre-existing cardiomyopathy as well as for those women with advanced heart failure who may be on left ventricular assist device support or have undergone heart transplantation. The purpose of this review is to discuss: 1) preconception counseling; 2) risk stratification and management strategies for pregnant women extending to the postpartum \"fourth trimester\" with pre-existing heart failure or \"pre-heart failure;\" 3) the safety of heart failure medications during pregnancy and lactation; and 4) management of pregnancy for women on left ventricular assist device support or after heart transplantation.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Sep 2023; 11:1165-1180</small></div>

<div><h4>Global Variations According to Sex in Patients Hospitalized for Heart Failure in the REPORT-HF Registry.</h4><i>Tromp J, Ezekowitz JA, Ouwerkerk W, Chandramouli C, ... Cleland JGF, Lam CSP</i><br /><b>Background</b><br />Previous reports suggest that risk factors, management, and outcomes of acute heart failure (AHF) may differ by sex, but they rarely extended analysis to low- and middle-income countries.<br /><b>Objectives</b><br />In this study, the authors sought to analyze sex differences in treatment and outcomes in patients hospitalized for AHF in 44 countries.<br /><b>Methods</b><br />The authors investigated differences between men and women in treatment and outcomes in 18,553 patients hospitalized for AHF in 44 countries in the REPORT-HF (Registry to Assess Medical Practice With Longitudinal Observation for the Treatment of Heart Failure) registry stratified by country income level, income disparity, and world region. The primary outcome was 1-year all-cause mortality.<br /><b>Results</b><br />Women (n = 7,181) were older than men (n = 11,372), were more likely to have heart failure with preserved left ventricular ejection fraction, had more comorbid conditions except for coronary artery disease, and had more severe signs and symptoms at admission. Coronary angiography, cardiac stress tests, and coronary revascularization were less frequently performed in women than in men. Women with AHF and reduced left ventricular ejection fraction were less likely to receive an implanted device, regardless of region or country income level. Women were more likely to receive treatments that could worsen HF than men (18% vs 13%; P < 0.0001). In countries with low-income disparity, women had better 1-year survival than men. This advantage was lost in countries with greater income disparity (P<sub>interaction</sub> < 0.001).<br /><b>Conclusions</b><br />Women were less likely to have diagnostic testing or receive guideline-directed care than men. A survival advantage for women was observed only in countries with low income disparity, suggesting that equity of HF care between sexes remains an unmet goal worldwide.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Sep 2023; 11:1262-1271</small></div>

<div><h4>Efficacy and Safety of Empagliflozin According to Background Diuretic Use in Heart Failure With Reduced Ejection Fraction: Post-Hoc Analysis of EMPEROR-Reduced.</h4><i>Dhingra NK, Verma S, Butler J, Anker SD, ... Packer M, EMPEROR-Reduced Trial Committees and Investigators</i><br /><b>Background</b><br />The EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial established the efficacy of empagliflozin in reducing heart failure (HF) outcomes among patients with heart failure with reduced ejection fraction (HFrEF).<br /><b>Objectives</b><br />The authors examined the outcomes of EMPEROR-Reduced as a function of background diuretic therapy.<br /><b>Methods</b><br />The EMPEROR-Reduced trial was a double-blind, randomized controlled trial of placebo vs empagliflozin 10 mg among 3,730 HFrEF patients. Herein, the population was stratified into 4 groups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline.<br /><b>Results</b><br />A total of 3,656 patients from the EMPEROR-Reduced trial were available for analysis. Of those patients, 482 (13.2%) were receiving no diuretic therapy, and 731 (20.0%), 1,411 (38.6%), and 1,032 (28.2%) were receiving <40 mg, 40 mg, and >40 mg, respectively. The efficacy of empagliflozin on the primary outcome (time to first event of hospitalization for HF or cardiovascular [CV] death) was consistent regardless of background diuretic therapy (>40 mg: HR: 0.88 [95% CI: 0.71-1.10]; 40 mg: HR: 0.65 [95% CI: 0.51-0.82]; <40 mg: HR: 0.65 [95% CI: 0.46-0.92]); no diuretic agents: HR: 0.78 [95% CI: 0.47-1.29]; P<sub>trend test</sub> = 0.192). Baseline diuretic doses did not influence the effect of empagliflozin on body weight, systolic blood pressure, NT-proBNP, or hematocrit at 52 weeks. The safety profile of empagliflozin vs placebo was unaffected by baseline diuretic dose; however, independently of treatment allocation, total rates of adverse events were higher among patients with higher baseline doses of diuretic agents.<br /><b>Conclusions</b><br />Empagliflozin exhibits a consistent effect on time to CV death or HF hospitalization and an unaltered safety profile regardless of baseline diuretic therapy. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 30 Aug 2023; epub ahead of print</small></div>