<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>

<div><h4>Pharmacological Treatments in Heart Failure With Mildly Reduced and Preserved Ejection Fraction: Systematic Review and Network Meta-Analysis.</h4><i>Zafeiropoulos S, Farmakis IT, Milioglou I, Doundoulakis I, ... Butler J, Giannakoulas G</i><br /><b>Background</b><br />Medical treatment for heart failure (HF) with preserved ejection (HFpEF) and with mildly reduced ejection fraction (HFmrEF) has weaker evidence compared with reduced ejection fraction, despite recent trials with an angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose cotransporter-2 inhibitors (SGLT2i).<br /><b>Objectives</b><br />We aimed to estimate the aggregate therapeutic benefit of drugs for HFmrEF and HFpEF.<br /><b>Methods</b><br />We performed a systematic review of MEDLINE, CENTRAL, and Web of Science for randomized trials including patients with HF and left ventricular ejection fraction (LVEF) >40%, treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (analyzed together as renin-angiotensin system inhibitors [RASi]), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), digoxin, ARNI, and SGLT2i. An additive component network meta-analysis was performed. The primary outcome was a composite of cardiovascular (CV) death and first hospitalization for heart failure (HHF); secondary outcomes were CV death, total HHF, and all-cause mortality.<br /><b>Results</b><br />We identified 13 studies with a total of 29,875 patients and a mean LVEF of 56.3% ± 8.7%. ARNI, MRA, and SGLT2i separately, but not RASi, BB, or digoxin, reduced the primary composite outcome compared with placebo. The combination of ARNI, BB, MRA, and SGLT2i was the most effective (HR: 0.47 [95% CI: 0.31-0.70]); this was largely explained by the triple combination of ARNI, MRA, and SGLT2i (HR: 0.56 [95% CI 0.43-0.71]). Results were similar for CV death (HR: 0.63 [95% CI 0.43-0.91] for ARNI, MRA, and SGLT2i) or total HHF (HR: 0.49 [95% CI 0.33-0.71] for ARNI, MRA, and SGLT2i) alone. In a subgroup analysis, only SGLT2i had a consistent benefit among all LVEF subgroups, whereas the triple combination had the greatest benefit in HFmrEF, robust benefit in patients with LVEF 50% to 59%, and a statistically marginal benefit in patients with LVEF ≥60%.<br /><b>Conclusions</b><br />In patients with HF and LVEF>40%, the quadruple combination of ARNI, BB, MRA, and SGLT2i provides the largest reduction in the risk of CV death and HHF; driven by the robust effect of the triple combination of ARNI, MRA, and SGLT2i. The benefit was more pronounced in HFmrEF patients.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 25 Aug 2023; epub ahead of print</small></div>

<div><h4>Emerging Individualized Approaches in the Management of Acute Cardiorenal Syndrome With Renal Assist Devices.</h4><i>Martens P, Burkhoff D, Cowger JA, Jorde UP, Kapur NK, Tang WHW</i><br /><AbstractText>Growing insights into the pathophysiology of acute cardiorenal syndrome (CRS) in acute decompensated heart failure have indicated that not every rise in creatinine is associated with adverse outcomes. Detection of persistent volume overload and diuretic resistance associated with creatinine rise may identify patients with true acute CRS. More in-depth phenotyping is needed to identify pathologic processes in renal arterial perfusion, venous outflow, and microcirculatory-interstitial-lymphatic axis alterations that can contribute to acute CRS. Recently, various novel device-based interventions designed to target different pathophysiologic components of acute CRS are in early feasibility and proof-of-concept studies. However, appropriate trial endpoints that reflect improvement in cardiorenal trajectories remain elusive and highly debated. In this review the authors describe the variety of physiological derangements leading to acute CRS and the opportunity to individualize the management of acute CRS with novel renal assist devices that can target specific components of these alterations.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 22 Aug 2023; epub ahead of print</small></div>

<div><h4>Short-Term Changes in Peak VO After Initiation of Dapagliflozin in Heart Failure Across Iron Status.</h4><i>Lorenzo M, Jacobs-Cachá C, Palau P, Amiguet M, ... Núñez J, DAPA-VO2 Investigators</i><br /><b>Background</b><br />Some studies have indicated that sodium-glucose cotransporter-2 (SGLT2) inhibitors promote an increase in cell iron use.<br /><b>Objectives</b><br />The aim of this study was to examine, in patients with stable heart failure with reduced left ventricular ejection fraction (HFrEF), the effect of dapagliflozin on ferrokinetic parameters and whether short-term changes in peak oxygen consumption (Vo<sub>2</sub>) after dapagliflozin treatment are influenced by baseline and serial ferrokinetic status.<br /><b>Methods</b><br />This was an exploratory analysis of a randomized, double-blind clinical trial that evaluated the effect of dapagliflozin vs placebo on peak Vo<sub>2</sub> in patients with HFrEF (NCT04197635) and included 76 of the 90 patients initially enrolled in the trial. Changes in peak Vo<sub>2</sub> at 1 and 3 months were explored according to baseline and longitudinal ferrokinetic parameters (natural logarithm [ln] ferritin, transferrin saturation index [TSAT], soluble transferrin receptor, and hepcidin). Linear mixed-effect regression was used for the analyses.<br /><b>Results</b><br />Compared with placebo, dapagliflozin led to a significant decrease in 3-month ln ferritin (P = 0.040) and an increase in 1-month ln soluble transferrin receptor (P = 0.023). Between-treatment comparisons revealed a stepwise increase in peak Vo<sub>2</sub> in the dapagliflozin group at 1 and 3 months, which was especially apparent at lower baseline values of TSAT and ferritin (P < 0.05). Lower time-varying values of TSAT (1 and 3 months) also identified patients with greater improvements in peak Vo<sub>2</sub>.<br /><b>Conclusions</b><br />In patients with stable HFrEF, treatment with dapagliflozin resulted in short-term increases in peak Vo<sub>2</sub>, which were most marked in patients with surrogates of greater iron deficiency at baseline and during treatment. (Short-Term Effects of Dapagliflozin on Peak Vo<sub>2</sub> in HFrEF [DAPA-VO<sub>2</sub>]; NCT04197635).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 22 Aug 2023; epub ahead of print</small></div>

<div><h4>Intrarenal Venous Flow Pattern Changes Do Relate With Renal Function Alterations in Acute Heart Failure.</h4><i>de la Espriella R, Núñez-Marín G, Cobo M, de Castro Campos D, ... Mullens W, Núñez J</i><br /><b>Background</b><br />There is scarce evidence supporting the clinical utility of congestive intrarenal venous flow (IRVF) patterns in patients with acute heart failure.<br /><b>Objectives</b><br />This study aims to: 1) investigate the association between IRVF patterns and the odds of worsening renal function (WRF); 2) track the longitudinal changes of serum creatinine (sCr) across IRVF at predetermined points and its association with decongestion; and 3) explore the relationship between IRVF/WRF categories and patient outcomes.<br /><b>Methods</b><br />IRVF was assessed at baseline (pre-decongestive therapy), 72 hours, and 30 and 90 days postdischarge. Changes in sCr trajectories across dynamic IRVF variations and parameters of decongestion were assessed using linear mixed effect models. The association between IRVF/WRF categories and outcomes was evaluated using univariable/multivariable models.<br /><b>Results</b><br />In this prospective, multicenter study with 188 participants, discontinuous IRVF patterns indicated higher odds of WRF (OR: 3.90 [95% CI: 1.24-12.20]; P = 0.020 at 72 hours; and OR: 5.76 [95% CI: 1.67-19.86]; P = 0.006 at 30 days) and an increase in sCr (Δ-72 hours 0.14 mg/dL [95% CI: 0.06-0.22]; P = 0.001; Δ-discharge 0.13 mg/dL [95% CI: 0.03-0.23]; P = 0.007). However, the diuretic response and decongestion significantly influenced the magnitude of these changes. Patients exhibiting both WRF and discontinuous IRVF at 30 days experienced an increased hazard of adverse events (HR: 5.96 [95% CI: 2.63-13.52]; P < 0.001).<br /><b>Conclusions</b><br />Discontinuous IRVF identifies patients with higher odds of WRF during admission and postdischarge periods. Nonetheless, adequate diuretic response and decongestion could modify this association. Patients showing both WRF and discontinuous IRVF at 30 days had increased rates of adverse events.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 22 Aug 2023; epub ahead of print</small></div>

<div><h4>Clonal Hematopoiesis has Prognostic Value in Dilated Cardiomyopathy independent of Age and Clone Size.</h4><i>Sikking MA, Stroeks SLVM, Henkens MTHM, Raafs AG, ... Verdonschot JAJ, Heymans SRB</i><br /><b>Background</b><br />Clonal hematopoiesis (CH) gives rise to mutated leukocyte clones that induce cardiovascular inflammation, and thereby impact the disease course in atherosclerosis and ischemic heart failure. Clonal hematopoiesis of indeterminate potential (CHIP) refers to a variant allele frequency (VAF; a marker for clone size) in blood of ≥2%. The impact of CH clones -including small clone sizes (VAF<0.5%)- in non-ischemic dilated cardiomyopathy (DCM) remains largely undetermined.<br /><b>Objectives</b><br />To establish the prognostic impact of CH in DCM including small clones.<br /><b>Methods</b><br />CH is determined using an ultrasensitive single-molecule Molecular Inversion Probe technique that allows detection of clones down to a VAF of 0.01%. Cardiac death and all-cause mortality were analyzed using receiver operating characteristic curve-optimized VAF cut-off values.<br /><b>Results</b><br />Five hundred twenty DCM patients have been included. One hundred and nine patients (21%) had CH driver mutations, of which 45 had a VAF of ≥2% and 31 <0.5%. The median follow-up duration is 6.5 years [interquartile range 4.7-9.7]. DCM patients with CH have a higher risk of cardiac death (HR 2.33 using a VAF cut-off of 0.36%, 95% confidence interval 1.24-4.40) and all-cause mortality (HR 1.72 using a VAF cut-off of 0.06%, 95% confidence interval 1.10-2.69), independent of age, sex, left ventricle ejection fraction and New York Heart Association classification.<br /><b>Conclusion</b><br />CH predicts cardiac death and all-cause mortality in DCM patients with an optimal threshold for clone size of 0.36% and 0.06%, respectively. Therefore, CH is prognostically relevant independent of clone size in patients with DCM.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 21 Aug 2023; epub ahead of print</small></div>

<div><h4>Identification of Subclinical Heart Failure With Preserved Ejection Fraction in Patients With Symptomatic Atrial Fibrillation.</h4><i>Ariyaratnam JP, Elliott AD, Mishima RS, Kadhim K, ... Lau DH, Sanders P</i><br /><b>Background</b><br />Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) commonly coexist. We hypothesize that patients with symptomatic AF but without overt clinical HF commonly exhibit subclinical HFpEF according to established hemodynamic criteria.<br /><b>Objectives</b><br />The authors sought to use invasive hemodynamics to investigate the prevalence and implications of subclinical HFpEF in AF ablation patients.<br /><b>Methods</b><br />Consecutive symptomatic AF ablation patients were prospectively recruited. Diagnosis of subclinical HFpEF was undertaken by invasive assessment of left atrial pressure (LAP). Participants had HFpEF if the baseline mean LAP was >15 mm Hg and early HFpEF if the mean LAP was >15 mm Hg after a 500-mL fluid challenge. LA compliance was assessed invasively by monitoring the LAP and LA diameter during direct LA infusion of 15 mL/kg normal saline. LA compliance was calculated as Δ LA diameter/ΔLAP. LA cardiomyopathy was further studied with exercise echocardiography and electrophysiology study. Functional impact was evaluated using cardiopulmonary exercise testing and the AF Symptom Severity questionnaire.<br /><b>Results</b><br />Of 120 participants, 57 (47.5%) had HFpEF, 31 (25.8%) had early HFpEF, and 32 (26.7%) had no HFpEF. Both HFpEF and early HFpEF were associated with lower LA compliance compared with those without HFpEF (P < 0.001). Participants with HFpEF and early HFpEF also displayed decreased LA emptying fraction (P = 0.004), decreased LA voltage (P = 0.001), decreased VO<sub>2peak</sub> (P < 0.001), and increased AF symptom burden (P = 0.002) compared with those without HFpEF.<br /><b>Conclusions</b><br />Subclinical HFpEF is common in AF ablation patients and is characterized by a LA cardiomyopathy, decreased cardiopulmonary reserve and increased symptom burden. The diagnosis of HFpEF may identify patients with AF with the potential to benefit from novel HFpEF therapies. (Characterising Left Atrial Function and Compliance in Atrial Fibrillation; ACTRN12620000639921).<br /><br />Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 21 Aug 2023; epub ahead of print</small></div>

<div><h4>Assessing Donor-Recipient Size Mismatch in Pediatric Heart Transplantation: Lessons Learned From Over 7,500 Transplants.</h4><i>Amdani S, Aljohani OA, Kirklin JK, Cantor R, ... Nasman C, Kemna MS</i><br /><b>Background</b><br />To date, no studies have identified an optimal metric to match donor-recipient (D-R) pairs in pediatric heart transplantation (HT).<br /><b>Objectives</b><br />The study sought to identify size mismatch metrics that predicted graft survival post-HT.<br /><b>Methods</b><br />D-R pairs undergoing HT in Pediatric Heart Transplant Society database from 1993 to 2021 were included. Effects of size mismatch by height, weight, body mass index, body surface area, predicted heart mass, and total cardiac volume (TCV) on 1- and 5-year graft survival and morbidity outcomes (rejection and cardiac allograft vasculopathy) were evaluated. Cox models with stepwise selection identified size metrics that independently predicted graft survival.<br /><b>Results</b><br />Of 7,715 D-R pairs, 36.0% were well matched (D-R ratio: -20% to +20%) by weight, 39.0% by predicted heart mass, 50.0% by body surface area, 57.0% by body mass index, 71.0% by height, and 93.0% by TCV. Of all size metrics, only D-R mismatch by height and TCV predicted graft survival at 1 and 5 years. Effects of D-R size mismatch on graft survival were nonlinear. At both 1 and 5 years post-HT, D-R undersizing and oversizing by height led to increased graft loss, with graft loss observed more frequently with undersizing. Moderately undersized donors by height (D-R ratio: <-30%) frequently experienced rejection post-HT (P < 0.001). Assessing D-R size matching by TCV, minimal donor undersizing was protective, while oversizing up to 25% was not associated with increased graft loss.<br /><b>Conclusions</b><br />In pediatric HT, D-R appear most optimally matched using TCV. Only D-R size mismatch by TCV and height independently predicts graft survival. Standardizing size matching across centers may reduce donor discard.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 21 Aug 2023; epub ahead of print</small></div>

<div><h4>Impact of Coronary Artery Disease in Women With Newly Diagnosed Heart Failure and Reduced Ejection Fraction.</h4><i>Nielsen RR, Anker N, Stødkilde-Jørgensen N, Thrane PG, ... Olesen KKW, Maeng M</i><br /><b>Background</b><br />The representation of women in heart failure studies has been inadequate, resulting in a knowledge gap regarding the prognostic impact of coronary artery disease (CAD) on all-cause mortality in women with newly diagnosed heart failure and reduced ejection fraction (HFrEF).<br /><b>Objectives</b><br />To assess the prognostic impact of CAD in women with HFrEF.<br /><b>Methods</b><br />Using the Western Denmark Heart Registry, we identified 891 women and 2,403 men referred for first-time coronary angiography because of HFrEF. We stratified for presence of CAD, estimated 10-year all-cause mortality, and calculated crude and adjusted HRs (aHRs) with 95% CIs.<br /><b>Results</b><br />The 10-year mortality was 60% in women with CAD and 27% in women without CAD; for men, the corresponding numbers were 54% and 36%. When adjusted for comorbidities, women without CAD had a lower relative 10-year mortality than men without CAD (aHR: 0.73; 95% CI: 0.58-0.91), whereas women with CAD had similar relative mortality as men with CAD (aHR: 1.00; 95% CI: 0.81-1.24) (P<sub>interaction</sub> = 0.037). Assessed by the number of coronary vessels with significant stenosis, CAD extent was associated with mortality for both women (P < 0.01) and men (P < 0.01). However, compared to those without CAD, the aHR was higher for women with any degree of CAD (aHR ranging from 1.61 [95% CI 1.09-2.38] for diffuse CAD to 2.01 [95% CI 1.19-3.40] for 3-vessel disease) than for men with 3-vessel disease (aHR: 1.51; 95% CI: 1.19-1.91).<br /><b>Conclusions</b><br />In patients with newly diagnosed HFrEF, the presence and extent of CAD has significantly greater prognostic impact among women than among men.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 14 Aug 2023; epub ahead of print</small></div>

<div><h4>Advanced Heart Failure Therapies for Hypertrophic Cardiomyopathy: State-of-the-Art Review and an Updated Analysis From UNOS.</h4><i>Liang LW, Lumish HS, Sewanan LR, Shimada YJ, ... Uriel N, Clerkin KJ</i><br /><AbstractText>Hypertrophic cardiomyopathy (HCM) is most commonly associated with obstructive symptoms and sudden cardiac death; however, predominantly nonobstructive advanced heart failure in HCM, marked by medically refractory disease with severe functional impairment, occurs in 5% to 7% of patients with HCM. The diagnosis relies on the integration of imaging (echocardiography/cardiac magnetic resonance), hemodynamic data, and cardiopulmonary exercise testing to identify the patients who will benefit from advanced heart failure therapies. Most advanced heart failure therapies focus on systolic dysfunction and are not always applicable to this patient population. Left ventricular assist devices may be an option in a highly selected population with left ventricular dilation. Heart transplantation is often the best option for patients with advanced heart failure in HCM with excellent posttransplantation survival.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 14 Aug 2023; epub ahead of print</small></div>

<div><h4>Cardiopulmonary Performance Among Heart Failure Patients Before and After Left Ventricular Assist Device Implantation.</h4><i>Buchanan C, Buchanan C, Riordan M, Byrd J, ... Levine BD, Cornwell WK</i><br /><b>Background</b><br />Patients with heart failure with reduced ejection fraction (HFrEF) have persistent impairments in functional capacity after continuous-flow left ventricular assist device (CF-LVAD) implantation.<br /><b>Objectives</b><br />This study aims to characterize longitudinal changes in exercise hemodynamics and functional capacity among patients with HFrEF before and after CF-LVAD implantation.<br /><b>Methods</b><br />Ten patients underwent 3 invasive cardiopulmonary exercise tests on upright cycle ergometry with pulmonary artery catheterization: 1) Visit 1 before CF-LVAD implantation; 2) Visit 2 after device implantation with CF-LVAD pump speed held constant at baseline speed; and 3) Visit 3 with increases in pump speed during exercise (median: 1,050 rpm [IQR: 750-1,150 rpm] and 220 rpm [IQR: 120-220 rpm] for Heartmate 3 and Heartware VAD, respectively). Hemodynamics and direct Fick cardiac output were monitored using pulmonary artery catheterization. Gas exchange metrics were determined using indirect calorimetry.<br /><b>Results</b><br />Maximal oxygen uptake (Visits 1, 2, and 3: 10.8 ± 2.5 mL/kg/min, 10.7 ± 2.2 mL/kg/min, and 11.5 ± 1.7 mL/kg/min; P = 0.92) did not improve after device implantation. Mean pulmonary arterial and pulmonary capillary wedge pressures increased significantly during submaximal and peak exercise on preimplantation testing (P < 0.01 for rest vs peak exercise) and remained elevated, with minimal change on Visits 2 and 3 regardless of whether pump speed was fixed or increased.<br /><b>Conclusions</b><br />Among patients with HFrEF, cardiovascular hemodynamics and exercise capacity were similar after CF-LVAD implantation, regardless of whether patients exercised at fixed or adjusted pump speeds during exercise. Further research is needed to determine methods by which LVADs may alleviate the HFrEF syndrome after device implantation. (Effect of mechanIcal circulatoRy support ON exercise capacity aMong pAtieNts with heart failure [IRONMAN]; NCT03078972).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 07 Aug 2023; epub ahead of print</small></div>

<div><h4>Understanding and Investigating Sex-Based Differences in Heart Transplantation: A Call to Action.</h4><i>DeFilippis EM, Nikolova A, Holzhauser L, Khush KK</i><br /><AbstractText>Women represent only about 25% of heart transplant recipients annually. Although the number of women living with advanced heart failure remains unknown, epidemiologic research suggests that more women should be receiving advanced heart failure therapies. Sex differences in risk factors, presentation, response to pharmacotherapy, and outcomes in heart failure have been well described. Yet, less is known about sex differences in heart transplant candidate selection, waitlist management, donor selection, perioperative considerations, and post-transplant management and outcomes. The purpose of this review was to summarize the existing published reports related to sex differences in heart transplantation, highlighting areas in which sex-based considerations are well described and supported by available evidence, and emphasizing topics that require further study.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 04 Aug 2023; epub ahead of print</small></div>

<div><h4>Advanced Heart Failure Characteristics and Outcomes in Commercially Insured U.S. Adults.</h4><i>Subramaniam A, van Houten H, Redfield MM, Sangaralingham LR, ... LeMond LM, Dunlay SM</i><br /><b>Background</b><br />The characteristics and outcomes of patients with advanced heart failure (HF) have been poorly defined due to challenges in applying the complex advanced HF definition broadly to populations.<br /><b>Objectives</b><br />In this study, the authors sought to apply a validated advanced HF algorithm to a large U.S. administrative claims database and describe the population and use of advanced HF therapies.<br /><b>Methods</b><br />This study included adults with advanced HF identified in the OptumLabs Data Warehouse from 2009 to 2019. The algorithm for advanced HF required 2 hospitalizations for HF plus 1 additional sign of advanced HF in a 12-month period. The association of baseline characteristics with mortality was examined with the use of Cox proportional hazards models. Associations of patient characteristics with advanced therapies were estimated with the use of cause-specific Cox proportional hazard models.<br /><b>Results</b><br />In 60,197 patients identified with advanced HF, the mean age was 73 years, 51.5% were men, and 64.3% were non-Hispanic White, 1.9% Asian, 21.2% Black, and 8.2% Hispanic. The median survival with advanced HF was 2.0 years (IQR: 0.4-5.5 years). Differences in mortality and use of advanced therapies by age, sex, and race/ethnicity were observed. Adjusted mortality was higher in patients who were older, male, non-Hispanic White, and from rural areas (P < 0.05 for all). Advanced therapies were used less in older patients and women (P < 0.05 for both). Black patients were more likely to be treated with a left ventricular assist device (P = 0.010) but less likely to receive a heart transplant compared with White patients (P = 0.034).<br /><b>Conclusions</b><br />In U.S. adults with advanced HF, variation in outcomes and use of advanced therapies exist by age, sex, and race/ethnicity.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 03 Aug 2023; epub ahead of print</small></div>

<div><h4>Effect of Sotagliflozin on Early Mortality and Heart Failure-Related Events: A Post Hoc Analysis of SOLOIST-WHF.</h4><i>Pitt B, Bhatt DL, Szarek M, Cannon CP, ... Steg PG, SOLOIST-WHF Investigators</i><br /><b>Background</b><br />Approximately 25% of patients admitted to hospitals for worsening heart failure (WHF) are readmitted within 30 days.<br /><b>Objectives</b><br />The authors conducted a post hoc analysis of the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post-WHF) trial to evaluate the efficacy of sotagliflozin versus placebo to decrease mortality and HF-related events among patients who began study treatment on or before discharge from their index hospitalization.<br /><b>Methods</b><br />The main endpoint of interest was cardiovascular death or HF-related event (HF hospitalization or urgent care visit) occurring within 90 and 30 days after discharge for the index WHF hospitalization. Treatment comparisons were by proportional hazards models, generating HRs, 95% CIs, and P values.<br /><b>Results</b><br />Of 1,222 randomized patients, 596 received study drug on or before their date of discharge. Sotagliflozin reduced the main endpoint at 90 days after discharge (HR: 0.54 [95% CI: 0.35-0.82]; P = 0.004) and at 30 days (HR: 0.49 [95% CI: 0.27-0.91]; P = 0.023) and all-cause mortality at 90 days (HR: 0.39 [95% CI: 0.17-0.88]; P = 0.024). In subgroup analyses, sotagliflozin reduced the 90-day main endpoint regardless of sex, age, estimated glomerular filtration rate, N-terminal pro-B-type natriuretic peptide, left ventricular ejection fraction, or mineralocorticoid receptor agonist use. Sotagliflozin was well-tolerated but with slightly higher rates of diarrhea and volume-related events than placebo.<br /><b>Conclusions</b><br />Starting sotagliflozin before discharge in patients with type 2 diabetes hospitalized for WHF significantly decreased cardiovascular deaths and HF events through 30 and 90 days after discharge, emphasizing the importance of beginning sodium glucose cotransporter treatment before discharge.<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Aug 2023; 11:879-889</small></div>

<div><h4>Device Interventions for Heart Failure.</h4><i>Salah HM, Fudim M, Burkhoff D</i><br /><AbstractText>Despite remarkable advances in drug therapy for heart failure (HF), the residual HF-related morbidity, mortality, and hospitalizations remain substantial across all HF phenotypes, and significant proportions of patients with HF remain symptomatic despite optimal drug therapy. Driven by these unmet clinical needs, the exponential growth of transcatheter interventions, and a recent shift in the regulatory landscape of device-based therapies, novel device-based interventions have emerged as a potential therapy for various phenotypes of HF. Device-based interventions can overcome some of the limitations of drug therapy (eg, intolerance, nonadherence, inconsistent delivery, and recurrent and long-term cost) and can target some HF-related pathophysiologic pathways more effectively than drug therapy. This paper reviews the current evolving landscape of device-based interventions in HF and highlights critical points related to implementation of these therapies in the current workflow of HF management.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Aug 2023; 11:1039-1054</small></div>

<div><h4>Mitral Interventions in Heart Failure.</h4><i>Lander MM, Brener MI, Goel K, Tang PC, ... Lindenfeld J, Kanwar MK</i><br /><AbstractText>Patients with heart failure with reduced ejection fraction who have secondary mitral regurgitation (SMR) have poorer outcomes and quality of life than those without SMR. Guideline-directed medical therapy is the cornerstone of SMR treatment. Careful evaluation of landmark trials using mitral transcatheter edge-to-edge repair in SMR has led to an improved understanding of who will benefit from percutaneous interventions with emphasis on a multidisciplinary approach. The success with mitral transcatheter edge-to-edge repair in SMR has also spurred the evaluation of its role in populations that were not initially studied, such as end-stage heart failure and cardiogenic shock. A spectrum of transcatheter devices in development and clinical trials promise to further provide a growing array of management options for heart failure with reduced ejection fraction patients with symptomatic SMR.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Aug 2023; 11:1055-1069</small></div>

<div><h4>Aortic Valve Disease, Transcatheter Aortic Valve Replacement, and the Heart Failure Patient: A State-of-the-Art Review.</h4><i>Okumus N, Abraham S, Puri R, Tang WHW</i><br /><AbstractText>Concomitant aortic stenosis (AS) in heart failure (HF) is associated with high rates of mortality and morbidity. Current guidelines recommend aortic valve replacement in patients with severe symptomatic AS and asymptomatic AS with left ventricular ejection fraction <50% and during other cardiac surgeries. Transcatheter aortic valve replacement (TAVR) has now allowed for the treatment of severe AS in previously inoperable or high-surgical-risk patients. Leveraging multimodality imaging techniques is increasingly recognized for reinforcing the rationale for intervening early, thus mitigating the risk of ongoing progression to advanced HF. There are increasing data in favor of TAVR in diverse clinical scenarios, particularly asymptomatic AS and moderate AS. Limited information is, however, available regarding the advantages of HF medical therapy before and after intervention. This review aims to comprehensively examine the phenotypes of AS in the context of HF progression, while exploring the evolving role of TAVR in specific populations.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Aug 2023; 11:1070-1083</small></div>

<div><h4>Tricuspid Regurgitation Management for Heart Failure.</h4><i>Hahn RT, Brener MI, Cox ZL, Pinney S, Lindenfeld J</i><br /><AbstractText>There is growing evidence that severe tricuspid regurgitation (TR) impacts clinical outcomes in a variety of cardiovascular disease states. The late presentation of patients with advanced TR highlights the underappreciation of the disease, as well as the pitfalls of current guideline-directed medical management. Given the high in-hospital mortality associated with isolated tricuspid valve surgery, transcatheter options continue to be explored with the hope of improved survival and reduced heart failure hospitalizations. In this review, we explore the physiology of TR, discuss the etiologic classes of TR, and explore the transcatheter options for treatment and who might benefit from device therapy.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Aug 2023; 11:1084-1102</small></div>

<div><h4>Clinical Inertia Among Outpatients With Heart Failure: Application of Treatment Nonintensification Taxonomy to EPIC-HF Trial.</h4><i>Swat SA, Helmkamp LJ, Tietbohl C, Thompson JS, ... Buttrick P, Allen LA</i><br /><b>Background</b><br />The contribution of clinical inertia to suboptimal guideline-directed medical therapy (GDMT) for patients with heart failure with reduced ejection fraction (HFrEF) remains unclear.<br /><b>Objectives</b><br />This study examined reasons for GDMT nonintensification and characterized clinical inertia.<br /><b>Methods</b><br />In this secondary analysis of EPIC-HF (Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction), a randomized clinical trial evaluating a patient-activation tool on GDMT utilization, we performed a sequential, explanatory mixed-methods study. Reasons for nonintensification among 4 medication classes were assigned according to an expanded published taxonomy using structured chart reviews. Audio transcripts of clinic encounters were analyzed to further characterize nonintensification reasons. Integration occurred during the interpretation phase.<br /><b>Results</b><br />Among 292 HFrEF patients who completed a cardiology visit, 185 (63.4%) experienced no treatment intensification, of whom 90 (48.6%) had at least 1 opportunity for intensification of a medication class with no documented contraindication or barriers (ie, clinical inertia). Nonintensification reasons varied by medication class, and included heightened risk of adverse effects (range 18.2%-31.6%), patient nonadherence (range 0.8%-1.1%), patient preferences and beliefs (range 0.6%-0.9%), comanagement with other providers (range 4.6%-5.6%), prioritization of other issues (range 15.6%-31.8%), multiple categories (range 16.5%-22.7%), and clinical inertia (range 22.7%-31.6%). A qualitative analysis of 32 clinic audio recordings demonstrated common characteristics of clinical inertia: 1) clinician review of medication regimens without education or intensification discussions; 2) patient stability as justification for nonintensification; and 3) shorter encounters for nonintensification vs intensification.<br /><b>Conclusions</b><br />In this comprehensive study exploring HFrEF prescribing, clinical inertia is a main contributor to nonintensification within an updated taxonomy classification for suboptimal GDMT prescribing. This approach should help target strategies overcoming GDMT underuse.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 31 Jul 2023; epub ahead of print</small></div>

<div><h4>Age, Sex, and Outcomes in Heart Failure With Reduced EF: Insights From the VICTORIA Trial.</h4><i>Lam CSP, Piña IL, Zheng Y, Bonderman D, ... Armstrong PW, VICTORIA Study Group</i><br /><b>Background</b><br />Age and sex influence treatment and outcomes in patients with heart failure (HF).<br /><b>Objectives</b><br />The authors examined the associations of age and sex with clinical characteristics, background therapies, outcomes, and response to vericiguat in this post hoc analysis of 5,050 VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) patients with HF and reduced ejection fraction; 1,568 (31%) were ≥75 years of age, of whom 445 (24%) were women.<br /><b>Methods</b><br />Clinical characteristics were compared across age (<65, 65 to <75, and ≥75 years) and sex. The treatment effect of vericiguat was estimated by age and sex on the primary composite outcome (time to first HF hospitalization or cardiovascular death) using Cox proportional hazards regression.<br /><b>Results</b><br />Compared with younger patients, those ≥75 years of age had more class III and IV symptoms, higher N-terminal pro-B-type natriuretic peptide levels, and worse kidney function but had the lowest use of triple therapy. No sex differences in triple therapy existed by age, but achieving target doses of triple therapy was less likely in older patients. Men ≥75 years of age were more than twice as likely to receive defibrillators and 65% more likely to undergo cardiac resynchronization than women. The primary composite outcome was nominally lower in women than men across all age groups. Vericiguat dosing did not differ between sexes in each age group, and its beneficial effect on the primary endpoint was not modified by age (continuous age, P<sub>interaction</sub> = 0.169; categorical age, P<sub>interaction</sub> = 0.189); and sex (3-way interaction; P = 0.847).<br /><b>Conclusions</b><br />Although elderly women received less intense background HF therapy than men, their prognosis was nominally better. The benefit of vericiguat was independent of age and sex. (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction [HFrEF] [MK-1242-001] [VICTORIA]; NCT02861534).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 29 Jul 2023; epub ahead of print</small></div>

<div><h4>Interleukin-6 in Patients With Heart Failure and Preserved Ejection Fraction.</h4><i>Alogna A, Koepp KE, Sabbah M, Espindola Netto JM, ... Redfield MM, Borlaug BA</i><br /><b>Background</b><br />Interleukin (IL)-6 is a central inflammatory mediator and potential therapeutic target in heart failure (HF). Prior studies have shown that IL-6 concentrations are elevated in patients with HF, but much fewer data are available in HF with preserved ejection fraction (HFpEF).<br /><b>Objectives</b><br />Determine how IL-6 relates to changes in cardiac function, congestion, body composition, and exercise tolerance in HFpEF.<br /><b>Methods</b><br />Clinical, laboratory, body composition, exercise capacity, physiologic and health status data across 4 National Heart, Lung, and Blood Institute-sponsored trials were analyzed according to the tertiles of IL-6.<br /><b>Results</b><br />IL-6 was measured in 374 patients with HFpEF. Patients with highest IL-6 levels had greater body mass index; higher N-terminal pro-B-type natriuretic peptide, C-reactive protein, and tumor necrosis factor-α levels; worse renal function; and lower hemoglobin levels, and were more likely to have diabetes. Although cardiac structure and function measured at rest were similar, patients with HFpEF and highest IL-6 concentrations had more severely impaired peak oxygen consumption (12.3 ± 3.3 mL/kg/mivs 13.1 ± 3.1 mL/kg/mivs 14.4 ± 3.9 mL/kg/min, P < 0.0001) as well as 6-minute walk distance (276 ± 107 m vs 332 ± 106 m vs 352 ± 116 m, P < 0.0001), even after accounting for increases in IL-6 related to excess body mass. IL-6 concentrations were associated with increases in total body fat and trunk fat, more severe symptoms during submaximal exercise, and poorer patient-reported health status.<br /><b>Conclusions</b><br />IL-6 levels are commonly elevated in HFpEF, and are associated with greater symptom severity, poorer exercise capacity, and more upper body fat accumulation. These findings support testing the hypothesis that therapies that inhibit IL-6 in patients with HFpEF may improve clinical status. (Clinical Trial Registrations: Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure [RELAX], NCT00763867; Nitrate\'s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction, NCT02053493; Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF, NCT02742129; Inorganic Nitrite to Enhance Benefits From Exercise Training in Heart Failure With Preserved Ejection Fraction [HFpEF], NCT02713126).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 29 Jul 2023; epub ahead of print</small></div>

<div><h4>Penetrance and Prognosis of MYH7 Variant-Associated Cardiomyopathies: Results From a Dutch Multicenter Cohort Study.</h4><i>Jansen M, de Brouwer R, Hassanzada F, Schoemaker AE, ... Asselbergs FW, Baas AF</i><br /><b>Background</b><br />MYH7 variants cause hypertrophic cardiomyopathy (HCM), noncompaction cardiomyopathy (NCCM), and dilated cardiomyopathy (DCM). Screening of relatives of patients with genetic cardiomyopathy is recommended from 10 to 12 years of age onward, irrespective of the affected gene.<br /><b>Objectives</b><br />This study sought to study the penetrance and prognosis of MYH7 variant-associated cardiomyopathies.<br /><b>Methods</b><br />In this multicenter cohort study, penetrance and major cardiomyopathy-related events (MCEs) were assessed in carriers of (likely) pathogenic MYH7 variants by using Kaplan-Meier curves and log-rank tests. Prognostic factors were evaluated using Cox regression with time-dependent coefficients.<br /><b>Results</b><br />In total, 581 subjects (30.1% index patients, 48.4% male, median age 37.0 years [IQR: 19.5-50.2 years]) were included. HCM was diagnosed in 226 subjects, NCCM in 70, and DCM in 55. Early penetrance and MCEs (age <12 years) were common among NCCM-associated variant carriers (21.2% and 12.0%, respectively) and DCM-associated variant carriers (15.3% and 10.0%, respectively), compared with HCM-associated variant carriers (2.9% and 2.1%, respectively). Penetrance was significantly increased in carriers of converter region variants (adjusted HR: 1.87; 95% CI: 1.15-3.04; P = 0.012) and at age ≤1 year in NCCM-associated or DCM-associated variant carriers (adjusted HR: 21.17; 95% CI: 4.81-93.20; P < 0.001) and subjects with a family history of early MCEs (adjusted HR: 2.45; 95% CI: 1.09-5.50; P = 0.030). The risk of MCE was increased in subjects with a family history of early MCEs (adjusted HR: 1.82; 95% CI: 1.15-2.87; P = 0.010) and at age ≤5 years in NCCM-associated or DCM-associated variant carriers (adjusted HR: 38.82; 95% CI: 5.16-291.88; P < 0.001).<br /><b>Conclusions</b><br />MYH7 variants can cause cardiomyopathies and MCEs at a young age. Screening at younger ages may be warranted, particularly in carriers of NCCM- or DCM-associated variants and/or with a family history of MCEs at <12 years.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 29 Jul 2023; epub ahead of print</small></div>

<div><h4>Frailty Status Modifies the Efficacy of ICD Therapy for Primary Prevention Among Patients With HF.</h4><i>Segar MW, Keshvani N, Singh S, Patel L, ... Kitzman DW, Pandey A</i><br /><b>Background</b><br />Implantable cardioverter-defibrillator (ICD) therapy is recommended to reduce mortality risk in patients with heart failure with reduced ejection fraction (HFrEF). Frailty is common among patients with HFrEF and is associated with increased mortality risk. Whether the therapeutic efficacy of ICD is consistent among frail and nonfrail patients with HFrEF remains unclear.<br /><b>Objective</b><br />The aim of this study was to evaluate the effect modification of baseline frailty burden on ICD efficacy for primary prevention among participants of the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial).<br /><b>Methods</b><br />Participants in SCD-HeFT with HFrEF randomized to ICD vs placebo were included. Baseline frailty was estimated using the Rockwood Frailty Index (FI), and participants were stratified into high (FI > median) vs low (FI ≤ median) frailty burden groups. Multivariable Cox models with multiplicative interaction terms (frailty × treatment arm) were constructed to evaluate whether baseline frailty status modified the treatment effect of ICD for all-cause mortality.<br /><b>Results</b><br />The study included 1,676 participants (mean age: 59 ± 12 years, 23% women) with a median FI of 0.30 (IQR: 0.23-0.37) in the low frailty group and 0.54 (IQR: 0.47-0.60) in the high frailty group. In adjusted Cox models, baseline frailty status significantly modified the treatment effect of ICD therapy (P<sub>interaction</sub> = 0.047). In separate stratified analysis by frailty status, ICD therapy was associated with a lower risk of all-cause mortality among participants with low frailty burden (HR: 0.56; 95% CI: 0.40-0.78) but not among those with high frailty burden (HR: 0.86; 95% CI: 0.68-1.09).<br /><b>Conclusions</b><br />Baseline frailty modified the efficacy of ICD therapy with a significant mortality benefit observed among participants with HFrEF and a low frailty burden but not among those with a high frailty burden.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 26 Jul 2023; epub ahead of print</small></div>

<div><h4>Use of Clinical and Echocardiographic Evaluation to Assess the Risk of Heart Failure.</h4><i>Potter E, Huynh Q, Haji K, Wong C, ... Wright L, Marwick TH</i><br /><b>Background</b><br />Clinical and echocardiographic features predict incident heart failure (HF), but the optimal strategy for combining them is unclear.<br /><b>Objectives</b><br />This study sought to define an effective means of using echocardiography in HF risk evaluation.<br /><b>Methods</b><br />The same clinical and echocardiographic evaluation was obtained in 2 groups with HF risk factors: a training group (n = 926, followed to 7 years) and a validation group (n = 355, followed to 10 years). Clinical risk was categorized as low, intermediate, and high using 4-year ARIC (Atherosclerosis Risk In Communities) HF risk score cutpoints of 9% and 33%. A risk stratification algorithm based on clinical risk and echocardiographic markers of stage B HF (SBHF) (abnormal global longitudinal strain [GLS], diastolic dysfunction, or left ventricular hypertrophy) was developed using a classification and regression tree analysis and was validated.<br /><b>Results</b><br />HF developed in 12% of the training group, including 9%, 18%, and 73% of low-, intermediate-, and high-risk patients. HF occurred in 8.6% of stage A HF and 19.4% of SBHF (P < 0.001), but stage A HF with clinical risk of ≥9% had similar outcome to SBHF. Abnormal GLS (HR: 2.92 [95% CI: 1.95-4.37]; P < 0.001) was the strongest independent predictor of HF. Normal GLS and diastolic function reclassified 61% of the intermediate-risk group into the low-risk group (HF incidence: 12%). In the validation group, 11% developed HF over 4.5 years; 4%, 17%, and 39% of low-, intermediate-, and high-risk groups. Similar results were obtained after exclusion of patients with known coronary artery disease. The echocardiographic parameters also provided significant incremental value to the ARIC score in predicting new HF admission (C-statistic: 0.78 [95% CI: 0.71-0.84] vs 0.83 [95% CI: 0.77-0.88]; P = 0.027).<br /><b>Conclusions</b><br />Clinical risk assessment is adequate to classify low and high HF risk. Echocardiographic evaluation reclassifies 61% of intermediate-risk patients.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 26 Jul 2023; epub ahead of print</small></div>

<div><h4>Serum Proteomic Analysis of Peripartum Cardiomyopathy Reveals Distinctive Dysregulation of Inflammatory and Cholesterol Metabolism Pathways.</h4><i>Lovell JP, Bermea K, Yu J, Rousseau S, ... IPAC, IMAC2 Investigators</i><br /><b>Background</b><br />The pathophysiology of peripartum cardiomyopathy (PPCM) and its distinctive biological features remain incompletely understood. High-throughput serum proteomic profiling, a powerful tool to gain insights into the pathophysiology of diseases at a systems biology level, has never been used to investigate PPCM relative to nonischemic cardiomyopathy.<br /><b>Objectives</b><br />To characterize the pathophysiology of PPCM through serum proteomic analysis.<br /><b>Methods</b><br />Aptamer-based proteomic analysis (SomaScan 7K) was performed on serum samples from women with PPCM (n = 67), women with nonischemic nonperipartum cardiomyopathy (NPCM) (n = 31), and age-matched healthy peripartum and nonperipartum women (n = 10 each). Serum samples were obtained from the IPAC (Investigation of Pregnancy-Associated Cardiomyopathy) and IMAC2 (Intervention in Myocarditis and Acute Cardiomyopathy) studies.<br /><b>Results</b><br />Principal component analysis revealed unique clustering of each patient group (P for difference <0.001). Biological pathway analyses of differentially measured proteins in PPCM relative to NPCM, before and after normalization to pertinent healthy controls, highlighted specific dysregulation of inflammatory pathways in PPCM, including the upregulation of the cholesterol metabolism-related anti-inflammatory pathway liver-X receptor/retinoid-X receptor (LXR/RXR) (P < 0.01, Z-score 1.9-2.1). Cardiac recovery by 12 months in PPCM was associated with the downregulation of pro-inflammatory pathways and the upregulation of LXR/RXR, and an additional RXR-dependent pathway involved in the regulation of inflammation and metabolism, peroxisome proliferator-activated receptor α/RXRα signaling.<br /><b>Conclusions</b><br />Serum proteomic profiling of PPCM relative to NPCM and healthy controls indicated that PPCM is a distinct disease entity characterized by the unique dysregulation of inflammation-related pathways and cholesterol metabolism-related anti-inflammatory pathways. These findings provide insight into the pathophysiology of PPCM and point to novel potential therapeutic targets.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 18 Jul 2023; epub ahead of print</small></div>

<div><h4>Geographic Variation in the Quality of Heart Failure Care Among U.S. Veterans.</h4><i>Kosaraju RS, Fonarow GC, Ong MK, Heidenreich PA, ... Wang X, Ziaeian B</i><br /><b>Background</b><br />The burden of heart failure is growing. Guideline-directed medical therapies (GDMT) reduce adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Whether there is geographic variation in HFrEF quality of care is not well described.<br /><b>Objectives</b><br />This study evaluated variation nationally for prescription of GDMT within the Veterans Health Administration.<br /><b>Methods</b><br />A cohort of Veterans with HFrEF had their address linked to hospital referral regions (HRRs). GDMT prescription was defined using pharmacy data between July 1, 2020, and July 1, 2021. Within HRRs, we calculated the percentage of Veterans prescribed GDMT and a composite GDMT z-score. National choropleth maps were created to evaluate prescription variation. Associations between GDMT performance and demographic characteristics were evaluated using linear regression.<br /><b>Results</b><br />Maps demonstrated significant variation in the HRR composite score and GDMT prescriptions. Within HRRs, the prescription of beta-blockers to Veterans was highest with a median of 80% (IQR: 77.3%-82.2%) followed by angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitors (69.3%; IQR: 66.4%-72.1%), sodium-glucose cotransporter 2 inhibitors (10.3%; IQR: 7.7%-12.8%), mineralocorticoid receptor antagonists (29.2%; IQR: 25.8%-33.9%), and angiotensin receptor-neprilysin inhibitors (12.2%; IQR: 8.6%-15.3%). HRR composite GDMT z-scores were inversely associated with the HRR median Gini coefficient (R = -0.13; P = 0.0218) and the percentage of low-income residents (R = -0.117; P = 0.0413).<br /><b>Conclusions</b><br />Wide geographic differences exist for HFrEF care. Targeted strategies may be required to increase GDMT prescription for Veterans in lower-performing regions, including those affected by income inequality and poverty.<br /><br />Copyright © 2023 American College of Cardiology Foundation. All rights reserved.<br /><br /><small>JACC Heart Fail: 17 Jul 2023; epub ahead of print</small></div>

<div><h4>Association Between Wearable Device Measured Activity and Patient-Reported Outcomes for Heart Failure.</h4><i>Golbus JR, Gosch K, Birmingham MC, Butler J, ... Spertus J, Nallamothu BK</i><br /><b>Background</b><br />Wearable devices are increasingly used in research and clinical care though the relevance of their data in the context of validated outcomes remains unknown.<br /><b>Objectives</b><br />The purpose of this study was to characterize the relationship between smartwatch activity and patient-centered outcomes in patients with heart failure.<br /><b>Methods</b><br />CHIEF-HF (Canagliflozin: Impact on Health Status, Quality of Life and Functional Status in Heart Failure) was a randomized-controlled clinical trial that enrolled participants with heart failure and a compatible smartphone. Participants were provided a Fitbit Versa 2 and completed serial Kansas City Cardiomyopathy Questionnaires (KCCQs) through a smartphone application. We evaluated the relationship between daily step count and floors climbed and KCCQ total symptom (TS) and physical limitation (PL) scores at baseline and their respective changes between 2 and 12 weeks using linear regression models, with restricted cubic splines for nonlinear associations.<br /><b>Results</b><br />In total, 425 patients were included: 44.5% women, 40.9% with reduced ejection fraction. Baseline daily step count increased across categories of KCCQ-TS scores (2,437.6 ± 1,419.5 steps/d for scores 0 to 24 vs 4,870.9 ± 3,171.3 steps/d for scores 75 to 100; P < 0.001) with similar results for KCCQ-PL scores. This relationship remained significant for KCCQ-TS and KCCQ-PL scores after multivariable adjustment. Importantly, changes in daily step count were significantly associated with nonlinear changes in KCCQ-TS (P = 0.004) and KCCQ-PL (P = 0.003) scores. Floors climbed was associated with baseline KCCQ scores alone.<br /><b>Conclusions</b><br />Daily step count was nonlinearly associated with health status at baseline and over time in patients with heart failure. These results may inform interpretation of wearable device data in clinical and research contexts. (A Study on Impact of Canagliflozin on Health Status, Quality of Life, and Functional Status in Heart Failure [CHIEF-HF]; NCT04252287).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 14 Jul 2023; epub ahead of print</small></div>

<div><h4>Atrial Fibrillation Burden and Atrial Shunt Therapy in Heart Failure With Preserved Ejection Fraction.</h4><i>Patel RB, Reddy VY, Komtebedde J, Wegerich SW, ... Auricchio A, Shah SJ</i><br /><b>Background</b><br />Atrial fibrillation (AF) is a common comorbidity in patients with heart failure with preserved ejection fraction (HFpEF) and in heart failure with mildly reduced ejection fraction (HFmrEF).<br /><b>Objectives</b><br />This study sought to describe AF burden and its clinical impact among individuals with HFpEF and HFmrEF who participated in a randomized clinical trial of atrial shunt therapy (REDUCE LAP-HF II [A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure]) and to evaluate the effect of atrial shunt therapy on AF burden.<br /><b>Methods</b><br />Study investigators characterized AF burden among patients in the REDUCE LAP-HF II trial by using ambulatory cardiac patch monitoring at baseline (median patch wear time, 6 days) and over a 12-month follow-up (median patch wear time, 125 days). The investigators determined the association of baseline AF burden with long-term clinical events and examined the effect of atrial shunt therapy on AF burden over time.<br /><b>Results</b><br />Among 367 patients with cardiac monitoring data at baseline and follow-up, 194 (53%) had a history of AF or atrial flutter (AFL), and median baseline AF burden was 0.012% (IQR: 0%-1.3%). After multivariable adjustment, baseline AF burden ≥0.012% was significantly associated with heart failure (HF) events (HR: 2.00; 95% CI: 1.17-3.44; P = 0.01) both with and without a history of AF or AFL (P for interaction = 0.68). Adjustment for left atrial reservoir strain attenuated the baseline AF burden-HF event association (HR: 1.71; 95% CI: 0.93-3.14; P = 0.08). Of the 367 patients, 141 (38%) had patch-detected AF during follow-up without a history of AF or AFL. Atrial shunt therapy did not change AF incidence or burden during follow-up.<br /><b>Conclusions</b><br />In HFpEF and HFmrEF, nearly 40% of patients have subclinical AF by 1 year. Baseline AF burden, even at low levels, is associated with HF events. Atrial shunt therapy does not affect AF incidence or burden. (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure [REDUCE LAP-HF II]; NCT03088033).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 10 Jul 2023; epub ahead of print</small></div>

<div><h4>The Metabolic Vulnerability Index: A Novel Marker for Mortality Prediction in Heart Failure.</h4><i>Conners KM, Shearer JJ, Joo J, Park H, ... Turecamo S, Roger VL</i><br /><b>Background</b><br />Inflammation and protein energy malnutrition are associated with heart failure (HF) mortality. The metabolic vulnerability index (MVX) is derived from markers of inflammation and malnutrition and measured by nuclear magnetic resonance spectroscopy. MVX has not been examined in HF.<br /><b>Objectives</b><br />The authors sought to examine the prognostic value of MVX in patients with HF.<br /><b>Methods</b><br />We prospectively assembled a population-based cohort of patients with HF from 2003 to 2012 and measured MVX scores with a nuclear magnetic resonance scan from plasma collected at enrollment. Patients were divided into 4 MVX score groups and followed until March 31, 2021.<br /><b>Results</b><br />We studied 1,382 patients (median age: 78 years; 48% women). The median MVX score was 64.6. Patients with higher MVX were older, more likely to be male, have atrial fibrillation, have higher New York Heart Association class, and have HF duration of >18 months. Higher MVX was associated with mortality independent of Meta-analysis Global Group in Chronic Heart Failure score, ejection fraction, and other prognostic biomarkers. Compared to those with the lowest MVX, the HRs for MVX groups 2, 3, and 4 were 1.2 (95% CI: 0.9-1.4), 1.6 (95% CI: 1.3-2.0), and 1.8 (95% CI: 1.4-2.2), respectively (P<sub>trend</sub> < 0.001). Measures of model improvement document the added value of MVX in HF for classifying the risk of death beyond the Meta-analysis Global Group in Chronic Heart Failure score and other biomarkers.<br /><b>Conclusions</b><br />In this HF community cohort, MVX was strongly associated with mortality independently of established clinical factors and improved mortality risk classification beyond clinically validated markers. These data underscore the potential of MVX to stratify risk in HF.<br /><br />Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 07 Jul 2023; epub ahead of print</small></div>

<div><h4>Beneficial Effects of Ketone Ester in Patients With Cardiogenic Shock: A Randomized, Controlled, Double-Blind Trial.</h4><i>Berg-Hansen K, Christensen KH, Gopalasingam N, Nielsen R, ... Christensen S, Wiggers H</i><br /><b>Background</b><br />Cardiogenic shock (CS) is a life-threatening condition with sparse treatment options. The ketone body 3-hydroxybutyrate has favorable hemodynamic effects in patients with stable chronic heart failure. Yet, the hemodynamic effects of exogenous ketone ester (KE) in patients with CS remain unknown.<br /><b>Objectives</b><br />The authors aimed to assess the hemodynamic effects of single-dose enteral treatment with KE in patients with CS.<br /><b>Methods</b><br />In a double-blind, crossover study, 12 patients with CS were randomized to an enteral bolus of KE and isocaloric, isovolumic placebo containing maltodextrin. Patients were assessed with pulmonary artery catheterization, arterial blood samples, echocardiography, and near-infrared spectroscopy for 3 hours following each intervention separated by a 3-hour washout period.<br /><b>Results</b><br />KE increased circulating 3-hydroxybutyrate (2.9 ± 0.3 mmol/L vs 0.2 ± 0.3 mmol/L, P < 0.001) and was associated with augmented cardiac output (area under the curve of relative change: 61 ± 22 L vs 1 ± 18 L, P = 0.044). Also, KE increased cardiac power output (0.07 W [95% CI: 0.01-0.14]; P = 0.037), mixed venous saturation (3 percentage points [95% CI: 1-5 percentage points]; P = 0.010), and forearm perfusion (3 percentage points [95% CI: 0-6 percentage points]; P = 0.026). Right (P = 0.048) and left (P = 0.017) ventricular filling pressures were reduced whereas heart rate and mean arterial and pulmonary arterial pressures remained similar. Left ventricular ejection fraction improved by 4 percentage points (95% CI: 2-6 percentage points; P = 0.005). Glucose levels decreased by 2.6 mmol/L (95% CI: -5.2 to 0.0; P = 0.047) whereas insulin levels remained unaltered.<br /><b>Conclusions</b><br />Treatment with KE improved cardiac output, biventricular function, tissue oxygenation, and glycemic control in patients with CS (Treatment With the Ketone Body 3-hydroxybutyrate in Patients With Cardiogenic Shock [KETO-SHOCK1]; NCT04642768).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jul 2023; epub ahead of print</small></div>

<div><h4>Cardiac Myosin Inhibitors for Managing Obstructive Hypertrophic Cardiomyopathy: JACC: Heart Failure State-of-the-Art Review.</h4><i>Ostrominski JW, Guo R, Elliott PM, Ho CY</i><br /><AbstractText>Hypertrophic cardiomyopathy (HCM) is frequently caused by pathogenic variants in genes encoding sarcomere proteins and is characterized by left ventricular (LV) hypertrophy, hypercontractility, and-in many cases-left ventricular outflow tract (LVOT) obstruction. Despite standard management, obstructive HCM (oHCM) can still cause substantial morbidity, highlighting the critical need for more effective disease-specific therapeutic approaches. Over the past decade, improved understanding of the molecular pathobiology of HCM has culminated in development of cardiac myosin inhibitors (CMIs), a novel drug class that in recent randomized clinical trials has been shown to decrease LVOT obstruction, improve exercise capacity, and ameliorate symptom burden in patients with oHCM. Although promising, areas of uncertainty remain, including the long-term safety and efficacy of CMIs and whether they have the potential to modify progression of disease. Herein, we review key milestones in the clinical development of CMIs, contextualize CMIs with established oHCM therapies, and discuss future challenges and opportunities for the use of CMIs across the HCM spectrum.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jul 2023; 11:735-748</small></div>

<div><h4>Prevalent and Incident Anemia in PARADIGM-HF and the Effect of Sacubitril/Valsartan.</h4><i>Curtain JP, Adamson C, Docherty KF, Jhund PS, ... Packer M, McMurray JJV</i><br /><b>Background</b><br />Anemia is common in patients with heart failure with reduced ejection fraction and is associated with poor clinical outcomes. Renin-angiotensin system blockers lower hemoglobin and may induce anemia.<br /><b>Objectives</b><br />The authors investigated whether concomitant neprilysin inhibition might ameliorate this effect of renin-angiotensin system blockers in PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure).<br /><b>Methods</b><br />Anemia was defined as hemoglobin <120 g/L in women and <130 g/L in men at screening. The authors investigated the effect of randomized treatment on clinical outcomes according to anemia status, change in hemoglobin from baseline, and the incidence of anemia.<br /><b>Results</b><br />Of 8,239 participants with a baseline hemoglobin measurement, 1,677 (20.4%) were anemic. Patients with anemia had a more severe heart failure profile, worse kidney function, greater neurohormonal derangement, and worse clinical outcomes. Sacubitril/valsartan, compared with enalapril, decreased the risk of cardiovascular death or heart failure hospitalization similarly in patients with (HR: 0.84; 95% CI: 0.71-1.00) and without anemia (HR: 0.78 [95% CI: 0.71-0.87]; P value for interaction = 0.478). Between baseline and 12 months, hemoglobin decreased by 1.5 g/L (95% CI: 1.2-1.7 g/L) with sacubitril/valsartan compared with 2.3 g/L (95% CI: 2.0-2.6 g/L) with enalapril: mean difference 0.8 g/L (95% CI: 0.5-1.2 g/L; P < 0.001). Patients assigned to sacubitril/valsartan were less likely to develop anemia at 12 months (321 of 2,806 [11.4%]) compared with patients randomized to enalapril (440 of 2,824 [15.6%]) (OR: 0.70 [95% CI: 0.60-0.81]; P < 0.001). These findings were similar in PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) (sacubitril/valsartan vs valsartan). There was biomarker evidence of increased iron utilization with sacubitril/valsartan.<br /><b>Conclusions</b><br />Irrespective of anemia status, sacubitril/valsartan compared with enalapril, decreased mortality and hospitalization. Hemoglobin decreased less with sacubitril/valsartan and the incidence of new anemia was lower with sacubitril/valsartan. (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure [PARADIGM-HF] trial; NCT01035255).<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jul 2023; 11:749-759</small></div>