<div><h4>Cardio-Renal-Metabolic Overlap, Outcomes, and Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction.</h4><i>Ostrominski JW, Thierer J, Claggett BL, Miao ZM, ... Solomon SD, Vaduganathan M</i><br /><b>Background</b><br />Cardio-renal-metabolic (CRM) conditions are individually common among patients with HF, but the prevalence and influence of overlapping CRM conditions in this population have not been well-studied.<br /><b>Objectives</b><br />To evaluate the impact of overlapping CRM conditions on clinical outcomes and treatment effects of dapagliflozin in HF.<br /><b>Methods</b><br />In this post-hoc analysis of DELIVER, we evaluated the prevalence of comorbid CRM conditions (atherosclerotic cardiovascular disease, chronic kidney disease, and type 2 diabetes), their impact on the primary outcome (cardiovascular death or worsening HF), and treatment effects of dapagliflozin by CRM status.<br /><b>Results</b><br />Among 6,263 participants, 1,952 (31%), 2,245 (36%), and 1,236 (20%) had 1, 2, and 3 additional CRM conditions, respectively. HF alone was uncommon (13%). Greater CRM multimorbidity was associated with older age, higher BMI, longer-duration HF, worse health status, and lower LVEF. Risk of the primary outcome increased with higher CRM overlap, with 3 CRM conditions independently associated with highest risk of primary events (adjusted HR, 2.16 [95% CI, 1.72-2.72]; P<0.001) compared with HF alone. Relative benefits of dapagliflozin on the primary outcome were consistent irrespective of the type of CRM overlap (P<sub>interaction</sub>=0.773) and by the number of CRM conditions (P<sub>interaction</sub>=0.734), with greatest absolute benefits among those with highest CRM multimorbidity. Estimated two-year numbers needed to treat with dapagliflozin to prevent one primary event were approximately 52, 39, 33, and 24 for participants with 0, 1, 2, and 3 additional CRM conditions at baseline, respectively. Adverse events between treatment arms were similar across the CRM spectrum.<br /><b>Conclusions</b><br />Cardio-renal-metabolic multimorbidity was common and associated with adverse outcomes among patients with HF and LVEF>40% in DELIVER. Dapagliflozin was safe and effective across the CRM spectrum, with greater absolute benefits among those with highest CRM overlap.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 22 May 2023; epub ahead of print</small></div>

<div><h4>Effect of Canagliflozin on Heart Failure Hospitalization in Diabetes According to Baseline Heart Failure Risk.</h4><i>Khan MS, Segar MW, Usman MS, Patel KV, ... Tang WHW, Pandey A</i><br /><b>Background</b><br />In the CANVAS (Canagliflozin Cardiovascular Assessment Study) program, canagliflozin reduced the risk of heart failure (HF) hospitalization among individuals with type 2 diabetes mellitus (T2DM).<br /><b>Objectives</b><br />The purpose of this study was to evaluate heterogeneity in absolute and relative treatment effects of canagliflozin on HF hospitalization according to baseline HF risk as assessed by diabetes-specific HF risk scores (WATCH-DM [Weight (body mass index), Age, hyperTension, Creatinine, HDL-C, Diabetes control (fasting plasma glucose) and QRS Duration, MI and CABG] and TRS-HF<sub>DM</sub> [TIMI Risk Score for HF in Diabetes]).<br /><b>Methods</b><br />Participants in the CANVAS trial were categorized into low, medium, and high risk for HF using the WATCH-DM score (for participants without prevalent HF) and the TRS-HF<sub>DM</sub> score (for all participants). The outcome of interest was time to first HF hospitalization. The treatment effect of canagliflozin vs placebo for HF hospitalization was compared across risk strata.<br /><b>Results</b><br />Among 10,137 participants with available HF data, 1,446 (14.3%) had HF at baseline. Among participants without baseline HF, WATCH-DM risk category did not modify the treatment effect of canagliflozin (vs placebo) on HF hospitalization (P interaction = 0.56). However, the absolute and relative risk reduction with canagliflozin was numerically greater in the high-risk group (cumulative incidence, canagliflozin vs placebo: 8.1% vs 12.7%; HR: 0.62 [95% CI: 0.37-0.93]; P = 0.03; number needed to treat: 22) than in the low- and intermediate-risk groups. When overall study participants were categorized according to the TRS-HF<sub>DM</sub> score, a statistically significant difference in the treatment effect of canagliflozin across risk strata was observed (P interaction = 0.04). Canagliflozin significantly reduced the risk of HF hospitalization by 39% in the high-risk group (HR: 0.61 [95% CI: 0.48-0.78]; P < 0.001; number needed to treat: 20) but not in the intermediate- or low-risk groups.<br /><b>Conclusions</b><br />Among participants with T2DM, the WATCH-DM and TRS-HF<sub>DM</sub> can reliably identify those at high risk for HF hospitalization and most likely to benefit from canagliflozin.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 11 May 2023; epub ahead of print</small></div>

<div><h4>Disentangling Heart Failure and Physical Frailty: Prospective Study of Patients Undergoing Percutaneous Mitral Valve Repair.</h4><i>Metze C, Iliadis C, Körber MI, von Stein J, ... Baldus S, Pfister R</i><br /><b>Background</b><br />Frailty and heart failure share pathophysiology and clinical characteristics.<br /><b>Objectives</b><br />The aim of this study was to analyze the contribution of heart failure to the physical frailty phenotype by examining patients with heart failure before and after percutaneous mitral valve repair (PMVR).<br /><b>Methods</b><br />Frailty according to the Fried criteria (weight loss, weakness, exhaustion, slowness, and low activity) was assessed in consecutive patients before and 6 weeks after PMVR.<br /><b>Results</b><br />118 of 258 patients (45.7%) (mean age: 78 ± 9 years, 42% female, 55% with secondary mitral regurgitation) were frail at baseline, which significantly decreased to 74 patients (28.7 %) at follow-up (P < 0.001). The frequency of frailty domains slowness, exhaustion, and inactivity significantly decreased, whereas weakness remained unchanged. Baseline frailty was significantly associated with comorbidities, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and functional capacity, whereas frailty after PMVR was not associated with NT-proBNP levels. Predictors of postprocedural reversibility of frailty were NYHA functional class <IV, absence of weakness, and lower frailty score. In comparison with patients who were persistently nonfrail (reference group HR: 1), the risk of mortality continuously increased for patients who experienced new frailty (HR: 1.41 [95% CI: 0.41-4.86]), those who had reversal of frailty (HR: 2.17 [95% CI: 1.03-4.57]), and those who were persistently frail (HR: 3.26 [95%: CI 1.62-6.57]; P = 0.006 for trend).<br /><b>Conclusions</b><br />Treatment of mitral regurgitation in patients with heart failure is associated with almost a halved burden of physical frailty, particularly in patients with a less advanced phenotype. Considering the prognostic relevance of frailty dynamics, this data warrants further evaluation of the concept of frailty as a primary treatment target.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 11 May 2023; epub ahead of print</small></div>

<div><h4>Utilization Rates of SGLT2 Inhibitors Among Patients With Type 2 Diabetes, Heart Failure, and Atherosclerotic Cardiovascular Disease: Insights From the Department of Veterans Affairs.</h4><i>Hussain A, Ramsey D, Lee M, Mahtta D, ... Navaneethan SD, Virani SS</i><br /><b>Background</b><br />Multiple clinical trials have demonstrated significant cardiovascular benefit with use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with type 2 diabetes (T2DM) and heart failure (HF) irrespective of ejection fraction. There are limited data evaluating real-world prescription and practice patterns of SGLT2 inhibitors.<br /><b>Objectives</b><br />The authors sought to assess utilization rates and facility-level variation in the use among patients with established atherosclerotic cardiovascular disease (ASCVD), HF, and T2DM using data from the nationwide Veterans Affairs health care system.<br /><b>Methods</b><br />The authors included patients with established ASCVD, HF, and T2DM seen by a primary care provider between January 1, 2020, and December 31, 2020. They assessed the use of SGLT2 inhibitors and the facility-level variation in their use. Facility-level variation was computed using median rate ratios, a measure of likelihood that 2 random facilities differ in use of SGLT2 inhibitors.<br /><b>Results</b><br />Among 105,799 patients with ASCVD, HF, and T2DM across 130 Veterans Affairs facilities, 14.6% received SGLT2 inhibitors. Patients receiving SGLT2 inhibitors were younger men with higher hemoglobin A1c and estimated glomerular filtration rate and were more likely to have HF with reduced ejection fraction and ischemic heart disease. There was significant facility-level variation of SGLT2 inhibitor use, with an adjusted median rate ratio of 1.55 (95% CI: 1.46-1.64), indicating a 55% residual difference in SGLT2 inhibitor use among similar patients with ASCVD, HF, and T2DM receiving care at 2 random facilities.<br /><b>Conclusions</b><br />Utilization rates of SGLT2 inhibitors are low in patients with ASCVD, HF, and T2DM, with high residual facility-level variation. These findings suggest opportunities to optimize SGLT2 inhibitor use to prevent future adverse cardiovascular events.<br /><br />Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 11 May 2023; epub ahead of print</small></div>

<div><h4>Long-Term Exposure to Road Traffic Noise and Incident Heart Failure: Evidence From UK Biobank.</h4><i>Yang T, Hu X, Wang J, Rao S, ... Huang J, Rahimi K</i><br /><b>Background</b><br />Evidence on road traffic noise and heart failure (HF) is limited, and little is known on the potential mediation roles of acute myocardial infarction (AMI), hypertension, or diabetes.<br /><b>Objectives</b><br />The purpose of this study was to evaluate the impacts of long-term road traffic noise exposure on the risk of incident HF considering air pollution, and explore the mediations of the previously mentioned diseases.<br /><b>Methods</b><br />This prospective study included 424,767 participants without HF at baseline in UK Biobank. The residential-level noise and air pollution exposure was estimated, and the incident HF was identified through linkages with medical records. Cox proportional hazard models were used to estimate HRs. Furthermore, time-dependent mediation was performed.<br /><b>Results</b><br />During a median 12.5 years of follow-up, 12,817 incident HF were ascertained. The HRs were 1.08 (95% CI: 1.00-1.16) per 10 dB[A] increase in weighted average 24-hour road traffic noise level (L<sub>den</sub>), and 1.15 (95% CI: 1.02-1.31) for exposure to L<sub>den</sub> >65dB[A] compared with the reference category (L<sub>den</sub> ≤55dB[A]), respectively. Furthermore, the strongest combined effects were found in those with both high exposures to road traffic noise and air pollution including fine particles and nitrogen dioxide. Prior AMI before HF within 2 years\' time interval mediated 12.5% of the association of road traffic noise with HF.<br /><b>Conclusions</b><br />More attention should be paid and a preventive strategy should be considered to alleviate the disease burden of HF related to road traffic noise exposure, especially in participants who survived AMI and developed HF within 2 years.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 10 May 2023; epub ahead of print</small></div>

<div><h4>Pre-Heart Failure Longitudinal Change in a Hispanic/Latino Population-Based Study: Insights From the Echocardiographic Study of Latinos.</h4><i>Kuno T, Vasquez N, April-Sanders AK, Swett K, ... Kitzman D, Rodriguez CJ</i><br /><b>Background</b><br />Pre-heart failure (pre-HF) is an entity known to progress to symptomatic heart failure (HF).<br /><b>Objectives</b><br />This study aimed to characterize pre-HF prevalence and incidence among Hispanics/Latinos.<br /><b>Methods</b><br />The Echo-SOL (Echocardiographic Study of Latinos) assessed cardiac parameters on 1,643 Hispanics/Latinos at baseline and 4.3 years later. Prevalent pre-HF was defined as the presence of any abnormal cardiac parameter (left ventricular [LV] ejection fraction <50%; absolute global longitudinal strain <15%; grade 1 or more diastolic dysfunction; LV mass index >115 g/m<sup>2</sup> for men, >95 g/m<sup>2</sup> for women; or relative wall thickness >0.42). Incident pre-HF was defined among those without pre-HF at baseline. Sampling weights and survey statistics were used.<br /><b>Results</b><br />Among this study population (mean age: 56.4 years; 56% female), HF risk factors, including prevalence of hypertension and diabetes, worsened during follow-up. Significant worsening of all cardiac parameters (except LV ejection fraction) was evidenced from baseline to follow-up (all P < 0.01). Overall, the prevalence of pre-HF was 66.7% at baseline and the incidence of pre-HF during follow-up was 66.3%. Prevalent and incident pre-HF were seen more with increasing baseline HF risk factor burden as well as with older age. In addition, increasing the number of HF risk factors increased the risk of prevalence of pre-HF and incidence of pre-HF (adjusted OR: 1.36 [95% CI: 1.16-1.58], and adjusted OR: 1.29 [95% CI: 1.00-1.68], respectively). Prevalent pre-HF was associated with incident clinical HF (HR: 10.9 [95% CI: 2.1-56.3]).<br /><b>Conclusions</b><br />Hispanics/Latinos exhibited significant worsening of pre-HF characteristics over time. Prevalence and incidence of pre-HF are high and are associated with increasing HF risk factor burden and with incidence of cardiac events.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 04 May 2023; epub ahead of print</small></div>

<div><h4>Beta-Blocker Use and Heart Failure Outcomes in Mildly Reduced and Preserved Ejection Fraction.</h4><i>Arnold SV, Silverman DN, Gosch K, Nassif ME, ... Meyer M, Fendler TJ</i><br /><b>Background</b><br />Although studies consistently show that beta-blockers reduce morbidity and mortality in patients with reduced ejection fraction (EF), data are inconsistent in patients with heart failure with mildly reduced ejection fraction (HFmrEF) and suggest potential negative effects in heart failure with preserved ejection fraction (HFpEF).<br /><b>Objectives</b><br />To examine the association of beta-blockers with heart failure (HF) hospitalization and death in patients with HF and EF ≥40% <br /><b>Methods:</b><br/>Beta-blocker use was assessed at first encounter in outpatients ≥65 years of age with HFmrEF and HFpEF in the U.S. PINNACLE Registry (2013-2017). The associations of beta-blockers with HF hospitalization, death, and the composite of HF hospitalization/death were assessed using propensity-score adjusted multivariable Cox regression models, including interactions of EF × beta-blocker use.<br /><b>Results</b><br />Among 435,897 patients with HF and EF ≥40% (75,674 HFmrEF; 360,223 HFpEF), 289,377 (66.4%) were using a beta-blocker at first encounter; more commonly in patients with HFmrEF vs HFpEF (77.7% vs 64.0%; P < 0.001). There were significant interactions between EF × beta-blocker use for HF hospitalization, death, and composite of HF hospitalization/death (P < 0.001 for all), with higher risk with beta-blocker use as EF increased. Beta-blockers were associated with decreased risk of HF hospitalization and death in patients with HFmrEF but a lack of survival benefit and a higher risk of HF hospitalization in patients with HFpEF, particularly when EF was >60%.<br /><b>Conclusions</b><br />In a large, real-world, propensity score-adjusted cohort of older outpatients with HF and EF ≥40%, beta-blocker use was associated with a higher risk of HF hospitalization as EF increased, with potential benefit in patients with HFmrEF and potential risk in patients with higher EF (particularly >60%). Further studies are needed to understand the appropriateness of beta-blocker use in patients with HFpEF in the absence of compelling indications.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 May 2023; epub ahead of print</small></div>

<div><h4>Ejection Fraction, Biomarkers, and Outcomes and Impact of Vericiguat on Outcomes Across EF in VICTORIA.</h4><i>Butler J, Zheng Y, Khan MS, Bonderman D, ... Armstrong PW, VICTORIA Study Group</i><br /><b>Background</b><br />Vericiguat reduced the risk of cardiovascular death (CVD) or hospitalization for heart failure (HF) in patients with worsening HF and reduced left ventricular ejection fraction (LVEF).<br /><b>Objectives</b><br />The authors assessed the association of LVEF with biomarker levels, risk of outcome, and whether the effect of vericiguat was homogeneous across LVEF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction) trial.<br /><b>Methods</b><br />Patients were grouped by LVEF tertiles (≤24%, 25%-33%, and >33%). Patient characteristics, clinical outcomes, and efficacy and safety of vericiguat were examined by tertile. Prespecified biomarkers including N-terminal pro-B-type natriuretic peptide, cardiac troponin T, growth differentiation factor 15, interleukin 6, high-sensitivity C-reactive protein, and cystatin C were examined.<br /><b>Results</b><br />The mean LVEF was 29% ± 8% (range: 5%-45%). A pattern of higher N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and interleukin 6 was evident in patients in the lowest LVEF tertile vs the other tertiles. Patients with lower LVEF experienced higher rates of the composite outcome (41.7%, 36.3%, and 33.4% for LVEF ≤24, 25-33, and >33; P < 0.001). There was no significant treatment effect heterogeneity of vericiguat across LVEF groups (adjusted HR from lowest to highest tertiles: 0.79 [95% CI: 0.68-0.94]; 0.95 [95% CI: 0.82-1.11]; 0.94 [95% CI: 0.79-1.11]; P for interaction = 0.222), although the HR was numerically lower in the lowest tertile. There was also no heterogeneity of effect for CVD and HF hospitalization individually (P interaction for CVD = 0.964; HF hospitalization = 0.438). Discontinuation of treatment because of adverse events, symptomatic hypotension, or syncope was consistent across the range of LVEF.<br /><b>Conclusions</b><br />Patients with lower LVEF had a distinctive biomarker profile and a higher risk for adverse clinical outcomes vs those with a higher LVEF. There was no significant interaction for the benefit of vericiguat across LVEF tertiles, although the largest signal for benefit in both the primary outcome and HF hospitalizations was noted in tertile 1 (LVEF ≤24%). (Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 May 2023; 11:583-592</small></div>

<div><h4>Pregnancy-Induced Hypertensive Disorder and Risks of Future Ischemic and Nonischemic Heart Failure.</h4><i>Mantel Ä, Sandström A, Faxén J, Andersson DC, ... Cnattingius S, Stephansson O</i><br /><b>Background</b><br />Although adverse pregnancy outcomes are associated with an increased risk of cardiovascular disease, studies on timing and subtypes of heart failure after a hypertensive pregnancy are lacking.<br /><b>Objectives</b><br />The goal of this study was to assess the association between pregnancy-induced hypertensive disorder and risk of heart failure, according to ischemic and nonischemic subtypes, and the impact of disease characteristics and the timing of heart failure risks.<br /><b>Methods</b><br />This was a population-based matched cohort study, comprising all primiparous women without a history of cardiovascular disease included in the Swedish Medical Birth Register between 1988 and 2019. Women with pregnancy-induced hypertensive disorder were matched with women with normotensive pregnancies. Through linkage with health care registers, all women were followed up for incident heart failure, classified as ischemic or nonischemic.<br /><b>Results</b><br />In total, 79,334 women with pregnancy-induced hypertensive disorder were matched with 396,531 women with normotensive pregnancies. During a median follow-up of 13 years, rates of all heart failure subtypes were more common among women with pregnancy-induced hypertensive disorder. Compared with women with normotensive pregnancies, adjusted HRs (aHRs) with 95% CIs were as follows: heart failure overall, aHR: 1.70 (95% CI: 1.51-1.91); ischemic heart failure, aHR: 2.28 (95% CI: 1.74-2.98); and nonischemic heart failure, aHR: 1.60 (95% CI: 1.40-1.83). Disease characteristics indicating severe hypertensive disorder were associated with higher heart failure rates, and rates were highest within the first years after the hypertensive pregnancy but remained significantly increased thereafter.<br /><b>Conclusions</b><br />Pregnancy-induced hypertensive disorder is associated with an increased short-term and long-term risk of incident ischemic and nonischemic heart failure. Disease characteristics indicating more severe forms of pregnancy-induced hypertensive disorder amplify the heart failure risks.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 29 Apr 2023; epub ahead of print</small></div>

<div><h4>Modifiable Mechanical Ventilation Targets Are Associated With Improved Survival in Ventilated VA-ECLS Patients.</h4><i>Rali AS, Tran LE, Auvil B, Xu M, ... Hernandez A, Lindenfeld J</i><br /><b>Background</b><br />In acute respiratory distress syndrome (ARDS), lung protective ventilation (LPV) improves patient outcomes by minimizing ventilator-induced lung injury. The value of LPV in ventilated patients with cardiogenic shock (CS) requiring venoarterial extracorporeal life support (VA-ECLS) is not known, but the extracorporeal circuit provides a unique opportunity to modify ventilatory parameters to improve outcomes.<br /><b>Objectives</b><br />The authors hypothesized that CS patients on VA-ECLS who require mechanical ventilation (MV) may benefit from low intrapulmonary pressure ventilation (LPPV), which has the same end goals as LPV.<br /><b>Methods</b><br />The authors queried the ELSO (Extracorporeal Life Support Organization) registry for hospital admissions between 2009 and 2019 for CS patients on VA-ECLS and MV. They defined LPPV as peak inspiratory pressure at 24 hours on ECLS of < 30 cm H<sub>2</sub>O. Positive end-expiration pressure and dynamic driving pressure DDP) at 24 hours were also studied as continuous variables. Their primary outcome was survival to discharge. Multivariable analyses were performed that adjusted for baseline Survival After Venoarterial Extracorporeal Membrane Oxygenation score, chronic lung conditions, and center extracorporeal membrane oxygenation volume.<br /><b>Results</b><br />A total of 2,226 CS patients on VA-ECLS were included: 1,904 received LPPV. The primary outcome was higher in the LPPV group vs the no-LPPV group (47.4% vs 32.6%; P < 0.001). Median peak inspiratory pressure (22 vs 24 cm H<sub>2</sub>O; P < 0.001) as well as DDP (14.5 vs 16 cm H<sub>2</sub>O; P < 0.001) were also significantly lower in those surviving to discharge. The adjusted OR for the primary outcome with LPPV was 1.69 (95% CI: 1.21-2.37; P = 0.0021).<br /><b>Conclusions</b><br />LPPV is associated with improved outcomes in CS patients on VA-ECLS requiring MV.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 28 Apr 2023; epub ahead of print</small></div>

<div><h4>Myeloperoxidase Inhibition Reverses Biomarker Profiles Associated With Clinical Outcomes in HFpEF.</h4><i>Michaëlsson E, Lund LH, Hage C, Shah SJ, ... Gan LM, Lam CSP</i><br /><b>Background</b><br />Systemic microvascular dysfunction and inflammation are postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF).<br /><b>Objectives</b><br />This study aimed to identify biomarker profiles associated with clinical outcomes in HFpEF and investigate how inhibition of the neutrophil-derived reactive oxygen species-producing enzyme, myeloperoxidase, affects these biomarkers.<br /><b>Methods</b><br />Using supervised principal component analyses, the investigators assessed the associations between baseline plasma proteomic Olink biomarkers and clinical outcomes in 3 independent observational HFpEF cohorts (n = 86, n = 216, and n = 242). These profiles were then compared with the biomarker profiles discriminating patients treated with active drug vs placebo in SATELLITE (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure), a double-blind randomized 3-month trial evaluating safety and tolerability of the myeloperoxidase inhibitor AZD4831 in HFpEF (n = 41). Pathophysiological pathways were inferred from the biomarker profiles by interrogation of the Ingenuity Knowledge database.<br /><b>Results</b><br />TNF-R1, TRAIL-R2, GDF15, U-PAR, and ADM were the top individual biomarkers associated with heart failure hospitalization or death, and FABP4, HGF, RARRES2, CSTB, and FGF23 were associated with lower functional capacity and poorer quality of life. AZD4831 downregulated many markers (most significantly CDCP1, PRELP, CX3CL1, LIFR, VSIG2). There was remarkable consistency among pathways associated with clinical outcomes in the observational HFpEF cohorts, the top canonical pathways being associated with tumor microenvironments, wound healing signaling, and cardiac hypertrophy signaling. These pathways were predicted to be downregulated in AZD4831 relative to placebo-treated patients.<br /><b>Conclusions</b><br />Biomarker pathways that were most strongly associated with clinical outcomes were also the ones reduced by AZD4831. These results support the further investigation of myeloperoxidase inhibition in HFpEF.<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 27 Apr 2023; epub ahead of print</small></div>

<div><h4>Role of Oxygen Starvation in Right Ventricular Decompensation and Failure in Pulmonary Arterial Hypertension.</h4><i>Oknińska M, Zajda K, Zambrowska Z, Grzanka M, ... Kieda C, Mączewski M</i><br /><AbstractText>Right ventricular (RV) function and eventually failure determine outcome in patients with pulmonary arterial hypertension (PAH). Initially, RV responds to an increased load caused by PAH with adaptive hypertrophy; however, eventually RV failure ensues. Unfortunately, it is unclear what causes the transition from compensated RV hypertrophy to decompensated RV failure. Moreover, at present, there are no therapies for RV failure; those for left ventricular (LV) failure are ineffective, and no therapies specifically targeting RV are available. Thus there is a clear need for understanding the biology of RV failure and differences in physiology and pathophysiology between RV and LV that can ultimately lead to development of such therapies. In this paper, we discuss RV adaptation and maladaptation in PAH, with a particular focus of oxygen delivery and hypoxia as the principal drivers of RV hypertrophy and failure, and attempt to pinpoint potential sites for therapy.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 24 Apr 2023; epub ahead of print</small></div>

<div><h4>How to Manage Heart Failure With Preserved Ejection Fraction: Practical Guidance for Clinicians.</h4><i>Desai AS, Lam CSP, McMurray JJV, Redfield MM</i><br /><AbstractText>Although patients with heart failure with preserved ejection fraction (HFpEF) (left ventricular ejection fraction ≥50%) comprise nearly half of those with chronic heart failure, evidence-based treatment options for this population have historically been limited. Recently, however, emerging data from prospective, randomized trials enrolling patients with HFpEF have greatly altered the range of pharmacologic options to modify disease progression in selected patients with HFpEF. In the context of this evolving landscape, clinicians are increasingly in need of practical guidance regarding the best approach to management of this growing population. In this review, we build on the recently published heart failure guidelines by integrating contemporary data from recent randomized trials to provide a contemporary framework for diagnosis and evidence-based treatment of patients with HFpEF. Where gaps in knowledge persist, we provide \"best available\" data from post hoc analyses of clinical trials or data from observational studies to guide management until more definitive studies are available.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 24 Apr 2023; epub ahead of print</small></div>

<div><h4>Guideline-Directed Medical Therapy Tolerability in Patients With Heart Failure and Mitral Regurgitation: The COAPT Trial.</h4><i>Cox ZL, Zalawadiya SK, Simonato M, Redfors B, ... Stone GW, Lindenfeld J</i><br /><b>Background</b><br />In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial, a central committee of heart failure (HF) specialists optimized guideline-directed medical therapies (GDMT) and documented medication and goal dose intolerances before patient enrollment.<br /><b>Objectives</b><br />The authors sought to assess the rates, reasons, and predictors of GDMT intolerance in the COAPT trial.<br /><b>Methods</b><br />Baseline use, dose, and intolerances of angiotensin-converting enzyme inhibitors (ACEIs) angiotensin II receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) were analyzed in patients with left ventricular ejection fraction (LVEF) ≤40%, in whom maximally tolerated doses of these agents as assessed by an independent HF specialist were required before enrollment.<br /><b>Results</b><br />A total of 464 patients had LVEF ≤40% and complete medication information. At baseline, 38.8%, 39.4%, and 19.8% of patients tolerated 3, 2, and 1 GDMT classes, respectively (any dose); only 1.9% could not tolerate any GDMT. Beta-blockers were the most frequently tolerated GDMT (93.1%), followed by ACEIs/ARBs/ARNIs (68.5%), and then MRAs (55.0%). Intolerances differed by GDMT class, but hypotension and kidney dysfunction were most common. Goal doses were uncommonly achieved for beta-blockers (32.3%) and ACEIs/ARBs/ARNIs (10.2%) due to intolerances limiting titration. Only 2.2% of patients tolerated goal doses of all 3 GDMT classes.<br /><b>Conclusions</b><br />In a contemporary trial population with HF, severe mitral regurgitation, and systematic HF specialist-directed GDMT optimization, most patients had medical intolerances prohibiting 1 or more GDMT classes and achieving goal doses. The specific intolerances noted and methods used for GDMT optimization provide important lessons for the implementation of GDMT optimization in future clinical trials. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] [COAPT]; NCT01626079).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 21 Apr 2023; epub ahead of print</small></div>

<div><h4>No-Implant Interatrial Shunt for HFpEF: Six-Month Outcomes From Multicenter Pilot Feasibility Studies.</h4><i>Udelson JE, Barker CM, Wilkins G, Wilkins B, ... Kriegel JM, Shaburishvili T</i><br /><b>Background</b><br />Most approaches to the creation of an interatrial shunt require placement of a permanent implant to maintain patency.<br /><b>Objectives</b><br />The goal of this study was to investigate the safety and efficacy of a no-implant interatrial shunt for patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF).<br /><b>Methods</b><br />This was a multicenter, uncontrolled study of patients with HFpEF/HFmrEF and New York Heart Association (NYHA) functional class ≥II, ejection fraction >40%, and pulmonary capillary wedge pressure (PCWP) during supine exercise ≥25 mm Hg with PCWP-to-right atrial gradient ≥5 mm Hg. Follow-up was through 6 months with imaging to assess shunt durability.<br /><b>Results</b><br />A total of 28 patients were enrolled: mean ± SD age was 68 ± 9 years, and 68% were female. Baseline resting and peak exercise PCWP were 19 ± 7 and 40 ± 11 mm Hg, respectively. All procedures displayed technical success with confirmation of left-to-right flow (shunt diameter 7.1 ± 0.9 mm). At 1 month, peak exercise PCWP decreased 5.4 ± 9.6 mm Hg (P = 0.011) with no change in right atrial pressure. There were no serious device or procedure-related adverse events through 6 months. Mean 6-minute walk distance increased 101 ± 71 meters (P < 0.001); Kansas City Cardiomyopathy Questionnaire overall summary score increased 26 ± 19 points (P < 0.001); N-terminal pro-B-type natriuretic peptide decreased 372 ± 857 pg/mL (P = 0.018); and shunt patency was confirmed with unchanged diameter.<br /><b>Conclusions</b><br />In these feasibility studies of a no-implant interatrial shunt, HFpEF/HFmrEF shunts exhibited stability with favorable safety and early efficacy signals. The results show promise toward this new approach for treating patients with HFpEF/HFmrEF and an appropriate hemodynamic profile. (Evaluation of the Safety and Feasibility of a Percutaneously Created Interatrial Shunt to Alleviate Heart Failure Symptoms in Patients With Chronic Heart Failure and Preserved or Mid-Range Left Ventricular Ejection Fraction [ALLEVIATE-HF-1]; NCT04583527; Evaluation of the Safety and Effectiveness of a Percutaneously Created Interatrial Shunt to Alleviate Heart Failure Symptoms in Patients With Chronic Heart Failure and Preserved or Mid-Range Left Ventricular Ejection Fraction [ALLEVIATE-HF-2]; NCT04838353).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 18 Apr 2023; epub ahead of print</small></div>

<div><h4>Female Reproductive Factors and Risk of New-Onset Heart Failure: Findings From UK Biobank.</h4><i>Zhu F, Qi H, Bos M, Boersma E, Kavousi M</i><br /><b>Background</b><br />A comprehensive evaluation of woman-specific risk factors in relation to incident heart failure (HF) is limited.<br /><b>Objectives</b><br />The study sought to investigate the association of multiple female reproductive factors with the risk of HF.<br /><b>Methods</b><br />Between 2007 and 2010, 229,026 women (mean age: 56.5 years) without prevalent HF from the UK Biobank cohort were included and followed until December 2020. The relation between (self-reported) reproductive factors and HF was analyzed using Cox proportional hazards models with adjustment for potential confounding.<br /><b>Results</b><br />Menarche at age <12 years, compared to age 12-13 years, carried a 9% larger risk of HF (HR: 1.09 [95% CI: 1.01-1.18]). Younger age at menopause was associated with a higher risk of HF (HR<sub>age < 45 y vs 50-51 y</sub>: 1.15 [95% CI: 1.03-1.28]; HR<sub>age 45-49 y vs 50-51 y</sub>: 1.11 [95% CI: 1.01-1.23]). Younger maternal age at first live birth (HR<sub>age < 21 y vs 24-26 y</sub>: 1.42 [95% CI: 1.28-1.59]; HR<sub>age 21-23 y vs 24-26 y</sub>: 1.14 [95% CI: 1.03-1.26]) and at last live birth (HR<sub>age < 26 y vs 29-31 y</sub>: 1.19 [95% CI: 1.07-1.33]) were associated with higher risk of HF. Compared to women with 1 or 2 children, having 3 or 4 children (HR: 1.09 [95% CI: 1.02-1.17]) or >4 children (HR: 1.24 [95% CI: 1.05-1.47]) was associated with higher HF risk. Experiencing miscarriages or abortions was not significantly associated with incident HF, whereas experiencing 1 stillbirth and recurrent stillbirths conferred a 20% and 43% larger risk of HF, respectively, compared to no stillbirth.<br /><b>Conclusions</b><br />The findings emphasize the importance of female reproductive history in the assessment of HF risk.<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 17 Apr 2023; epub ahead of print</small></div>

<div><h4>Polypharmacy and Optimization of Guideline-Directed Medical Therapy in Heart Failure: The GUIDE-IT Trial.</h4><i>Khan MS, Singh S, Segar MW, Usman MS, ... Butler J, Pandey A</i><br /><b>Background</b><br />Polypharmacy is common among patients with heart failure with reduced ejection fraction (HFrEF). However, its impact on the use of optimal guideline-directed medical therapy (GDMT) is not well established.<br /><b>Objectives</b><br />This study sought to evaluate the association between polypharmacy and odds of receiving optimal GDMT over time among patients with HFrEF.<br /><b>Methods</b><br />The authors conducted a post hoc analysis of the GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment) trial. Polypharmacy was defined as receiving ≥5 medications (excluding HFrEF GDMT) at baseline. The outcome of interest was optimal triple therapy GDMT (concurrent administration of a renin-angiotensin-aldosterone blocker and beta-blocker at 50% of the target dose and a mineralocorticoid receptor antagonist at any dose) achieved over the 12-month follow-up. Multivariable adjusted mixed-effect logistic regression models with multiplicative interaction terms (time × polypharmacy) were constructed to evaluate how polypharmacy at baseline modified the odds of achieving optimal GDMT on follow-up.<br /><b>Results</b><br />The study included 891 participants with HFrEF. The median number of non-GDMT medications at baseline was 4 (IQR: 3-6), with 414 (46.5%) prescribed ≥5 and identified as being on polypharmacy. The proportion of participants who achieved optimal GDMT at the end of the 12-month follow-up was lower with vs without polypharmacy at baseline (15% vs 19%, respectively). In adjusted mixed models, the odds of achieving optimal GDMT over time were modified by baseline polypharmacy status (P-interaction < 0.001). Patients without polypharmacy at baseline had increased odds of achieving GDMT (odds ratio [OR]: 1.16 [95% CI: 1.12-1.21] per 1-month increase; P < 0.001) but not patients with polypharmacy (OR: 1.01 [95% CI: 0.96-1.06)] per 1-month increase).<br /><b>Conclusions</b><br />Patients with HFrEF who are on non-GDMT polypharmacy have lower odds of achieving optimal GDMT on follow-up.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 15 Apr 2023; epub ahead of print</small></div>

<div><h4>Chronic Kidney Disease, Heart Failure, and Adverse Cardiac Remodeling in Older Adults: The ARIC Study.</h4><i>Buckley LF, Claggett BL, Matsushita K, McMahon GM, ... Mosley TH, Shah AM</i><br /><b>Background</b><br />The associations of kidney dysfunction and damage with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), as well as adverse cardiac remodeling, in late-life remain incompletely understood.<br /><b>Objectives</b><br />The authors sought to define the associations between kidney dysfunction and damage and incident HFrEF and HFpEF and cardiac structure and function in late-life.<br /><b>Methods</b><br />This study included 5,170 adults initially free of a heart failure (HF) diagnosis who had estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) measured at visit 5 (2011-2013) of the Atherosclerosis Risk in Communities study. Multivariable Cox proportional hazards models were used to estimate the associations of eGFR and UACR with incident HF, HFrEF, and HFpEF through 2019. Multivariable linear regression models were used to investigate the associations of eGFR and UACR at visit 5 with changes in cardiac structure and function between visits 5 and 7 in 2,313 participants with available echocardiograms.<br /><b>Results</b><br />The mean age of participants was 76 ± 5 years, and 2,225 (43%) were men. The mean eGFR and median UACR were 66 ± 18 mL/min per 1.73 m<sup>2</sup> and 11 mg/g (25th, 75th percentile: 6 mg/g, 22 mg/g), respectively. In fully adjusted models, both lower eGFR and higher UACR were associated with greater risk of any HF, HFrEF, and HFpEF. Lower eGFR was associated with larger increases in left ventricular end-diastolic volume index and worsening of diastolic measures. UACR did not associate with changes in cardiac structure or function.<br /><b>Conclusions</b><br />Mild to moderate kidney dysfunction and damage associate with incident HF and adverse cardiac remodeling in late-life.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 07 Apr 2023; epub ahead of print</small></div>

<div><h4>Microbially Produced Imidazole Propionate Is Associated With Heart Failure and Mortality.</h4><i>Molinaro A, Nemet I, Bel Lassen P, Chakaroun R, ... Bäckhed F, MetaCardis consortium</i><br /><b>Background</b><br />Over the past years, it has become clear that the microbial ecosystem in the gut has a profound capacity to interact with the host through the production of a wide range of bioactive metabolites. The microbially produced metabolite imidazole propionate (ImP) is clinically and mechanistically linked with insulin resistance and type 2 diabetes, but it is unclear how ImP is associated with heart failure.<br /><b>Objectives</b><br />The authors aimed to explore whether ImP is associated with heart failure and mortality.<br /><b>Methods</b><br />ImP serum measurements in 2 large and independent clinical cohorts of patients (European [n = 1,985] and North American [n = 2,155]) with a range of severity of cardiovascular disease including heart failure. Univariate and multivariate Cox regression analyses were performed to delineate the impact of ImP on 5-year mortality in the North American cohort, independent of other covariates.<br /><b>Results</b><br />ImP is independently associated with reduced ejection fraction and heart failure in both cohorts, even after adjusting for traditional risk factors. Elevated ImP was a significant independent predictor of 5-year mortality (for the highest quartile, adjusted HR: 1.85 [95% CI: 1.20-2.88]; P < 0.01).<br /><b>Conclusions</b><br />The gut microbial metabolite ImP is increased in individuals with heart failure and is a predictor of overall survival.<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Apr 2023; epub ahead of print</small></div>

<div><h4>Shedding Light on Latent Pulmonary Vascular Disease in Heart Failure With Preserved Ejection Fraction.</h4><i>Caravita S, Baratto C, Filippo A, Soranna D, ... Vachiéry JL, Fudim M</i><br /><b>Background</b><br />Among patients with heart failure with preserved ejection fraction (HFpEF), a distinct hemodynamic phenotype has been recently described, ie, latent pulmonary vascular disease (HFpEF-latentPVD), defined by exercise pulmonary vascular resistance (PVR) >1.74 WU.<br /><b>Objectives</b><br />This study aims to explore the pathophysiological significance of HFpEF-latentPVD.<br /><b>Methods</b><br />The authors analyzed a cohort of patients who had undergone supine exercise right heart catheterization with cardiac output (CO) measured by direct Fick method, between 2016 and 2021. HFpEF-latentPVD patients were compared with HFpEF control patients.<br /><b>Results</b><br />Out of 86 HFpEF patients, 21% qualified as having HFpEF-latentPVD, 78% of whom had PVR >2 WU at rest. Patients with HFpEF-latentPVD were older, with a higher pretest probability of HFpEF, and more frequently experienced atrial fibrillation and at least moderate tricuspid regurgitation (P < 0.05). PVR trajectories differed between HFpEF-latentPVD patients and HFpEF control patients (P<sub>interaction</sub> = 0.008), slightly increasing in the former and reducing in the latter. HFpEF-latentPVD patients displayed more frequent hemodynamically significant tricuspid regurgitation during exercise (P = 0.002) and had more impaired CO and stroke volume reserve (P < 0.05). Exercise PVR was correlated with mixed venous O<sub>2</sub> tension (R<sup>2</sup> = 0.33) and stroke volume (R<sup>2</sup> = 0.31) in HFpEF-latentPVD patients. The HFpEF-latentPVD patients had had higher dead space ventilation during exercise and higher PaCO<sub>2</sub> (P < 0.05), which correlated with resting PVR (R<sup>2</sup> = 0.21). Event-free survival was reduced in HFpEF-latentPVD patients (P < 0.05).<br /><b>Conclusions</b><br />The results suggest that when CO is measured by direct Fick, few HFpEF patients have isolated latent PVD (ie, normal PVR at rest, becoming abnormal during exercise). HFpEF-latentPVD patients present with CO limitation to exercise, associated with dynamic tricuspid regurgitation, altered ventilatory control, and pulmonary vascular hyperreactivity, portending a poor prognosis.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 27 Mar 2023; epub ahead of print</small></div>

<div><h4>The Lure of Cardiac Metabolism in the Diagnosis, Prevention, and Treatment of Heart Failure.</h4><i>Rodolico D, Schiattarella GG, Taegtmeyer H</i><br /><AbstractText>Energy substrate metabolism and contractile function are tightly coupled in the heart. Within this framework, heart failure may be viewed as a state of impaired energy transfer. The metabolic changes in the failing heart are linked to functional and structural changes. A worthwhile goal is to measure metabolic flux and its regulation quantitatively, and to do this in a manner that leads to targeted interventions. For several good reasons, this goal has been elusive until now. The development of new analytical and imaging techniques offers the potential of exploring the landscape of metabolic changes across the different stages of heart failure. In this Review Topic of the Month, we focus on concepts and brevity to provide a strategic overview of cardiac metabolism in the diagnosis, prevention, and treatment of nonischemic heart failure.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 17 Mar 2023; epub ahead of print</small></div>

<div><h4>SERCA2a Agonist Effects on Cardiac Performance During Exercise in Heart Failure With Preserved Ejection Fraction.</h4><i>Sarma S, MacNamara JP, Hieda M, Howden EJ, ... Samels M, Levine BD</i><br /><b>Background</b><br />Impaired ventricular relaxation influences left ventricular pressures during exercise in heart failure with preserved ejection fraction (HFpEF). Sarco/endoplasmic reticulum calcium-adenosine triphosphatase (SERCA2a) facilitates myocardial relaxation by increasing calcium reuptake and is impaired in HFpEF.<br /><b>Objectives</b><br />This study sought to investigate the effects of istaroxime, a SERCA2 agonist, on lusitropic and hemodynamic function during exercise in patients with HFpEF and control subjects.<br /><b>Methods</b><br />Eleven control subjects (7 male, 4 female) and 15 patients with HFpEF (8 male, 7 female) performed upright cycle exercise with right-sided heart catheterization. Participants received istaroxime (0.5 mg/kg/min) or saline placebo (single-blind, crossover design). Cardiac output, pulmonary capillary wedge pressure (PCWP), and diastolic function were measured at rest and during submaximal exercise. In an exploratory analysis (Hedges\' g), 7 patients with HFpEF received higher-dose istaroxime (1.0 mg/kg/min). End-systolic elastance (Ees) was calculated by dividing systolic blood pressure (SBP) × 0.9 by end-systolic volume (ESV; on 3-dimensional echocardiography).<br /><b>Results</b><br />Patients with HFpEF had higher PCWP (25 ± 10 mm Hg vs 12 ± 5 mm Hg; P < 0.001) and lower tissue Doppler velocities during exercise. Istaroxime (0.5 mg/kg/min) had no effect on resting or exercise measures in patients with HFpEF or control subjects. Control subjects had a larger increase in Ees (Δ 1.55 ± 0.99 mm Hg/mL vs D 0.86 ± 1.31 mm Hg/mL; P = 0.03), driven by lower ESV. Comparing placebo and istaroxime 1.0 mg /kg/min during exercise, PCWP during the 1.0 mg /kg/min istaroxime dose was slightly lower (Δ 2.2 mm Hg; Hedges\' g = 0.30). There were no effects on diastolic function, but there were increases in SBP and s\', suggesting a mild inotropic effect.<br /><b>Conclusions</b><br />Low-dose istaroxime had no effect on cardiac filling pressure or parameters of relaxation in patients with HFpEF during exercise. Higher doses of istaroxime may have been more effective in reducing exercise PCWP in patients with HFpEF. (Hemodynamic Response to Exercise in HFpEF Patients After Upregulation of SERCA2a; NCT02772068).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 15 Mar 2023; epub ahead of print</small></div>

<div><h4>The Accuracy of Initial U.S. Heart Transplant Candidate Rankings.</h4><i>Pelzer KM, Zhang KC, Lazenby KA, Narang N, ... Anderson AS, Parker WF</i><br /><b>Background</b><br />The U.S. heart allocation system ranks candidates with only 6 treatment-based categorical \"statuses\" and ignores many objective patient characteristics.<br /><b>Objectives</b><br />This study sought to determine the effectiveness of the standard 6-status ranking system and several novel prediction models in identifying the most urgent heart transplant candidates.<br /><b>Methods</b><br />The primary outcome was death before receipt of a heart transplant. The accuracy of the 6-status system was evaluated using Harrell\'s C-index and log-rank tests of Kaplan-Meier estimated survival by status for candidates listed postpolicy (November 2018 to March 2020) in the Scientific Registry of Transplant Recipients data set. The authors then developed Cox proportional hazards models and random survival forest models using prepolicy data (2010-2017). The predictor variables included age, diagnosis, laboratory measurements, hemodynamics, and supportive treatment at the time of listing. The performance of these models was compared with the candidate\'s 6-status ranking in the postpolicy data.<br /><b>Results</b><br />Since policy implementation, the 6-status ranking at listing has had moderate ability to rank-order candidates (C-index: 0.67). Statuses 4 and 6 had no significant difference in survival (P = 0.8), and status 5 had lower survival than status 4 (P < 0.001). Novel multivariable prediction models derived with prepolicy data ranked candidates correctly more often than the 6-status rankings (Cox proportional hazards model C-index: 0.76; random survival forest model C-index: 0.74). Objective physiologic measurements, such as glomerular filtration rate, had high variable importance.<br /><b>Conclusions</b><br />The treatment-based 6-status heart allocation system has only moderate ability to rank-order candidates by medical urgency. Predictive models that incorporate physiologic measurements can more effectively rank-order heart transplant candidates by urgency.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 15 Mar 2023; epub ahead of print</small></div>

<div><h4>Exercise-Induced Left Atrial Hypertension in Heart Failure With Preserved Ejection Fraction.</h4><i>Litwin SE, Komtebedde J, Hu M, Burkhoff D, ... Shah SJ, REDUCE LAP-HF Investigators and Research Staff</i><br /><b>Background</b><br />Many patients with heart failure and preserved ejection fraction have no overt volume overload and normal resting left atrial (LA) pressure.<br /><b>Objectives</b><br />This study sought to characterize patients with normal resting LA pressure (pulmonary capillary wedge pressure [PCWP] <15 mm Hg) but exercise-induced left atrial hypertension (EILAH).<br /><b>Methods</b><br />The REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc. IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) trial randomized 626 patients with ejection fraction ≥40% and exercise PCWP ≥25 mm Hg to atrial shunt or sham procedure. The primary trial outcome, a hierarchical composite of death, heart failure hospitalization, intensification of diuretics, and change in health status was compared between patients with EILAH and those with heart failure and resting left atrial hypertension (RELAH).<br /><b>Results</b><br />Patients with EILAH (29%) had similar symptom severity, but lower natriuretic peptide levels, higher 6-minute walk distance, less atrial fibrillation, lower left ventricular mass, smaller LA volumes, lower E/e\', and better LA strain. PCWP was lower at rest, but had a larger increase with exercise in EILAH. Neither group as a whole had a significant effect from shunt therapy vs sham. Patients with EILAH were more likely to have characteristics associated with atrial shunt responsiveness (peak exercise pulmonary vascular resistance <1.74 WU and no pacemaker (63% vs 46%; P < 0.001). The win ratio for the primary outcome was 1.56 (P = 0.08) in patients with EILAH and 1.51 (P = 0.04) in those with RELAH when responder characteristics were present.<br /><b>Conclusions</b><br />Patients with EILAH had similar symptom severity but less advanced myocardial and pulmonary vascular disease. This important subgroup may be difficult to diagnose without invasive exercise hemodynamics, but it has characteristics associated with favorable response to atrial shunt therapy. (A Study to Evaluate the Corvia Medical, Inc. IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure [REDUCE LAP-HF TRIAL II]; NCT03088033).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 14 Mar 2023; epub ahead of print</small></div>

<div><h4>Cardiovascular Disease and Mortality in Black Women Carrying the Amyloidogenic V122I Transthyretin Gene Variant.</h4><i>Haring B, Hunt RP, Shadyab AH, Eaton C, ... Kooperberg C, Wassertheil-Smoller S</i><br /><b>Background</b><br />Long-term data on cardiovascular disease (CVD) and mortality in female carriers of the transthyretin (TTR) V122I (pV142I) variant, one of the most common variants of hereditary transthyretin cardiac amyloidosis, are sparse and the effects of blood pressure, heart rate, body mass index, and physical activity on CVD outcomes remain largely unknown.<br /><b>Objectives</b><br />The aim was to first examine the relationship of TTR V122I (pV142I) carrier status with CVD and mortality and second to investigate the effects of blood pressure, heart rate, body mass index, and physical activity in a large cohort of postmenopausal women.<br /><b>Methods</b><br />The study population consisted of 9,862 non-Hispanic Black/African American women, 9,529 noncarriers and 333 TTR V122I carriers, enrolled in the Women\'s Health Initiative at 40 centers in the United States. Women were generally healthy and postmenopausal at the time of enrollment (1993-1998). CVD was defined as a composite endpoint consisting of coronary heart disease, stroke, acute heart failure or CVD death, and all-cause mortality. CVD cases were based on self-reported annual mailed health updates. All information was centrally adjudicated by trained physicians. HRs and 95% CIs were obtained from adjusted Cox proportional hazards models.<br /><b>Results</b><br />Among 9,862 Black female participants (mean age: 62 years [IQR: 56-67 years]), the population frequency of the TTR V122I variant was 3.4% (333 variant carriers and 9,529 noncarriers). During a mean follow-up of 16.1 years (IQR: 9.7-22.2 years), incident CVD occurred in 2,229 noncarriers and 96 carriers, whereas 2,689 noncarriers and 108 carriers died. In adjusted models including demographic, lifestyle, and medical history covariates, TTR V122I carriers were at higher risk of the composite endpoint CVD (HR: 1.52; 95% CI: 1.22-1.88), acute heart failure (HR: 2.21; 95% CI: 1.53-3.18), coronary heart disease (HR: 1.80; 95% CI: 1.30-2.47), CVD death (HR: 1.70; 95% CI: 1.26-2.30), and all-cause mortality (HR: 1.28; 95% CI: 1.04-1.56). The authors found a significant interaction by age but not by blood pressure, heart rate, body mass index, or physical activity.<br /><b>Conclusions</b><br />Black female TTR V122I (pV142I) carriers have a higher CVD and all-cause mortality risk compared to noncarriers. In case of clinical suspicion of amyloidosis, they should be screened for TTR V122I (pV142I) carrier status to ensure early treatment onset.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 05 Mar 2023; epub ahead of print</small></div>

<div><h4>Longer-Term Effects of Remote Patient Management Following Hospital Discharge After Acute Systolic Heart Failure: The Randomized E-INH Trial.</h4><i>Angermann CE, Sehner S, Faller H, Güder G, ... Störk ST, INH Study Group and of the Competence Network Heart Failure</i><br /><b>Background</b><br />The randomized INH (Interdisciplinary Network Heart Failure) trial (N = 715) reported that 6 months\' remote patient management (RPM) (HeartNetCare-HF) did not reduce the primary outcome (time to all-cause death/rehospitalization) vs usual care (UC) in patients discharged after admission for acute heart failure, but suggested lower mortality and better quality of life in the RPM group.<br /><b>Objectives</b><br />The Extended (E)-INH trial investigated the effects of 18 months\' HeartNetCare-HF on the same primary outcome in an expanded population (N = 1,022) and followed survivors up to 60 months (primary outcome events) or up to 120 months (mortality) after RPM termination.<br /><b>Methods</b><br />Eligible patients aged ≥18 years, hospitalized for acute heart failure, and with predischarge ejection fraction ≤40% were randomized to RPM (RPM+UC; n = 509) or control (UC; n = 513). Follow-up visits were every 6 months during RPM, and then at 36, 60, and 120 months.<br /><b>Results</b><br />The primary outcome did not differ between groups at 18 months (60.7% [95% CI: 56.5%-65.0%] vs 61.2% [95% CI: 57.0%-65.4%]) or 60 months (78.1% [95% CI: 74.4%-81.6%] vs 82.8% [95% CI: 79.5%-86.0%]). At 60 and 120 months, all-cause mortality was lower in patients previously undergoing RPM (41.1% [95% CI: 37.0%-45.5%] vs 47.4% [95% CI: 43.2%-51.8%]; P = 0.040 and 64.0% [95% CI: 59.8%-68.2%] vs 69.6% [95% CI: 65.6%-73.5%]; P = 0.019). At all visits, health-related quality of life was better in patients exposed to HeartNetCare-HF vs UC.<br /><b>Conclusions</b><br />Although 18 months\' HeartNetCare-HF did not significantly reduce the primary outcome of death or rehospitalization at 60 months, lower 120-month mortality in patients previously undergoing HeartNetCare-HF suggested beneficial longer-term effects, although the possibility of a chance finding remains.<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Mar 2023; 11:191-206</small></div>

<div><h4>Atrial Fibrillation Ablation for Heart Failure With Preserved Ejection Fraction: A Randomized Controlled Trial.</h4><i>Chieng D, Sugumar H, Segan L, Tan C, ... Kaye DM, Ling LH</i><br /><b>Background</b><br />Patients with heart failure with preserved ejection fraction (HFpEF) frequently develop atrial fibrillation (AF). There are no randomized trials examining the effects of AF ablation on HFpEF outcomes.<br /><b>Objectives</b><br />The aim of this study is to compare the effects of AF ablation vs usual medical therapy on markers of HFpEF severity, including exercise hemodynamics, natriuretic peptide levels, and patient symptoms.<br /><b>Methods</b><br />Patients with concomitant AF and HFpEF underwent exercise right heart catheterization and cardiopulmonary exercise testing. HFpEF was confirmed with pulmonary capillary wedge pressure (PCWP) of 15 mm Hg at rest or ≥25 mm Hg on exercise. Patients were randomized to AF ablation vs medical therapy, with investigations repeated at 6 months. The primary outcome was change in peak exercise PCWP on follow-up.<br /><b>Results</b><br />A total of 31 patients (mean age: 66.1 years; 51.6% females, 80.6% persistent AF) were randomized to AF ablation (n = 16) vs medical therapy (n = 15). Baseline characteristics were comparable across both groups. At 6 months, ablation reduced the primary outcome of peak PCWP from baseline (30.4 ± 4.2 to 25.4 ± 4.5 mm Hg; P < 0.01). Improvements were also seen in peak relative VO<sub>2</sub> (20.2 ± 5.9 to 23.1 ± 7.2 mL/kg per minute; P < 0.01), N-terminal pro brain natriuretic peptide levels (794 ± 698 to 141 ± 60 ng/L; P = 0.04), and MLHF (Minnesota Living with Heart Failure) score (51 ± -21.9 to 16.6 ± 17.5; P < 0.01). No differences were detected in the medical arm. Following ablation, 50% no longer met exercise right heart catheterization-based criteria for HFpEF vs 7% in the medical arm (P = 0.02).<br /><b>Conclusions</b><br />AF ablation improves invasive exercise hemodynamic parameters, exercise capacity, and quality of life in patients with concomitant AF and HFpEF.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 28 Feb 2023; epub ahead of print</small></div>

<div><h4>Recency of Heart Failure Hospitalization, Outcomes, and the Effect of Empagliflozin: An EMPEROR-Pooled Analysis.</h4><i>Ferreira JP, Zannad F, Butler J, Filippatos G, ... Anker SD, Packer M</i><br /><b>Background</b><br />Patients with a recent heart failure (HF) hospitalization have a high risk of rehospitalization and mortality. Early treatment may have a substantial impact on patient outcomes.<br /><b>Objectives</b><br />The study sought to study the outcomes and effect of empagliflozin according to timing of prior HF hospitalization.<br /><b>Methods</b><br />EMPEROR-Pooled (EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) and EMPEROR-Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction) combined) included 9,718 HF patients who were grouped according to the recency of HF hospitalization (none, <3 months, 3-6 months, 6-12 months, >12 months). The primary outcome was a composite of time to first of HF hospitalization or cardiovascular death, over a median follow-up of 21 months.<br /><b>Results</b><br />The primary outcome event rates (per 100 person-years) in the placebo group were 26.7, 18.1, 13.7, and 2.8 for patients hospitalized within 3 months, 3-6 months, 6-12 months, and >12 months, respectively. The relative risk reduction of primary outcome events with empagliflozin was similar across HF hospitalization categories (P interaction = 0.67). The primary outcome absolute risk reduction was more pronounced among patients with a recent HF hospitalization but without statistical heterogeneity of treatment effect: -6.9, -5.5, -0.8, and -0.6 events prevented per 100 person-years for patients hospitalized within <3 months, 3-6 months, 6-12 months, and >12 months, respectively, and -2.4 events prevented per 100 person-years of follow-up in those without a prior HF hospitalization (P interaction = 0.64). Empagliflozin was safe irrespective of HF hospitalization recency.<br /><b>Conclusions</b><br />Patients with a recent HF hospitalization have a high risk of events. Empagliflozin reduced HF events regardless of HF hospitalization recency.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 20 Feb 2023; epub ahead of print</small></div>

<div><h4>Impact of the 2018 UNOS Heart Transplant Policy Changes on Patient Outcomes.</h4><i>Maitra NS, Dugger SJ, Balachandran IC, Civitello AB, Khazanie P, Rogers JG</i><br /><AbstractText>In 2018, the United Network for Organ Sharing implemented a 6-tier allocation policy to replace the prior 3-tier system. Given increasing listings of critically ill candidates for heart transplantation and lengthening waitlist times, the new policy aimed to better stratify candidates by waitlist mortality, shorten waiting times for high priority candidates, add objective criteria for common cardiac conditions, and further broaden sharing of donor hearts. There have been significant shifts in cardiac transplantation practices and patient outcomes following the implementation of the new policy, including changes in listing practices, waitlist time and mortality, transplant donor characteristics, post-transplantation outcomes, and mechanical circulatory support use. This review aims to highlight emerging trends in United States heart transplantation practice and outcomes following the implementation of the 2018 United Network for Organ Sharing heart allocation policy and to address areas for future modification.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 16 Feb 2023; epub ahead of print</small></div>

<div><h4>Effect of Training on Vascular Function and Repair in Heart Failure With Preserved Ejection Fraction.</h4><i>Gevaert AB, Böhm B, Hartmann H, Goovaerts I, ... Halle M, Van Craenenbroeck EM</i><br /><b>Background</b><br />Exercise training improves peak oxygen uptake (V̇O<sub>2</sub>peak) in heart failure with preserved ejection fraction (HFpEF). Multiple adaptations have been addressed, but the role of circulating endothelium-repairing cells and vascular function have not been well defined.<br /><b>Objectives</b><br />The authors investigated effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on vascular function and repair in HFpEF.<br /><b>Methods</b><br />This study is a subanalysis of the OptimEx-Clin Study randomizing patients with HFpEF (n = 180) to HIIT, MICT, or guideline control. At baseline, 3, and 12 months, the authors measured peripheral arterial tonometry (valid baseline measurement in n = 109), flow-mediated dilation (n = 59), augmentation index (n = 94), and flow cytometry (n = 136) for endothelial progenitor cells and angiogenic T cells. Abnormal values were defined as outside 90% of published sex-specific reference values.<br /><b>Results</b><br />At baseline, abnormal values (%) were observed for augmentation index in 66%, peripheral arterial tonometry in 17%, flow-mediated dilation in 25%, endothelial progenitor cells in 42%, and angiogenic T cells in 18%. These parameters did not change significantly after 3 or 12 months of HIIT or MICT. Results remained unchanged when confining analysis to patients with high adherence to training.<br /><b>Conclusions</b><br />In patients with HFpEF, high augmentation index was common, but endothelial function and levels of endothelium-repairing cells were normal in most patients. Aerobic exercise training did not change vascular function or cellular endothelial repair. Improved vascular function did not significantly contribute to the V̇O<sub>2</sub>peak improvement after different training intensities in HFpEF, contrary to previous studies in heart failure with reduced ejection fraction and coronary artery disease. (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure [OptimEx-Clin]; NCT02078947).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 15 Feb 2023; epub ahead of print</small></div>

<div><h4>Degree of Joint Risk Factor Control and Incident Heart Failure in Hypertensive Patients.</h4><i>Kou M, Wang X, Ma H, Li X, Heianza Y, Qi L</i><br /><b>Background</b><br />Heart failure (HF) is a major complication in patients with hypertension.<br /><b>Objectives</b><br />This study aimed to investigate the extent to which joint risk factor control could attenuate hypertension-related excess risk of HF.<br /><b>Methods</b><br />The study included a total of 75,293 participants with diagnosed hypertension from the UK Biobank and matched with 256,619 nonhypertensive control subjects, followed up until May 31, 2021. The degree of joint risk factor control was assessed on the basis of the major cardiovascular risk factors, including blood pressure, body mass index, low-density lipoprotein cholesterol, hemoglobin A1c, albuminuria, smoking, and physical activity. The Cox proportional hazards models were used to estimate associations between the degree of risk factor control and risk of HF.<br /><b>Results</b><br />Among hypertensive patients, joint risk factor control showed an association with a stepwise reduction of incident HF risk. Each additional risk factor control was related to a 20% lower risk, and the optimal risk factor control (controlling ≥6 risk factors) was associated with a 62% lower risk (HR: 0.38; 95% CI: 0.31-0.45). In addition, the study found that the hypertension-related excess risk of HF among participants jointly controlling ≥6 risk factors were even lower than in nonhypertensive control subjects (HR: 0.79; 95% CI: 0.67-0.94). The protective associations of joint risk factor control and risk of incident HF were broadly stronger among men than women and among medication users than nonusers (P for interaction < 0.05).<br /><b>Conclusions</b><br />The joint risk factor control is associated with a lower risk of incident HF in an accumulative and sex-specific manner. Optimal risk factor control may eliminate hypertension-related excess risk of HF.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 13 Feb 2023; epub ahead of print</small></div>

<div><h4>Cost-Effectiveness of Comprehensive Quadruple Therapy for Heart Failure With Reduced Ejection Fraction.</h4><i>Dixit NM, Parikh NU, Ziaeian B, Jackson N, Fonarow GC</i><br /><b>Background</b><br />Heart failure with reduced ejection fraction (HFrEF) is one of the most costly and deadly chronic disease states. The cost effectiveness of a comprehensive quadruple therapy regimen for HFrEF has not been studied.<br /><b>Objectives</b><br />The authors sought to determine the cost-effectiveness of quadruple therapy comprised of beta-blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, and sodium glucose cotransporter-2 inhibitors vs regimens composed of only beta-blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists (triple therapy), and angiotensin-converting enzyme inhibitors and beta-blockers (double therapy).<br /><b>Methods</b><br />Using a 2-state Markov model, the authors performed a cost-effectiveness study using simulated populations of 1,000 patients with HFrEF based on the participants in the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial and compared them by treatment strategy (quadruple therapy vs triple and double therapy) from a United States health care system perspective. The authors also performed 10,000 probabilistic simulations.<br /><b>Results</b><br />Treatment with quadruple therapy resulted in an increase of 1.73 and 2.87 life-years compared with triple therapy and double therapy, respectively, and an increase in quality-adjusted life-years of 1.12 and 1.85 years, respectively. The incremental cost-effectiveness ratios of quadruple therapy vs triple therapy and double therapy were $81,000 and $51,081, respectively. In 91.7% and 99.9% of probabilistic simulations quadruple therapy had an incremental cost-effectiveness ratio of <$150,000 compared with triple therapy and double therapy, respectively.<br /><b>Conclusions</b><br />At current pricing, the use of quadruple therapy in patients with HFrEF was cost effective compared with triple therapy and double therapy. These findings highlight the need for improved access and optimal implementation of comprehensive quadruple therapy in eligible patients with HFrEF.<br /><br />Copyright © 2023 American College of Cardiology Foundation. All rights reserved.<br /><br /><small>JACC Heart Fail: 10 Feb 2023; epub ahead of print</small></div>

<div><h4>Approaches to Genetic Screening in Cardiomyopathies: Practical Guidance for Clinicians.</h4><i>Kontorovich AR</i><br /><AbstractText>Patients and families benefit when the genetic etiology of cardiomyopathy is elucidated through a multidisciplinary approach including genetic counseling and judicious use of genetic testing. The yield of genetic testing is optimized when performed on a proband with a clear phenotype, and interrogates genes that are validated in association with that specific form of cardiomyopathy. Variants of uncertain significance are frequently uncovered and should not be overinterpreted. Identifying an impactful genetic variant as the cause of a patient\'s cardiomyopathy can have important prognostic impact, and enable streamlined cascade testing to highlight at risk relatives. Certain genotypes are associated with unique potential cardiac and noncardiac risk factors and may dictate personalized approaches to treatment.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Feb 2023; 11:133-142</small></div>

<div><h4>Applicability of Vericiguat to Patients Hospitalized for Heart Failure in the United States.</h4><i>Khan MS, Xu H, Fonarow GC, Lautsch D, ... Butler J, Greene SJ</i><br /><b>Background</b><br />In January 2021, vericiguat, a soluble guanylate cyclase stimulator, was approved by the U.S. Food and Drug Administration (FDA) to reduce the risk of cardiovascular death and heart failure (HF) hospitalization among patients with a recent worsening HF event based on the VICTORIA (VerICiguaT Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial.<br /><b>Objectives</b><br />This study sought to leverage a contemporary U.S. registry of patients hospitalized for heart failure (HF) to characterize patients who may be candidates for vericiguat based on FDA label and the VICTORIA trial eligibility criteria.<br /><b>Methods</b><br />The authors studied patients hospitalized for HF with ejection fraction (EF) <45% across 525 sites in the GWTG-HF (Get With The Guidelines-Heart Failure) registry between January 2014 and December 2020. Approximate FDA label criteria (excluding estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m<sup>2</sup>, dialysis, or patients with heart transplantation or durable mechanical circulatory support) and eligibility criteria for the VICTORIA trial were applied to the GWTG-HF cohort.<br /><b>Results</b><br />Among 241,057 patients with EF <45% in the GWTG-HF registry, 221,730 (92%) could be candidates for vericiguat under the FDA label and 92,249 (38%) would have been eligible for the VICTORIA trial. The most frequent reasons for ineligibility for the FDA label were eGFR <15 mL/min/1.73 m<sup>2</sup> (5.7%) and dialysis (1.6%). Although there were greater proportions of women and Black patients in the GWTG-HF registry, most clinical characteristics were qualitatively similar with patients enrolled in the VICTORIA trial. Among Medicare beneficiaries in the GWTG-HF registry eligible for vericiguat by either FDA label or VICTORIA trial criteria, 12-month postdischarge rates of mortality (36%-37%), HF hospitalization (33%-35%), all-cause hospitalization (64%-66%), and mean health care expenditure (U.S. $25,106-$25,428) were high.<br /><b>Conclusions</b><br />Data from a large, contemporary U.S. registry of patients actively hospitalized for HF with EF <45% suggest that approximately 4 in 10 patients meet the criteria of the VICTORIA trial and that more than 9 in 10 patients are potential candidates for vericiguat based on the FDA label. Contemporary Medicare beneficiaries hospitalized for HF with EF <45% and eligible for vericiguat face high rates of postdischarge mortality and readmission and accrue substantial health care costs.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Feb 2023; 11:211-223</small></div>

<div><h4>Association of Social Isolation and Loneliness With Incident Heart Failure in a Population-Based Cohort Study.</h4><i>Liang YY, Chen Y, Feng H, Liu X, ... Geng Q, Zhang J</i><br /><b>Background</b><br />Social isolation and loneliness have emerged as important risk factors for cardiovascular diseases, particularly during the coronavirus disease pandemic. However, it is unclear whether social isolation and loneliness had independent and joint associations with incident heart failure (HF).<br /><b>Objectives</b><br />This study sought to examine the association of social isolation, loneliness, and their combination with incident HF.<br /><b>Methods</b><br />The UK Biobank study is a population-based cohort study. Social isolation and loneliness were assessed using self-reported questionnaires. HF cases were identified by linking hospital records and death registries. The weighted polygenic risk score associated with HF was calculated.<br /><b>Results</b><br />Among the 464,773 participants (mean age: 56.5 ± 8.1 years, 45.3% male), 12,898 incident HF cases were documented during a median follow-up of 12.3 years. Social isolation (most vs least: adjusted HR: 1.17; 95% CI:1.11-1.23) and loneliness (yes vs no: adjusted HR: 1.19; 95% CI: 1.11-1.27) were significantly associated with an increased risk of incident HF. The association between an elevated risk of HF and social isolation was modified by loneliness (P<sub>interaction</sub> = 0.034). A gradient of association between social isolation and the risk of incident HF was found only among individuals without loneliness (P<sub>trend</sub> < 0.001), but not among those with loneliness (P<sub>trend</sub> = 0.829). These associations were independent of the genetic risk of HF.<br /><b>Conclusions</b><br />Social isolation and loneliness were independently associated with a higher likelihood of incident HF regardless of genetic risk. The association between social isolation and incident HF was potentially modified by loneliness status.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 20 Jan 2023; epub ahead of print</small></div>

<div><h4>Medication-Attributable Adverse Events in Heart Failure Trials.</h4><i>Harrington J, Fonarow GC, Khan MS, Hernandez A, ... Vaduganathan M, Butler J</i><br /><b>Background</b><br />Initiation and up-titration of guideline-directed medical therapies (GDMTs) for heart failure with reduced ejection fraction (HFrEF) remains suboptimal, in part because of concerns regarding tolerability and adverse events (AEs).<br /><b>Objectives</b><br />The authors sought to compare rates of AE in patients randomized to GDMT medication vs placebo in a meta-analysis of landmark cardiovascular outcomes trials.<br /><b>Methods</b><br />The authors assessed rates of reported AE in 17 landmark HFrEF clinical trials across each class of GDMT in the placebo and intervention arms. The overall rates of AE for each drug class, the absolute difference in frequency in AEs between the placebo and intervention arms, and the odds of each AE according based on randomization strata were calculated.<br /><b>Results</b><br />AE were reported commonly in trials across each class of GDMT, with 75% to 85% of participants reporting at least 1 AE. There was no significant difference in the frequency of AE between the intervention and placebo arms, except for angiotensin-converting enzyme inhibitors (87.0% [95% CI: 85.0%-88.8%] vs 82.0% [95% CI: 79.8%-84.0%], absolute difference: +5% with intervention; P < 0.001). There was no significant difference in drug discontinuation because of AE between placebo and intervention arms in angiotensin-converting enzyme inhibitors, mineralocorticoid receptor antagonists, sodium glucose cotransporter 2 inhibitors, or angiotensin receptor neprilysin inhibitor/angiotensin II receptor blocker trials. Patients randomized to beta-blocker were significantly less likely to stop study drug because of AE than placebo (11.3% [95% CI: 10.3%-12.3%] vs 13.7% [95% CI: 12.5%-14.9%], absolute difference: -1.1%; P = 0.015). When individual types of AE were assessed, the initiation of an intervention vs placebo resulted in small differences in absolute frequency of AE that were largely not statistically significant.<br /><b>Conclusions</b><br />In clinical trials of GDMT for HFrEF, AEs are observed frequently. However, rates of AE are similar between active medication and control, suggesting these may reflect the high risk nature of the heart failure disease state rather than be attributive to a specific therapy.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 12 Jan 2023; epub ahead of print</small></div>

<div><h4>Patient Eligibility for Established and Novel Guideline-Directed Medical Therapies After Acute Heart Failure Hospitalization.</h4><i>Moghaddam N, Hawkins NM, McKelvie R, Poon S, ... Zieroth S, Virani SA</i><br /><b>Background</b><br />Acute heart failure (AHF) hospitalization presents an opportunity to optimize pharmacotherapy to improve outcomes.<br /><b>Objectives</b><br />This study\'s aim was to define eligibility for initiation of guideline-directed medical therapy and newer heart failure (HF) agents from recent clinical trials in the AHF population.<br /><b>Methods</b><br />The authors analyzed patients with an AHF admission within the CAN-HF (Canadian Heart Failure) registry between January 2017 and April 2020. Heart failure with reduced ejection fraction (HFrEF) was defined as left ventricular ejection fraction (LVEF) ≤40% and heart failure with preserved ejection fraction (HFpEF) as LVEF >40%. Eligibility was assessed according to the major society guidelines or enrollment criteria from recent landmark clinical trials.<br /><b>Results</b><br />A total of 809 patients with documented LVEF were discharged alive from hospital: 455 with HFrEF and 354 with HFpEF; of these patients, 284 had a de novo presentation and 525 had chronic HF. In HFrEF patients, eligibility for therapies was 73.6% for angiotensin receptor-neprilysin inhibitors (ARNIs), 94.9% for beta-blockers, 84.4% for mineralocorticoid receptor antagonists (MRAs), 81.1% for sodium/glucose cotransporter 2 (SGLT2) inhibitors, and 15.6% for ivabradine. Additionally, 25.9% and 30.1% met trial criteria for vericiguat and omecamtiv mecarbil, respectively. Overall, 71.6% of patients with HFrEF (75.5% de novo, 69.5% chronic HF) were eligible for foundational quadruple therapy. In the HFpEF population, 37.6% and 59.9% were eligible for ARNIs and SGLT2 inhibitors based on recent trial criteria, respectively.<br /><b>Conclusions</b><br />The majority of patients admitted with AHF are eligible for foundational quadruple therapy and additional novel medications across a spectrum of HF phenotypes.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 11 Jan 2023; epub ahead of print</small></div>

<div><h4>The End of Endomyocardial Biopsy?: A Practical Guide for Noninvasive Heart Transplant Rejection Surveillance.</h4><i>Holzhauser L, DeFilippis EM, Nikolova A, Byku M, ... Khush KK, Vest AR</i><br /><AbstractText>Noninvasive heart transplant rejection surveillance using gene expression profiling (GEP) to monitor immune activation is widely used among heart transplant programs. With the new development of donor-derived cell-free DNA (dd-cfDNA) assays, more programs are transitioning to a predominantly noninvasive rejection surveillance protocol with a reduced frequency of endomyocardial biopsies. As a result, many practical questions arise that potentially delay implementation of these valuable new tools. The purpose of this review is to provide practical guidance for clinicians transitioning toward a less invasive acute rejection monitoring protocol after heart transplantation, and to answer 10 common questions about the GEP and dd-cfDNA assays. Evidence supporting GEP and dd-cfDNA testing is reviewed, as well as guidance on test interpretation and future directions.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 11 Jan 2023; epub ahead of print</small></div>

<div><h4>Reclassification of Pre-Heart Failure Stages Using Cardiac Biomarkers: Atherosclerosis Risk in Communities (ARIC) Study.</h4><i>Jia X, Al Rifai M, Ndumele CE, Virani SS, ... Ballantyne CM, Nambi V</i><br /><b>Background</b><br />The recent heart failure (HF) guideline recommends the inclusion of cardiac biomarkers in defining Stage B HF.<br /><b>Objectives</b><br />The authors evaluated the impact of incorporating cardiac biomarkers to reclassify HF in 5,324 participants (mean age: 75.8 years) without prevalent HF enrolled in the Atherosclerosis Risk in Communities study and assessed prognosis of Stage B using cardiac biomarkers.<br /><b>Methods</b><br />Using N-terminal pro-B-type natriuretic peptide (<125 pg/mL or ≥125 pg/mL), high-sensitivity troponin T (<14 ng/L or ≥14 ng/L), and abnormal cardiac structure/function by echocardiography, individuals were classified as Stage A<sub>new</sub> and Stage B<sub>new</sub> HF, respectively. Stage B<sub>new</sub> was further evaluated as elevated biomarker only, abnormal echocardiogram only, and abnormalities in both (echo + biomarker). The authors assessed risk for incident HF and all-cause death using Cox regression.<br /><b>Results</b><br />Overall, 4,326 (81.3%) individuals were classified as Stage B<sub>new</sub> with 1,123 (21.1%) meeting criteria for elevated biomarkers only. Compared with Stage A<sub>new</sub>, Stage B<sub>new</sub> was associated with increased risk for incident HF (HR: 3.70 [95% CI: 2.58-5.30]) and death (HR: 1.94 [95% CI: 1.53-2.46]). Stage B<sub>biomarkers only</sub> and Stage B<sub>echo only</sub> were associated with increased HF risk, whereas Stage B<sub>biomarkers only</sub> was also associated with increased death. Stage B<sub>echo+biomarker</sub> had the highest risk for HF (HR: 6.34 [95% CI: 4.37-9.19]) and death (HR: 2.53 [95% CI: 1.98-3.23]).<br /><b>Conclusions</b><br />Incorporating biomarkers based on the new HF guideline reclassified approximately 1 in 5 older adults without prevalent HF to Stage B. The routine measurement of biomarkers can help to identify individuals at higher HF risk who may benefit most from HF prevention efforts.<br /><br />Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 09 Jan 2023; epub ahead of print</small></div>

<div><h4>Omecamtiv Mecarbil in Black Patients With Heart Failure and Reduced Ejection Fraction: Insights From GALACTIC-HF.</h4><i>Lanfear DE, Njoroge JN, Adams KF, Anand I, ... Malik FI, Teerlink JR</i><br /><b>Background</b><br />Omecamtiv mecarbil improves cardiovascular outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Consistency of drug benefit across race is a key public health topic.<br /><b>Objectives</b><br />The purpose of this study was to evaluate the effect of omecamtiv mecarbil among self-identified Black patients.<br /><b>Methods</b><br />In GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) patients with symptomatic HF, elevated natriuretic peptides, and left ventricular ejection fraction (LVEF) ≤35% were randomized to omecamtiv mecarbil or placebo. The primary outcome was a composite of time to first event of HF or cardiovascular death. The authors analyzed treatment effects in Black vs White patients in countries contributing at least 10 Black participants.<br /><b>Results</b><br />Black patients accounted for 6.8% (n = 562) of overall enrollment and 29% of U.S. enrollment. Most Black patients enrolled in the United States, South Africa, and Brazil (n = 535, 95%). Compared with White patients enrolled from these countries (n = 1,129), Black patients differed in demographics, comorbid conditions, received higher rates of medical therapy and lower rates of device therapies, and experienced higher overall event rates. The effect of omecamtiv mecarbil was consistent in Black vs White patients, with no difference in the primary endpoint (HR = 0.83 vs 0.88, P-interaction = 0.66), similar improvements in heart rate and N-terminal pro-B-type natriuretic peptide, and no significant safety signals. Among endpoints, the only nominally significant treatment-by-race interaction was the placebo-corrected change in blood pressure from baseline in Black vs White patients (+3.4 vs -0.7 mm Hg, P-interaction = 0.02).<br /><b>Conclusions</b><br />GALACTIC-HF enrolled more Black patients than other recent HF trials. Black patients treated with omecamtiv mecarbil had similar benefit and safety compared with White counterparts.<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 04 Jan 2023; epub ahead of print</small></div>

<div><h4>Patient-Reported Frailty and Functional Status in Heart Failure With Preserved Ejection Fraction: Insights From VITALITY-HFpEF.</h4><i>Kaul P, Rathwell S, Lam CSP, Westerhout CM, ... Armstrong PW, VITALITY-HFpEF Study Group</i><br /><b>Background</b><br />The association between frailty and health status in patients with heart failure with preserved ejection fraction (HFpEF) is not well known.<br /><b>Objectives</b><br />The authors examined the association between: 1) patient-reported frailty, measured by the Fried frailty phenotype, Kansas City Cardiomyopathy Questionnaire physical limitation score (KCCQ-PLS), 6-minute walking distance (6MWD), and other baseline characteristics; 2) baseline frailty compared with KCCQ-PLS and 24-week 6MWD; 3) frailty and changes in KCCQ-PLS and 6MWD; and 4) vericiguat and frailty at 24 weeks.<br /><b>Methods</b><br />In a post hoc analysis, patients in the VITALITY-HFpEF (Patient-reported Outcomes in Vericiguat-treated Patients With HFpEF) trial were categorized as not frail (0 symptoms), prefrail (1-2 symptoms), and frail (≥3 symptoms) according to patient-reported number of frailty symptoms. Correlations and linear regression models were used to examine the association between frailty and other measures, and between frailty and KCCQ-PLS at baseline with 24-week 6MWD.<br /><b>Results</b><br />Among 739 patients, 27.3% were not frail, 37.6% were prefrail, and 35.0% were frail at baseline. Frail patients were older, more likely to be women, and less likely to be from Asia. Baseline KCCQ-PLS and 6MWD (mean ± SD) among not frail, prefrail, and frail patients was 68.2 ± 23.2, 61.7 ± 22.6, and 48.4 ± 23.8 and 328.5 ± 117.1 m, 310.8 ± 98.9 m, and 250.7 ± 104.3 m (P < 0.01 for both). After accounting for baseline 6MWD, frailty status at baseline, but not KCCQ-PLS, was significantly associated with 6MWD at 24 weeks. By 24 weeks, 47.5% of patients had no change in frailty, 45.5% had become less frail, and 7.0% had become more frail. Treatment with vericiguat did not alter frailty status at 24 weeks.<br /><b>Conclusions</b><br />Patient-reported frailty is modestly correlated with both the KCCQ-PLS and 6MWD but offers prognostic insight into 6MWD at 24 weeks. (Patient-reported Outcomes in Vericiguat-treated Patients With HFpEF [VITALITY-HFpEF]; NCT03547583).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 03 Jan 2023; epub ahead of print</small></div>

<div><h4>Blood Pressure and Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: DELIVER.</h4><i>Selvaraj S, Vaduganathan M, Claggett BL, Miao ZM, ... McMurray JJV, Solomon SD</i><br /><b>Background</b><br />Optimizing systolic blood pressure (SBP) in heart failure (HF) with preserved ejection fraction carries a Class I recommendation but with limited evidence. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have antihypertensive effects across cardiovascular disease.<br /><b>Objectives</b><br />The authors examined the interplay between SBP and treatment effects of dapagliflozin on SBP and cardiovascular outcomes.<br /><b>Methods</b><br />The authors analyzed 6,263 DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) participants and related baseline and mean achieved SBP categories (<120, 120-129, 130-139, ≥140 mm Hg) to the primary outcome (cardiovascular death or worsening HF), secondary outcomes, and safety events. They analyzed whether the blood pressure-lowering effects of dapagliflozin accounted for its treatment effects by adjusting for the change in SBP from baseline to 1 month.<br /><b>Results</b><br />The average age was 72 ± 10 years and 44% were women. SBP <120 mm Hg was associated with higher HF and mortality events, although amputation and stroke risk increased with higher SBP. Dapagliflozin reduced SBP by 1.8 (95% CI: 1.1-2.5) mm Hg compared with placebo at 1 month. The treatment effect of dapagliflozin on the primary outcome and Kansas City Cardiomyopathy Questionnaire total symptom score was consistent across SBP (interaction P = 0.15 and P = 0.98, respectively). Adverse events between arms were similar across SBP categories. The treatment effect was not accounted for by reducing blood pressure.<br /><b>Conclusions</b><br />In DELIVER, risk by SBP was augmented in the lowest and highest categories and varied by endpoint examined. Dapagliflozin modestly decreased SBP compared with placebo. Dapagliflozin was similarly efficacious and safe across the range of baseline SBP. The beneficial effects of dapagliflozin were not accounted for the changes in SBP. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jan 2023; 11:76-89</small></div>

<div><h4>Race and Socioeconomic Bias in Pediatric Cardiac Transplantation.</h4><i>Amdani S, Conway J, Kleinmahon J, Auerbach S, ... Kirklin JK, Asante-Korang A</i><br /><b>Background</b><br />To date, no studies evaluated implicit bias among clinicians caring for children with advanced heart failure.<br /><b>Objectives</b><br />This study aims to evaluate implicit racial and socioeconomic bias among pediatric heart transplant clinicians.<br /><b>Methods</b><br />A cross-sectional survey of transplant clinicians from the Pediatric Heart Transplant Society was conducted between June and August 2021. The survey consisted of demographic questions along with explicit and validated race and socioeconomic status (SES) implicit association tests (IATs). Implicit and explicit biases among survey group members were studied and associations were tested between implicit and explicit measures.<br /><b>Results</b><br />Of 500 members, 91 (18.2%) individuals completed the race IAT and 70 (14%) completed the SES IAT. Race IAT scores indicated moderate levels of implicit bias (mean = 0.33, d = 0.76; P < 0.001; ie, preference for White individuals). SES IAT scores indicated strong implicit bias (mean = 0.52, d = 1.53; P < 0.001; ie, preference for people from upper SES). There were weak levels of explicit race and wealth bias. There was a strong level of explicit education bias (mean = 5.22, d = 1.19; P < 0.001; ie, preference for educated people). There were nonsignificant correlations between the race and the SES IAT and explicit measures (P > 0.05 for all).<br /><b>Conclusions</b><br />As observed across other health care disciplines, among a group of pediatric heart transplant clinicians, there is an implicit preference for individuals who are White and from higher SES, and an explicit preference for educated people. Future studies should evaluate how implicit biases affect clinician behavior and assess the impact of efforts to reduce such biases.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jan 2023; 11:19-26</small></div>

<div><h4>Comparison of Demographic, Clinical, Biochemical, and Imaging Findings in Hypertrophic Cardiomyopathy Prognosis: A Network Meta-Analysis.</h4><i>Georgiopoulos G, Figliozzi S, Pateras K, Nicoli F, ... Masci PG, Olivotto I</i><br /><b>Background</b><br />Despite hypertrophic cardiomyopathy (HCM) being the most common inherited heart disease and conferring increased risk for heart failure (HF) and sudden cardiac death (SCD), risk assessment in HCM patients is still largely unresolved.<br /><b>Objectives</b><br />This study aims to synthesize and compare the prognostic impact of demographic, clinical, biochemical, and imaging findings in patients with HCM.<br /><b>Methods</b><br />The authors searched PubMed, Embase, and Cochrane Library for studies published from 1955 to November 2020, and the endpoints were: 1) all-cause death; 2) an arrhythmic endpoint including SCD, sustained ventricular tachycardia, ventricular fibrillation, or aborted SCD; and 3) a composite endpoint including (1) or (2) plus hospitalization for HF or cardiac transplantation. The authors performed a pairwise meta-analysis obtaining the pooled estimate separately for the association between baseline variables and study endpoints. A random-effects network meta-analysis was subsequently used to comparatively assess the prognostic value of outcome associates.<br /><b>Results</b><br />A total of 112 studies with 58,732 HCM patients were included. Among others, increased brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide, late gadolinium enhancement (LGE), positive genotype, impaired global longitudinal strain, and presence of apical aneurysm conferred increased risk for the composite endpoint. At network meta-analysis, LGE showed the highest prognostic value for all endpoints and was superior to all other associates except New York Heart Association functional class >class II. A multiparametric imaging-based model was superior in predicting the composite endpoint compared to a prespecified model based on conventional risk factors.<br /><b>Conclusions</b><br />This network meta-analysis supports the development of multiparametric risk prediction algorithms, including advanced imaging markers additively to conventional risk factors, for refined risk stratification in HCM. (Long-term prognosis of hypertrophic cardiomyopathy according to genetic, clinical, biochemical and imaging findings: a systemic review and meta-analysis; CRD42020185219).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jan 2023; 11:30-41</small></div>

<div><h4>Prediction of Left Ventricular Ejection Fraction Change Following Treatment With Sacubitril/Valsartan.</h4><i>Mohebi R, Liu Y, Felker GM, Prescott MF, ... Solomon SD, Januzzi JL</i><br /><b>Background</b><br />Sacubitril/valsartan (Sac/Val) improves left ventricular ejection fraction (LVEF) in heart failure (HF) with reduced ejection fraction regardless of previous treatments. Improvements in LVEF may change eligibility for primary implantable cardioverter-defibrillator (ICD) placement. Awaiting LVEF improvement may expose patients to potential risks for arrhythmic complications.<br /><b>Objectives</b><br />The authors sought to develop a model predicting LVEF change after Sac/Val therapy.<br /><b>Methods</b><br />A total of 416 persons with HF and LVEF of <35% were included in this analysis. Following initiation of Sac/Val, echocardiographic parameters were measured serially for 1 year. A machine learning algorithm was implemented to develop a risk model for predicting the persistence of LVEF of <35% after 1 year and was validated in a separate group of study participants.<br /><b>Results</b><br />Baseline LVEF, left ventricular mass index, HF duration, age, N-terminal pro-B-type natriuretic peptide concentration at baseline and change by day 14, and body mass index were the most significant factors for identifying lack of LVEF improvement to ≥35% after 1 year. In the training and validation cohorts, the areas under the model curve for predicting lack of LVEF improvement were 0.92 and 0.86, respectively. Three categories of likelihood for LVEF of <35% after 1 year of Sac/Val treatment were developed based on the model predictions: 3.8%, 30.1%, and 83.7%. During follow-up, arrhythmia event rates were 0.9%, 2.9%, and 6.7% in these groups, respectively.<br /><b>Conclusions</b><br />Many persons with HF with reduced ejection fraction eligible for ICD insertion experience an increase in LVEF to ≥35% after treatment with Sac/Val. Early identification of those less likely to improve their LVEF might allow for more refined selection of primary ICD candidates. (Effects of Sacubitril/Valsartan Therapy on biomarkers, Myocardial Remodeling, and Outcomes [PROVE-HF]; NCT02887183).<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jan 2023; 11:44-54</small></div>

<div><h4>Prediction of Left Ventricular Reverse Remodeling and Outcomes by Circulating Collagen-Derived Peptides.</h4><i>Ravassa S, Lupón J, López B, Codina P, ... Bayés-Genís A, González A</i><br /><b>Background</b><br />Myocardial fibrosis may increase vulnerability to poor prognosis in patients with heart failure (HF), even in those patients exhibiting left ventricular reverse remodeling (LVRR) after guideline-based therapies.<br /><b>Objectives</b><br />This study sought to characterize fibrosis at baseline in patients with HF with left ventricular ejection fraction (LVEF) <50% by determining serum collagen type I-derived peptides (procollagen type I C-terminal propeptide [PICP] and ratio of collagen type I C-terminal telopeptide to matrix metalloproteinase-1) and to evaluate their association with LVRR and prognosis.<br /><b>Methods</b><br />Peptides were determined in 1,034 patients with HF at baseline. One-year echocardiography was available in 665 patients. Associations of peptides with 1-year changes in echocardiographic variables were analyzed by multivariable linear mixed models. LVEF was considered improved if it increased by ≥15% or to ≥50% or if it increased by ≥10% to >40% in patients with LVEF ≤40%. Cardiovascular death and HF-related outcomes were analyzed in all patients randomized to derivation (n = 648) and validation (n = 386) cohorts.<br /><b>Results</b><br />Continuous associations with echocardiographic changes were observed only for PICP. Compared with high-PICP (≥108.1 ng/mL) patients, low-PICP (<108.1 ng/mL) patients exhibited enhanced LVRR and a lower risk of HF-related outcomes (P ≤ 0.018), with women and nonischemic patients with HF showing a stronger LVEF increase (interaction P ≤ 0.010). LVEF increase was associated with a better prognosis, particularly in low-PICP patients (interaction P ≤ 0.029). Only patients with both low PICP and improved LVEF exhibited a better clinical evolution than patients with nonimproved LVEF (P < 0.001).<br /><b>Conclusions</b><br />Phenotyping with PICP, a peptide associated with myocardial fibrosis, may be useful to differentiate patients with HF who are more likely to experience clinical myocardial recovery from those with partial myocardial improvement.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Jan 2023; 11:58-72</small></div>

<div><h4>Predictors of Incident Heart Failure Diagnosis Setting: Insights From the Veterans Affairs Healthcare System.</h4><i>Tisdale RL, Fan J, Calma J, Cyr K, ... Heidenreich PA, Sandhu AT</i><br /><b>Background</b><br />Early recognition of heart failure (HF) can reduce morbidity, yet HF is often diagnosed only after symptoms require urgent treatment.<br /><b>Objectives</b><br />The authors sought to describe predictors of HF diagnosis in the acute care vs outpatient setting within the Veterans Health Administration (VHA).<br /><b>Methods</b><br />The authors estimated whether incident HF diagnoses occurred in acute care (inpatient hospital or emergency department) vs outpatient settings within the VHA between 2014 and 2019. After excluding new-onset HF potentially caused by acute concurrent conditions, they identified sociodemographic and clinical variables associated with diagnosis setting and assessed variation across 130 VHA facilities using multivariable regression analysis.<br /><b>Results</b><br />The authors identified 303,632 patients with new HF, with 160,454 (52.8%) diagnosed in acute care settings. In the prior year, 44% had HF symptoms and 11% had a natriuretic peptide tested, 88% of which were elevated. Patients with housing insecurity and high neighborhood social vulnerability had higher odds of acute care diagnosis (adjusted odds ratio: 1.22 [95% CI: 1.17-1.27] and 1.17 [95% CI: 1.14-1.21], respectively) adjusting for medical comorbidities. Better outpatient quality of care (blood pressure control and cholesterol and diabetes monitoring within the prior 2 years) predicted a lower odds of acute care diagnosis. Likelihood of acute care HF diagnosis varied from 41% to 68% across facilities after adjusting for patient-level risk factors.<br /><b>Conclusions</b><br />Many first HF diagnoses occur in the acute care setting, especially among socioeconomically vulnerable populations. Better outpatient care was associated with lower rates of an acute care diagnosis. These findings highlight opportunities for timelier HF diagnosis that may improve patient outcomes.<br /><br />Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 28 Dec 2022; epub ahead of print</small></div>

<div><h4>Comparison of Investigator-Reported and Centrally Adjudicated Heart Failure Outcomes in the EMPEROR-Reduced Trial.</h4><i>Carson P, Teerlink JR, Komajda M, Anand I, ... Zannad F, Packer M</i><br /><b>Background</b><br />There is limited published information on outcome adjudication in heart failure (HF).<br /><b>Objective</b><br />The authors sought to compare investigator reports (IRs) to a Clinical Events Committee (CEC) and the impact of Standardized Clinical Trial Initiative definitions (SCTI).<br /><b>Methods</b><br />In EMPEROR-Reduced, the authors compared IR to CEC for concordance; treatment effect on primary composite outcome events; and the components first event hospitalization primarily for HF (HHF) or cardiovascular mortality (CVM), prognosis after HHF, total HHFs, and trial duration with and without SCTI.<br /><b>Results</b><br />The CEC confirmed 76.3% of IR events for the primary outcome (CVM: 89.1%; HHF: 73.7%). The HR for treatment effect did not differ between adjudication methods for the primary outcome (IR: 0.75 [95% CI: 0.66-0.85]; CEC: 0.75 [95% CI: 0.65-0.86]), its components, or total HHFs. The prognosis after first HHF for all-cause mortality and CVM also did not differ between IR or CEC. Interestingly, IR primary HHF with different CEC primary cause had the highest subsequent fatal event rate. Full SCTI criteria were present in 90% of CEC HHFs-with a similar treatment effect to non-SCTI. The IR primary event reached the protocol target number (841) 3 months earlier than CEC (4 months with full SCTI criteria).<br /><b>Conclusions</b><br />Investigator adjudication is an alternative to a CEC with similar accuracy and faster event accumulation. The use of granular (SCTI) criteria did not improve trial performance. Finally, our data suggest that consideration be given to broadening the HHF definition to include \"for or with\" worsening disease. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).<br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 28 Dec 2022; epub ahead of print</small></div>

<div><h4>Dapagliflozin in Black and White Patients With Heart Failure Across the Ejection Fraction Spectrum.</h4><i>Butt JH, Docherty KF, Claggett BL, Desai AS, ... Solomon SD, McMurray JJV</i><br /><b>Background</b><br />Black people have a higher incidence and prevalence of heart failure (HF) than White people, and once HF has developed, they may have worse outcomes. There is also evidence that the response to several pharmacologic therapies may differ between Black and White patients.<br /><b>Objectives</b><br />The authors sought to examine the outcomes and response to treatment with dapagliflozin according to Black or White race in a pooled analysis of 2 trials comparing dapagliflozin to placebo in patients with heart failure with reduced ejection fraction (DAPA-HF [Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure]) and heart failure with Mildly reduced ejection fraction/heart failure with preserved ejection fraction (DELIVER [Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure]).<br /><b>Methods</b><br />Because most self-identified Black patients were enrolled in the Americas, the comparator group was White patients randomized in the same regions. The primary outcome was the composite of worsening HF or cardiovascular death.<br /><b>Results</b><br />Of the 3,526 patients randomized in the Americas, 2,626 (74.5%) identified as White and 381 (10.8%) as Black. The primary outcome occurred at a rate of 16.8 (95% CI: 13.8-20.4) in Black patients compared with 11.6 (95% CI: 10.6-12.7) per 100 person-years in White patients (adjusted HR: 1.27; 95% CI: 1.01-1.59). Compared with placebo, dapagliflozin decreased the risk of the primary endpoint to the same extent in Black (HR: 0.69; 95% CI: 0.47-1.02) and White patients (HR: 0.73 [95% CI: 0.61-0.88]; P<sub>interaction</sub> = 0.73). The number of patients needed to treat with dapagliflozin to prevent one event over the median follow-up was 17 in White and 12 in Black patients. The beneficial effects and favorable safety profile of dapagliflozin were consistent across the range of left ventricular ejection fractions in both Black and White patients.<br /><b>Conclusions</b><br />The relative benefits of dapagliflozin were consistent in Black and White patients across the range of left ventricular ejection fraction, with greater absolute benefits in Black patients. (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure [DAPA-HF]; NCT03036124) (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).<br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 21 Dec 2022; epub ahead of print</small></div>

<div><h4>Negative Predictive Value and Prognostic Associations of Rb-82 PET/CT with Myocardial Blood Flow in CAV.</h4><i>Abadie BQ, Chan N, Sharalaya Z, Bhat P, ... Cremer PC, Jaber WA</i><br /><b>Background</b><br />Invasive coronary angiography (ICA) is the traditional screening modality for cardiac allograft vasculopathy (CAV). Positron emission tomography/computed tomography (PET/CT) scan with myocardial blood flow (MBF) quantification has emerged as a potential noninvasive alternative.<br /><b>Objectives</b><br />The aim of the study was to validate the diagnostic and prognostic value of a previously published algorithm for diagnosing CAV via PET/CT scans with MBF in a larger population. The study also sought to assess the downstream use of ICA when using PET/CT scanning as a screening modality.<br /><b>Methods</b><br />Patients with heart transplantation without prior revascularization who underwent PET/CT scans with MBF were identified retrospectively. The accuracy of the algorithm was assessed in patients who underwent PET/CT scanning within 1 year of ICA. The prognostic value was assessed via a composite outcome of heart failure hospitalization, myocardial infarction, retransplantation, and all-cause mortality.<br /><b>Results</b><br />A total of 88 patients for the diagnostic portion and 401 patients for the prognostic portion were included. PET CAV 0 had high negative predictive value for moderate to severe CAV (97%) and PET CAV 2/3 had a high positive predictive value for moderate to severe CAV (68%) by ICA. The cohort was followed for a median of 1.2 (IQR: 1.0-1.8) years with 46 patients having an adverse event. The annualized event rates were 6.9%, 9.3%, and 30.8% for PET CAV 0, 1, and 2/3, respectively (P < 0.001).<br /><b>Conclusions</b><br />An algorithm using PET/CT scanning with MBF demonstrates high a negative predictive value for CAV. PET CAV 2/3 is associated with a higher risk of adverse events and need for revascularization. PET/CT scanning with MBF is a reasonable alternative to ICA for screening for CAV.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 20 Dec 2022; epub ahead of print</small></div>

<div><h4>Augmentation of Natriuretic Peptide Bioactivity via Combined Inhibition of Neprilysin and Phosphodiesterase-9 in Heart Failure.</h4><i>Scott NJA, Prickett TCR, Charles CJ, Frampton CM, Richards AM, Rademaker MT</i><br /><b>Background</b><br />The natriuretic peptides (NPs) are potent natriuretic/diuretic and vasodilatory factors, and augmentation of their levels or signaling via inhibition of the enzymes neprilysin (NEP) and phosphodiesterase 9 (PDE9), respectively, has beneficial actions in heart failure (HF).<br /><b>Objectives</b><br />The authors investigated dual enhancement of NP bioactivity by combining PDE9 inhibition and NEP inhibition in HF using an ovine model.<br /><b>Methods</b><br />Eight sheep with pacing-induced HF received on 4 separate days intravenous PDE9 inhibition (PF-04749982), NEP inhibition (SCH-32615), PDE9 inhibition + NEP inhibition (PI+NI), and vehicle control treatment.<br /><b>Results</b><br />Compared with the control treatment, NEP inhibition significantly increased plasma NP concentrations with a corresponding rise in second messenger cyclic guanosine monophosphate (cGMP), whereas PDE9 inhibition increased circulating cGMP with a negligible effect on NP levels. Combined PI+NI elevated plasma NPs to an extent comparable to that seen with NEP inhibition alone but further increased cGMP, resulting in a rise in the cGMP-to-NP ratio. All active treatments reduced mean arterial pressure, left atrial pressure, pulmonary arterial pressure, and peripheral resistance, with combined PI+NI further reducing mean arterial pressure and left atrial pressure relative to either inhibitor separately. Active treatments increased urine volume and sodium, potassium and creatinine excretion, and creatinine clearance, in association with rises in urine cGMP levels. PI+NI induced a significantly greater natriuresis and increase in urinary cGMP relative to either inhibitor singly.<br /><b>Conclusions</b><br />The present study demonstrates for the first time that combined PI+NI has additional beneficial hemodynamic and renal effects when compared with either PDE9 inhibition or NEP inhibition alone. The superior efficacy of this 2-pronged augmentation of NP bioactivity supports PI+NI as a potential therapeutic strategy for HF.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 15 Dec 2022; epub ahead of print</small></div>

<div><h4>Timing of Active Left Ventricular Unloading in Patients on Venoarterial Extracorporeal Membrane Oxygenation Therapy.</h4><i>Schrage B, Sundermeyer J, Blankenberg S, Colson P, ... Wechsler L, Westermann D</i><br /><b>Background</b><br />It is currently unclear if active left ventricular (LV) unloading should be used as a primary treatment strategy or as a bailout in patients with cardiogenic shock (CS) treated with venoarterial extracorporeal membrane oxygenation (VA-ECMO).<br /><b>Objectives</b><br />The study sought to evaluate the association between timing of active LV unloading and implantation of VA-ECMO with outcomes of patients with CS.<br /><b>Methods</b><br />Data from 421 patients with CS treated with VA-ECMO and active LV unloading at 18 tertiary care centers in 4 countries were analyzed. Patients were stratified by timing of device implantation in early vs delayed active LV unloading (defined by implantation before up to 2 hours after VA-ECMO). Adjusted Cox and logistic regression models were fitted to evaluate the association between early active LV unloading and 30-day mortality as well as successful weaning from ventilation.<br /><b>Results</b><br />Overall, 310 (73.6%) patients with CS were treated with early active LV unloading. Early active LV unloading was associated with a lower 30-day mortality risk (HR: 0.64; 95% CI: 0.46-0.88) and a higher likelihood of successful weaning from ventilation (OR: 2.17; 95% CI: 1.19-3.93) but not with more complications. Importantly, the relative mortality risk increased and the likelihood of successful weaning from ventilation decreased almost proportionally with the time interval between VA-ECMO implantation and (delayed) initiation of active LV unloading.<br /><b>Conclusions</b><br />This exploratory study lends support to the use of early active LV unloading in CS patients on VA-ECMO, although the findings need to be validated in a randomized controlled trial.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 13 Dec 2022; epub ahead of print</small></div>

<div><h4>Functional and Symptomatic Clinical Trial Endpoints: The HFC-ARC Scientific Expert Panel.</h4><i>Psotka MA, Abraham WT, Fiuzat M, Filippatos G, ... Anker SD, O\'Connor CM</i><br /><AbstractText>The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and the Academic Research Consortium (ARC) composed of patients, academic investigators from the United States and Europe, the U.S. Food and Drug Administration, the National Institutes of Health, payers, and industry. Members discussed the measure, remote capture, and clinical utility of functional and quality-of-life endpoints for use in clinical trials of heart failure and cardiovascular therapeutics, with the goal of improving the efficiency of heart failure and cardiovascular clinical research, evidence generation, and thereby patient quality of life, functional status, and survival. Assessments of patient-reported outcomes and maximal and submaximal exercise tolerance are standardized and validated, but actigraphy remains inconsistent as a potential endpoint. This paper details those discussions and consensus recommendations.</AbstractText><br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Dec 2022; 10:889-901</small></div>

<div><h4>Hemodynamically-Guided Management of Heart Failure Across the Ejection Fraction Spectrum: The GUIDE-HF Trial.</h4><i>Zile MR, Mehra MR, Ducharme A, Sears SF, ... Costanzo MR, Lindenfeld J</i><br /><b>Background</b><br />Hemodynamically-guided management using an implanted pulmonary artery pressure sensor is indicated to reduce heart failure (HF) hospitalizations in patients with New York Heart Association (NYHA) functional class II-III with a prior HF hospitalization or those with elevated natriuretic peptides.<br /><b>Objectives</b><br />The authors sought to evaluate the effect of left ventricular ejection fraction (EF) on treatment outcomes in the GUIDE-HF (Hemodynamic-GUIDEd management of Heart Failure) randomized trial.<br /><b>Methods</b><br />The GUIDE-HF randomized arm included 1,000 NYHA functional class II-IV patients (with HF hospitalization within the prior 12 months or elevated natriuretic peptides adjusted for EF and body mass index) implanted with a pulmonary artery pressure sensor, randomized 1:1 to a hemodynamically-guided management group (treatment) or a control group (control). The primary endpoint was the composite of HF hospitalizations, urgent HF visits, and all-cause mortality at 12 months. The authors assessed outcomes by EF in guideline-defined subgroups ≤40%, 41%-49%, and ≥50%, within the trial specified pre-COVID-19 period cohort.<br /><b>Results</b><br />There were 177 primary events (0.553/patient-year) in the treatment group and 224 events (0.682/patient-year) in the control group (HR: 0.81 [95% CI: 0.66-1.00]; P = 0.049); HF hospitalization was lower in the treatment vs control group (HR: 0.72 [95% CI: 0.57-0.92]; P = 0.0072). Within each EF subgroup, primary endpoint and HF hospitalization rates were lower in the treatment group (HR <1.0 across the EF spectrum). Event rate reduction by EF in the treatment groups was correlated with reduction in pulmonary artery pressures and medication changes.<br /><b>Conclusions</b><br />Hemodynamically-guided HF management decreases HF-related endpoints across the EF spectrum in an expanded patient population of patients with HF. (Hemodynamic-GUIDEd Management of Heart Failure [GUIDE-HF]; NCT03387813).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Dec 2022; 10:931-944</small></div>

<div><h4>Prediction of Survival After Implantation of a Fully Magnetically Levitated Left Ventricular Assist Device.</h4><i>Mehra MR, Nayak A, Morris AA, Lanfear DE, ... Chuang J, Estep JD</i><br /><b>Background</b><br />Clinical trials inform on average efficacy, but individualized risk assessments for outcome prediction are important in guiding treatment implementation.<br /><b>Objectives</b><br />The authors developed and validated a patient-specific risk score to predict survival at 1 and 2 years after HeartMate 3 (HM3) left ventricular assist device (LVAD) implantation.<br /><b>Methods</b><br />The MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial includes 2,200 HM3 LVAD patients in the pivotal trial and Continued Access Protocol study (2014-2018). The authors randomly assigned all patients to a derivation cohort (n = 1,540) or validation cohort (n = 660). Univariate mortality predictors were screened for potential model inclusion, stepwise selection was used to build the multivariable Cox proportional hazards regression model, and performance (discrimination and calibration) was evaluated.<br /><b>Results</b><br />Age, prior cardiac surgery (coronary artery bypass grafting [CABG] or valve procedure), lower serum sodium, higher blood urea nitrogen (BUN), small left ventricular size, and right atrial pressure-to-pulmonary capillary wedge pressure (RAP/PCWP) ratio >0.6 were significant risk factors for mortality. Receiver-operating characteristic (ROC) analysis in the validation cohort demonstrated an area under the curve (AUC) of 0.76 (95% CI: 0.70-0.81) at 1 year and 0.71 (95% CI: 0.66-0.77) at 2 years. Calibration between predicted and observed survival of the risk quintiles was high, with Pearson correlation coefficients of 0.986 and 0.994 at 1 and 2 years, respectively. Patients were successfully stratified into tertiles with higher-than-average, average, and lower-than-average survival, and observed mortality risk increased by 2-fold from one tertile to the next.<br /><b>Conclusions</b><br />A practical, easy-to-use HM3 Survival Risk Score with 6 components was developed to accurately predict 1- and 2-year survival after HM3 LVAD implantation. The survival risk score can be used to provide individual survival estimates to facilitate shared decision making when considering HM3 LVAD therapy. (MOMENTUM 3 Trial Portfolio; NCT02224755, NCT02892955).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Dec 2022; 10:948-959</small></div>

<div><h4>Safety of Right and Left Ventricular Endomyocardial Biopsy in Heart Transplantation and Cardiomyopathy Patients.</h4><i>Bermpeis K, Esposito G, Gallinoro E, Paolisso P, ... Bartunek J, Vanderheyden M</i><br /><b>Background</b><br />Endomyocardial biopsy (EMB) facilitates a histopathologic diagnosis with unique prognostic and therapeutic implications in both native and donor hearts. It is a relatively safe procedure, with an overall complication rate ranging from <1% to 6% depending on the experience of the operator, the clinical status of the patient, the presence or absence of left bundle branch block, the access site, and the site of procurement (right ventricular [RV] vs left ventricular [LV] approach).<br /><b>Objectives</b><br />This study aimed to assess the incidence of procedure-related complications in a real-world population. EMBs were performed either for surveillance of rejection episodes after heart transplantation or for diagnosis of etiology of cardiomyopathy.<br /><b>Methods</b><br />The authors retrospectively analyzed 1,368 biopsies obtained in 561 consecutive patients between May 2011 and May 2021. Patients were stratified according to the underlying heart disease, sex, age, access site, body mass index, and RV vs LV approach.<br /><b>Results</b><br />The analysis revealed an overall complication rate of 4.1%. Serious life-threatening cardiac complications occurred in <1% of EMBs, with tamponade necessitating pericardiocentesis in 0.2% and urgent cardiac surgery in 0.1% of the procedures. Minor complications occurred in 3.3% of the overall population and were more often encountered during LV EMBs (3.9%) and when the native heart was sampled (5.3%).<br /><b>Conclusions</b><br />In experienced hands, LV and RV EMB for heart transplantation rejection surveillance and cardiomyopathy diagnosis is a safe procedure with low risk of complications. Older, female patients and those undergoing native heart EMB were more prone to complications following EMB.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Dec 2022; 10:963-973</small></div>

<div><h4>Age Differences in Effects of Sacubitril/Valsartan on Cardiac Remodeling, Biomarkers, and Health Status.</h4><i>Murphy SP, Ward JH, Piña IL, Felker GM, ... Solomon SD, Januzzi JL</i><br /><b>Background</b><br />Sacubitril/valsartan (Sac/Val) improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF).<br /><b>Objectives</b><br />In this study, the authors sought to explore age differences in effects of Sac/Val on biomarkers, Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores and cardiac remodeling.<br /><b>Methods</b><br />After initiation and titration of Sac/Val, concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-cTnT), and soluble suppressor of tumorigenicity 2 (sST2) were measured and KCCQ-23 scores obtained from baseline to 12 months. Left ventricular ejection fraction (LVEF), and indexed left ventricular end-systolic (LVESVi) and indexed left ventricular end-diastolic (LVEDVi) and left atrial volume index (LAVi) volumes were measured with the use of echocardiography. Safety end points were assessed. Age-stratified analysis was performed for groups aged <65, 65-74, and ≥75 years.<br /><b>Results</b><br />Among 794 participants with HFrEF (mean age 65.1 years, 28.5% women), compared with patients aged <65 years (n = 369), 65-74 years (n = 237), and those aged ≥75 years (n = 188), had similar reductions in hs-cTnT and sST2, but less NT-proBNP reduction (-45.6% vs -40.2% vs -30.5%, respectively; P = 0.02). Gains in KCCQ-23 were smaller (+11.8 vs +11.4 vs +6.0 points; P = 0.03) in patients aged ≥75 years, although similar proportions of each age group achieved ≥10-point and ≥20-point increases in KCCQ-23 by month 12. Improvements in LVEF, LVEDVi, LVESVi, and LAVi were similar among age groups. Incidence of safety end points was also similar.<br /><b>Conclusions</b><br />Sac/Val resulted in significant improvements in prognostic biomarkers and measures of cardiac remodeling and health status from baseline to month 12 across age categories. Older study participants showed somewhat blunted reduction in NT-proBNP and less improvement in KCCQ-23 overall summary scores. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling, and Outcomes [PROVE-HF]; NCT02887183).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Dec 2022; 10:976-988</small></div>

<div><h4>Temporal Characteristics of Device-Based Individual and Integrated Risk Metrics in Patients With Chronic Heart Failure.</h4><i>Zile MR, Kahwash R, Sarkar S, Koehler J, Butler J</i><br /><b>Background</b><br />Temporal characteristics of a multimetric risk score and its individual parameters before, during, and after a heart failure (HF) event have not been defined.<br /><b>Objectives</b><br />A large real-world patient cohort with implantable cardioverter-defibrillators and cardiac resynchronization therapy (CRT) defibrillators was used to define these temporal characteristics.<br /><b>Methods</b><br />Deidentified health records were linked to manufacturer\'s device database in 17,886 patients. Multimetric risk score combined daily measures of impedance, heart rate, activity, heart rate variability, and atrial fibrillation (AF) burden, AF ventricular rate, CRT pacing, and ventricular tachycardia episodes and shocks. HF event was defined as an inpatient, emergency department, or observation unit stay with primary diagnosis of HF and intravenous diuretic agents administration. Changes in risk parameters during 60 days before, during, and after an HF event were compared in patients with no HF readmissions vs patients with HF readmission.<br /><b>Results</b><br />A total of 1,174 patients had HF events with no HF readmission, and 282 patients had HF events with HF readmission. Diagnostic risk score was higher on all 60 days before and after a HF event in patients with HF readmission compared with patients with no readmission (P < 0.001). Change in risk score from admission to discharge was similar in patients with and without HF readmission, but the risk score fell more significantly 7 after discharge and 30 days after admission in patients without HF readmission (P < 0.001).<br /><b>Conclusions</b><br />Temporal characteristics of risk metrics were significantly different in patients with no HF readmissions vs patients with HF readmission; patients without HF recurrence had larger recovery of risk metrics values toward normal.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 30 Nov 2022; epub ahead of print</small></div>

<div><h4>Structural and Functional Brain Changes in Acute Takotsubo Syndrome.</h4><i>Khan H, Gamble DT, Rudd A, Mezincescu AM, ... Waiter GD, Dawson DK</i><br /><b>Background</b><br />Takotsubo syndrome mimics an acute myocardial infarction, typically in the aftermath of mental or physical stress.<br /><b>Objectives</b><br />The mechanism by which emotional processing in the context of stress leads to significant cardiac injury is poorly understood, so a full exploration of brain structure and function in takotsubo syndrome patients merits investigation.<br /><b>Methods</b><br />Twenty-five acute (<5 days) takotsubo patients and 25 control subjects were recruited into this observational cross-sectional study. Surface-based morphometry was carried out on magnetic resonance imaging (MRI) brain scans to extract cortical morphology based on volume, thickness, and surface area with the use of Freesurfer. Cortical morphology general linear models were corrected for age, sex, photoperiod, and total brain volume. Resting-state functional MRI and diffusion tensor tractography images were preprocessed and analyzed with the use of the Functional Magnetic Resonance Imaging of the Brain Diffusion Toolbox and Functional Connectivity Toolbox.<br /><b>Results</b><br />There was significantly smaller total white matter and subcortical gray matter volumes in takotsubo (P < 0.001), with smaller total brain surface area but increased total cortical thickness (both P < 0.001). Individual gray matter regions (hippocampus and others) were significantly smaller in takotsubo (P < 0.001); only thalamus and insula were larger (P < 0.001). There was significant hyperfunctional and hypofunctional connectivity in multiple areas, including thalamus-amygdala-insula and basal ganglia (P < 0.05). All structural tractography connections were increased in takotsubo (P < 0.05).<br /><b>Conclusions</b><br />The authors showed smaller gray and white matter volumes driven by smaller cortical surface area, but increased cortical thickness and structural tractography connections with bidirectional changes in functional connectivity linked to emotion, language, reasoning, perception, and autonomic control. These are interventional targets in takotsubo patients\' rehabilitation.<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 30 Nov 2022; epub ahead of print</small></div>

<div><h4>Plasma Amyloid-β in Relation to Cardiac Function and Risk of Heart Failure in General Population.</h4><i>Zhu F, Wolters FJ, Yaqub A, Leening MJG, ... Ikram MA, Kavousi M</i><br /><b>Background</b><br />Amyloid-β (Aβ) may be related to cardiac function. However, there are limited data on the association of plasma Aβ with cardiac function and risk of heart failure (HF) in the general population.<br /><b>Objectives</b><br />This study sought to determine the associations of plasma amyloid-β40 (Aβ40) and amyloid-β42 (Aβ42) with echocardiographic measurements of cardiac dysfunction and with incident HF in the general population.<br /><b>Methods</b><br />The study included 4,156 participants of the population-based Rotterdam Study (mean age: 71.4 years; 57.1% women), who had plasma Aβ samples collected between 2002 and 2005 and had no established dementia and HF at baseline. Multivariable linear regression models were used to explore the cross-sectional association of plasma Aβ with echocardiographic measures. Participants were followed up until December 2016. Cox proportional hazards models were used to assess the association of Aβ levels with incident HF. Models were adjusted for cardiovascular risk factors.<br /><b>Results</b><br />A per 1-SD increase in log-transformed plasma Aβ40 was associated with a 0.39% (95% CI: -0.68 to -0.10) lower left ventricular ejection fraction and a 0.70 g/m<sup>2</sup> (95% CI: 0.06-1.34) larger left ventricular mass indexed by body surface area. Aβ42 was not significantly associated with echocardiographic measures cross-sectionally. During follow-up (median: 10.2 years), 472 incident HF cases were identified. A per 1-SD increase in log-transformed Aβ40 was associated with a 32% greater risk of HF (HR: 1.32; 95% CI: 1.15-1.51), and the association was significant in men, but not in women. Higher plasma Aβ42 levels were associated with an increased risk of HF (HR: 1.12; 95% CI: 1.02-1.24), although the association was attenuated after further adjustment for concomitant Aβ40 (HR: 1.03; 95% CI: 0.92-1.16).<br /><b>Conclusions</b><br />Higher levels of Aβ40 were associated with worse cardiac function and higher risk of new onset HF in the general population, in particular among men.<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 09 Nov 2022; epub ahead of print</small></div>

<div><h4>Potential Interactions When Prescribing SGLT2 Inhibitors and Intravenous Iron in Combination in Heart Failure.</h4><i>Packer M</i><br /><AbstractText>In patients with heart failure, sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to decrease hepcidin and ferritin and increase transferrin receptor protein, changes that are typically indicative of worsening absolute iron deficiency, as would be seen with poor dietary intake or gastrointestinal bleeding, neither of which is provoked by SGLT2 inhibitors. Therefore, 2 alternative conceptual frameworks may explain the observed pattern of changes in iron homeostasis proteins. According to the \"cytosolic iron depletion hypothesis,\" the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor is related to a decline in cytosolic Fe<sup>2+</sup> that occurs after drug-induced erythropoietin-related increase in iron use. Erythropoietin-mimetics (eg, darbepoietin) elicit this type of iron-deficiency pattern of response, and it is typically accompanied by erythropoietin resistance that is alleviated by intravenous iron supplementation. In contrast, according to the \"cytosolic iron repletion hypothesis,\" the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor represents a direct action of these drugs: 1) to reverse inflammation-related increases in hepcidin and ferritin, and, thus, alleviate functional blocks on iron utilization; and 2) to increase in sirtuin-1 signaling, which suppresses hepcidin, accelerates the degradation of ferritin, and up-regulates transferrin receptor protein. Through either or both mechanisms, direct suppression of hepcidin and ferritin would be expected to increase cytosolic Fe<sup>2+</sup>, thus allowing an unattenuated erythrocytic response to erythropoietin without the need for intravenous iron supplementation. The totality of clinical evidence supports the \"cytosolic iron repletion hypothesis\" because SGLT2 inhibitors elicit a full and sustained erythrocytosis in response to erythropoietin, even in overtly iron-deficient patients and in the absence of intravenous iron therapy. Therefore, the emergence of an iron-deficiency pattern of response during SGLT2 inhibition does not reflect worsening iron stores that are in need of replenishment, but instead, represents potential alleviation of a state of inflammation-related functional iron deficiency that is commonly seen in patients with chronic heart failure. Treatment with intravenous iron may be unnecessary and theoretically deleterious.</AbstractText><br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 05 Nov 2022; epub ahead of print</small></div>

<div><h4>Retinal Microvasculature: A Potential Window Into Heart Failure Prevention.</h4><i>Chaikijurajai T, Ehlers JP, Tang WHW</i><br /><AbstractText>Endothelial dysfunction and microvascular disease have been shown to play an important role in the development and progression of heart failure (HF). Retinal imaging provides a unique opportunity to noninvasively assess vascular structure and function, vessel features, and microcirculation within the retina. Accumulating evidence suggests that retinal vessel caliber, microvascular features, and vascular characteristics extracted from various imaging modalities are associated with alterations in left ventricular structure and function in stage B HF, as well as incident development of symptomatic HF in the general population. Moreover, dynamic retinal vessel analysis has been shown to differentiate HF patients based on their phenotypes. Given the increasing availability of rapid image acquisition devices (eg, nonmydriatic widefield systems and smartphone-based retinal cameras) and the integration of artificial intelligence-based interrogation/assessment techniques, retinal imaging is a promising noninvasive tool, in conjunction with cardiac imaging and biomarkers, to prevent HF and risk stratify those at risk of developing HF. This review focuses on the current evidence on retinal microvasculature changes, and potential clinical relevance and promising utility of retinal imaging in HF.</AbstractText><br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:785-791</small></div>

<div><h4>Family Screening in Dilated Cardiomyopathy: Prevalence, Incidence, and Potential for Limiting Follow-Up.</h4><i>Vissing CR, Espersen K, Mills HL, Bartels ED, ... Christensen AH, Bundgaard H</i><br /><b>Background</b><br />According to patterns of inheritance and incomplete penetrance, fewer than half of relatives to dilated cardiomyopathy probands will develop disease.<br /><b>Objectives</b><br />The purpose of this study was to investigate the prevalence and incidence, and to identify predictors of developing familial dilated cardiomyopathy (FDC) in relatives participating in family screening.<br /><b>Methods</b><br />The study was a retrospective, longitudinal cohort study of families screened and followed from 2006 to 2020 at a regional assembly of clinics for inherited cardiomyopathies.<br /><b>Results</b><br />In total, 211 families (563 relatives, 50% women) were included. At baseline, 124 relatives (22%) were diagnosed with FDC. Genetic sequencing identified the etiology in 37% of screened families and classified 101 (18%) relatives as unaffected carriers (n = 43) or noncarriers (ie, not at risk of FDC [n = 58]). The combined clinical and genetic baseline yield was 30%. During follow-up (2,313 person-years, median 5.0 years), 45 developed FDC (incidence rate of 2.0% per person-year; 95% CI: 1.4%-2.8%), increasing the overall yield to 34%. The incidence rate of FDC was high in relatives with baseline abnormalities on electrocardiogram or echocardiography compared with relatives with normal findings (4.7% vs 0.4% per person-year; HR: 12.9; P < 0.001). In total, baseline screening identified 326 (58%) relatives to be at low risk of FDC.<br /><b>Conclusions</b><br />Family screening identified a genetic predisposition to or overt FDC in 1 of 3 relatives at baseline. Genetic and clinical screening was normal in more than half of relatives, and these relatives had a low risk of developing FDC during follow-up. Thus, baseline screening identified a large proportion, in whom follow-up may safely be reduced, allowing focused follow-up of relatives at risk.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:792-803</small></div>

<div><h4>Trends in Ischemic Evaluation in New-Onset Heart Failure Without Known Coronary Artery Disease.</h4><i>Andersson C, Schou M, Boden WE, Schwartz B, ... Gislason GH, Torp-Pedersen C</i><br /><b>Background</b><br />Guidelines recommend consideration of an ischemic evaluation (Class IIa-IIb) in new-onset heart failure (HF), but it is not well-known how often this is performed and leads to revascularization.<br /><b>Objectives</b><br />The authors investigated temporal trends in ischemic evaluation and revascularization within 90 days of HF onset in Denmark 2008-2018.<br /><b>Methods</b><br />From the Danish nationwide administrative registries, diagnostic tests and revascularizations within 90 days were identified among patients with new-onset HF between 2008 and 2018, alive 90 days after diagnosis.<br /><b>Results</b><br />Of 61,475 patients (mean age: 72.6 ± 13.8 years, 46% women), 12,503 (20%) underwent an ischemic evaluation, of whom 10,547 (84%) underwent invasive coronary angiography, and 1,956 (16%) underwent an initial noninvasive test, most frequently coronary computed tomographic angiography (n = 1,813, 93%). Of those who were initially referred for coronary computed tomographic angiography, 374 (21%) had a subsequent invasive coronary angiogram undertaken. Among individuals undergoing ischemic testing, percutaneous coronary intervention and coronary artery bypass graft surgery were performed in 1,354 (11%) and 619 (5%), respectively, corresponding to 2.2% and 1.0% of the entire sample. Between 2008 and 2018, the number of patients referred for ischemic evaluations increased, adjusted OR for 1.07 (95% CI: 1.06-1.07) per year high, and was greater among older versus younger individuals (OR: 1.01 [95% CI: 0.99-1.03], OR: 1.04 [95% CI: 1.03-1.06], OR: 1.06 [95% CI: 1.05-1.07], OR: 1.11 [95% CI: 1.09-1.12], and OR: 1.14 [95% CI: 1.10-1.18] per year increase for age group <50, 51-60, 61-75, 76-85, and >85 years, respectively, P for interaction <0.0001).<br /><b>Conclusions</b><br />In clinical practice, few patients with new-onset HF are referred for an ischemic evaluation and a minority undergo revascularization. Studies are needed to establish the appropriateness of this practice.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:807-815</small></div>

<div><h4>Risks of Depression and Suicide After Diagnosis With Heart Failure: A National Cohort Study.</h4><i>Crump C, Sundquist J, Kendler KS, Sieh W, Edwards AC, Sundquist K</i><br /><b>Background</b><br />Heart failure (HF) has been associated with psychosocial distress, but other long-term mental health sequelae are unclear.<br /><b>Objectives</b><br />In this study, the authors sought to determine risks of major depression and suicide, susceptible time periods, and sex-specific differences after HF diagnosis in a large population-based cohort.<br /><b>Methods</b><br />A national cohort study was conducted of all 154,572 persons diagnosed with HF at ages 18-75 years during 2002-2017 in Sweden and 1,545,720 age- and sex-matched population-based control subjects who were followed up for major depression and suicide ascertained from nationwide inpatient, outpatient, and death records through 2018. Poisson regression was used to compute incidence rate ratios (IRRs) while adjusting for sociodemographic factors and comorbidities.<br /><b>Results</b><br />HF was associated with increased risks of major depression and death by suicide in both men and women, with highest risks in the first 3 months, then declining to modest risks at ≥12 months after HF diagnosis. Within 3 months after HF diagnosis, adjusted IRRs for new-onset major depression were 3.34 (95% CI: 3.04-3.68) in men and 2.78 (95% CI: 2.51-3.09) in women, and for suicide death were 4.47 (95% CI: 2.62-7.62) in men and 2.82 (95% CI: 1.11-7.12) in women. These risks were elevated regardless of age at HF diagnosis. HF was associated with significantly more depression cases in women (P < 0.001).<br /><b>Conclusions</b><br />In this large national cohort, HF was associated with substantially increased risks of depression and suicide in men and women, with highest risks occurring within 3 months after HF diagnosis. Men and women with HF need timely detection and treatment of depression and suicidality.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:819-827</small></div>

<div><h4>Posterior Wall Thickness Associates With Survival Following Septal Myectomy for Obstructive Hypertrophic Cardiomyopathy.</h4><i>Sun D, Schaff HV, Nishimura RA, Geske JB, ... Ducharme MT, Ommen SR</i><br /><b>Background</b><br />The left ventricular (LV) posterior wall thickness (PWT) is a predictor of sudden cardiac death in pediatric patients with hypertrophic cardiomyopathy (HCM), but the prognostic importance of PWT in adults has not been examined.<br /><b>Objectives</b><br />The goal of this study was to evaluate the association of LV PWT with late survival in adult patients undergoing septal myectomy for obstructive HCM.<br /><b>Methods</b><br />This single-center study reviewed 2,418 patients who underwent transaortic septal myectomy for obstructive HCM.<br /><b>Results</b><br />The median preoperative PWT was 13 (IQR: 11-15) mm. Patients with PWT >13 mm tended to have systemic hypertension (55.4% vs 49.1%; P = 0.002) and a larger body mass index (median: 30.8 [IQR: 27.1-35.1] kg/m<sup>2</sup> vs 29.6 [IQR: 26.1-33.9] kg/m<sup>2</sup>; P < 0.001). Preoperatively, PWT >13 mm was associated with increased septal thickness (median: 21 [IQR: 18-24] mm vs 19 [IQR: 17-22] mm; P < 0.001), greater maximum instantaneous left ventricular outflow tract (LVOT) gradient at rest (median: 67 [IQR: 36-96] mm Hg vs 47 [IQR: 19-79] mm Hg), and increased likelihood of moderate or greater mitral valve regurgitation (54.3% vs 47.3%; P = 0.001). However, PWT was not related to the severity of limitations measured by New York Heart Association functional class (P = 0.674). After adjusting for baseline covariates, greater PWT was an independent risk factor for late mortality after septal myectomy (P = 0.003).<br /><b>Conclusions</b><br />PWT is a newly identified predictor of reduced long-term survival after septal myectomy that is independent of septal thickness and severity of LVOT gradient. Future studies are warranted to investigate the mechanisms underlying the association and the potential usefulness of PWT in patient management.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:831-837</small></div>

<div><h4>Steroidal MRA Across the Spectrum of Renal Function: A Pooled Analysis of RCTs.</h4><i>Ferreira JP, Pitt B, McMurray JJV, Pocock SJ, ... Zannad F, Rossignol P</i><br /><b>Background</b><br />Mineralocorticoid receptor antagonists (MRAs) are underused in patients with kidney dysfunction, and their efficacy among patients with chronic kidney disease (CKD) is uncertain.<br /><b>Objectives</b><br />The goal of this study was to analyze the efficacy and safety of steroidal MRAs across the spectrum of estimated glomerular filtration rates (eGFRs) in randomized controlled trials. The study included patients with heart failure (HF) or myocardial infarction and advanced CKD who participated in the RALES (Randomized Aldactone Evaluation Study), EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) in the Americas, and EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study) trials.<br /><b>Methods</b><br />This study used individual patient data meta-analysis using Cox models stratified by trial with treatment-by-eGFR interaction terms. eGFR was recalculated by using the Chronic Kidney Disease Epidemiology Collaboration creatinine formula.<br /><b>Results</b><br />A total of 12,700 patients were included, of whom 331 (2.6%) had an eGFR ≤30 mL/min/1.73 m<sup>2</sup> (mean eGFR: 26.8 ± 3.2 mL/min/1.73 m<sup>2</sup>). Patients with advanced CKD had higher annualized event rates for all studied outcomes: placebo event rate for the composite of cardiovascular death or HF hospitalization was ∼3-fold higher in patients with eGFR ≤30 compared with those with eGFR >90 mL/min/1.73 m<sup>2</sup>: 41.6 vs 14.6 events per 100 person-years. MRAs (vs placebo) reduced the composite of cardiovascular death or HF hospitalization, but the effect was attenuated as eGFR decreased: the corresponding HRs by eGFR categories were: HR for >90 mL/min/1.73 m<sup>2</sup>: 0.62 (95% CI: 0.49-0.78); HR for 61-90 mL/min/1.73 m<sup>2</sup>: 0.69 (95% CI: 0.61-0.77); HR for 46-60 mL/min/1.73 m<sup>2</sup>: 0.84 (95% CI: 0.74-0.95); HR for 31-45 mL/min/1.73 m<sup>2</sup>: 0.79 (95% CI: 0.68-0.91); and HR for ≤30 mL/min/1.73 m<sup>2</sup>: 0.96 (95% CI: 0.70-1.32) (treatment-by-eGFR interaction P for trend = 0.033). Investigator-reported hyperkalemia and worsening renal function were more frequent (2- to 3-fold) among MRA users, and hyperkalemia was more frequent as eGFR decreased (treatment-by-eGFR interaction P for trend = 0.002).<br /><b>Conclusions</b><br />Steroidal MRAs reduced HF hospitalizations and mortality across a wide range of eGFR. However, declining benefit and worsening safety may limit their use in patients with lower eGFR, particularly those with levels ≤30 mL/min/1.73 m<sup>2</sup>.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:842-850</small></div>

<div><h4>Trends in Heart Failure-Related Mortality Among Older Adults in the United States From 1999-2019.</h4><i>Siddiqi TJ, Khan Minhas AM, Greene SJ, Van Spall HGC, ... Butler J, Khan MS</i><br /><b>Background</b><br />The U.S. population is aging with concurrent increases in heart failure (HF) burden. However, HF-related mortality trends among adults ≥75 years have not been investigated.<br /><b>Objectives</b><br />The purpose of this study was to assess the trends and regional differences in HF-related mortality among older adults in the United States.<br /><b>Methods</b><br />Death certificates from the CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging OnLine Data for Epidemiologic Research) database were examined from 1999 to 2019 for HF-related mortality in adults ≥75 years of age. Age-adjusted mortality rates (AAMRs) per 10,000 persons and annual percent change (APC) were calculated and stratified by year, sex, race/ethnicity, and geographic region.<br /><b>Results</b><br />Between 1999 and 2019, 5,014,919 HF-related deaths occurred among adults ≥75 years. The AAMR declined from 141.0 in 1999 to 108.3 in 2012 (APC: -2.1; 95% CI: -2.4 to -1.9), after which it increased to 121.3 in 2019 (APC: 1.7; 95% CI: 1.2-2.2). Men had consistently higher AAMR than women from 1999 (AAMR men: 158.3 vs women: 131.0) to 2019 (AAMR men: 141.1 vs women: 107.8). Non-Hispanic (NH) White adults had the highest overall AAMR (127.2), followed by NH Black (108.7), NH American Indian/Alaska Native (102.0), Hispanic or Latino (78.0), and NH Asian or Pacific Islander adults (57.1) AAMR also varied substantially by region (overall AAMR: Midwest 133.9; South: 119.2; West: 116.3; Northeast: 113.5), and nonmetropolitan areas had higher HF-related AAMR (147.0) than metropolitan areas (115.2). States in the top 90th percentile of HF-related AAMR were Mississippi, Oklahoma, West Virginia, Oregon, and Indiana, which had approximately double the AAMRs compared with states that fell into the lower 10th percentile.<br /><b>Conclusions</b><br />Following a period of steady decline, HF-related mortality in U.S. adults ≥75 years has increased since 2012. The highest AAMRs were observed among White adults and men, and among patients living in the Midwestern and nonmetropolitan United States. Targeted strategies are needed to prevent and treat HF among older adults to curb increasing levels of HF-related mortality.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:851-859</small></div>

<div><h4>Finerenone and Heart Failure Outcomes by Kidney Function/Albuminuria in Chronic Kidney Disease and Diabetes.</h4><i>Filippatos G, Anker SD, Pitt B, Rossing P, ... Ruilope LM, Agarwal R</i><br /><b>Background</b><br />In patients with type 2 diabetes (T2D), risks of cardiovascular mortality and heart failure (HF) increase with decreasing kidney function (estimated glomerular filtration rate [eGFR]) and increasing albuminuria (urine albumin-to-creatinine ratio [UACR]). Finerenone, a selective, nonsteroidal mineralocorticoid receptor antagonist, improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and T2D in FIDELITY (Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial Programme Analysis).<br /><b>Objectives</b><br />This study sought to evaluate the effects of finerenone on HF outcomes by eGFR and/or UACR categories.<br /><b>Methods</b><br />FIDELITY included 13,026 patients with T2D and CKD (UACR 30-5,000 mg/g and eGFR ≥25 mL/min/1.73 m<sup>2</sup>) randomized to finerenone or placebo. Time-to-event outcomes were first hospitalization for heart failure (HHF), cardiovascular death or first HHF, recurrent HHF, and cardiovascular death or recurrent HHF, analyzed in subgroups by baseline eGFR (<60 and ≥60 mL/min/1.73 m<sup>2</sup>) and/or UACR (<300 and ≥300 mg/g).<br /><b>Results</b><br />Compared with placebo, finerenone significantly reduced risk of first HHF (HR: 0.78 [95% CI: 0.66-0.92]; P = 0.003), cardiovascular death or first HHF (HR: 0.83 [95% CI: 0.74-0.93]; P = 0.002), recurrent HHF (HR: 0.79 [95% CI: 0.64-0.96]; P = 0.021), and cardiovascular death or recurrent HHF (HR: 0.82 [95% CI: 0.72-0.95]; P = 0.006). The risk of outcomes increased across baseline eGFR and UACR categories; lowest incidences were seen in patients with an eGFR ≥60 mL/min/1.73 m<sup>2</sup> and a UACR <300 mg/g. Finerenone improved HF outcomes irrespective of baseline eGFR and/or UACR categories (all P interaction values >0.10).<br /><b>Conclusions</b><br />Compared with placebo, finerenone improved HF-related outcomes in patients with CKD and T2D, with consistent benefits across eGFR and/or UACR categories. (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD], NCT02540993; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Chronic Kidney Disease [FIGARO-DKD], NCT02545049).<br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 01 Nov 2022; 10:860-870</small></div>

<div><h4>Treatment Differences in Medical Therapy for Heart Failure With Reduced Ejection Fraction Between Sociodemographic Groups.</h4><i>Witting C, Zheng J, Tisdale RL, Shannon E, ... Heidenreich P, Sandhu A</i><br /><b>Background</b><br />There are sociodemographic disparities in outcomes of heart failure with reduced ejection fraction (HFrEF), but disparities in guideline-directed medical therapy (GDMT) remain poorly characterized.<br /><b>Objectives</b><br />This study aimed to analyze GDMT treatment rates in eligible patients with recently diagnosed HFrEF, and to determine how rates vary by sociodemographic characteristics.<br /><b>Methods</b><br />This retrospective cohort study included patients diagnosed with HFrEF at Veterans Affairs (VA) hospitals from 2013 to 2019. The authors analyzed GDMT treatment rates and doses, excluding patients with contraindications. Therapies of interest were evidence-based beta-blockers (BBs), renin-angiotensin system inhibitors (RASIs), angiotensin receptor-neprilysin inhibitors (ARNIs), and mineralocorticoid antagonists (MRAs). The authors compared adjusted treatment rates by race and ethnicity, neighborhood social vulnerability, rurality, distance to medical care, and sex.<br /><b>Results</b><br />The cohort comprised 126,670 VA patients with recently diagnosed HFrEF. The study found that racial and ethnic minorities had similar or higher treatment rates than White patients. Patients residing in socially vulnerable neighborhoods had 3.4% lower ARNI (95% CI: 1.9%-5.0%) treatment rates. Patients residing farther from specialty care had similar rates of GDMT therapy overall, but were less likely to be taking at least 50% of the target doses of either BBs (4.0% less likely; 95% CI: 3.1%-5.0%) or RASIs (5.0% less likely; 95% CI: 4.1%-6.0%) compared with those closer to care.<br /><b>Conclusions</b><br />Among VA patients with recently diagnosed HFrEF, the authors did not find that racial and ethnic minority patients were less likely to receive GDMT. However, appropriate dose up-titration may occur less frequently in more remote patients.<br /><br />Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 26 Oct 2022; epub ahead of print</small></div>

<div><h4>IGFBP-7 and Outcomes in Heart Failure With Reduced Ejection Fraction: Findings From DAPA-HF.</h4><i>Adamson C, Welsh P, Docherty KF, de Boer RA, ... McMurray JJV, Jhund PS</i><br /><b>Background</b><br />Insulin-like growth factor-binding protein-7 (IGFBP-7) has been proposed as a potential prognostic biomarker in heart failure (HF), but the association between elevation in IGFBP-7 and HF outcomes in ambulant patients with heart failure with reduced ejection fraction (HFrEF) is unknown.<br /><b>Objectives</b><br />The authors addressed this question in a post hoc analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial.<br /><b>Methods</b><br />The primary outcome was a composite of cardiovascular death or a worsening HF event. The risk of adverse outcome was compared across tertiles of IGFBP-7 concentration by means of Cox proportional hazard models adjusted for N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT). The efficacy of randomized treatment across IGFBP-7 tertiles was assessed. Change in IGFBP-7 at 12 months was compared with the use of geometric means.<br /><b>Results</b><br />A total of 3,158 patients had IGFBP-7 measured at baseline, and 2,493 had a repeated measure at 12 months. Patients in the highest tertile of IGFBP-7 had evidence of more advanced HFrEF. The adjusted HR for the primary endpoint in tertile 3, compared with tertile 1, was 1.48 (95% CI: 1.17-1.88). There was no modification of the benefit of dapagliflozin by baseline IGFBP-7 (P interaction = 0.34). Dapagliflozin did not change IGFBP-7 levels over 1 year (P = 0.34).<br /><b>Conclusions</b><br />Higher IGFBP-7 in patients with HFrEF was associated with worse clinical profile and an increased risk of adverse clinical outcomes. IGFBP-7 provided prognostic information incremental to clinical variables, NT-proBNP, and hsTnT. The benefit of dapagliflozin was not modulated by IGFBP-7 level. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 20 Oct 2022; epub ahead of print</small></div>

<div><h4>Clinical Presentation and In-Hospital Trajectory of Heart Failure Cardiogenic Shock.</h4><i>Hernandez-Montfort J, Kanwar M, Sinha SS, Garan AR, ... Burkhoff D, Kapur NK</i><br /><b>Background</b><br />HF-CS remains an understudied distinct clinical entity.<br /><b>Objectives</b><br />We sought to profile a large cohort of patients with heart failure related cardiogenic shock (HF-CS) focused on practical application of the SCAI staging system to define baseline and maximal shock severity, in-hospital management with AMCS support, and clinical outcomes.<br /><b>Methods</b><br />The Cardiogenic Shock Working Group (CSWG) registry includes patients with CS, regardless of etiology, from 17 clinical sites enrolled between 2016-2020. Patients with HF-CS (non-AMI) were analyzed and classified based on clinical presentation, outcomes at discharge and shock severity defined by SCAI stages.<br /><b>Results</b><br />A total of 1,767 patients with HF-CS were included, of which 349 (19.8%) had de novo HF-CS (DNHF-CS). Patients were more likely to present in SCAI Stage C or D and achieve maximum SCAI stage D. Patients with DNHF-CS were more likely to experience in-hospital death, in- and out of hospital cardiac arrest (IHCA or OHCA), and escalated more rapidly to a maximum achieved SCAI stage, compared to patients with acute on chronic HF-CS (ACHF-CS). IHCA was associated with greater in-hospital death regardless of clinical presentation (de novo: 63% vs 21%; ACHF 65% vs 17%; both p<0.001). Forty-five percent of HF-CS patients were exposed to at least one acute mechanical circulatory support (AMCS) device throughout hospitalization.<br /><b>Conclusions</b><br />In a large contemporary HF-CS cohort, we identified a greater incidence of in-hospital death, cardiac arrest, and more rapid escalation to maximum SCAI Stage severity among DNHF-CS. AMCS use in HF-CS was common with significant heterogeneity among device type.<br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 19 Oct 2022; epub ahead of print</small></div>

<div><h4>Acute Myocarditis Associated With Desmosomal Gene Variants.</h4><i>Ammirati E, Raimondi F, Piriou N, Sardo Infirri L, ... Camici PG, Cooper LT</i><br /><b>Background</b><br />The risk of adverse cardiovascular events in patients with acute myocarditis (AM) and desmosomal gene variants (DGV) remains unknown.<br /><b>Objectives</b><br />The purpose of this study was to ascertain the risk of death, ventricular arrhythmias, recurrent myocarditis, and heart failure (main endpoint) in patients with AM and pathogenic or likely pathogenetic DGV.<br /><b>Methods</b><br />In a retrospective international study from 23 hospitals, 97 patients were included: 36 with AM and DGV (DGV[+]), 25 with AM and negative gene testing (DGV[-]), and 36 with AM without genetics testing. All patients had troponin elevation plus findings consistent with AM on histology or at cardiac magnetic resonance (CMR). In 86 patients, CMR changes in function and structure were re-assessed at follow-up.<br /><b>Results</b><br />In the DGV(+) AM group (88.9% DSP variants), median age was 24 years, 91.7% presented with chest pain, and median left ventricular ejection fraction (LVEF) was 56% on CMR (P = NS vs the other 2 groups). Kaplan-Meier curves demonstrated a higher risk of the main endpoint in DGV(+) AM compared with DGV(-) and without genetics testing patients (62.3% vs 17.5% vs 5.3% at 5 years, respectively; P < 0.0001), driven by myocarditis recurrence and ventricular arrhythmias. At follow-up CMR, a higher number of late gadolinium enhanced segments was found in DGV(+) AM.<br /><b>Conclusions</b><br />Patients with AM and evidence of DGV have a higher incidence of adverse cardiovascular events compared with patients with AM without DGV. Further prospective studies are needed to ascertain if genetic testing might improve risk stratification of patients with AM who are considered at low risk.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Oct 2022; 10:714-727</small></div>

<div><h4>Periodontal Status, C-Reactive Protein, NT-proBNP, and Incident Heart Failure: The ARIC Study.</h4><i>Molinsky RL, Yuzefpolskaya M, Norby FL, Yu B, ... Colombo PC, Demmer RT</i><br /><b>Background</b><br />Periodontal disease (PD), resulting from inflammatory host response to dysbiotic subgingival microbiota, has been linked to cardiovascular disease; however, its relationship to heart failure (HF) and its subtypes (heart failure with reduced ejection fraction [HFrEF] and heart failure with preserved ejection fraction [HFpEF]) is unexplored.<br /><b>Objectives</b><br />The authors hypothesize that the presence of PD is associated with increased risk of incident HF, HFpEF, and HFrEF.<br /><b>Methods</b><br />A total of 6,707 participants (mean age 63 ± 6 years) of the ARIC (Atherosclerosis Risk In Communities) study with full-mouth periodontal examination at visit 4 (1996-1998) and longitudinal follow-up for any incident HF (visit 4 to 2018), or incident HFpEF and HFrEF (2005-2018) were included. Periodontal status was classified as follows: healthy, PD (as per Periodontal Profile Classification [PPC]), or edentulous. Multivariable-adjusted Cox proportional hazards models were used to calculate HRs and 95% CIs for the association between PPC levels and incident HF, HFpEF, or HFrEF. Additionally, biomarkers of inflammation (C-reactive protein [CRP]) and congestion (N-terminal brain natriuretic peptide [NT-proBNP]) were assessed.<br /><b>Results</b><br />In total, 1,178 incident HF cases occurred (350 HFpEF, 319 HFrEF, and 509 HF of unknown type) over a median of 13 years. Of these cases, 59% had PD, whereas 18% were edentulous. PD was associated with an increased risk for HFpEF (HR: 1.35 [95% CI: 0.98-1.86]) and significantly increased risk for HFrEF (HR: 1.69 [95% CI: 1.18-2.43]), as was edentulism: HFpEF (HR: 2.00 [95% CI: 1.37-2.93]), HFrEF (HR: 2.19 [95% CI: 1.43-3.36]). Edentulism was associated with unfavorable change in CRP and NT-proBNP, whereas PD was associated only with CRP.<br /><b>Conclusions</b><br />Periodontal status was associated with incident HF, HFpEF, and HFrEF, as well as unfavorable changes in CRP and NT-proBNP.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Oct 2022; 10:731-741</small></div>

<div><h4>Transvenous Right Greater Splanchnic Nerve Ablation in Heart Failure and Preserved Ejection Fraction: First-in-Human Study.</h4><i>Fudim M, Zirakashvili T, Shaburishvili N, Shaishmelashvili G, ... Shaburishvili T, Shah SJ</i><br /><b>Background</b><br />Ablation of the right-sided greater splanchnic nerve (GSN) can reduce excessive splanchnic vasoconstriction, potentially improving the handling of volume shifts in patients with heart failure with preserved ejection fraction (HFpEF).<br /><b>Objectives</b><br />The purpose of this study was to assess a novel catheter procedure of right-sided GSN ablation to treat HFpEF: splanchnic ablation for volume management.<br /><b>Methods</b><br />This trial included 11 HFpEF patients (8 women, age 70 ± 8 years) with New York Heart Association functional class II or III symptoms, ejection fraction ≥50%, and elevated pulmonary capillary wedge pressure at rest or with exercise. After splanchnic ablation for volume management, follow-up at 1, 3, 6, and 12 months included 6-minute walk test, Kansas City Cardiomyopathy Questionnaire (KCCQ), and echocardiography.<br /><b>Results</b><br />There were no device-related adverse cardiac events or clinical sequelae following right GSN ablation through 12 months. Patients experienced clinical improvements by 1 month that were sustained through 12 months. KCCQ score improved from baseline median 48 (IQR: 35-52) to 65 (IQR: 58-77) at 1 month and 80 (IQR: 77-88) at 12 months (P < 0.05). The 6-minute walk test distance increased from baseline 292 ± 82 m to 341 ± 88 m at 1 month and 359 ± 75 m at 12 months (P < 0.05). The NT-proBNP decreased from a baseline mean of 1,292 ± 1,186 pg/mL to 1,202 ± 797 pg/mL (P = 0.585) at 1 month, to 472 ± 226 pg/mL (P = 0.028) at 6 months, and to 379 ± 165 pg/mL (P = 0.039) at 12 months.<br /><b>Conclusions</b><br />In this open-label, single-arm feasibility study, right-sided GSN ablation was safe and improved mostly subjective clinical metrics in patients with HFpEF over 12 months. (Endovascular GSN Ablation in Subjects With HFpEF; NCT04287946).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Oct 2022; 10:744-752</small></div>

<div><h4>Bereavement and Prognosis in Heart Failure: A Swedish Cohort Study.</h4><i>Chen H, Wei D, Janszky I, Dahlström U, Rostila M, László KD</i><br /><b>Background</b><br />The role of stress in the prognosis of heart failure (HF) is unclear. This study investigated whether the death of a close family member, a severe source of stress, is associated with mortality in HF.<br /><b>Objectives</b><br />This study assessed whether the death of a close family member is associated with mortality in HF.<br /><b>Methods</b><br />Patients from the Swedish Heart Failure Registry during 2000-2018 and/or in the Swedish Patient Register with a primary diagnosis of HF during 1987-2018 (N = 490,527) were included in this study. Information was obtained on death of family members (children, partner, grandchildren, siblings, and parents), mortality, sociodemographic variables, and health-related factors from several population-based registers. The association between bereavement and mortality was analyzed by using Poisson regression.<br /><b>Results</b><br />Loss of a family member was associated with an increased risk of dying (adjusted relative risk: 1.29; 95% CI: 1.27-1.30). The association was present not only in case of the family member\'s cardiovascular deaths and other natural deaths but also in case of unnatural deaths. The risk was higher for 2 losses than for 1 loss and highest in the first week after the loss. The association between bereavement and an increased mortality risk was observed for the death of a child, spouse/partner, grandchild, and sibling but not of a parent.<br /><b>Conclusions</b><br />Death of a family member was associated with an increased risk of mortality among patients with HF. Further studies are needed to investigate whether less severe sources of stress can also contribute to poor prognosis in HF and to explore the mechanisms underlying this association.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Oct 2022; 10:753-764</small></div>

<div><h4>A Standardized and Regionalized Network of Care for Cardiogenic Shock.</h4><i>Tehrani BN, Sherwood MW, Rosner C, Truesdell AG, ... O\'Connor CM, Batchelor WB</i><br /><b>Background</b><br />The benefits of standardized care for cardiogenic shock (CS) across regional care networks are poorly understood.<br /><b>Objectives</b><br />The authors compared the management and outcomes of CS patients initially presenting to hub versus spoke hospitals within a regional care network.<br /><b>Methods</b><br />The authors stratified consecutive patients enrolled in their CS registry (January 2017 to December 2019) by presentation to a spoke versus the hub hospital. The primary endpoint was 30-day mortality. Secondary endpoints included bleeding, stroke, or major adverse cardiovascular and cerebrovascular events.<br /><b>Results</b><br />Of 520 CS patients, 286 (55%) initially presented to 34 spoke hospitals. No difference in mean age (62 years vs 61 years; P = 0.38), sex (25% vs 32% women; P = 0.10), and race (54% vs 52% white; P = 0.82) between spoke and hub patients was noted. Spoke patients more often presented with acute myocardial infarction (50% vs 32%; P < 0.01), received vasopressors (74% vs 66%; P = 0.04), and intra-aortic balloon pumps (88% vs 37%; P < 0.01). Hub patients were more often supported with percutaneous ventricular assist devices (44% vs 11%; P < 0.01) and veno-arterial extracorporeal membrane oxygenation (13% vs 0%; P < 0.01). Initial presentation to a spoke was not associated with increased risk-adjusted 30-day mortality (adjusted OR: 0.87 [95% CI: 0.49-1.55]; P = 0.64), bleeding (adjusted OR: 0.89 [95% CI: 0.49-1.62]; P = 0.70), stroke (adjusted OR: 0.74 [95% CI: 0.31-1.75]; P = 0.49), or major adverse cardiovascular and cerebrovascular events (adjusted OR 0.83 [95% CI: 0.50-1.35]; P = 0.44).<br /><b>Conclusions</b><br />Spoke and hub patients experienced similar short-term outcomes within a regionalized CS network. The optimal strategy to promote standardized care and improved outcomes across regional CS networks merits further investigation.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Oct 2022; 10:768-781</small></div>

<div><h4>Heart Failure Drug Treatment-Inertia, Titration, and Discontinuation: A Multinational Observational Study (EVOLUTION HF).</h4><i>Savarese G, Kishi T, Vardeny O, Adamsson Eryd S, ... Thuresson M, Bozkurt B</i><br /><b>Background</b><br />Guidelines recommend early initiation of multiple guideline-directed medical therapies (GDMTs) to reduce mortality/rehospitalization in patients with heart failure and reduced ejection fraction. Understanding GDMT use is critical to improving clinical practice.<br /><b>Objectives</b><br />This study sought to describe GDMT use in Japan, Sweden, and the United States in contemporary real-world settings.<br /><b>Methods</b><br />EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) is an observational cohort study using routine-care databases. Patients initiating any GDMT within 12 months of a hospitalization for heart failure (hHF) discharge were included. Dapagliflozin (the only sodium-glucose cotransporter-2 inhibitor approved at study onset), sacubitril/valsartan, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) were considered separately. Doses and discontinuation were assessed in the 12 months following initiation. Target dose was defined as ≥100% of the guideline-recommended dose.<br /><b>Results</b><br />Overall, 266,589 patients were included. Mean times from hHF to GDMT initiation were longer for novel GDMTs (dapagliflozin or sacubitril/valsartan) than for other GDMTs: 39 and 44 vs 12 to 13 days (Japan), 44 and 33 vs 22 to 31 days (Sweden), and 33 and 19 vs 18 to 24 days (United States). Pooled across countries, proportions of patients who discontinued therapy (not including switches from ACE inhibitor or ARB to sacubitril/valsartan) within 12 months were 23.5% (dapagliflozin), 26.4% (sacubitril/valsartan), 38.4% (ACE inhibitors), 33.4% (ARBs), 25.2% (beta-blockers), and 42.2% (MRAs). Corresponding target dose achievements were 75.7%, 28.2%, 20.1%, 6.7%, 7.2%, and 5.1%, respectively.<br /><b>Conclusions</b><br />Initiation of novel GDMTs is delayed compared with other GDMTs. Few patients received target doses of GDMTs requiring uptitration. Persistence was higher for dapagliflozin than other GDMTs.<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 07 Sep 2022; epub ahead of print</small></div>

<div><h4>Contemporary Applications of Machine Learning for Device Therapy in Heart Failure.</h4><i>Gautam N, Ghanta SN, Clausen A, Saluja P, ... Fudim M, Al\'Aref SJ</i><br /><AbstractText>Despite a better understanding of the underlying pathogenesis of heart failure (HF), pharmacotherapy, surgical, and percutaneous interventions do not prevent disease progression in all patients, and a significant proportion of patients end up requiring advanced therapies. Machine learning (ML) is gaining wider acceptance in cardiovascular medicine because of its ability to incorporate large, complex, and multidimensional data and to potentially facilitate the creation of predictive models not constrained by many of the limitations of traditional statistical approaches. With the coexistence of \"big data\" and novel advanced analytic techniques using ML, there is ever-increasing research into applying ML in the context of HF with the goal of improving patient outcomes. Through this review, the authors describe the basics of ML and summarize the existing published reports regarding contemporary applications of ML in device therapy for HF while highlighting the limitations to widespread implementation and its future promises.</AbstractText><br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Sep 2022; 10:603-622</small></div>

<div><h4>Pathophysiologic Processes and Novel Biomarkers Associated With Congestion in Heart Failure.</h4><i>Pandhi P, Ter Maaten JM, Anker SD, Ng LL, ... Voors AA, Sama IE</i><br /><b>Background</b><br />Congestion is the main driver behind symptoms of heart failure (HF), but pathophysiology related to congestion remains poorly understood.<br /><b>Objectives</b><br />Using pathway and differential expression analyses, the authors aim to identify biological processes and biomarkers associated with congestion in HF.<br /><b>Methods</b><br />A congestion score (sum of jugular venous pressure, orthopnea, and peripheral edema) was calculated in 1,245 BIOSTAT-CHF patients with acute or worsening HF. Patients with a score ranking in the bottom or top categories of congestion were deemed noncongested (n = 408) and severely congested (n = 142), respectively. Plasma concentrations of 363 unique proteins (Olink Proteomics Multiplex CVD-II, CVD-III, Immune Response and Oncology II panels) were compared between noncongested and severely congested patients. Results were validated in an independent validation cohort of 1,342 HF patients (436 noncongested and 232 severely congested).<br /><b>Results</b><br />Differential protein expression analysis showed 107/363 up-regulated and 6/363 down-regulated proteins in patients with congestion compared with those without. FGF-23, FGF-21, CA-125, soluble ST2, GDF-15, FABP4, IL-6, and BNP were the strongest up-regulated proteins (fold change [FC] >1.30, false discovery rate [FDR], P < 0.05). KITLG, EGF, and PON3 were the strongest down-regulated proteins (FC <-1.30, FDR P < 0.05). Pathways most prominently involved in congestion were related to inflammation, endothelial activation, and response to mechanical stimulus. The validation cohort yielded similar findings.<br /><b>Conclusions</b><br />Severe congestion in HF is mainly associated with inflammation, endothelial activation, and mechanical stress. Whether these pathways play a causal role in the onset or progression of congestion remains to be established. The identified biomarkers may become useful for diagnosing and monitoring congestion status.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Sep 2022; 10:623-632</small></div>

<div><h4>Electronic Health Record-Based Deep Learning Prediction of Death or Severe Decompensation in Heart Failure Patients.</h4><i>McGilvray MMO, Heaton J, Guo A, Masood MF, ... Pasque MK, Foraker R</i><br /><b>Background</b><br />Surgical mechanical ventricular assistance and cardiac replacement therapies, although life-saving in many heart failure (HF) patients, remain high-risk. Despite this, the difficulty in timely identification of medical therapy nonresponders and the dire consequences of nonresponse have fueled early, less selective surgical referral. Patients who would have ultimately responded to medical therapy are therefore subjected to the risk and life disruption of surgical therapy.<br /><b>Objectives</b><br />The purpose of this study was to develop deep learning models based upon commonly-available electronic health record (EHR) variables to assist clinicians in the timely and accurate identification of HF medical therapy nonresponders.<br /><b>Methods</b><br />The study cohort consisted of all patients (age 18 to 90 years) admitted to a single tertiary care institution from January 2009 through December 2018, with International Classification of Disease HF diagnostic coding. Ensemble deep learning models employing time-series and densely-connected networks were developed from standard EHR data. The positive class included all observations resulting in severe progression (death from any cause or referral for HF surgical intervention) within 1 year.<br /><b>Results</b><br />A total of 79,850 distinct admissions from 52,265 HF patients met observation criteria and contributed >350 million EHR datapoints for model training, validation, and testing. A total of 20% of model observations fit positive class criteria. The model C-statistic was 0.91.<br /><b>Conclusions</b><br />The demonstrated accuracy of EHR-based deep learning model prediction of 1-year all-cause death or referral for HF surgical therapy supports clinical relevance. EHR-based deep learning models have considerable potential to assist HF clinicians in improving the application of advanced HF surgical therapy in medical therapy nonresponders.<br /><br />Copyright © 2022 American College of Cardiology Foundation. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Sep 2022; 10:637-647</small></div>

<div><h4>Chemoreflex and Baroreflex Sensitivity Hold a Strong Prognostic Value in Chronic Heart Failure.</h4><i>Giannoni A, Gentile F, Buoncristiani F, Borrelli C, ... Emdin M, Passino C</i><br /><b>Background</b><br />Novel treatments targeting in baroreflex sensitivity (BRS) and chemoreflex sensitivity (CRS) heart failure (HF) are grounded on small prognostic studies, partly performed in the pre-beta-blockade era.<br /><b>Objectives</b><br />This study assesses the clinical/prognostic significance of BRS and CRS in a large cohort of patients with chronic HF on modern treatments.<br /><b>Methods</b><br />Outpatients with chronic HF with either reduced (≤40%) or mildly reduced left ventricular ejection fraction (LVEF) (41% to 49%) underwent BRS (SD method) and CRS to hypoxia and hypercapnia (rebreathing technique) assessment and were followed up for a composite endpoint of cardiac death, implantable cardioverter-defibrillator shock, or HF hospitalization.<br /><b>Results</b><br />A total of 425 patients were enrolled (65 ± 12 years of age, LVEF 32% [IQR: 25%-38%], 94% on beta blockers). Patients with decreased BRS (n = 96 of 267, 36%) had lower exercise tolerance and heart rate variability (P < 0.05), whereas those with increased CRS to both hypoxia and hypercapnia (n = 74 of 369, 20%) had higher plasma norepinephrine and central apneas across the 24-hour period (P < 0.01). During a median 50-month follow-up (IQR: 24-94 months), the primary endpoint occurred more often in patients with decreased BRS (log-rank: 11.64; P = 0.001), mainly for increased cardiac deaths/implantable cardioverter-defibrillator shocks, and in those with increased CRS (log-rank: 34.81; P < 0.001), mainly for increased HF hospitalizations. Patients with both abnormal BRS and CRS showed the worst outcome. Reduced BRS (HR: 2.76 [95% CI: 1.36-5.63]; P = 0.005) and increased CRS (HR: 2.91 [95% CI: 1.34-6.31]; P = 0.007) were independently associated with the primary outcome and increased risk stratification when added to standard HF prognosticators (P < 0.05).<br /><b>Conclusions</b><br />In subjects with HF on modern treatment, abnormal BRS and CRS are frequently observed. BRS and CRS elicit autonomic imbalance, exercise limitation, unstable ventilation, and predict adverse outcomes.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Sep 2022; 10:662-676</small></div>

<div><h4>Sequential Evaluation of NT-proBNP in Heart Failure: Insights Into Clinical Outcomes and Efficacy of Vericiguat.</h4><i>Armstrong PW, Zheng Y, Troughton RW, Lund LH, ... Ezekowitz JA, VICTORIA Study Group</i><br /><b>Background</b><br />The effect of vericiguat on sequential N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and influence of this relationship on clinical outcomes is unknown.<br /><b>Objectives</b><br />This study assessed the relationship between changes in NT-proBNP and the primary outcome (cardiovascular death or heart failure hospitalization); evaluated the effect of vericiguat on changes in NT-proBNP; and explored the association between the efficacy of vericiguat and changes in NT-proBNP.<br /><b>Methods</b><br />NT-proBNP was measured at randomization and at 16, 32, 48, and 96 weeks in 4,805 of 5,050 patients. The association between NT-proBNP change at week 16 and the primary outcome was assessed. The relationship between changes in NT-proBNP and the primary outcome according to treatment group was assessed by using joint modeling and mediation analysis.<br /><b>Results</b><br />A significant and sustained decline in NT-proBNP levels was seen in both treatment groups. After week 16, NT-proBNP levels decreased more with vericiguat vs placebo (any reduction: odds ratio [OR]: 1.45 [95% CI: 1.28-1.65]; P < 0.001; ≥50% reduction: OR: 1.27 [95% CI: 1.10-1.47]; P = 0.001) and were less likely to increase (≥20% increase: OR: 0.68 [95% CI: 0.59-0.78]; P < 0.001; ≥50% increase: OR: 0.70 [95% CI: 0.59-0.82]; P < 0.001). The treatment effect related to serial NT-proBNP on the primary composite outcome was HR: 0.96 (95% CI: 0.95-0.99) at week 16, which increased to HR: 0.90 (95% CI: 0.85-0.96) at week 48; the average extent of mediation of the composite outcome related to NT-proBNP was 45%.<br /><b>Conclusions</b><br />In patients with worsening HFrEF, vericiguat significantly decreased NT-proBNP levels compared with placebo. This change appeared associated with a modest relative improvement in the primary outcome of cardiovascular death or heart failure hospitalization. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534).<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Sep 2022; 10:677-688</small></div>

<div><h4>Influence of NT-proBNP on Efficacy of Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction.</h4><i>Myhre PL, Vaduganathan M, Claggett BL, Miao ZM, ... McMurray JJV, Solomon SD</i><br /><b>Background</b><br />N-terminal pro-B-type natriuretic peptide (NT-proBNP) is used for diagnostic and prognostic evaluation in heart failure (HF). Previous clinical trials in heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) have shown potential heterogeneity in the treatment response by baseline NT-proBNP levels.<br /><b>Objectives</b><br />To assess the treatment effect of dapagliflozin across baseline levels of NT-proBNP among patients with HFmrEF or HFpEF.<br /><b>Methods</b><br />This was a post hoc analysis from DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure), a randomized, placebo-controlled trial of dapagliflozin in patients with HFmrEF or HFpEF. Elevated NT-proBNP was part of the inclusion criteria (≥300 ng/L for non-atrial fibrillation or flutter [AFF]; ≥600 ng/L for AFF). Baseline NT-proBNP was categorized in quartiles and additionally analyzed continuously. The primary composite outcome was cardiovascular death or worsening HF events.<br /><b>Results</b><br />Among the 6,262 included patients (mean 71.7 years and 3,516 [56%] men), the median (Q1-Q3) baseline concentration of NT-proBNP was 716 (469-1,280) ng/L and 1,399 (962-2,212) ng/L for non-AFF and AFF, respectively. Higher NT-proBNP levels were linearly associated with a greater risk of the primary outcome (adjusted HR for log<sub>2</sub>NTpro-BNP was 1.53 [1.46, 1.62] and Q4 vs Q1: 3.46 [95%CI 2.48-4.22]; P < 0.001), with consistent results regardless of AFF status. The clinical benefit of dapagliflozin was present irrespective of baseline NT-proBNP concentration (P for interaction = 0.40 by quartiles and = 0.19 continuously for the primary outcome) and the absolute risk reduction was, therefore, greater with higher NT-proBNP concentrations. The effect on health status and safety of dapagliflozin was similarly consistent across NT-proBNP quartiles.<br /><b>Conclusions</b><br />Dapagliflozin is safe and improves outcomes irrespective of baseline NT-proBNP concentrations in HFmrEF or HFpEF, with the greatest absolute benefit likely seen in patients with higher NT-proBNP concentrations. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).<br /><br />Copyright © 2022. Published by Elsevier Inc.<br /><br /><small>JACC Heart Fail: 27 Aug 2022; epub ahead of print</small></div>

<div><h4>Obesity Status and Physical Rehabilitation in Older Patients Hospitalized With Acute HF: Insights From REHAB-HF.</h4><i>Peters AE, Kitzman DW, Chen H, Nelson MB, ... Whellan DJ, Mentz RJ</i><br /><b>Background</b><br />In the REHAB-HF trial, a novel, early, transitional, multidomain rehabilitation intervention improved physical function, frailty, quality of life (QOL), and depression in older patients hospitalized for acute decompensated heart failure (ADHF), but the potential impact of baseline obesity on this intervention has not been studied.<br /><b>Objectives</b><br />This study assessed for treatment interactions by body mass index (BMI) subgroups for a novel rehabilitation intervention in ADHF.<br /><b>Methods</b><br />Three-month outcomes including Short Physical Performance Battery (SPPB) (primary outcome), 6-minute walk distance (6MWD), and Kansas City Cardiomyopathy Questionnaire (KCCQ) were assessed by baseline BMI (≥30 kg/m<sup>2</sup> vs <30 kg/m<sup>2</sup>). Six-month end points included all-cause rehospitalization and death. All analyses were adjusted for age, sex, clinical site, and ejection fraction category, and 3-month outcomes were also adjusted for baseline measure. The prespecified significance level for treatment interaction by BMI category was P ≤ 0.10.<br /><b>Results</b><br />Of 349 trial participants, 204 (58%) had BMI ≥30 kg/m<sup>2</sup> and 145 (42%) <30 kg/m<sup>2</sup>. Compared with patients with BMI <30 kg/m<sup>2</sup>, participants with BMI ≥30 kg/m<sup>2</sup> were younger (age 71 ± 7 years vs 75 ± 9 years), more frequently women (57% vs 46%), and had significantly worse baseline physical function and QOL. Although interaction P values for 3-month outcomes by BMI were not significant (interaction P > 0.15 for overall measures), adjusted SPPB effect sizes were nominally larger for participants with BMI ≥30 kg/m<sup>2</sup> compared with those with BMI <30 kg/m<sup>2</sup>: +1.7 (95% CI: 0.8-2.7) vs +1.1 (95% CI: -0.1 to 2.2). This difference in SPPB effect size was due largely to improvements in the balance component of the SPPB for participants with BMI ≥30 kg/m<sup>2</sup>: +0.6 (95% CI: 0.2-1.0) vs 0.0 (-0.6 to 0.5) for those with BMI <30 kg/m<sup>2</sup> (interaction P = 0.02). In contrast, adjusted 6MWD and KCCQ effect sizes were smaller for participants with BMI ≥30 kg/m<sup>2</sup> compared with those with BMI <30 kg/m<sup>2</sup>: +21 meters (-17 to 59) vs +53 meters (6-100), and +5.0 (-4 to 14) vs +11 (-0.5 to 22), respectively. There was no significant interaction by BMI for 6-month clinical outcomes (all interaction P > 0.3).<br /><b>Conclusions</b><br />Older patients with ADHF benefit from the rehabilitation therapy regardless of BMI. Benefits for patients with obesity may be more evident in the multidomain measure of physical function (SPPB), compared with the 6MWD or KCCQ, which may be driven, in part, by the unique aspects of the novel rehabilitation intervention. (A Trial of Rehabilitation Therapy in Older Acute Heart Failure Patients [REHAB-HF]; NCT02196038).<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 17 Aug 2022; epub ahead of print</small></div>

<div><h4>Smoking Cessation Reduces the Risk of Heart Failure: A Nationwide Cohort Study.</h4><i>Yoo JE, Jeong SM, Yeo Y, Jung W, ... Park KW, Shin DW</i><br /><b>Background</b><br />There is a lack of data for the incidence of heart failure (HF) according to changes in smoking behaviors.<br /><b>Objectives</b><br />The authors aimed to investigate the effects of smoking behavior change on development of HF.<br /><b>Methods</b><br />In this population-based, retrospective cohort study using the Korean National Health Insurance System database, the authors identified 778,608 current smokers who participated in a health screening program in 2009 and in a follow-up screening in 2011. Participants were categorized into quitters, reducers I (≥50% reduction) and II (<50% reduction), sustainers, and increasers.<br /><b>Results</b><br />During a median follow-up of 6.3 years, there were 23,329 HF events (4.8 per 1,000 person-years). Compared with sustainers, the risk of HF was increased among increasers (adjusted hazard ratio [aHR]: 1.06; 95% CI: 1.02-1.10). By contrast, quitters had a reduced risk for HF (aHR: 0.86; 95% CI: 0.83-0.90). Even heavy smokers who quit smoking had a lower risk for HF than those who sustained heavy smoking (aHR: 0.90; 95% CI: 0.85-0.95). In reducers, the risk of HF was not reduced but rather increased slightly (≥50% reduction, aHR: 1.06; 95% CI: 1.01-1.11; <50% reduction, aHR: 1.04; 95% CI: 1.00-1.08).<br /><b>Conclusions</b><br />Current smokers who increased their smoking amount were associated with a higher risk for HF development compared to sustainers, whereas self-reported smoking cessation was associated with a lower risk of HF. There was no benefit from reduction in smoking amount. Self-reported smoking cessation should be reinforced whenever possible to prevent HF.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 12 Aug 2022; epub ahead of print</small></div>

<div><h4>Angiotensinogen: More Than Its Downstream Products: Evidence From Population Studies and Novel Therapeutics.</h4><i>Kahlon T, Carlisle S, Otero Mostacero D, Williams N, Trainor P, DeFilippis AP</i><br /><AbstractText>The renin-angiotensin-aldosterone system (RAAS) is a well-defined pathway playing a key role in maintaining circulatory homeostasis. Abnormal activation of RAAS contributes to development of cardiovascular disease, including heart failure, cardiac hypertrophy, hypertension, and atherosclerosis. Although several key RAAS enzymes and peptide hormones have been thoroughly investigated, the role of angiotensinogen-the precursor substrate of the RAAS pathway-remains less understood. The study of angiotensinogen single-nucleotide polymorphisms (SNPs) has provided insight into associations between angiotensinogen and hypertension, congestive heart failure, and atherosclerotic cardiovascular disease. Targeted drug therapy of RAAS has dramatically improved clinical outcomes for patients with heart failure, myocardial infarction, and hypertension. However, all such therapeutics block RAAS components downstream of angiotensinogen and elicit compensatory pathways that limit their therapeutic efficacy as monotherapy. Upstream RAAS targeting by an angiotensinogen inhibitor has the potential to be more efficacious in patients with suboptimal RAAS inhibition and has a better safety profile than multiagent RAAS blockade. Newly developed therapeutics that target angiotensinogen through antisense oligonucleotides or silencer RNA technologies are providing a novel perspective into the pathobiology of angiotensinogen and show promise as the next frontier in the treatment of cardiovascular disease.</AbstractText><br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 04 Aug 2022; epub ahead of print</small></div>

<div><h4>Validation of the Kansas City Cardiomyopathy Questionnaire in Symptomatic Obstructive Hypertrophic Cardiomyopathy.</h4><i>Nassif M, Fine JT, Dolan C, Reaney M, ... Gosch K, Spertus JA</i><br /><b>Background</b><br />The primary goal for treating patients with obstructive hypertrophic cardiomyopathy (oHCM) is to improve their symptoms, function, and quality of life. Although the Kansas City Cardiomyopathy Questionnaire (KCCQ) is a valid, reliable, and sensitive measure for other etiologies of heart failure, its appropriateness for patients with oHCM is unknown.<br /><b>Objectives</b><br />The purpose of this study was to establish the interpretability, validity, reliability, and responsiveness of the KCCQ in patients with oHCM.<br /><b>Methods</b><br />Cognitive debriefing of the KCCQ was performed in 26 patients with oHCM. The validity, reliability, responsiveness, and interpretability of the KCCQ were tested in 196 participants from the EXPLORER-HCM trial by comparing each scale with relevant comparators, describing the internal reliability and the mean change in stable patients, and comparing the mean change in patients who reported different degrees of clinical change using a patient-reported global impression of change (PGIC).<br /><b>Results</b><br />All KCCQ domains demonstrated strong correlations with external standards of symptoms, function, social limitation, and quality of life, including a recently designed instrument measuring symptoms not captured by the KCCQ (P < 0.0001 for all). Mean changes in stable patients were nonsignificant, ranging from 0.21 to 2.3 points (P > 0.30 for all), with high intraclass correlation coefficients. The mean changes in patients with small, moderate, and large clinical changes were consistent with the 5-, 10-, and 20-point mean differences observed in other etiologies of heart failure.<br /><b>Conclusions</b><br />The KCCQ is well understood by patients with oHCM and has strong evidence of good psychometric performance. It can not only serve as a relevant endpoint in clinical trials of oHCM therapy, but may also prove useful in the clinical care of patients with oHCM. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy [EXPLORER-HCM]; NCT03470545).<br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Aug 2022; 10:531-539</small></div>

<div><h4>Effects of Dapagliflozin According to the Heart Failure Collaboratory Medical Therapy Score: Insights From DAPA-HF.</h4><i>Butt JH, Dewan P, DeFilippis EM, Biering-Sørensen T, ... Fiuzat M, McMurray JJV</i><br /><b>Background</b><br />The Heart Failure Collaboratory (HFC) has developed a score integrating classes and doses of guideline-directed medical therapies prescribed for patients with heart failure (HF) and reduced ejection fraction. One potential use of this score is to test whether new treatments demonstrate incremental benefits, even in patients receiving comprehensive guideline-directed medical therapy.<br /><b>Objectives</b><br />The authors investigated the efficacy of dapagliflozin according to a modified HFC score in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial.<br /><b>Methods</b><br />In DAPA-HF, 4,744 patients with HF and reduced ejection fraction were randomized to dapagliflozin or placebo. The modified HFC score accounted for race and electrocardiogram rhythm and rate, with a maximum possible score of 100%. The primary outcome was the composite of worsening HF or cardiovascular death.<br /><b>Results</b><br />The median modified HFC score was 50% (IQR: 27.5%-62.5%; range 0%-100%). Compared with the lowest tertile, the highest tertile of the treatment score was associated with a lower risk of worsening HF or cardiovascular death (tertile 1, reference; tertile 2, HR: 0.97 [95% CI: 0.82-1.14]; tertile 3, HR: 0.83 [95% CI: 0.70-0.99]). Dapagliflozin reduced the risk of worsening HF or cardiovascular death, irrespective of treatment score (the HRs for dapagliflozin vs placebo from tertile 1 to 3 were: 0.76 [95% CI: 0.61-0.94], 0.76 [95% CI: 0.60-0.97], and 0.71 [95% CI: 0.55-0.90]), respectively; P<sub>interaction</sub> = 0.89). Consistent benefits were observed for HF hospitalization, cardiovascular death, all-cause mortality, and improvement in the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TTS).<br /><b>Conclusions</b><br />Dapagliflozin, compared with placebo, improved all outcomes examined, regardless of the modified HFC score. This score can be easily calculated in clinical trials and used to evaluate the incremental effects of new treatments. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Aug 2022; 10:543-555</small></div>

<div><h4>Sodium-Glucose Co-Transporter-2 Inhibitors and Cardiac Outcomes Among Patients Treated With Anthracyclines.</h4><i>Gongora CA, Drobni ZD, Quinaglia Araujo Costa Silva T, Zafar A, ... Nohria A, Neilan TG</i><br /><b>Background</b><br />Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve outcomes among patients with established heart failure. Despite supportive basic science studies, there are no data on the value of SGLT2 inhibitors among patients treated with anthracyclines.<br /><b>Objectives</b><br />This study sought to test the cardiac efficacy and overall safety of SGLT2 inhibitors in patients treated with anthracyclines.<br /><b>Methods</b><br />This study identified 3,033 patients with diabetes mellitus (DM) and cancer who were treated with anthracyclines. Cases were patients with cancer and DM who were on SGLT2 inhibitor therapy during anthracycline treatment (n = 32). Control participants (n = 96) were patients with cancer and DM who were also treated with anthracyclines, but were not on an SGLT2 inhibitor. The primary cardiac outcome was a composite of cardiac events (heart failure incidence, heart failure admissions, new cardiomyopathy [>10% decline in ejection fraction to <53%], and clinically significant arrhythmias). The primary safety outcome was overall mortality.<br /><b>Results</b><br />Age, sex, ethnicity, cancer type, cancer stage, and other cardiac risk factors were similar between groups. There were 20 cardiac events over a median follow-up period of 1.5 years. The cardiac event incidence was lower among case patients in comparison to control participants (3% vs 20%; P = 0.025). Case patients also experienced lower overall mortality when compared with control participants (9% vs 43%; P < 0.001) and a lower composite of sepsis and neutropenic fever (16% vs 40%; P = 0.013).<br /><b>Conclusions</b><br />SGLT2 inhibitors were associated with lower rate of cardiac events among patients with cancer and DM who were treated with anthracyclines. Additionally, SGLT2 inhibitors appeared to be safe. These data support the conducting of a randomized clinical trial testing SGLT2 inhibitors in patients at high cardiac risk treated with anthracyclines.<br /><br />Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>JACC Heart Fail: 01 Aug 2022; 10:559-567</small></div>