<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>