Importance:Patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) or preserved EF (HFpEF) show substantial heterogeneity in prognosis. Objectives:To evaluate the performance of biomarker-driven prognostic models derived from the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved) Trial in the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) and to examine whether baseline risk modified the therapeutic effect of finerenone. Design, Setting, and Participants:This is a prespecified secondary analysis of the FINEARTS-HF trial, which was conducted across 653 sites in 37 countries among adults aged 40 years and older with symptomatic HF and left ventricular EF (LVEF) of 40% or greater. Patients were randomized between September 2020 and January 2023, and data analysis for this study was conducted from September to October 2025. The median (IQR) follow-up period was 32 (23-37) months. Intervention:Finerenone (titrated to 20 mg or 40 mg) or placebo. Main Outcomes and Measures:EMPEROR-Preserved risk scores for the outcomes of first HF hospitalization or cardiovascular death, cardiovascular death, and all-cause death were calculated in FINEARTS-HF using models incorporating N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, New York Heart Association functional class, history of chronic obstructive pulmonary disease and diabetes, insulin use, and-depending on outcome-age, hemoglobin and albumin levels, HF duration, time from prior HF hospitalization, and sodium-glucose transporter 2 inhibitor use. Estimated risks were compared with observed event rates, and model performance was assessed using Harrell C statistic. Treatment effects were evaluated across risk quintiles (Q1 to Q5) and across the continuous risk distribution. Results:Among 6001 patients (mean [SD] age, 72.0 [9.6] years; 2732 [45.5%] women; 3003 randomized to finerenone and 2998 randomized to placebo), the EMPEROR-Preserved risk model estimated risk of outcomes, with Q5 vs Q1 hazard ratios (HRs) of 10.49 (95% CI, 8.14-13.52) for the composite of HF hospitalization or cardiovascular death and 13.47 (95% CI, 8.79-20.64) for cardiovascular death. The model demonstrated good discrimination. The treatment effect of finerenone was consistent across risk quintiles for first HF hospitalization or cardiovascular death (Q1: HR, 0.93 [95% CI, 0.58-1.49]; Q2: HR, 1.04 [95% CI, 0.76-1.43]; Q3: HR, 0.82 [95% CI, 0.62-1.07]; Q4: HR, 0.81 [95% CI, 0.65-1.01]; and Q5: HR, 0.88 [95% CI, 0.74-1.05]; P for interaction = .68) and remained uniform across the continuous risk spectrum. Conclusions and Relevance:The EMPEROR-Preserved risk models demonstrated good performance in FINEARTS-HF. Baseline risk did not modify the relative treatment effect of finerenone. Trial Registration:ClinicalTrials.gov Identifier: NCT04435626.

Background The HFpEF-ABA score is a simple diagnostic tool developed to estimate the probability of heart failure with preserved ejection fraction (HFpEF) using age, body mass index, and history of atrial fibrillation. Objectives This study aims to evaluate the HFpEF-ABA score in patients with confirmed heart failure (HF) in the FINEARTS-HF trial, its prognostic implications, and the effect of finerenone treatment according to the HFpEF-ABA score. Methods FINEARTS-HF was a randomized, placebo-controlled trial enrolling patients with HF with a left ventricular ejection fraction ≥40%. HFpEF-ABA scores (as a probability between 0% and 100%) were calculated at baseline and categorized as <75%, 75%-90%, or >90%. The association between HFpEF-ABA score and clinical outcomes was examined as well as the effect of finerenone across the range of HFpEF-ABA scores. Results Among 5,988 patients with available HFpEF-ABA scores, 1,940 (32.4%) had a score <75% (low probability), 1,241 (20.7%) had a score 75%-90% (intermediate probability), and 2,807 (46.9%) had a score >90% (high probability). Rates of HF outcomes were higher in patients with higher HFpEF-ABA scores. Examination of HFpEF-ABA score as a continuous variable showed a strikingly nonlinear association with outcomes; the rate of events was similar up to a score of ∼75%, above which there was a steep increase in the event rate. Finerenone reduced events consistently across HFpEF-ABA scores. Conclusions Despite a proven diagnosis of HF with mildly reduced ejection fraction/HFpEF, one-third of participants in FINEARTS-HF had an HFpEF-ABA score <75%, yet the therapeutic effect of finerenone was consistent across the range of HFpEF-ABA scores included. Higher HFpEF-ABA scores were associated with a greater risk of HF events. (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure [FINEARTS-HF]; NCT04435626)

AIMS:Blood pressure (BP) control is a Class I recommendation for the management of heart failure with preserved ejection fraction (HFpEF); however, evidence supporting systolic BP (SBP) targets remains limited. We investigated associations between BP control and subsequent outcomes in patients with HF with mildly reduced EF (HFmrEF)/HFpEF. METHODS:We pooled TOPCAT (Americas), PARAGON-HF, DELIVER, and FINEARTS-HF, which tested spironolactone, sacubitril/valsartan, dapagliflozin, and finerenone, respectively, versus placebo or active control in patients with HF and an LVEF >40% (DELIVER), ≥40% (FINEARTS-HF), or ≥45% (TOPCAT-Americas, PARAGON-HF). Daily BPs were estimated by interpolation from standardized office measurements obtained at randomization and prespecified visits. Time in target range (TIR) was the percentage of the first year after randomization during which SBP was 110-<130 mmHg. Continuous associations between TIR and subsequent risk of HF hospitalization or cardiovascular death, its individual components, and all-cause death was assessed using landmark Cox proportional hazards models with linear splines, adjusted for baseline cardiovascular risk factors. RESULTS:Among 17,788 patients (mean age 72±9 years; 47% women; mean baseline SBP 129±15 mmHg), the median TIR was 38% (≈139 days). Randomization to active therapies increased TIR by 2% (95% CI: -2 to 6) with spironolactone, 7% (5 to 9) with sacubitril/valsartan, 2% (0 to 4) with dapagliflozin, and 3% (1 to 5) with finerenone. Higher TIR was associated with lower subsequent risk of the composite outcome (P=0.021), primarily driven by lower HF hospitalization risk (P=0.007); associations with cardiovascular death and all-cause death were not significant. Sensitivity analyses using stricter (120-<130 mmHg) or more liberal ranges (100-<130 and 120-<140 mmHg) yielded qualitatively similar findings. CONCLUSIONS:In patients with HFmrEF/HFpEF, BP control during the first year was associated with a lower subsequent risk of HF hospitalization. CLINICAL TRIALS REGISTRATION:ClinicalTrials.gov ID NCT00094302 (TOPCAT), NCT01920711 (PARAGON-HF), NCT03619213 (DELIVER), NCT04435626 (FINEARTS-HF).

Background Patients with recurrent myocardial infarction (MI) are a heterogenous group with high comorbidity burden, risk of complex coronary disease, and at risk of poor outcomes. However, contemporary comparative data are lacking. Methods Consecutive patients with recurrent MI (defined as a new hospital admission for MI >28 days following a first-time MI) in Denmark between 2015 and 2022 were identified through the nationwide registries and matched 1:1 on age and sex to patients with first-time MI. The primary outcome was a composite of all-cause mortality, hospitalization for heart failure (HHF), and further recurrent MI. Standardized risks with 95% confidence intervals (CI) were estimated using cause-specific Cox regression models with first-time MI serving as the reference group. Results A total of 8,397 patients with recurrent MI and 8,397 with first-time MI were included (median age 73, 70.7% male). Patients with recurrent MI had more comorbidities. For the primary composite outcome, patients with recurrent MI had a standardized 1-year risk of 24.0% versus 17.2% among those with first MI (standardized risk ratio [sRR] 1.39 [95% CI: 1.34-1.44]). They also had higher risks of: all-cause mortality, 14.6% versus 11.3% (sRR 1.29 [1.24-1.35]); HHF, 6.6% versus 6.0% (sRR 1.11 [1.00-1.21]), and recurrent MI 6.7% versus 2.2% (sRR 3.01 [2.71-3.45]). Use of guideline-recommended treatments post-dicharge was high, albeit lower than for first-time MI: percutaneous coronary intervention (53.7% versus 64.3%, p<0.001), lipid-lowering treatment (78.1% versus 83.2%, p<0.001), and P2Y12 inhibitor (77.3% versus 82.6%, p<0.001). Conclusion Recurrent MI is associated with a higher risk of all-cause mortality, HHF, and further recurrent MI compared with first-time MI.

Background Patients with heart failure (HF) with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) have a high comorbidity burden, which may require management with numerous medications. Patients and clinicians may be hesitant about initiating another medication, especially among individuals with polypharmacy. Objective This study sought to examine the efficacy and safety of adding finerenone based on the number of concomitant medications in patients with HFmrEF/HFpEF. Methods In this post hoc analysis of the FINEARTS-HF trial, baseline medication use was collected in all 6,001 participants with HFmrEF/HFpEF who were randomized to finerenone or placebo. Clinical outcomes were assessed by medication use categories (“non-polypharmacy”: <5 medications; “polypharmacy”: 5 to 9 medications; and “hyper-polypharmacy”: ≥10 medications) and continuously, adjusted for covariates including age. The primary outcome was a composite of cardiovascular death and total (first and recurrent) HF events. Results Overall (age: 72±10 years; 46% women), the total number of medications at baseline ranged from 0 to 29 and the mean number of medications was 8.4±3.6, with 3,588 (60%) patients met polypharmacy and 1,878 (31%) met hyper-polypharmacy. Patients with higher medication use were older and had a greater burden of comorbidities. Incidence rates for the primary outcome increased across medication categories: non-polypharmacy (10.2 per 100py), polypharmacy (12.3 per 100py), and hyper-polypharmacy (26.1 per 100py) (Figure A). The treatment benefits of finerenone in reducing risks of cardiovascular death and total HF events were consistent across the spectrum of total medication use (P for interaction = 0.94; Figure B). Although adverse events leading to study drug discontinuation increased with the higher number of medications, they were not more frequent with finerenone vs. placebo, regardless of polypharmacy categories. Conclusions In the FINEARTS-HF trial, >90% of patients with HFmrEF/HFpEF met the criteria for polypharmacy and these patients faced excess risks of cardiovascular events. Finerenone safely reduced cardiovascular death and total HF events across a broad range of baseline medication use, including among individuals with polypharmacy.

BACKGROUND AND AIMS:It remains unclear what the safe serum potassium range is in heart failure (HF) and whether it is the same in HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). METHODS:A patient-level pooled analysis from 12 randomized controlled trials including 32 346 HFrEF and 13 723 HFpEF patients was performed. Baseline serum potassium level was categorized into six groups (<3.5, ≥3.5-<4.0, ≥4.0-<4.5, ≥4.5-<5.0, ≥5.0-<5.5, and ≥5.5 mmol/L) and serum potassium level at baseline was also analysed as a continuous variable using restricted cubic splines. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular death, sudden death, pump failure death, first HF hospitalization, and composites of HF hospitalization and cardiovascular or all-cause death. RESULTS:The median follow-up was 24.2 and 36.8 months in HFrEF and HFpEF trials, respectively. In HFrEF, serum potassium levels showed a reverse J-shaped association with outcomes. Compared with ≥4.0-4.5 mmol/L (reference), potassium <3.5 mmol/L was associated with higher risks of all-cause mortality (adjusted hazard ratio 1.49; 95% confidence interval, 1.27-1.76), as well as cardiovascular, sudden, and pump failure death. The lowest risk for all outcomes was observed within the baseline serum potassium range of 4.2-5.0 mmol/L, but even 'mild hyperkalaemia' (5.0-5.5 mmol/L) was not associated with worse outcomes in HFrEF. Although the risk curve was U-shaped and flatter in HFpEF, the lowest incidence of all outcomes was observed over the same potassium range as HFrEF. CONCLUSION:In HFrEF, hypokalaemia is strongly associated with worse outcomes and should be avoided. In terms of safety, the optimal serum potassium concentration in both HFrEF and HFpEF appears to be in the range 4.2-5.0 mmol/L.

AIMS:Clinicians may be less inclined to consider new therapies in patients with long-standing heart failure (HF) due in part to clinical inertia. Whether the treatment effects of the non-steroidal mineralocorticoid receptor antagonist finerenone vary according to HF duration remains uncertain. METHODS:In this prespecified analysis of the FINEARTS-HF trial, HF duration (defined as the time from diagnosis) was categorized into four groups: <3 months, ≥3 months to 2 years, ≥2 to 5 years, or ≥5 years. The primary outcome was a composite of cardiovascular death and total HF events. The efficacy and safety of finerenone were analyzed across the duration of HF. RESULTS:Among 5,977 participants with available data (age: 72±10 years; 46% female), those with longer duration HF were older and had a higher comorbidity burden, while most patients, irrespective of HF duration, had NYHA class II functional status. Compared with HF duration <3 months, longer HF duration experienced a significantly higher adjusted risk of the primary outcome. The benefit of finerenone was consistent across HF duration categories: the rate ratio (95%CI) for the primary outcome in the <3-month group was 0.84 (0.61-1.16); ≥3 months to 2 years, 0.95 (0.74-1.23); ≥2 to 5 years, 0.77 (0.61-0.98); and ≥5 years, 0.81 (0.64-1.02) (Pinteraction=0.46). Drug discontinuation due to serious adverse events was similar between finerenone and placebo, regardless of HF duration. CONCLUSIONS:These findings suggest that even patients with long-standing HF with only mild functional status limitation may still benefit from further therapeutic optimization with therapies such as finerenone.

In the evolving landscape of heart failure (HF) management, the identification and analysis of subgroups and special populations within clinical trials are crucial for enhancing clinical decision-making, guiding further research, and understanding heterogeneity in study outcomes. This expert consensus document results from the collaborative efforts of the Heart Failure Collaboratory and the Heart Failure Collaboratory Academic Research Consortium, which brought together stakeholders from academia, industry, the U.S. Food and Drug Administration, and patient representatives. The purpose of this assembly was to propose standardized definitions and critical endpoint considerations essential for shaping the design and conduct of clinical trials for drugs and devices in the field of HF. In this context, we propose definitions and endpoints for specific subgroups and special populations in the spectrum of HF. We enhanced the precision, efficacy, and applicability of clinical research and promote more “personalized” approaches to interpretation of clinical trials. Furthermore, we explore the burgeoning field of gene therapy as a promising avenue for addressing the genetic basis of certain cardiomyopathies within these specialized patient groups. We focus especially on methodological considerations for subgroup analyses in large-scale trials, highlighting the importance of proper interpretation of subgroups and best practices for identifying heterogeneity suggestive of differential treatment effects, including when these analyses should be considered hypothesis-generating and requiring subsequent validation. We advocate for a methodical approach to clinical trial design, one that prioritizes the strategic identification of subgroups and employs appropriate statistical methodologies to ensure the reliability and clinical relevance of findings. Through this lens, we envision a pathway toward more personalized and effective treatments for HF, ultimately aiming to improve patient outcomes by leveraging the insights garnered from meticulously designed and comprehensively analyzed clinical trials.

BACKGROUND:Lactate dehydrogenase (LDH) is a cytoplasmic enzyme found in most cells. Increased LDH levels are a nonspecific measure of cellular injury and may be prognostically important in heart failure (HF). OBJECTIVES:This study aims to assess the relationship between LDH and clinical characteristics and outcomes in heart failure and reduced ejection fraction (HFrEF). METHODS:Using data from GALACTIC-HF, a phase 3, randomized, placebo-controlled trial evaluating the efficacy and safety of omecamtiv mecarbil (OM) in patients with HFrEF, the relationship between LDH and clinical outcomes was analyzed. The incremental value of LDH added to a validated prognostic model (PREDICT-HF) was also calculated using Harrell's C statistic, integrated discrimination index (IDI), and net reclassification index (NRI). RESULTS:In GALACTIC-HF, baseline LDH data were available for 8,179 patients, including 6,138 outpatients. Patients with higher LDH were more frequently female and had worse HF status. They were also more likely to have elevated serum creatinine, liver enzymes, creatine kinase, NT-proBNP, and high-sensitivity troponin I. Compared with patients in the lowest LDH (Q1: 155 U/L [25th-75th percentile: 144-163 U/L]), the HRs for the primary outcome (first HF event or cardiovascular death) were Q2: 183 U/L (25th-75th percentile: 177-188 U/L); HR: 1.15 [95% CI: 1.02-1.31]; Q3: 207 U/L (25th-75th percentile: 201-215 U/L); HR: 1.39 [95% CI: 1.23-1.58]; and Q4: 253 U/L (25th-75th percentile: 236-280 U/L); HR: 1.84 [95% CI: 1.62-2.08], respectively. Even after adjustment, elevated LDH remained independently associated with higher HR. When added to the PREDICT-HF risk model, baseline LDH improved Harrell's C statistic, IDI, and NRI for the primary outcome. CONCLUSIONS:In GALACTIC-HF, higher LDH levels were independently associated with a higher risk of clinical outcomes in HFrEF. (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure [GALACTIC-HF]; NCT02929329; EudraCT number: 2016-002299-28).

Importance:Sudden death remains a leading cause of mortality in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HF with preserved ejection fraction (HFpEF), but whether these events are preceded by clinical deterioration remains unclear. Objective:To characterize clinical trajectories preceding sudden death in patients with HFmrEF or HFpEF and compare them with trajectories before other modes of death and survival. Design, Setting, and Participants:This was a post hoc analysis of the Finerenone Trial to Investigate the Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) randomized clinical trial evaluating trajectories of functional status, patient-reported health status, and natriuretic peptide levels preceding adjudicated modes of death. This was a global, event-driven clinical trial. Patients with symptomatic HF, left ventricular EF of 40% or greater, New York Heart Association class (NYHA) II to IV, and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) were enrolled between September 14, 2020, and January 10, 2023. Data analysis was conducted in December 2025. Interventions:Finerenone vs placebo. Main Outcomes and Measures:Longitudinal trajectories of NYHA class, Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS), and NT-proBNP levels preceding sudden death were compared with trajectories in survivors and those who died of HF-related, nonsudden cardiovascular, or noncardiovascular causes, using linear mixed-effects models with restricted cubic splines. Results:Included in this analysis were 6001 patients (mean [SD] age, 72.0 [9.6] years; 3269 male [54%]). Over a median (IQR) follow-up of 2.7 (1.9-3.0) years, 215 sudden deaths occurred. In the 6 months before death, sudden death was preceded by a slight worsening in physician-assigned NYHA class (from approximately 2.3 to 2.4), worsening self-reported health status (an approximately 8-point decline in KCCQ-TSS), and a gradual rise in NT-proBNP levels (from approximately 1800 to 2000 pg/mL). In contrast, among patients who survived, NYHA class improved (from approximately 2.3 to 2.1), KCCQ-TSS increased (from approximately 68 to 77), and NT-proBNP levels declined (from approximately 800 to 650 pg/mL) over the 18 months before the end of follow-up. Comparable patterns of deterioration to those preceding sudden death, often more pronounced, were observed before other modes of death. Conclusions and Relevance:Results of this post hoc analysis of the FINEARTS-HF randomized clinical trial reveal that in this contemporary HFmrEF or HFpEF cohort, sudden death was preceded by modest worsening of symptoms, declining quality of life, and rising natriuretic peptide levels, suggesting many of these events may not have been entirely sudden. However, similar deterioration preceding other modes of death suggests limited specificity for sudden death. Trial Registration:ClinicalTrials.gov Identifier: NCT04435626.

Introduction Transthyretin amyloidosis (ATTR) is a progressive and fatal condition caused by deposition of misfolded transthyretin (TTR) as amyloid fibrils in multiple tissues. ATTR is classified as either hereditary (hATTR) or wild-type (wtATTR), depending on the presence or absence of amyloidogenic TTR gene variants, and manifests as either primarily cardiomyopathy (ATTR-CM), polyneuropathy, or a mixed phenotype. RNA interference (RNAi) therapeutics suppress the hepatic production of TTR by targeting wild-type and variant TTR mRNA for degradation. Previous studies showed that rapid TTR knockdown with RNAi therapeutics improves outcomes for ATTR patients regardless of etiology or manifestation. Most recently, vutrisiran was shown to improve outcomes for patients with ATTR-CM across multiple domains in the HELIOS-B study, including reducing cardiovascular events and all-cause mortality, and improving functional capacity and quality of life. Larger reductions in TTR levels correlated with greater clinical benefit in patients with hATTR and polyneuropathy, suggesting that greater TTR knockdown may offer similar benefits in ATTR-CM. Nucresiran (ALN-TTRsc04) is a next-generation RNAi therapeutic designed for the treatment of ATTR. In a Phase 1, ascending-single-dose study in healthy adults (NCT05661916), nucresiran led to rapid and sustained knockdown of TTR. Up to 95% knockdown by Day 15 and >90% mean reductions through Month 6 were achieved with subcutaneously administered doses ≥300 mg that were well tolerated. Hypothesis The efficacy, safety, and pharmacokinetics/pharmacodynamics (PK/PD) of nucresiran in patients with ATTR-CM will be evaluated in a global, Phase 3, randomized, placebo-controlled study, the rationale and design of which will be described. Methods The study design, including inclusion and exclusion criteria, will be finalized in Q1 2025. Enrollment of adult patients with ATTR-CM is expected to begin in 2025. Key endpoints will assess mortality and cardiovascular events. Results The nucresiran Phase 3 ATTR-CM study design and rationale will be presented. Conclusions The Phase 3 study will investigate the efficacy, safety, and PK/PD of nucresiran in patients with ATTR-CM. Nucresiran has the potential to provide greater and more sustained TTR knockdown with lower inter-patient variability and less frequent dosing than current TTR-lowering therapies. This abstract will be presented at HFA 2025, May 17-20, 2025, Belgrade, Serbia.

AIMS:Atrial fibrillation and flutter (AF) are common in patients with Type 2 diabetes and are associated with worse outcomes. METHODS AND RESULTS:Harmony Outcomes was a multi-centre, event-driven, double-blind, placebo-controlled trial comparing the effects of albiglutide, a glucagon-like peptide-1 receptor agonist, with placebo on a composite of major adverse cardiac events (MACEs; non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) in 9463 patients aged >40 years with Type 2 diabetes and established cardiovascular disease. Herein, the cardiovascular effects of albiglutide in patients with and without AF, as well as the effects on AF events during follow-up, were analysed. Patients with a history of AF (8.9%) exhibited a higher event rate for the primary composite MACE endpoint during 1.6 years of follow-up {12.7 vs. 6.3 events/100 person-years, adjusted hazard ratio [aHR] 1.41 [95% confidence interval (CI) 1.14-1.74], P = 0.001}. Treatment with albiglutide reduced the occurrence of the primary endpoint irrespective of history of AF at baseline (history of AF: aHR 0.83 [0.58-1.19], no history of AF: aHR 0.77 [0.66-0.90]; Pinteraction = 0.71). During follow-up, 239 patients (2.5%) experienced an AF event. Overall, albiglutide was associated with numerically fewer AF events [108 vs. 131; hazard ratio 0.82 (0.63-1.06), P = 0.12], irrespective of baseline history of AF (Pinteraction = 0.92). CONCLUSION:In patients with Type 2 diabetes, treatment with albiglutide, compared with placebo, reduced the risk of cardiovascular events irrespective of history of AF. Further, albiglutide treatment did not increase AF adverse events but was associated with a trend to a lower rate of AF events during follow-up without reaching statistical significance.

INTRODUCTION:Myocardial injury is a hallmark of heart failure (HF). It is unknown whether established (e.g. troponin) or novel biomarkers of myocardial injury [e.g. cardiac myosin-binding protein C (cMyBP-C)] provide additive diagnostic value beyond natriuretic peptides in community patients with suspected HF. METHODS:Community-based patients with suspected HF and elevated NT-proBNP levels were recruited into a multicentre, prospective, observational study at five sites (NCT04724200). Venous blood sampling was performed at the time of echocardiography. HF was classified according to left ventricular ejection fraction: HF with reduced ejection fraction (HFrEF) = ≤40%, HF with mildly reduced ejection (HFmrEF) = 41-49%, and HF with preserved ejection fraction (HFpEF) = ≥50% with HFA-PEFF score ≥5. NT-proBNP (Roche Elecsys® assay), high-sensitivity cardiac troponin T (hs-cTnT, Roche Elecsys® assay) and cMyBP-C (Roche precommercial assay) were measured. Diagnostic accuracy of each biomarker alone and in combination was examined using the area under the receiver operating characteristic curve (AUROC). RESULTS:Of 867 patients, 751 (87%) had measurable left ventricular ejection fraction and available biomarker data. Of these, 43 (6%) had HFrEF, 75 (10%) HFmrEF, and 278 (37%) HFpEF. NT-proBNP levels were highest in patients with HFrEF, with similar patterns observed for hsTnT and cMyBP-C. For the diagnosis of HF versus no HF, the combination of NT-proBNP and cMyBP-C had the highest AUROC of 0.77 (95%CI 0.73-0.80) versus NT-proBNP alone [0.74 (0.71-0.78); P = .003]. For detection of HFrEF versus no HF, the AUROC was 0.90 (0.86-0.95) for the combination of NT-proBNP and cMyBP-C compared with 0.85 (0.80-0.90) for NT-proBNP alone (P = .006). CONCLUSION:Measurement of cMyBP-C improved the diagnostic accuracy of NT-proBNP in community-based patients with suspected HF, with greatest additive value for identifying HFrEF, and may help in the prioritization of echocardiography.

BACKGROUND:Chagas disease, caused by Trypanosoma cruzi parasites, is a common cause of heart failure (HF) in Latin America and has recently been declared endemic in the United States. The authors compared outcomes in Chagasic HF vs ischemic and other nonischemic etiologies of HF with reduced ejection fraction (HFrEF). OBJECTIVES:The aim of this study was to compare clinical outcomes of Chagasic HFrEF vs ischemic and other nonischemic etiologies. METHODS:Investigator-reported etiology of HFrEF in the ATMOSPHERE, PARADIGM-HF, and GALACTIC-HF trials was categorized as ischemic, valvular, alcoholic, hypertensive, idiopathic, viral, Chagasic, or "other." Time to the composite of first HF hospitalization or cardiovascular death, its components, all-cause death, and stroke was analyzed using Cox models adjusted for baseline characteristics, patient setting, trial, and other potential confounders. RESULTS:Among 23,647 patients (13,381 ischemic, 4,344 idiopathic, 2,559 hypertensive, 1,923 others, 423 alcoholic, 412 valvular, 297 viral, and 308 Chagasic), Chagasic HF had the highest incidence rates of all clinical outcomes compared with other etiologies. Compared with patients with ischemic etiology, the adjusted HRs in Chagasic HF were significantly higher for the composite outcome (HR: 1.65; 95% CI: 1.36-2.02), HF hospitalization (HR: 1.75; 95% CI: 1.36-2.25), cardiovascular death (HR: 1.86; 95% CI: 1.47-2.35), all-cause death (HR: 1.82; 95% CI: 1.47-2.25), and stroke (HR: 2.16; 95% CI: 1.20-3.88). CONCLUSIONS:Patients with Chagasic HFrEF have a distinct clinical course associated not only with excess mortality but also with an increased risk for stroke compared with other etiologies except for valvular and "other" etiologies. (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure [ATMOSPHERE], NCT00853658; Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial [PARADIGM-HF], NCT01035255; Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure [GALACTIC-HF], NCT02929329).

AIMS:Experimental evidence suggests that adipose tissue may secrete aldosterone, and mineralocorticoid receptor antagonists (MRAs) appear to be more effective in patients with obesity. Therefore, we examined aldosterone levels according to measures of adiposity in patients with heart failure and reduced ejection fraction (HFrEF) participating in two large trials. METHODS AND RESULTS:Aldosterone, N-terminal pro B-type natriuretic peptide (NT-proBNP), and B-type natriuretic peptide (BNP) levels were compared according to body mass index (BMI) categories: normal weight (<25.0 kg/m2), overweight (25.0-29.9 kg/m2), obesity class I (30.0-34.9 kg/m2), and obesity class II/III (≥35.0 kg/m2). Of the 2201 patients not treated with an MRA, in whom aldosterone levels were measured at baseline in ATMOSPHERE and PARADIGM-HF, the mean age was 67.8 years, and 440 (20.0%) were female. Patients with higher BMI had a higher left ventricular ejection fraction but worse New York Heart Association functional class than those with normal weight. Higher BMI was associated with higher aldosterone levels but lower NT-proBNP and BNP levels (P for trend < 0.001), compared to those with normal weight. This natriuretic peptide trend was also seen for other anthropometric measures. CONCLUSION:Greater adiposity was associated with higher concentrations of aldosterone but lower levels of B-type natriuretic peptides in patients with HFrEF. Adipose tissue may influence the neurohumoral milieu in HFrEF, including the secretion of aldosterone.