AIMS:In FIDELITY, finerenone improved kidney and cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines categorise CKD progression risk based on estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). This FIDELITY post hoc subanalysis investigated KDIGO risk category changes associated with finerenone. METHODS:Improvement or worsening in KDIGO risk category was defined by variation from baseline, with specified eGFR and UACR changes. Association of these category changes with a CV composite outcome was assessed. RESULTS:Finerenone therapy led to a higher likelihood of KDIGO risk category improvement (odds ratio [OR], month 36: 1.47; 95% confidence interval [CI], 1.31-1.65; p < 0.0001) and lower likelihood of worsening (OR, month 36: 0.83; 95% CI, 0.77-0.90; p < 0.0001) vs. placebo. Risk category improvement reduced the CV composite outcome risk (hazard ratio [HR]: 0.82; 95% CI, 0.68-0.99; p = 0.043) while worsening increased this risk (HR: 1.29; 95% CI, 1.06-1.56; p = 0.01). CONCLUSIONS:Finerenone therapy is associated with greater improvement and less worsening in KDIGO risk vs. placebo. The category changes are associated with lower risk of CV events in patients with CKD and T2D. TRIAL REGISTRATION NUMBER:FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049) are registered with ClinicalTrials.gov (funded by Bayer AG).

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.

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 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:In patients with heart failure with reduced ejection fraction (HFrEF), target-dose (vs. below-target-dose) angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) improve clinical outcomes but worsen kidney function. Less is known about their effect on kidney failure (KF), especially in those with advanced chronic kidney disease (CKD), the examination of which was the objective of our study. METHODS AND RESULTS:Of the 154,945 Veterans with HFrEF (EF≤40%) and no baseline KF, 134,046 were initiated on ACEIs (target-dose, n=37,667) and 20,899 were initiated on ARBs (target-dose, n=4017) during 2000-2018. While remaining blinded to study outcomes, we assembled two propensity score-matched cohorts: ACEI (N=70,860; target-dose, n=35,430) and ARB (N=7900; target-dose, n=3950), balanced on 76 baseline characteristics. Hazard ratios (95% CIs) associated with target doses were estimated for 5-year KF and all-cause mortality, up to December 31, 2023. In the ACEI cohort, target-dose was associated with a 18% lower risk of KF (HR, 0.82; 95% CI, 0.75-0.89) and a 6% lower risk of death (HR, 0.94; 95% CI, 0.92-0.97). Subgroup and spline analyses showed that while the KF association was significant for those with baseline eGFR <35 ml/min/1.73m2, the mortality association was significant for those with eGFR ≥35 ml/min/1.73m2. In the ARB cohort, target-dose had no association with outcomes. CONCLUSIONS:In patients with HFrEF, target-dose (vs. below-target-dose) ACEIs, but not ARBs, were associated with lower risk of KF, which was significant in those with advanced CKD. The survival benefit was modest and limited to those without advanced CKD.

BACKGROUND:After acute myocardial infarction (AMI) with left ventricular (LV) dysfunction, guideline-recommended reassessment at 40-90 days primarily addresses arrhythmic risk and implantable cardioverter-defibrillator (ICD) candidacy. In this setting, a complementary evaluation of heart failure (HF)-related event risk may refine risk stratification. OBJECTIVE:We aimed to quantify post-ICD HF event risk and develop a simple score usable at the time of ICD decision. METHODS:We analyzed 1,015 patients from the WICD-MI study (41 French centers) with LVEF ≤35% after AMI, equipped with a wearable cardioverter-defibrillator (WCD) and subsequently implanted with an ICD. We hypothesized that early HF features after MI could predict subsequent HF outcomes and therefore assessed five pre-implant HF features: HF history before AMI; cardiogenic shock, congestive HF during AMI; acute HF hospitalization during WCD period; and NYHA status at ICD implantation. The primary outcome was a composite of death or HF events (hospitalization, LV assist device, transplantation) at 1 year post-ICD. RESULTS:The 1-year risk of the composite outcome was 12.7%. All HF features except prior HF independently predicted the primary outcome: cardiogenic shock (aHR=1.63, p=0.013), congestive HF (aHR=2.02, p=0.0004), acute HF hospitalization (aHR=2.96, p<0.0001), and NYHA III/IV (aHR=1.64, p=0.025). Risk increased from 5% (no points/HF features) to 38% (≥3 points/HF features). External validation in HRMI (n=22,418) showed improved discrimination for HF hospitalization versus GRACE (ΔC-index +0.026; p=0.001) and similar performance to VALIANT-HF, with greater simplicity. CONCLUSION:In post-MI patients undergoing ICD implantation, a simple HF-based score identifies patients at higher risk of early post-implant HF events and may support integrated management, including timely HF referral.

Understanding hormonal mechanisms of obesity-related hypertension may inform targeted therapy. Participants with obesity and hypertension underwent deep-phenotyping procedures to detect the primary aldosteronism phenotype, low-renin phenotype, renin-dependent aldosteronism phenotype, and ACTH-independent hypercortisolism. In total, 51.9% of participants had a primary aldosteronism phenotype, of which approximately one-half also had superimposed renin-dependent aldosteronism. Another 23.4% of participants had only renin-dependent aldosteronism that was characterized by higher aldosterone levels and kaliuresis, and 9.2% of participants also had hypercortisolism. Over 80% of individuals with obesity-related hypertension exhibited overlapping pathologic phenotypes of aldosteronism and/or hypercortisolism, providing mechanistic evidence to support the efficacy of aldosterone- and cortisol-directed therapy.

BACKGROUND:There are concerns that renin-angiotensin system inhibitors are less effective in Black patients than non-Black patients with heart failure (HF). We examined the efficacy and safety of mineralocorticoid-receptor antagonists (MRAs), compared with placebo, in patients with HF with reduced ejection fraction or HF with mildly reduced/preserved ejection fraction, according to self-reported race (Black or non-Black). METHODS:This was a post hoc individual participant data meta-analysis of the 4 large placebo-controlled trials comparing MRAs to placebo in patients with HF with reduced ejection fraction (RALES [Randomized Aldactone Evaluation Study], EMPHASIS-HF [Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure]) and HF with mildly reduced/preserved ejection fraction (TOPCAT [Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist], FINEARTS-HF [Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure]). The primary outcome was a composite of cardiovascular death or first HF hospitalization. RESULTS:Of the 13 846 patients randomized in the 4 trials, 577 (4.2%) identified as Black. Despite being younger (64 versus 70 years), rates of HF hospitalizations and death were higher in Black than non-Black patients. The hazard ratio for MRA versus placebo for the primary composite outcome was 0.87 (95% CI, 0.66-1.15) in Black patients and 0.77 (95% CI, 0.72-0.82) in non-Black patients (Pinteraction=0.34), with 3.9 and 2.7 fewer events per 100 person-years of treatment, respectively. For first HF hospitalization, the hazard ratios were 0.86 (95% CI, 0.63-1.17) and 0.73 (95% CI, 0.68-0.80) for Black and non-Black patients, respectively (Pinteraction=0.36). The corresponding hazard ratios for cardiovascular death were 0.75 (95% CI, 0.48-1.17) and 0.81 (95% CI, 0.74-0.90), respectively (Pinteraction=0.80). Adverse events with MRAs, compared with placebo, were not modified by race. The effects of MRAs in patients with HF with reduced ejection fraction and HF with preserved ejection fraction, individually, were not modified by race. CONCLUSIONS:There was no statistically significant evidence of heterogeneity in the absolute or relative effects of MRAs on clinical outcomes between Black and non-Black patients with HF, regardless of HF phenotype.

There is strong evidence that hypertension is a major risk factor for heart failure (HF). Hypertension contributes to incident HF through direct and indirect effects. Indirect effects are consequences of ischaemic heart disease because hypertension facilitates atherosclerotic obstructive coronary artery disease. The direct effects are straightly related to hypertensive heart disease (HHD). Hypertensive heart disease poses a significant challenge with substantial medical and public health implications. Efforts should be made to recognize and manage HHD in a timely manner and optimize hypertension treatment. Reducing blood pressure (BP) and/or reassessing antihypertensive therapy using traditional or novel approaches can halt or delay progression to HF in patients with HHD and possibly prevent it. However, HHD's importance as a risk factor for overt HF is often overlooked in clinical practice. This document aims to summarize the current understanding of the burden of HHD and its risk for incident HF, discuss the mechanisms underlying HHD-related HF onset and progression, consider how diagnostic tools contribute to individualized phenotyping and HF risk stratification of HHD, address how therapeutic measures ameliorating or even preventing structural and functional alterations of HHD, along with BP control influence HHD-associated HF risk.

BACKGROUND:The central problem in heart failure with reduced ejection fraction (HFrEF) is reduced contractility. Existing inotropes are associated with adverse effects. In this exploratory study, we aimed to assess the safety and tolerability of AC01, a novel oral calcium-sensitising inotrope and ghrelin receptor agonist, in patients with HFrEF. METHODS:In this phase 1b/2a, randomised, double-blind, placebo-controlled study, adults aged 18-80 years with heart failure for at least 6 months and an ejection fraction of 40% or lower were enrolled at 14 sites in the Netherlands, the UK, Sweden, and Italy. All patients had a transvenous implantable cardioverter defibrillator for primary prevention, with back-up pacing to protect against excessive bradycardia. Other eligibility criteria included sinus rhythm or permanent, persistent, or paroxysmal atrial fibrillation or flutter (only allowed in phase 2a), with a mean resting heart rate of 55-90 beats per min. Randomisation used permuted blocks, with block sizes of four for phase 1b and three for phase 2a. In phase 1b, patients were enrolled in four sequential dose cohorts and randomly assigned 3:1 to ascending doses of AC01 (0·1 mg, 0·3 mg, 1·0 mg, or 3·0 mg) or placebo twice daily for 7 days. In phase 2a, patients were randomly assigned 1:1:1 to parallel groups receiving 1·0 mg AC01, 3·0 mg AC01 (1·0 mg AC01 on days 1 and 2 and 3·0 mg thereafter), or placebo orally twice daily for 28 days. Patients, study personnel, outcomes assessors, those analysing the data, and the sponsor were masked to treatment assignment. The primary outcome was safety and tolerability. Safety was monitored by physical examination, vital signs, safety laboratory assessments, and 12-lead electrocardiograms (ECGs) periodically during the treatment period and until the end-of-study visit (day 12 in phase 1b and day 42 in phase 2a), and cardiac rhythm was continuously monitored remotely using a patch device until day 9 in phase 1b and until day 4 in phase 2a. Adverse or unexpected events, signs, or symptoms were recorded. This study is registered with ClinicalTrials.gov, NCT05642507, and has been completed. FINDINGS:Between Feb 23, 2023, and Aug 28, 2025, 58 patients (53 [91%] male and five [9%] female patients with a median age of 66·0 years [IQR 60·3-72·0]) were randomly assigned: 32 in phase 1b and 26 in phase 2a. In phase 1b, four cohorts of eight patients were enrolled; in each cohort, six patients were allocated to AC01 and two to placebo, with AC01 dose cohorts of 0·1 mg, 0·3 mg, 1·0 mg, and 3·0 mg. In phase 2a, nine patients were allocated to 1·0 mg AC01, eight to 3·0 mg AC01, and nine to placebo. There were 12 AC01-related adverse events in phase 1b and 18 in phase 2a. There were no AC01-related serious adverse events; one treatment-related serious adverse event of increased high-sensitivity cardiac troponin I concentration occurred in a patient receiving placebo in phase 1b. Mild or moderate treatment-emergent adverse events were reported in 33 (80%) of 41 patients receiving AC01 and 12 (71%) of 17 patients receiving placebo. The most common treatment-emergent adverse events were hypotension, non-sustained ventricular tachycardia, dyspnoea, hyperglycaemia, dizziness or vertigo, and headache. ECG data showed no apparent signs of tachycardia, new-onset tachyarrhythmias, myocardial ischaemia, or morphological or conduction abnormalities. No case of symptomatic hypotension was reported, and there were no apparent effects of AC01 on high-sensitivity cardiac troponin I or NT-proBNP. There were no deaths during the study. INTERPRETATION:In patients with HFrEF, AC01 over 28 days appeared safe and well tolerated, and no major harms were identified in this early-phase study. These findings support further investigations of AC01 in larger studies. FUNDING:AnaCardio.

AIMS:The association between heart rate (HR) and clinical outcomes is well understood in patients with heart failure with reduced ejection fraction (HFrEF) but less clear in those with HFmrEF/HFpEF, especially among individuals with atrial fibrillation (AF). In a prespecified analysis of the FINEARTS-HF trial, we examined the association between baseline HR and clinical outcomes by heart rhythm and evaluated finerenone's effect across the spectrum of HR. METHODS:The primary outcome was a composite of cardiovascular death and total (first and recurrent) HF events. Heart rhythm (sinus rhythm or AF) was determined from the baseline ECG. Patients with pacemaker rhythm or missing HR/rhythm data were excluded. RESULTS:Among patients with sinus rhythm (SR n = 3497; 62%), higher baseline HR was associated with a higher incidence rate for the primary outcome. In patients with AF (n = 2190; 38%), no association between HR and outcomes was observed. The effect of finerenone on the primary outcome was consistent across the HR spectrum, regardless of rhythm (P for interaction = 0.96 in SR; 0.49 in AF). In patients with SR, there was no significant HR change with finerenone versus placebo. In AF patients, finerenone led to a small but statistically significant HR reduction: a placebo-corrected decrease of 1.35 bpm (95% CI: 0.41-2.29) from baseline to 12 months. CONCLUSIONS:Among patients with HFpEF/HFmrEF in FINEARTS-HF, higher baseline HR was associated with a higher risk of the primary outcome in patients with SR but not in those with AF. Finerenone's effect on the primary outcome was consistent across the HR spectrum, irrespective of rhythm. TRIAL REGISTRATION:ClinicalTrials.gov NCT04435626.