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)

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.

INTRODUCTION:Atrial fibrillation (AF) and heart failure (HF) frequently coexist, and their combination is associated with poorer outcomes. The bidirectional risk and the impact of which disease develops first on mortality remain unclear. METHODS:We studied 31 374 UK Biobank participants with new-onset AF or HF (2006-22). Multivariable Cox models assessed risk factors, incidence, and mortality risk. RESULTS:The risk of developing HF was higher in patients with AF than in those without AF (45.1 vs 3.87 per 1000 person-years; aHR 3.15, 95% CI 3.0-3.31). The risk of developing AF in patients with HF was higher than in those without HF (25.4 vs 2.27 per 1000 person-years; aHR 2.75, 95% CI 2.62-2.90). HF patients had a 31% higher risk of subsequent AF, compared with the risk of AF patients developing HF (P < .05). Mortality risk was substantially higher in patients with both conditions. AF before HF conferred a nearly four-fold increased risk (aHR 3.8, 95% CI 3.5-4.2), while HF before AF more than doubled risk (aHR 2.0, 95% CI 2.1-2.6), compared with either condition alone. Regardless of which disease was diagnosed first, there was no significant difference in mortality risk (aHR 0.95, 95% CI 0.85-1.07). CONCLUSIONS:AF and HF strongly predispose to each other, with HF conferring a higher relative risk for incident AF. The coexistence of both diseases substantially increases mortality regardless of which disease developed first, emphasizing the need for strategies to prevent the development of HF in patients with AF and vice versa.

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.

INTRODUCTION:Left ventricular assist device (LVAD) therapy is an established treatment modality for patients with advanced heart failure with reduced ejection fraction (HFrEF). This study aimed to evaluate the long-term outcomes of patients implanted with a Heartmate 3 LVAD. METHODS:We included 176 patients who were implanted with a HeartMate 3 LVAD at the University Medical Center Groningen (UMCG) between 2016 and 2025. The primary outcome of interest was on device survival. Secondary outcomes were major adverse events (including device dysfunction, major bleeding, device-related infections, ventricular tachycardia, cerebrovascular events and heart failure hospitalizations) stratified according to LVAD treatment strategy. RESULTS:Mean age at implantation was 56 ± 11 years, and 26% were female. The initial device strategy was bridge to transplant (BTT) in 24%, destination therapy (DT) in 34%, and bridge to decision (BTD) in 42%. Overall survival was 87%, 82% and 61% at 1, 2 and 5 years respectively. Kaplan-Meier analysis suggested longer on-device survival in BTT compared with DT patients, although interpretation is limited by differential censoring due to transplantation. Device-related infections and heart failure hospitalizations were the most common major adverse events, occurring 0.29 and 0.18 events per patient-year at risk, respectively. Device dysfunction and cerebrovascular events were rare, with incidence rates of 0.04 and 0.02 events per patient-year at risk, respectively. No LVAD pump thrombosis events were recorded during this time period. CONCLUSION:Long-term survival on HeartMate 3 LVAD support exceeded 60% at 5 years in this single-centre cohort. While adverse events such as device related infections and heart failure hospitalizations continue to pose a substantial clinical challenge, the incidence of thrombotic complications was low, underscoring improvement in clinical outcomes with current generation centrifugal LVAD devices.

AIMS:This report describes the baseline characteristics of the DECISION trial (Digoxin Evaluation in Chronic heart failure: Investigational Study In Outpatients in the Netherlands) and compares these with the other trials of cardiac glycosides in heart failure (HF): DIG and DIGIT-HF. METHODS:The DECISION trial is a randomized, double-blind, parallel-group, placebo-controlled outcome trial investigating of low-dose digoxin in contemporary patients with heart failure with a left ventricular ejection fraction (LVEF) ≤50%. Patients were randomized 1:1 to low-dose digoxin or placebo. During follow-up, serum digoxin concentrations were monitored to achieve concentrations of 0.5-0.9 ng/ml. The primary endpoint is a composite of cardiovascular mortality, total HF-hospitalizations and urgent HF hospital visits. RESULTS:A total of 1002 patients were randomized to digoxin or placebo and 1001 patients were included in the full analysis set. Mean age was 73 ± 9 years, 28% were women and 88% were in New York Heart Association class II. Mean LVEF was 33 ± 9%, and 79% had a LVEF ≤40%. At baseline, 71% had sinus rhythm and 29% had atrial fibrillation. Median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1404 pg/ml [930-2359].Patients were well-treated with guideline-directed medical therapy (GDMT): beta-blockers (86%), ACE inhibitors or ARBs or angiotensin receptor-neprilysin inhibitors (89%), mineralocorticoid receptor antagonists (72%), and sodium-glucose co-transporter 2 inhibitors (41%) and loop-diuretics (74%). Compare to other digitalis trials, DECISION-patients were older, more often women and had high prevalence of GDMT. CONCLUSION:DECISION enrolled a contemporary and well-treated population of patients with HFrEF and HFmrEF and will provide important evidence regarding the efficacy and safety of low-dose digoxin on outcome in patients with reduced or mildly reduced LVEF.

BACKGROUND:In EMPULSE (A Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart Failure), the sodium-glucose cotransporter 2 inhibitor empagliflozin improved clinical outcomes in patients hospitalized for heart failure (HF). OBJECTIVES:This prespecified analysis examined efficacy, safety, and tolerability of empagliflozin in subgroups with de novo heart failure (NHF) vs acute decompensated heart failure (ADHF). METHODS:After stabilization, participants were randomized 1:1 to empagliflozin 10 mg/d or placebo, stratified by HF status (NHF: n = 175; ADHF: n = 355). The primary endpoint was a hierarchical composite of death, worsening HF, or ≥5-point difference in Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) change at day 90, assessed using a win ratio. RESULTS:Participants with NHF were younger, had fewer comorbidities, had higher blood pressure and heart rate, and better KCCQ-TSS. Prescription of diuretic agents was similar between subgroups. The win ratio was 1.29 (95% CI: 0.89-1.89) for NHF and 1.39 (95% CI: 1.07-1.81) for ADHF (Pinteraction = 0.759). There were no interactions between NHF and ADHF for the primary endpoint, its components, or secondary endpoints, except diuretic response, which was greater with empagliflozin in NHF than in ADHF from day 15 (mean difference vs placebo: -5.11 [Q1-Q3: -7.89 to -2.32] vs -0.97 [Q1-Q3: -2.91 to 0.96] kg per mean daily loop diuretic dose, Pinteraction = 0.017), with even greater between-group differences at days 30 and 90. Frequencies of adverse events were consistently lower with empagliflozin vs placebo. CONCLUSIONS:In-hospital initiation of empagliflozin produced similar clinical benefits in NHF and ADHF despite the reduced diuretic response in participants with ADHF and was well tolerated. This supports in-hospital initiation of empagliflozin in all patients with acute HF (A Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart Failure [EMPULSE]; NCT04157751).

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.

BACKGROUND:Heart failure (HF) progression is closely linked to oxidative stress. 5-Oxoproline (5-OP), a product of glutathione degradation, is normally metabolized by 5-oxoprolinase (OPLAH) but accumulates when the gamma-glutamyl cycle is disrupted. Here, we investigated the clinical characteristics of circulating 5-OP, its proteomic correlates, and the associations to outcome in HF. METHODS:In serum of 823 BIOSTAT-CHF patients, 5-OP was quantified by validated liquid chromatography-mass spectrometry and analyzed for associations with clinical outcomes. Proteomic correlates were identified across 355 OLINK proteins using stability selection with Minimax Concave Penalty regression. Mechanistic context was evaluated in a multi-comorbidity, large-animal cardio-kidney-metabolic (CKM) model with regional OPLAH assessment. RESULTS:Higher 5-OP was associated with worse renal function (eGFR declining across 5-OP tertiles, 67.9 to 60.2 mL/min/1.73 m2; p = 0.0012) and higher all-cause mortality (HR 1.55, 95% CI 1.11-2.17, p = 0.010). Per SD increase in log-5-OP, risk for the 2-year composite endpoint increased (HR 1.27, 95% CI 1.05-1.53), with broadly similar associations across CKD strata (interaction p = 0.63). TGF-α was the most robust proteomic correlate (π = 0.70; empirical permutation p = 0.001). In CKM swine, circulating 5-OP was elevated and renal cortical OPLAH protein, but not cardiac OPLAH, was selectively reduced, consistent with a renal contribution to systemic 5-OP elevation. CONCLUSION:Circulating 5-OP identifies HF patients at higher risk and is robustly associated with TGF-α. In a translational swine model, selective loss of renal cortical OPLAH provides tissue context supporting a renal contribution to systemic 5-OP elevation in cardiorenal syndrome.

BACKGROUND:Peptides such as angiotensin II and brain natriuretic peptide are pivotal in diagnosing and treating heart failure (HF). However, unbiased systematic studies of the peptidome in patients with HF are lacking. Deciphering the plasma peptidome might significantly improve the diagnosis, prognostication, and treatment of patients with HF. METHODS:To systematically explore the low molecular peptidome, we conducted a cross-sectional mass spectrometry analysis from 486 patients with HF and 98 age-matched non-HF controls. We quantified 21 694 unique peptides in plasma, which were ranked according to (1) the relative upregulation in HF versus controls, (2) pattern similarity to bioactive peptides by an adapted machine learning method, and (3) association with clinical outcome. RESULTS:We observed 1924 differentially expressed peptides between patients with HF and non-HF controls. Among high-ranking peptides in patients with HF were angiotensin-related peptides (eg, angiotensin 1-9), propeptides from GIP (gastric inhibitory polypeptide), osteocalcin and cholecystokinin, and peptides mapping to the extracellular part of the natriuretic peptide clearance receptor and integrin alpha-7. Among the regulated peptides, 141 were scored in the top 5% by our machine learning approach, and 65 peptides herein were independently associated with clinical outcome. A hierarchical clustering analysis of patients with HF revealed 3 major patient clusters based on the peptide signature. The patient cluster with the lowest survival probability exhibited a specific peptide degradation pattern with a higher proportion of peptides linked to the acute phase response and increased inflammation. CONCLUSIONS:This study uniquely identifies peptides according to their regulation and likelihood of being a bioactive peptide in patients with HF compared with non-HF controls. The study provides crucial peptide-level information to complement protein-based methodologies. The most promising peptides were related to the renin-angiotensin system, natriuretic peptides, and cardiometabolic regulation. The stepwise ranking highlights the HF peptide signal important for outcome and provides a rich resource for additional exploration.

BACKGROUND:Angiotensin-(1-7) promotes vasodilation and counteracts angiotensin II in the vasculature and kidneys, while dipeptidyl peptidase 3 (DPP3) inactivates Ang-(1-7). Although circulating DPP3 (cDPP3) has been studied in chronic heart failure (HF), data in acute HF are limited. We evaluated cDPP3 levels and their association with clinical characteristics, decongestive response, and outcomes in acute HF. METHOD:We analyzed patients enrolled in the randomized PUSH-AHF trial comparing natriuresis-guided diuretic therapy with standard of care (SOC) in acute HF. cDPP3 levels were measured at baseline, 24, 48 and 72 hours, and at discharge. Associations between cDPP3 levels, clinical characteristics, 24-hour natriuresis, and the combined endpoint of 180-day all-cause mortality or HF hospitalization were assessed. Additionally, we evaluated whether diuretic treatment strategy modified these associations. RESULTS:Baseline cDPP3 was available in 287/310 patients (93%; mean age 73±12, 43% female) with a median concentration of 39 (26-62) ng/mL. cDPP3 decreased significantly within 24 hours (-17%, p<0.01) and stabilized thereafter. Both the lowest and highest quartiles were associated with lower eGFR, higher urea, and higher NT-proBNP levels (all p<0.03). In higher cDPP3 quartiles, natriuresis-guided diuretic therapy resulted in greater 24-hour natriuresis and diuresis compared with SOC; however, no significant treatment-cDPP3 interaction was observed. cDPP3 levels did not modify the treatment effect on the overall neutral combined endpoint. CONCLUSION:Higher cDPP3 concentrations are associated with impaired kidney function and reduced diuretic response in acute HF. Natriuresis-guided therapy improved decongestion across cDPP3 strata. Further studies should clarify the clinical role of cDPP3 in acute HF.

Abstract Background Diagnosis of heart failure with preserved ejection fraction (HFpEF) using the HFA-PEFF and H2FPEF scores remains challenging in clinical practice, and relies on echocardiographic assessment. We aimed to determine whether diagnostic scoring based on automated deep learning interpretation of echocardiograms performs similar to manual measurements in diagnosing HFpEF. Methods We analyzed echocardiograms using an automated deep learning algorithm and manually in three cohorts: a test cohort (102 HFpEF patients diagnosed by right heart catheterization and echocardiography), an ambulatory validation cohort (129 HFpEF patients), and a diagnostic validation cohort (n = 427, of which 182 HFpEF and 245 non-HFpEF patients). We evaluated correlations between automated and manual HFA-PEFF and H2FPEF scores across cohorts, their correlation with pulmonary capillary wedge pressures (PCWP), and compared diagnostic accuracy using the area-under-the-curve (AUC). Results Automated and manual measurements showed good agreement across cohorts, with good correlations between HFA-PEFF (0.78-0.86) and H2FPEF (0.96-0.98) scores and similar correlations with PCWP. One in five patients with high-likelihood HFpEF based on manual HFA-PEFF scores were classified as intermediate-likelihood by automated scores due to lower estimated left atrial volumes, without consistent interaction with atrial fibrillation. AUCs for automated HFA-PEFF and H2FPEF scores did not consistently differ from manual scores (0.70 [95% confidence interval (CI): 0.66-0.74] vs. 0.71 [95% CI: 0.66-0.75], and 0.78 [95% CI: 0.73-0.82] vs. 0.75 [95% CI: 0.71-0.80], respectively). Conclusion HFA-PEFF and H2FPEF scores based on automated and manual echocardiographic analysis showed similar diagnostic accuracy, suggesting automated HFpEF diagnosis using deep learning analysis of echocardiograms is feasible.

BACKGROUND:In patients undergoing transcatheter aortic valve implantation (TAVI), low flow, low-gradient (LF-LG) often reflects reduced left ventricular ejection fraction (LVEF). However, characteristics and causes of worse outcomes in patients with paradoxical LF-LG and preserved ejection fraction (pEF) remains poorly understood. OBJECTIVES:To phenotype LF-LG pEF patients using unsupervised echocardiographic clustering. METHODS:We included 827 patients undergoing TAVI (UMCG, the Netherlands). LF-LG pEF was defined as LVEF ≥50%, aortic valve area: ≤1.0 cm2, mean gradient <40 mmHg, and a stroke volume index <35 ml/m2. Principal component analysis on 323 AI-assessed echocardiographic parameters (US2.ai) was followed by K-means clustering, with internal (n = 405) and external (n = 173) (TUMunich, Germany) validation. RESULTS:216/628 patients with complete data (34%) had LF-LG pEF (mean age of 78.8 (± 7.19) years, 57.9% female). Two clusters were identified: cluster 1 (n = 77) showed distinct echocardiographic features related to HFpEF, including larger left and right atrial dimensions (volume, area, length, width, and circumference), and impaired left ventricular global longitudinal strain and a reduced left atrial reservoir strain (across multiple views). They were older and had higher rates of atrial fibrillation (AF) and heart failure (HF), and higher HFpEF scores (49.4% H2FPEF score ≥6 and 71.4% HFA-pEFF score ≥5), versus cluster 2 (n = 139). Cluster 1 had higher 1- and 5-year cardiovascular mortality and HF-hospitalization risk, comparable to that of classical LF-LG patients. Validation reproduced theseresults. CONCLUSION:One-third of TAVI patients with LF-LG aortic stenosis have an typical HFpEF/AF phenotype and a poor prognosis. They may benefit from guideline-directed HFpEF therapy, including SGLT-2 inhibitors and MRA.