Body mass index (BMI) and waist-based anthropometric indices are widely used to estimate adiposity and cardiometabolic risk. Yet in established heart failure (HF), modestly higher BMI is associated with improved survival, while waist-based measures show a linear association with worse outcomes. This apparent discrepancy suggests that the biological interpretation of BMI and body composition changes once HF develops. In HF, BMI reflects the composite of adipose tissue, fluid accumulation, and skeletal muscle wasting, whereas waist-based indices primarily reflect central adiposity. In this narrative review, we explore the challenges of body composition interpretation in HF and propose a conceptual, phenotype-informed framework for body composition assessment and management. Within this framework, BMI may mask biologically distinct yet clinically relevant phenotypes defined by adiposity, congestion, and skeletal muscle integrity. By integrating these interacting components, the framework highlights that similar BMI values may represent biologically distinct phenotypes with different risk profiles and potential management implications. Across BMI categories, preserved muscle mass and limited congestion are associated with more favorable outcomes, whereas central adiposity, congestion, and muscle wasting identify higher-risk states. This conceptual framework provides a foundation for future research and may ultimately inform more individualized body composition assessment, risk stratification, and management of patients with HF.
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.
The management of advanced heart failure has been transformed by 2 parallel developments that have not yet been fully translated into clinical practice. Heart transplantation and durable left ventricular assist device (LVAD) support confer contemporary 1-year survival approaching 90%; yet, these therapies frequently are deployed only after the onset of progressive right ventricular dysfunction, cardiorenal injury, severe frailty, and hemodynamic instability, which are conditions that elevate procedural risk, impair long-term outcomes, and may ultimately preclude candidacy for advanced therapies altogether. The central limitation in advanced heart failure is therefore no longer the absence of effective therapies but the failure to identify and refer patients during the therapeutic window when physiologic reserve remains intact. This special communication advances 2 related but distinct objectives. First, we propose PREVENT 2-LATE (PReserve Eligibility Via Early, Necessary Transfer), a pragmatic referral framework in which the presence of any 2 of 4 early signals including escalating Loop diuretic requirements, recurrent Admissions, Therapy intolerance, and Early electrical, echocardiographic, or end-organ deterioration supplemented by persistently elevated natriuretic peptides—should prompt consideration for referral through shared care to an advanced heart failure program. These LATE criteria are designed to identify patients earlier in the disease trajectory than existing frameworks, when the full breadth of advanced therapy options is still intact. We further propose a multidisciplinary in-reach model, embedding advanced heart failure expertise within high-risk cardiovascular programs, including electrophysiology, structural heart, cardiogenic shock, cardiac surgery, and specialized cardiomyopathy services, to proactively identify and intercept residual risk before conventional referral triggers emerge. Second, and equally important, this communication provides a consolidated framework for contemporary LVAD best practices, an area in which clinical evidence has advanced rapidly but awareness and adoption remain inconsistent. We synthesize current evidence on morbidity decompression, pharmacologic optimization including renin-angiotensin-aldosterone system inhibition, myocardial recovery, frailty reversibility, and therapeutic sequencing including LVAD-first strategies, with the explicit goal of equipping clinicians to deploy these therapies earlier and more confidently. Critically, PREVENT 2-LATE is not designed to increase use of any single modality. Both heart transplantation and LVAD support are effective, and the framework exists precisely to preserve optionality across the full spectrum of advanced heart failure therapies, enabling expert multidisciplinary teams to match the right intervention to the right patient at the right time. The future of advanced heart failure lies not in increasingly urgent rescue after irreversible decline but in systematic interception while options remain.
BACKGROUND:Hemodynamic-guided management improves outcomes in heart failure (HF), but implantable pulmonary artery pressure monitoring is limited by cost and invasiveness. Non-Invasive Venous Waveform Analysis for Heart Failure (NIVAHF) is a machine learning-based device estimating pulmonary capillary wedge pressure (PCWP) from peripheral venous waveforms. OBJECTIVES:To describe the development and multicenter validation of the NIVAHF device by evaluating agreement between the NIVA Score and invasively measured PCWP. METHODS:In this prospective, multicenter study, peripheral venous waveforms were acquired non-invasively with the NIVAHF Device and analyzed by a supervised neural network using a 60:20:20 training, validation, and independent test allocation, with one site held out as the dominant contributor to the locked test cohort. Agreement between the NIVA Score and invasively measured PCWP was assessed by Bland-Altman analysis in the locked, independent, right heart catheterization (RHC) test cohort. Discrimination for elevated filling pressure (PCWP >15 mmHg) was evaluated by receiver operating characteristic (ROC) analysis, with PCWP-LVEDP and PAD-LVEDP agreement analyzed for context. RESULTS:In the independent RHC test cohort (n=122), NIVA Score showed a mean bias of -1.06 mmHg (SD 5.57) and 95% limits of agreement -11.98 to 9.87 mmHg versus PCWP, falling between the invasive surrogate comparisons (PCWP-LVEDP, -9.31 to 7.54; PAD-LVEDP, -14.85 to 8.63). The AUC for PCWP >15 mmHg was 0.71 (95% CI, 0.61-0.80; P<0.0001; 89% sensitivity, 36% specificity). CONCLUSIONS:NIVA Score demonstrated agreement with PCWP comparable to accepted invasive surrogates and detected elevated filling pressures with high sensitivity, supporting NIVAHF as a non-invasive congestion marker in heart failure.
BACKGROUND:In patients with relatively stable heart failure with reduced ejection fraction (HFrEF), target-dose angiotensin-converting enzyme inhibitors (ACEIs), compared with below-target doses, reduce the risks of death and kidney failure (KF). Whether these benefits extend to hospitalized patients, who are less likely to receive target doses due to hemodynamic instability and impaired kidney function, remains uncertain. METHODS:Of the 15,152 Veterans with HFrEF (LVEF ≤40%) without baseline KF, who were hospitalized for acute decompensated HF between 2000-2018 and newly initiated on ACEIs prior to discharge, 3143 (20.7%) received guideline‑recommended target doses. Propensity scores for the receipt of target-dose were calculated for each of the 15,152 patients and used to match 2884 (91.8% of 3143) target-dose patients to 2884 below-target-dose patients. Hazard ratios (HRs) for mortality and KF associated with target-dose ACEIs were estimated. RESULTS:Matched patients (n=5768) had mean (±SD) age 66 (±12) years, LVEF 26% (±9%), eGFR 76 (±23) mL/min/1.73 m², 99% were men, and 36% were African American. Patients in the two dose groups were balanced on 76 baseline characteristics. During 5 years of follow‑up, all‑cause mortality occurred in 56.1% of below‑target‑dose patients and 52.6% of target‑dose patients. KF occurred in 4.2% and 3.6%, respectively. Target‑dose ACEIs were associated with a 9% lower risk of death (HR 0.91; 95% CI, 0.85-0.98). The HR for KF was 0.83 (95% CI, 0.64-1.08), and for the composite endpoint of KF or death was 0.90 (95% CI, 0.84-0.97). CONCLUSION:The observed renal safety and lower mortality in patients with HFrEF newly initiated on ACEIs at higher target doses before discharge support the use of this inpatient strategy and suggest it may help mitigate the persistent outpatient inertia in the initiation and up‑titration of evidence‑based HF therapies.
AIMS:To develop and externally validate an artificial intelligence (AI)-driven model to predict effort intolerance (i.e., peak oxygen uptake [VO₂] <16 mL/kg/min) in patients at risk or with established heart failure (HF). METHODS:We enrolled a consecutive sample of adults referred for dyspnea or suspected HF. The derivation cohort (Pisa, Italy) included 1,333 participants - 351 with reduced (<50%, HFrEF), 371 with preserved (≥50%, HFpEF) left ventricular ejection fraction (LVEF), and 611 with cardiovascular risk factors and/or structural heart disease without overt HF (Stages A-B); the external validation cohort (Hasselt, Belgium) included 1,101 participants. All participants underwent clinical evaluation, laboratory test, rest echocardiography, and cardiopulmonary exercise testing. RESULTS:A neural network including age, sex, body mass index (BMI), haemoglobin, left ventricular systolic mitral annulus tissue velocity (LV S'), systolic pulmonary artery pressure (sPAP), and β-blocker therapy achieved the best discrimination (AUC 0.86±0.01 in derivation; 0.76±0.06 in validation). A simplified four-variable AI-VO₂ score (BMI, haemoglobin, LV S', sPAP) showed good performance (AUC 0.79±0.05) and independently predicted HF hospitalization or all-cause death (adjusted HR 1.06 per point; 95% CI 1.03-1.10) in the derivation cohort. External validation confirmed the predictive and prognostic performance (AUC 0.73±0.02; unadjusted HR 1.18 per point, 95% CI 1.13-1.24). Score-based risk strata (<10, low; 10-13, intermediate; >13, high) showed a significant prognostic gradient (log-rank χ² = 36.8, p<0.001). CONCLUSION:The AI-VO₂ score is a clinically interpretable, externally validated tool for identifying patients with effort intolerance and adverse outcomes across the HF spectrum, supporting personalized risk stratification and management.
BACKGROUND:Prior studies demonstrated that lung impedance (LI)-guided therapy reduces heart failure (HF) hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS:In this proof-of-concept, single-blind, single-center randomized controlled trial (NCT02661841), 150 HFpEF patients (NYHA class I-IV, LVEF >50%, elevated NT-proBNP, prior HF hospitalization) were randomized 1:1 to LI-guided management or usual care. LI was measured noninvasively at monthly outpatient visits using the FDA-approved CardioSet device. The primary endpoint was recurrent HF hospitalization. Mean follow-up was 38.4±22.8 months. HF hospitalizations were significantly reduced in the LI-guided group (HR 0.26; 95% CI 0.14-0.49; p<0.001; 20 vs 95 events). All-cause mortality (HR 0.40; 95% CI 0.18-0.87; p=0.02) and HF-specific mortality (HR 0.26; 95% CI 0.08-0.80; p=0.02) were also significantly lower. The Lung Impedance Ratio (LIR), reflecting each patient's degree of pulmonary congestion relative to their individual normal dry state, was used as a real-time fluid index to assess fluid status and guide diuretic titration at each visit. LI-guided patients spent significantly more time within the therapeutic LIR range, median 97% vs 49%; p<0.001, achieved through earlier treatment escalation (median LIR -20.8% vs -35.4%; p<0.01) and more conservative de-escalation (-13.7% vs -2.3%; p<0.01). Diuretic adjustment efficacy was similar between groups (LIR improvement +1.01% vs +1.36%; p=0.63), confirming benefit derived from precision timing rather than superior drug response. CONCLUSIONS:In this proof-of-concept randomized trial, LI-guided management significantly reduced HF hospitalizations, all-cause mortality, and HF-specific mortality in HFpEF through precision timing of decongestion.
BACKGROUND:Beta-blockers are commonly used among patients with heart failure and preserved or improved ejection fraction (HFpEF or HFimpEF). The benefits of beta-blockers in these populations are not clear, which may raise consideration of discontinuation. We conducted a systematic review on the effects of beta-blocker discontinuation versus continuation among adults ≥18 years with HFpEF or HFimpEF. METHODS:We searched MEDLINE, Embase, Cochrane CENTRAL, Google Scholar, Epistemonikos, and reference lists of eligible studies from inception to September 11, 2025. Eligible studies were randomized controlled trials (RCT), quasi-randomized studies, and non-randomized studies. Outcomes were mortality, major adverse cardiovascular events (MACE), HF hospitalizations, function, quality of life, as well as cardiovascular (CV) physiological and echocardiographic parameters. We conducted a narrative synthesis. RESULTS:We screened 4103 titles/abstracts, and 4 studies were eligible (1 RCT in HFpEF, 1 RCT in HFimpEF, and 2 cohort studies in HFimpEF). In HFpEF, beta-blocker discontinuation improved functional capacity and quality-of-life at 2 weeks compared with continuation with no clear effect on cognition, echocardiographic parameters or CV biomarkers. Long-term effects of beta-blocker discontinuation, and the effect on important clinical outcomes were unclear for HFpEF. In HFimpEF, available evidence suggests beta-blocker discontinuation might not lead to significant changes in CV physiology parameters, biomarkers, echocardiographic parameters, or clinical status compared with continuation, but findings on important long-term clinical outcomes was conflicting. CONCLUSIONS:Evidence on beta-blocker discontinuation in HFpEF or HFimpEF is limited and comes from heterogenous populations/subgroups. Future RCTs examining long-term, clinical outcomes can clarify uncertainty around the benefits/harms of beta-blocker discontinuation.
BACKGROUND:Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) face high but modifiable risks of incident heart failure (HF). We aimed to ascertain whether the HFpEF-ABA score, a simple 3-variable tool to facilitate timely diagnosis of HFpEF, is associated with adverse cardiovascular (CV) outcomes in patients with CKD and T2D but without HF. METHODS:In this participant-level pooled analysis of the FIDELITY program, including FIDELIO-DKD and FIGARO-DKD, HFpEF-ABA scores (based on age, body mass index, and atrial fibrillation status) were calculated at baseline. Clinical outcomes and treatment effects of finerenone versus placebo were evaluated according to continuous and categorical (low/intermediate, <75%; high, ≥75%) HFpEF-ABA score among FIDELITY participants without HF. RESULTS:Among 12,990 FIDELITY participants, 11,950 (mean age, 65±10 years; 30% female; median HFpEF-ABA score, 62%[47%,77%]) had a calculable HFpEF-ABA. Among FIDELITY patients without HF, those with a high (28%) vs. low/intermediate (72%) HFpEF-ABA score had a higher rate of CV death or incident HF hospitalization (HR, 2.18; 95%CI, 1.86-2.55; P<0.001), incident HF hospitalization (HR, 2.61; 95%CI, 2.13-3.19; P<0.001), and CV death (HR, 1.79; 95%CI, 1.41-2.26; P<0.001). Finerenone reduced CV death or incident HF hospitalization irrespective of baseline HFpEF-ABA score category (Pinteraction=0.68), with greater absolute benefits among those with a high (absolute rate reduction [ARR], 0.8 per 100 person-years) vs. low/intermediate (ARR, 0.2 per 100 person-years) HFpEF-ABA score. Serious adverse events were less common with finerenone vs. placebo in both HFpEF-ABA score categories. CONCLUSIONS:Among persons with CKD and T2D, the HFpEF-ABA model identified increased risks of incident HF and CV death. Finerenone consistently reduced CV events across a broad HFpEF-ABA score spectrum.
BACKGROUND:Real-world data regarding diuretic strategies and associated outcomes in patients hospitalized for heart failure (HF) in community health systems are limited. OBJECTIVES:Evaluate associations between initial diuretic therapy, markers of decongestion, and clinical outcomes in patients hospitalized for HF. METHODS:Patients hospitalized for HF from 2015-2022 across 30 health systems in the U.S. were identified in the Truveta national database. High dose loop diuretics were defined as >2.5X home dose or >160 mg IV furosemide equivalent over 24 hours. Four study groups were defined based on most intensive diuretic strategy used within 48 hours of admission: 1) high dose loop diuretics with adjuvant therapy (thiazide or acetazolamide), 2) high dose loop diuretics alone, 3) low dose loop diuretics with adjuvant therapy, and 4) low-dose loop diuretics alone. Multivariable logistic and linear regression models adjusted for clinical and demographic covariates were developed to evaluate associations between initial diuretic strategies and both in-hospital outcomes (acute kidney injury [AKI]), hemoconcentration, and weight change) and the composite of readmission or death. RESULTS:Patients were treated with low dose loop diuretics (N=81,734; 74.9%), high dose loop diuretics (N=17,187; 15.7%), low dose loop diuretics plus adjuvant therapy (N=7,027; 6.4%), and high dose loop diuretics plus adjuvant therapy (N=3,210; 2.9%). Patients treated with more intensive strategies had greater illness severity, including more frequent prior HF hospitalizations and worse kidney function. Adjusted weight loss during hospitalization was greater for patients treated with more intensive strategies (high dose loop with adjuvant: 4.6 lbs [4.0-5.2]; high dose loop alone: 2.1 lbs [1.9-2.4]; low dose loop with adjuvant: 1.4 lbs [1.0-1.8]), as were adjusted odds of AKI. The adjusted odds of 90-day readmission/death were not lower with more intensive initial diuretic strategies. However, odds of 90-day readmission/death were lower for every 5 lbs of achieved weight loss (adjusted odds ratio: 0.97, 95% confidence interval 0.96-0.97). CONCLUSIONS:More intensive diuretic strategies were used in sicker patients, improved in-hospital decongestion, but were not associated with improved 90-day outcomes. However, greater weight loss was associated with modestly lower risk of death or readmission. These data highlight the need for prospective studies to evaluate if enhancing decongestion can improve outcomes in patients hospitalized for HF.
BACKGROUND AND METHODS:The Trivandrum Heart Failure Registry (THFR) is a prospective cohort study of patients hospitalized with acute decompensated heart failure (HF) in 18 hospitals across Trivandrum, Kerala, from January to December 2013. Trained nurses collected detailed clinical and treatment data, and participants were followed every 3-6 months for ten years. We used Kaplan-Meier survival curves and the Cox proportional hazards model to analyze factors associated with mortality in HF. RESULTS:A total of 1,205 patients were enrolled (mean age 61.2 ± 13.6 years), with a male predominance (n=834, 69%). The majority (n=752, 62.4%) had heart failure with reduced ejection fraction (HFrEF), 21.8% had mildly reduced EF (HFmrEF), and 15.8% had preserved EF (HFpEF). Comorbid conditions were common, with 55% having diabetes and 58% hypertension. Ischemic heart disease was the leading cause of HF (71.9%), followed by dilated cardiomyopathy (12.9%) and rheumatic heart disease (7.9%). At discharge, only 25.4% of HFrEF patients received guideline-directed medical therapy (GDMT), a combination of an ACE inhibitor or ARB, a beta-blocker, and a mineralocorticoid receptor antagonist. Complete follow-up data was available for 88.8% of participants. The overall mortality at 10 years was 875 (82.7%) out of 1,058 patients available for follow-up, with cardiovascular causes accounting for 838 (96%) of deaths; the remainder were attributed to COVID-19 and other non-cardiovascular conditions. Mortality was highest among those with HFrEF (85.3%), followed by HFmrEF (82.1%) and HFpEF (72.7%) (Log-rank p<0.001). Among patients with HFrEF on follow-up, the mortality was 126 (75.9%) for those prescribed GDMT at baseline, compared with 437 (88.6%) for those not prescribed GDMT (HR=0.71; 95% CI 0.57-0.88, p=0.002). CONCLUSIONS:In this Indian HF registry, 83% of patients died over 10 years, reflecting high mortality. GDMT for HFrEF showed lasting survival benefits, while patients with HFpEF had lower mortality than HFrEF and HFmrEF. The findings stress the need for better implementation of GDMT and wider preventive strategies to reduce HF burden.
BACKGROUND:Circulating dipeptidyl peptidase-3 (cDPP3), a protease involved in angiotensin II degradation, has demonstrated prognostic properties, including organ dysfunction and/or mortality in patients with cardiogenic shock (CS) or at risk of developing CS. However, the prognostic properties of cDPP3 have not yet been investigated in patients with the most severe CS who require venoarterial extracorporeal membrane oxygenation (VA-ECMO). METHODS AND RESULTS:This is a post hoc analysis of ADRECMO(Adrenoreceptor Expressions on Inflammatory Pattern in Refractory Cardiogenic Shock Under VA ECMO), a prospective cohort of 50 patients primarily designed to investigate the association between inflammation and adrenoreceptor expression in patients with CS receiving VA-ECMO. cDPP3 measurements were performed before VA-ECMO device implantation, 3-5 days later while VA-ECMO was ongoing, and before device explantation. Associations between cDPP3 concentrations at the predefined timepoints and level of organ dysfunction and 30-day survival were investigated. Forty-seven patients were analyzed. The median cDPP3 concentration was 73 ng/mL (interquartile range [IQR] 46-151 ng/mL) at VA-ECMO device implantation decreasing to 47 ng/mL (IQR 30-64 ng/mL) at days 3-5 and ng/mL 39 (IQR 29-50 ng/mL) on the day of device explantation (P < .001). Patients with a cDPP3 concentration of >73 ng/mL at VA-ECMO device implantation exhibited higher lactate concentrations (3.5 mmol/L [2.5-5.9 mmol/L] vs 1.9 mmol/L [1.3-3 mmol/L], P < .001), a worse estimated glomerular filtration rate (26 mL/min/1.73 m2 [15-40 mL/min/1.73 m2] vs 75 mL/min/1.73 m2 [48-102 mL/min/1.73 m2], P < .001), higher aspartate aminotransferase levels (1127 IU/L [587-1970 IU/L] vs 195 IU/L [50-646 IU/L], P < .001), and a greater norepinephrine cumulated dose (682 μg/kg [326-2258 μg/kg] vs 93 μg/kg [0-349 μg/kg], P = .001) compared with patients with lower cDPP3 concentrations. After adjustment for the cause of the CS, timing of VA-ECMO device implantation, and cardiac arrest before implantation, patients with a high cDPP3 concentration before implantation exhibited lower survival compared with patients with a low cDPP3 concentration (adjusted hazard ratio 4.13, 95% confidence interval 1.55-10.98). No significant association was observed between cDPP3 concentrations at later timepoints and 30-day survival. CONCLUSIONS:In a population of patients with CS on VA-ECMO, a high cDPP3 concentration measured before implantation was associated with greater severity of organ dysfunction and lower 30-day survival rates.
