Circulation: Heart Failure

Abstract Background: Despite widespread adoption of contemporary guideline-directed medical therapy (GDMT), patients with heart failure with reduced ejection fraction (HFrEF) continue to experience substantial residual morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated cardiometabolic benefits in diabetes and obesity, but their role in HFrEF remains uncertain. Objectives: To evaluate whether the addition of GLP-1RAs to optimized GDMT is associated with improved clinical outcomes in patients with HFrEF (NYHA class II-IV). Methods: We conducted a retrospective, multicenter cohort study using the TriNetX Research Network. Adults ([&ge;]18 years) with HFrEF (LVEF [&le;]40%) receiving GDMT between January 2020 and October 2024 were included. Patients treated with GLP-1RAs were compared with those on GDMT alone. After 1:1 propensity score matching, 1,518 patients were included in each cohort. Outcomes over 2 years included all-cause mortality, major adverse cardiovascular events (MACE), critical care utilization, and acute kidney failure. Time-to-event analyses were performed using Kaplan-Meier methods and Cox proportional hazards models. Results: In the matched cohort (mean age [~]63 years, [~]33% female), GLP-1RA use was associated with significantly lower all-cause mortality compared with GDMT alone (12.8% vs 23.8%; hazard ratio [HR] 0.48; 95% CI 0.40-0.57; p<0.001), corresponding to an absolute risk reduction of 11.0%. MACE was also reduced (35.8% vs 47.4%; HR 0.64; 95% CI 0.58-0.72; p<0.001). Additionally, GLP-1RA therapy was associated with lower critical care utilization (18.4% vs 28.9%; HR 0.55; 95% CI 0.47-0.64; p<0.001) and reduced acute kidney failure (29.2% vs 37.3%; HR 0.67; 95% CI 0.59-0.76; p<0.001). Rates of pancreatitis and substance-related disorders were low and not significantly different between groups. Conclusions: Among patients with HFrEF receiving contemporary GDMT, adjunctive GLP-1RA therapy was associated with significant reductions in mortality, cardiovascular events, and healthcare utilization. These findings support the potential role of GLP-1RAs as a novel, mechanism-complementary therapy in HFrEF. Prospective randomized trials are needed to confirm these observations and determine whether GLP-1RAs should be incorporated as a fifth pillar of GDMT.

BackgroundHeart failure (HF) is an increasingly common complication among patients with type 2 diabetes (T2D), yet its early detection remains challenging, especially in those with concomitant chronic kidney disease (CKD). NT-proBNP is a key biomarker for diagnosing and prognosticating HF, but its reference thresholds are influenced by renal function, age, and ethnicity. Current guideline cutoffs, largely derived from Western populations, may not apply to Asian patients. MethodsThis retrospective cohort study included 10,587 adults with T2D who underwent NT-proBNP testing between 2006 and 2021 at the National Taiwan University Hospital. Patients with prior HF were excluded. Generalized additive models identified NT-proBNP thresholds associated with HF hospitalization, and Kaplan-Meier analysis validated outcome separation. Subgroup analyses were stratified by age, sex, body mass index (BMI), and estimated glomerular filtration rate (eGFR). ResultsDuring a mean follow-up of 3.5 years, 1,892 (17.9%) patients were hospitalized for HF. NT-proBNP levels of 179 pg/mL (outpatient) and 728 pg/mL (emergency) marked inflection points for rising event risk (log-rank p < 0.0001). Age-specific analyses showed progressive increases in optimal thresholds: from 85 (<50 years old), 150 (50-74 years old) and 290 pg/mL ([&ge;]75 years old) in outpatients, and from 310, 600 and 1,165 pg/mL, respectively, in emergency settings. In the BMI-stratified analysis, NT-proBNP thresholds demonstrated an inverse relation with BMI. Considering renal function, the optimal cutoffs were 100, 310, and 935 pg/mL for eGFR > 60, 30-60, and < 30 mL/min/1.73 m{superscript 2}, respectively; in the emergency cohort, the corresponding thresholds were 290, 835, and 3,905 pg/mL. ConclusionsThis large Asian cohort defines setting- and renal function-specific NT-proBNP thresholds for predicting HF hospitalization in patients with T2D. The lower optimal cutoffs compared with Western guidelines highlight the need for ethnicity-adjusted diagnostic criteria to improve early identification and risk stratification of HF in clinical practice. What is new?O_LIIn a large real-world Asian cohort of patients with type 2 diabetes, we identified setting-specific NT-proBNP thresholds (179 pg/mL outpatient; 728 pg/mL emergency) associated with heart failure hospitalization risk. C_LIO_LIAge-, BMI-, and kidney function-stratified cutoffs revealed substantial heterogeneity in optimal NT-proBNP thresholds. C_LIO_LICompared with guideline-recommended values, Asian-specific thresholds were consistently lower ([~]30-40%), supporting ethnic differences in natriuretic peptide biology. C_LIO_LIA generalized additive model (GAM) captured nonlinear biomarker-risk relationships, enabling data-driven and clinically interpretable cutoff identification. C_LI What are the clinical implications?O_LIUse of ethnicity- and context-specific NT-proBNP thresholds may improve early detection of heart failure in Asian patients with type 2 diabetes. C_LIO_LIIncorporating kidney function and BMI into NT-proBNP interpretation enhances risk stratification, particularly in patients with CKD. C_LIO_LIReliance on Western guideline cutoffs may underestimate heart failure risk in Asian populations. C_LIO_LIThese findings support a precision medicine approach to biomarker interpretation and highlight the need for population-specific guideline refinement. C_LI

Background: The prevalence of heart failure (HF) is increasing worldwide, and rehospitalizations due to exacerbations remain a major clinical and economic burden. Beyond medical triggers, insufficient patient understanding and inadequate self-management often contribute to recurrent admissions. The Kurume-HEARTS program was developed to provide regular planned hospitalizations incorporating structured education, cardiac rehabilitation, and medication adjustment for patients with recurrent HF. Objective: To retrospectively evaluate the clinical and economic impact of the Kurume-HEARTS program. Methods: We enrolled consecutive patients with recurrent HF hospitalizations who underwent the program at Kurume University Hospital between January 2020 and October 2025. Outcomes compared planned versus unplanned hospitalizations within the same patients. Co-primary endpoints were total hospitalization cost and total length of stay per person-year. Secondary endpoints included per-hospitalization cost, length of stay, unplanned and planned admission frequency, and NT-proBNP levels at admission. Results: Of 31 screened patients, 20 with recurrent heart failure were included. During a median follow-up of 27.1 months, 135 hospitalizations occurred (69 unplanned and 66 program-based). Total hospitalization cost per person-year was significantly lower during the Kurume-HEARTS program than during unplanned hospitalizations, while length of stay per person-year tended to be shorter. Per-admission cost and length of stay were significantly lower with the program, without differences in admission frequency. NT-proBNP levels at admission were higher during unplanned hospitalizations, indicating greater clinical instability. Conclusions: The Kurume-HEARTS program can help reduce the cost and hospitalization length of unplanned admissions by enabling earlier intervention and structured inpatient management.

Background. Patients with heart failure and reduced ejection fraction (HFrEF) commonly show signs of systemic inflammation. Interleukin-1 (IL-1) is a pro-inflammatory cytokine, known to modulate cardiac function. We aimed to determine the effects of treatment with anakinra, recombinant IL-1 receptor antagonist (IL-1Ra), on plasma IL-1Ra levels. Methods. We measured IL-1Ra levels at baseline and longest available follow-up to 24 weeks in 63 patients (44 males, 40 self-identified Black-Americans) with recent hospitalization for HFrEF, and systemic inflammation (C reactive protein [CRP] levels >2 mg/L) who were assigned to anakinra (N=42 [66.7%]) or placebo (N=21 [33.3%]) as part of the REDHART2 clinical trial (NCT0014686). Cardiorespiratory fitness was measured as peak oxygen consumption (peak VO2). Results. Baseline plasma IL-1Ra levels were 380 pg/ml (290 to 1046). On-treatment IL-1Ra levels were significantly higher in the patients treated with anakinra vs placebo (3,994 pg/ml [3,372 to 5,000] vs 492 pg/ml [304 to 1370], P<0.001). The longest available follow-up was 6 weeks in 10 patients (15.9%), 12 weeks in 12 patients (19%) and 24 weeks in 41 patients (65.1%). On-treatment IL-1Ra levels and interval change in IL-1Ra showed a modest inverse correlation with on-treatment CRP levels (R=-0.269, P=0.033 and R=-0.355, P=0.004, respectively) and no statistically significant correlations with peak VO2 values (P>0.05). Conclusions. Patients with recently decompensated HFrEF and systemic inflammation treated with recombinant IL-1Ra, anakinra, have a significant several-fold increase in plasma IL-1Ra levels. On-treatment IL-1Ra levels however show only a modest correlation with CRP levels and not with peak VO2.

PurposeDespite strong evidence, real-world adoption of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) remains suboptimal. The Get With The Guidelines-Heart Failure (GWTG-HF) program was designed to close gaps in care. We evaluated whether hospital participation in GWTG-HF is associated with greater GDMT intensity and improved outcomes. MethodsWe conducted a retrospective analysis (2013-2021) of Medicare beneficiaries with Part A and Part D hospitalized with HFrEF. Using a multiple baseline time series design, we compared changes in GDMT prescribing and outcomes at hospitals before and after GWTG-HF enrollment with hospitals that never participated. The primary outcome was a 90-day post-discharge prescription-fill GDMT score summarizing use and dose of beta blockers, renin-angiotensin system inhibitors (RASI; ACE inhibitor/ARB/ARNI), and mineralocorticoid receptor antagonists (MRA). Secondary outcomes included class-specific medication fills, achievement of [&ge;]50% target doses, and 30-day, 90-day, and 1-year all-cause and HF readmission and mortality. We adjusted for baseline hospital performance, patient characteristics, and temporal trends. ResultsAmong 1,274,863 Medicare beneficiaries hospitalized for HFrEF, 53.5% were treated at hospitals that never participated in GWTG-HF and 9.6% at hospitals that joined GWTG-HF before hospitalization. Unadjusted median GDMT scores increased from 3.0 in both groups to 4.0 in non-participating hospitals and 4.5 in GWTG-HF hospitals at 90 days (p<0.001). Hospital enrollment was associated with a higher 90-day GDMT score (+0.15 points; 95% CI 0.12-0.18; p<0.001), and greater use of beta blockers, RASI, and MRA, but not ARNI. HF readmission did not differ significantly; however, GWTG-HF participation was associated with lower all-cause mortality at 30 days (OR 0.95; 95% CI:0.92-0.98), 90 days (OR: 0.97; 95% CI: 0.95-0.99), and 1 year (0.97; 95% CI: 0.95-.0.99; all p<0.05). ConclusionHospital participation in GWTG-HF was associated with higher GDMT intensity and lower mortality, supporting structured quality programs to improve HFrEF care.

BackgroundSodium-glucose co-transporter 2 (SGLT2) inhibitors have emerged as a cornerstone of heart failure (HF) therapy, yet the totality of randomized evidence -- including smaller trials -- has not been comprehensively synthesized. We aimed to evaluate the efficacy and safety of SGLT2 inhibitors across the full spectrum of HF. MethodsWe searched PubMed, Cochrane CENTRAL, ClinicalTrials.gov, and WHO ICTRP from inception to March 2026 for randomized controlled trials comparing any SGLT2 inhibitor with placebo or standard care in adults with HF. Primary outcomes were all-cause mortality (ACM) and HF hospitalization (HFH). We used random-effects models with Mantel-Haenszel risk ratios and Hartung-Knapp-Sidik-Jonkman confidence intervals. Certainty of evidence was assessed using GRADE. The protocol was registered prospectively (PROSPERO CRD420251167908). ResultsOf 6,239 records identified, 114 studies met inclusion criteria and 59 RCTs (29,692 participants) were included in quantitative synthesis. SGLT2 inhibitors significantly reduced ACM (RR 0.90 [0.83, 0.98], p = 0.016; 26 trials; I2 = 0%; low certainty) and HFH (RR 0.74 [0.69, 0.79], p < 0.001; 15 trials; I2 = 0%; moderate certainty). The composite of CVD and HFH was reduced (RR 0.80 [0.75, 0.85], p < 0.001; high certainty). Genital infections were significantly increased (RR 3.75 [1.72, 8.19], p = 0.007). Results were robust across 12 sensitivity analyses and 4 alternative statistical models. ConclusionsSGLT2 inhibitors reduce all-cause mortality, HF hospitalization, cardiovascular death, and serious adverse events in adults with HF, with an acceptable safety profile apart from increased genital infections. These findings support the use of SGLT2 inhibitors as a foundational therapy across the HF spectrum.

We performed a systematic review and meta-analysis of randomized controlled trials evaluating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus placebo in adults with heart failure (HF), searching PubMed, Cochrane CENTRAL, and ClinicalTrials.gov through February 2026. The primary outcome was the composite of cardiovascular death and first HF hospitalization. Random-effects meta-analysis used restricted maximum likelihood estimation with Hartung-Knapp-Sidik-Jonkman adjustment. We included 14 studies (6 dedicated HF trials and 8 cardiovascular outcomes trial HF subgroup analyses) encompassing 18,558 patients, of whom 2,499 were randomized in dedicated HF trials. The primary composite did not reach statistical significance (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.73-1.01; P=0.067; I2=47%). GLP-1 RAs significantly reduced all-cause mortality (HR 0.87, 95% CI 0.81-0.93; P<0.001; I2=0%), major adverse cardiovascular events (HR 0.83, 95% CI 0.73-0.95; P=0.019), and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (+7.4 points, 95% CI 6.3-8.5) and 6-minute walk distance (+17.6 m, 95% CI 13.4-21.7). Excluding the FIGHT trial (acute HFrEF) yielded a significant primary composite (HR 0.83, P=0.011). The mortality signal was driven primarily by CVOT subgroups; the largest dedicated HFpEF trial (SUMMIT) showed numerically higher mortality (HR 1.25). The strongest evidence supports GLP-1 RAs in HFpEF with obesity. HighlightsO_LIPrimary composite of CV death + HHF was not significant (HR 0.86, P=0.067) C_LIO_LIGLP-1 RAs reduced all-cause mortality (HR 0.87) with no heterogeneity C_LIO_LIKCCQ-CSS improved by 7.4 points and 6MWD by 17.6 m in HFpEF trials C_LIO_LIMortality benefit driven by CVOT subgroups, not dedicated HF trials C_LIO_LIStrongest evidence supports GLP-1 RAs in HFpEF with obesity C_LI

AimsThe activation of inflammatory cells, particularly macrophages, plays a pivotal role in the pathogenesis of cardiac remodelling and heart failure. Emerging evidence indicates that extracellular traps released from inflammatory immune cells contribute to the progression of various pathologies. However, the clinical relevance and mechanistic role of macrophage extracellular traps (METs) in heart failure remain to be elucidated. Methods and ResultsEndomyocardial biopsy specimens from 69 patients with heart failure were analysed by fluorescent immunostaining to identify and quantify METs. The numbers of METs per myocardial tissue area in patients with heart failure showed a negative correlation with left ventricular (LV) ejection fraction and a positive correlation with LV end-diastolic diameter. Patients with higher MET counts had significantly lower event-free survival from the composite cardiac events. In a murine model of pressure overload by transverse aortic constriction (TAC), METs were most abundantly observed at 3 days post-TAC and remained detectable throughout the 4-week observation period. In vitro, time-dependent MET formation was induced by an intrinsic trigger of mitochondrial DNA in bone marrow-derived macrophages from wild-type (WT) mice, but not in peptidyl arginine deiminase 4 (PAD4)-deficient macrophages, indicating that PAD4 activity is indispensable for MET formation. The recipient mice transplanted with bone marrow cells from PAD4 knockout mice showed more preserved cardiac function, reduced myocardial fibrosis, and improved survival in response to TAC, compared to those transplanted with WT mice. Ex vivo analyses demonstrated that conditioned medium containing METs from WT macrophages induced fibroblast-to-myofibroblast transition via Toll-like receptor 4 signalling. ConclusionsPAD4-dependent MET formation from bone marrow-derived macrophages represents a novel driver of cardiac remodelling. Targeting MET formation may offer a potential therapeutic strategy for heart failure. Translational PerspectiveMacrophage extracellular traps (METs) are abundant in myocardial tissue from patients with heart failure with reduced ejection fraction and are associated with adverse left ventricular remodelling and worse clinical outcomes. These findings support myocardial MET burden as a potential tissue biomarker to improve risk stratification in heart failure patients. In mice, pressure overload induces MET formation, and hematopoietic PAD4 deficiency suppresses myocardial METs, attenuates fibrosis, preserves cardiac function, and improves survival. Mechanistically, mitochondrial DNA-enriched cardiomyocyte-derived exophers trigger PAD4-dependent METs, which activate cardiac fibroblasts through TLR4 signalling. Suppressing METs represents a potential therapeutic strategy to attenuate the progression of heart failure. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/711858v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1c6a637org.highwire.dtl.DTLVardef@caa356org.highwire.dtl.DTLVardef@1a994bforg.highwire.dtl.DTLVardef@6493bb_HPS_FORMAT_FIGEXP M_FIG C_FIG

Rationale: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with substantial unmet diagnostic and therapeutic needs. Circulating lipid metabolism is increasingly implicated in HFpEF pathophysiology but has not been systematically leveraged for molecular stratification. Objective: To determine whether plasma lipidomics can identify molecular phenogroups of HFpEF associated with distinct clinical characteristics and outcomes. Methods and Results: Untargeted plasma lipidomics was performed in non-HF subjects and HFpEF patients from a primary Belgian cohort and an independent Canadian cohort (n=177 in each cohort). In the Belgian cohort, 235 unique lipids spanning 19 subclasses were annotated, including 96 significantly associated with HFpEF (q<0.02). Unsupervised analyses revealed marked lipidomic heterogeneity, with a distinct HFpEF subgroup separable from non-HF subjects. Hierarchical clustering identified three phenogroups with divergent lipid profiles and clinical features. One phenogroup exhibited severe atrial dysfunction, congestion-related biomarkers, elevated indices of cardiac and liver fibrosis, and markedly reduced survival, a second was characterized by prominent metabolic syndrome features, and a third by preserved renal function. Cross-cohort comparison using a supervised classifier trained on 158 shared lipids confirmed analogous lower-risk phenogroups in the Canadian cohort, while the high-risk phenotype was underrepresented. A signature of 10 lipids across six subclasses, including long-chain acylcarnitines, ether phosphatidylcholines, and oxidized sphingomyelins, discriminated the high-risk group and correlated with markers of disease severity. Conclusion: Our findings demonstrate that HFpEF comprises metabolically distinct patient subgroups across cohorts, revealing specific lipidomic dysfunctions that deepen our understanding of HFpEF heterogeneity and underlying pathophysiology.

Background Current management of pediatric dilated cardiomyopathy (DCM) in children relies on guideline-directed medical therapy (GDMT) extrapolated from adult heart failure. However, due to small sample size, randomized trials of GDMT agents in children have failed to demonstrate efficacy and mortality benefits seen in adults, suggesting fundamental differences in disease mechanisms. We hypothesized that distinct age-dependent transcriptional programs underlie this therapeutic discordance. Methods We performed comparative transcriptomic profiling using bulk RNA sequencing on explanted left ventricular tissue from pediatric (n=29) and adult (n=35) DCM patients (adult DCM from previously published data) compared with age-matched non-failing controls (n=22 pediatric, 14 adult). We analyzed differential gene expressions, pathway enrichment across disease etiologies, and the regulation of a conserved 430-gene {beta}1-adrenergic receptor gene signaling network ({beta}1-GSN) known to modulate remodeling in adult heart failure. Results Transcriptional signatures were profoundly distinct, with only 7.4% of differentially expressed genes shared between adult and pediatric cohorts. Pediatric DCM was characterized by transcriptional reprogramming and the activation of developmental pathways, including WNT/{beta}-catenin and Notch signaling. Conversely, adult DCM hearts were enriched for pathways associated with metabolic dysfunction, mitochondrial deficits, and inflammation. Crucially, while the {beta}1-GSN was desensitized and extensively remodeled in adults, the pathway remained activated in children, with only 4 of 430 network genes showing antithetical regulation. Conclusion The lack of pathological {beta}-adrenergic remodeling in children could provide a molecular explanation for the lack of clear efficacy of {beta}-blockers in this population. Collectively, these results suggest pediatric DCM represents a biologically distinct disease entity rather than an earlier manifestation of adult heart failure, and future therapeutic strategies must move beyond adult extrapolation to target pediatric-specific pathways.

Whether the cumulative evidence for remote patient monitoring (RPM) in heart failure (HF) has reached a definitive threshold -- and whether benefits extend to geographically underserved populations -- remains uncertain. We conducted a systematic review, meta-analysis, and trial sequential analysis (TSA) of 65 RCTs (59 poolable; [~]23,000 participants) across four databases through February 2026, encompassing structured telephone support (15 trials), non-invasive telemonitoring (33), and invasive hemodynamic monitoring (11). Random-effects meta-analysis used REML with Hartung-Knapp-Sidik-Jonkman adjustment. RPM significantly reduced all-cause mortality (RR 0.890, 95% CI 0.819-0.966; P=0.007; I2=2.3%; k=41; NNT 84/year; prediction interval 0.820-0.965). TSA confirmed that accrued evidence exceeded the required information size, establishing firm evidence that additional RPM-versus-control trials are unlikely to overturn the mortality benefit. HF hospitalization was reduced (RR 0.782, 95% CI 0.711-0.859; P<0.001; k=39; NNT 17/year), though the prediction interval crossed 1.0 (0.589-1.038), indicating that in some settings the effect may be attenuated. No interaction by RPM type was observed (Pinteraction=0.15-0.24). GRADE certainty was moderate for mortality and low for HF hospitalization. A pre-specified geographic access analysis revealed that only 2 of 59 trials reported rural/urban subgroups -- a critical evidence gap that precludes conclusions about whether RPM differentially benefits underserved populations. HighlightsO_LITrial sequential analysis confirms firm evidence for RPM mortality benefit C_LIO_LIAll-cause mortality reduced 11% (NNT 84/yr, prediction interval excludes null) C_LIO_LIHF hospitalization reduced 22% (NNT 17/yr), though prediction interval crosses 1.0 C_LIO_LINo differential benefit by RPM type (STS vs TM vs invasive; Pinteraction=0.24-0.34) C_LIO_LIOnly 2 of 59 trials reported rural/urban subgroups -- a critical geographic evidence gap C_LI

BackgroundDyspnea and exercise intolerance are the primary clinical symptoms of heart failure. Heart failure patients experience frequent hypoxemic episodes, yet underlying mechanisms and relevance remain poorly understood. In a cohort of heart failure patients and multiple animal models, we identify pulmonary capillary rarefaction driven by excessive autophagy in endothelial cells as a novel mechanism of hypoxemia and cardiac disease progression. MethodsA cohort of heart failure with preserved ejection fraction (HFpEF) patients was analyzed for parameters of left ventricular (LV) dysfunction and pulmonary gas exchange. Morphological and cellular mechanisms of impaired pulmonary oxygenation were assessed in three animal models of heart failure, namely two HFpEF models, SU5416-treated ZSF1 obese rats and high fat diet/L-NAME treated mice, and in rats subjected to aortic banding. Lung microvascular rarefaction was quantified by micro-computed tomography, stereology, flow cytometry and dye efflux. Cellular mechanisms of capillary loss were analyzed by single-cell transcriptomics, electron microscopy and immunofluorescence, and in mice with endothelial-specific deletion of the autophagy gene Atg7 (Atg7EN-KO). ResultsIn 234 HFpEF patients, advancing NYHA class was associated with progressive worsening of arterial oxygen saturation at rest and during exercise and a reduced lung diffusing capacity. Impaired gas diffusion correlated with indices of LV diastolic dysfunction. Impaired oxygenation and reduced exercise capacity were similarly evident in animal models of left heart disease, which showed a distinct loss of pulmonary microvessels and capillaries. Lung microvascular endothelial cells in HFpEF showed characteristics of increased autophagic flux and apoptosis. Relative to their wild type HFpEF controls, Atg7EN-KO mice had less capillary loss, restored normoxemia, improved exercise tolerance, and mitigated LV diastolic dysfunction. Additional studies in HFpEF mice corroborated the functional relevance of impaired gas exchange for the progression of left heart disease by demonstrating that additional hypoxia aggravated, whereas moderate hyperoxia improved LV function. ConclusionOur findings identify pulmonary microvascular rarefaction as a novel pathomechanism in heart failure that i) contributes to dyspnea and exercise intolerance, ii) impairs pulmonary gas exchange and iii) accelerates LV disease progression. Strategies targeting this axis such as moderate oxygen therapy may mitigate cardiopulmonary morbidity in heart failure. Clinical Trial RegistrationRegistered in the DRKS (Deutsches Register fur klinische Studien) as trial# DRKS00032974 at https://drks.de/search/en/trial/DRKS00032974.

Aims: Assessment of treatment response in HFrEF has largely relied on left ventricular (LV)-centric parameters, yet the left atrium (LA) plays a central role in modulating LV filling and reflects the cumulative hemodynamic burden. Whether discordant recovery between LV and LA function carries distinct prognostic implications in patients treated with ARNI-based therapy remains unknown. Methods and results: From the multicenter STRATS-HF-ARNI registry, 1,182 patients with HFrEF who underwent serial echocardiography at baseline and one-year follow-up were included. Patients were classified into four strain recovery phenotypes according to the direction of change in LVGLS and LASr at one year: Group A, concordant recovery (57.4%); Group B, discordant atrial non-recovery (11.2%); Group C, discordant ventricular non-recovery (15.6%); and Group D, concordant non-recovery (16.0%). Clinical outcomes included all-cause mortality, cardiovascular mortality, and HF hospitalization. Despite achieving LV functional improvement, Group B exhibited persistent LASr deterioration, accompanied by less favorable hemodynamic trajectories compared with Group A. On multivariable Cox regression, Group B was associated with significantly higher risks of all-cause mortality (adjusted hazard ratio [aHR] 3.53, 95% confidence interval [CI] 1.60-7.79) and cardiovascular mortality (aHR 5.68, 95% CI 1.91-16.92), comparable to Group D. Group C demonstrated higher HF hospitalization risk (aHR 2.25, 95% CI 1.31-3.86). The adverse prognostic impact of discordant atrial non-recovery was consistently observed across subgroups stratified by baseline LVGLS and LASr levels. Conclusion: In HFrEF patients treated with ARNI-based therapy, persistent LA dysfunction despite LV functional improvement identifies a high-risk phenotype comparable to concordant non-recovery. These findings suggest that concurrent assessment of LV and LA strain may provide incremental prognostic value beyond LV-centric metrics alone.

Background: Anemia is nearly ubiquitous in hospitalized patients with congestive heart failure (CHF), yet little data informs the decision to transfuse blood in this population. Objectives: To determine average and heterogenous effects of blood transfusion in hospitalized patients with CHF. Methods: We performed a multicenter retrospective cohort study with individual treatment effect analysis using the Premier Healthcare Database (2022-2024). Adult patients with CHF hemoglobin concentrations between 6.5-7.4 g/dL were included. The exposure was blood transfusion based on hemoglobin concentration threshold of <7.0 g/dL. The primary outcome was hospital free days by day 28 (HFDs). We determined the average effect of transfusion using instrumental variable analysis based on a hemoglobin threshold of 7.0 g/dL and estimated the predicted effects of transfusions on HFDs (i.e., conditional average treatment effects) for individual patients using causal forest machine learning models. Results: We included 31,408 patients in a derivation cohort and 30,677 in a validation cohort, of which 13,437 (42.8%) and 13,334 (43.5%) received transfusions, respectively. The average association between transfusion and HFDs suggested harm (derivation mean difference -1.8 [95% CI -2.3, -1.3] days; validation mean difference -1.5 [95% CI -2.0, -1.0] days). However, the effects of transfusion were heterogenous (p=0.001) with the strongest drivers of transfusion benefit being transfusion on hospital day 1 and low serum bicarbonate concentration. Conclusions: The average association between transfusion and HFDs in hospitalized patients with CHF suggested harm; however, there were potential small benefits early in hospitalization and in those with low serum bicarbonate concentrations.

BackgroundKetone bodies have shown potential to improve cardiac metabolism and function in patients with heart failure (HF). ObjectiveTo evaluate the effects of exogenous ketone-based interventions on cardiac function in patients with HF or related cardiometabolic risk factors. MethodsWe conducted a systematic review based on a search of MEDLINE, EMBASE, CINAHL, Cochrane Library, and Scopus from inception to January 2025. Eligible studies included randomized controlled trials evaluating exogenous ketones (oral ketones or ketone infusions) compared to placebo in adults with HF or patients with risk factors for HF including type 2 diabetes mellitus, hypertension, or coronary artery disease. Paired reviewers independently screened and identified hits at title-and-abstract and full-text levels to determine eligibility and extracted data from eligible studies. Random-effects meta-analysis was performed. Effects of interventions were summarized as mean differences (MD). Risk of bias was assessed using Cochrane RoB 2.0 tool. Certainty of evidence was evaluated using the GRADE (grading of recommendations assessment, development and evaluation) approach. ResultsOut of 565 unique records, 22 full-text articles were reviewed, and 8 studies met inclusion criteria. Exogenous ketone administration increased left ventricular ejection fraction (LVEF) (MD = 3.94, 95% CI 2.18-5.70, p = 0.001), cardiac output (CO) (MD = 1.11 L/min, 95% CI 0.55-1.67, p = 0.002), heart rate (4.85 bpm, 95% CI 2.24-7.46, p = 0.003), and stroke volume (SV) (MD = 10.21 mL, 95% CI 4.06-16.35, p = 0.005). Pulmonary capillary wedge pressure (PCWP) decreased (MD = -0.93 mmHg, 95% CI -1.44 to -0.43, p = 0.003), while mean arterial pressure showed no change (MD = -1.37 mmHg, 95% CI -3.53 to 0.79, p = 0.18). ConclusionsExogenous ketone-based therapies are associated with improvements in hemodynamic markers of cardiac function, including increases in LVEF, CO, and SV, along with a reduction in PCWP. These findings suggest that ketone supplementation may offer clinical benefits for patients with HF or vascular disease.

Structured AbstractO_ST_ABSBackgroundC_ST_ABSVericiguat and sacubitril/valsartan both modulate the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling pathway and may improve myocardial function in patients with heart failure. ObjectivesTo compare the effects of vericiguat, sacubitril/valsartan, and their combination on left ventricular function and clinical outcomes in heart failure with nonpreserved ejection fraction patients. MethodsIn this retrospective real-world study, patients were classified into three groups: vericiguat added to guideline-directed medical therapy (vericiguat group), sacubitril/valsartan-based therapy (sacubitril/valsartan group), and combined sacubitril/valsartan plus vericiguat therapy (add-vericiguat group). Changes in left ventricular ejection fraction ({Delta}LVEF), in stroke volume ({Delta}SV), and in log-transformed N-terminal pro-B-type natriuretic peptide ({Delta}Log10 NT-pro BNP) from baseline to 1 year were evaluated. Clinical outcomes were also assessed. ResultsAt 1 year, LVEF significantly improved in both the vericiguat group (p = 0.02) and the sacubitril/valsartan group (p < 0.001). There was no significant difference in {Delta}LVEF between these two groups (p = 0.25). In contrast, the add-vericiguat group demonstrated a significantly greater improvement in {Delta}LVEF compared with the vericiguat group alone (p = 0.01). ConclusionsIn a real-world setting, vericiguat was associated with improvements in left ventricular function comparable to those of sacubitril/valsartan, and combination therapy provided incremental benefits. Vericiguat may serve as an alternative or adjunctive treatment option, particularly in patients unable to tolerate or maintain angiotensin receptor-neprilysin inhibitor therapy.

Background: Progression of transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) can lead to worsening congestion requiring diuretic intensification (DI), heart failure (HF)-related hospitalizations (HFH), and death. Tafamidis was the only approved ATTR-CM therapy in the US from 2019 until the 2024 approval of acoramidis, which achieves near-complete ([&ge;]90%) TTR stabilization. As head-to-head trials are lacking, real-world comparative effectiveness (CE) data are needed to guide treatment selection. Objective: To evaluate real-world CE of acoramidis versus tafamidis in newly treated patients with ATTR-CM. Methods: Retrospective study using Komodo Healthcare Map (R) US claims data tokenized to Claritas. Patients newly initiating acoramidis or tafamidis between 12/11/2024 and 04/30/2025 with [&ge;]1 prescription claim (first defined as index date) and [&ge;]6 months of continuous enrollment preindex date were included and followed until disenrollment, death, treatment switch, or study end date (07/31/2025). Outcomes included DI (initiation or dose-equivalent escalation of oral loop diuretics, parenteral loop diuretic use, or addition of thiazide-like diuretic) and a composite of DI, HFH (inpatient admission with a HF-related ICD-10-CM diagnosis code in any position), and mortality. Propensity score weighting balanced baseline characteristics, disease severity, comorbidity burden, and baseline medication use. Time-to-event outcomes were assessed using weighted Cox proportional hazards models. Results: After weighting, acoramidis (n=170) and tafamidis (weighted sample size=448) patients were comparable at baseline (mean age, 78.6 vs 78.7 years; male, 80.0% vs 80.2%) with mean follow-up of 139 and 143 days, respectively. DI cumulative incidence curves separated early and remained divergent, with acoramidis significantly reducing the hazard of DI events by 43% compared with tafamidis (11.8% vs 20.5%; HR, 0.57; 95% CI, 0.35-0.92; P=0.021). Acoramidis also had a significantly lower risk of composite events, with a 34% reduction in hazard compared with tafamidis (17.6% vs 26.4%; HR, 0.66; 95% CI, 0.44-0.99; P=0.046). Conclusions: In this first real-world CE study of newly treated patients, acoramidis had significantly lower risk of DI events and composite events of DI, HFH, and mortality than tafamidis, potentially supporting improved clinical stability with acoramidis initiation. Additional evaluation with longer follow-up, larger cohorts, and/or prospective clinical outcomes is warranted.

Background and aimsIron deficiency (ID) and myocardial iron depletion (MID) are causally linked to heart failure (HF) in the general population and in preclinical models. ID is common amongst pregnant women, but its impact on cardiac adaptations to pregnancy is unknown. This study examines that impact, and its potential relevance to peripartum cardiomyopathy (PPCM). MethodsWe provided female mice with iron-replete or iron-deficient diets, and monitored cardiac function and morphology longitudinally in pregnancy and postpartum. In women with no HF (n=64), we explored the associations between antenatal iron parameters and echocardiographic parameters in late pregnancy and at 6-12 months postpartum. We also performed a case (n=55), control (n=170) study comparing iron markers and assessing their association with PPCM risk. ResultsIn mice, ID prevented postpartum reversal of pregnancy-induced hypertrophy, reduced postpartum LVEF, and caused profound MID. In women with no HF, low hepcidin, high transferrin and low serum iron were respectively associated with higher LVESV, lower LVEF and higher CMR T1-mapping (lower myocardial iron) in postpartum. In the PPCM study, serum iron, hepcidin and haemoglobin were significantly lower in cases than controls, and were independently associated with risk of PPCM. Mechanistically, myocardial proteomics revealed that ID caused sustained postpartum activation of pyruvate dehydrogenase kinase 4, a master cardiometabolic switch enzyme with a well-recognised role in HF. ConclusionsThis study links antenatal maternal ID to postpartum systolic dysfunction, and implicates MID and cardiometabolic switching as potential mechanisms. It suggests these links may potentially contribute to the pathophysiology of PPCM. TRANSLATIONAL PERSPECTIVEO_LIIron deficiency (ID), even without anaemia, is linked to risk of incident HF in the general population and to worse outcomes in those with pre-existing HF. Preclinical studies demonstrated a causal role for myocardial iron depletion (MID) in this context. C_LIO_LIID is common during pregnancy, but its impact on the maternal heart, and its adaptations to the haemodynamic stress of pregnancy are unknown C_LIO_LIBy revealing that antenatal ID is associated with postpartum systolic dysfunction and with PPCM, this study points to ID as a novel risk factor for maternal HF. C_LIO_LIBy revealing the role of MID in this context, this study highlights the potential of intravenous iron therapies, which we have previously shown to raise myocardial iron, to reduce risk of maternal HF. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/26347784v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@9cebe0org.highwire.dtl.DTLVardef@41da1corg.highwire.dtl.DTLVardef@15679f0org.highwire.dtl.DTLVardef@5fa12d_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG

BackgroundHeart failure with preserved ejection fraction (HFpEF) is a major clinical challenge characterized by diastolic dysfunction. Left ventricular stiffening and inflammation are hallmarks of HFpEF, yet the contribution of extracellular matrix (ECM) stiffness and the immune-stromal mechanisms driving ECM stiffening in cardiometabolic HFpEF remain poorly understood. MethodsWe used the murine "2-hit model" of cardiometabolic HFpEF, in which the combination of high fat diet and hypertension induced by L-NAME causes diastolic dysfunction. We evaluated diastolic function by echocardiography and ECM mechanics by uniaxial tensile testing of decellularized cardiac tissue. Functional in vivo studies included genetic depletion of T cells, interferon-{gamma} (IFN{gamma}) knockout mice, and pharmacological lysyl oxidase inhibition. We combined co-cultures of CD4+ T cells and cardiac fibroblasts (CFB) with mechanical testing of cardiac ECM and molecular biology to elucidate cellular and molecular mechanisms. ResultsLeft ventricular ECM stiffness strongly correlated with impaired diastolic function in experimental cardiometabolic HFpEF. Cardiac CD4 T cell infiltration was required for ECM stiffening and upregulation of lysyl oxidase enzymes in CFB. CD4+ T cell-derived IFN{gamma} was both necessary and sufficient to induce LOXL3 in CFB, which increased ECM stiffness in vitro. Mechanistically, IFN{gamma} signaling activated hypoxia-inducible factor-1 (HIF1) in CFB, driving LOXL3 expression and subsequent collagen crosslinking. Genetic or pharmacologic disruption of this IFN{gamma}-HIF1-LOXL3 axis in vivo attenuated adverse ECM remodeling and improved diastolic function. ConclusionsCD4 T cells promote pathological ECM stiffening in cardiometabolic HFpEF through IFN{gamma}-mediated, LOXL3-dependent ECM crosslinking by CFB. Targeting this immune-stromal pathway may offer a novel therapeutic strategy for HFpEF.

BACKGROUNDPeak oxygen uptake (pVO2) is a strong, independent predictor of adverse cardiovascular outcomes, supporting cardiopulmonary exercise testing as a primary end point assessing efficacy of novel drug therapies in obstructive hypertrophic cardiomyopathy (oHCM) clinical trials. However, characterizing changes in pVO2 that patients perceive as beneficial or meaningful (ie, minimal important difference [MID]) has not been determined. METHODSData from patients with symptomatic oHCM enrolled in SEQUOIA-HCM and MAPLE-HCM were pooled. A total of 282 patients were randomized 1:1 to aficamten (5-20 mg daily) or matching placebo in SEQUOIA-HCM, and 175 patients were randomized 1:1 to aficamten (5-20mg daily) or to metoprolol (50-200 mg) in MAPLE-HCM; follow-up in both trials was 24 weeks. Primary outcome was change from baseline to week 24 ({Delta}) in pVO2 using Patient Global Impression of Change with anchor-based analysis to define MID. RESULTSAt week 24, {Delta}pVO2 (mL/kg/min) that corresponded to no change, one-category improvement, and one-category worsening were -0.05 (95% CI, -0.58 to 0.48), +0.35 (95% CI, -0.22 to 0.91), and -0.61 (95% CI, -1.36 to 0.13), respectively. Similarly, minute ventilation to carbon dioxide production ratio (VE/VCO2) slope that corresponded to no change, one-category improvement, and one-category worsening were 0.16 (95% CI, -0.59 to 0.90), -1.15 (95% CI, - 1.89 to -0.42), and 0.88 (95% CI, -0.42 to 2.19), respectively. In a responder analysis using this new threshold for pVO2, 60% of patients receiving aficamten achieved a {Delta}pVO2 [&ge;]0.35 versus 31% of patients on placebo or metoprolol (odds ratio, 3.4 [95% CI, 2.3-4.9], P<0.001). Consistent findings were seen with VE/VCO2 responder analysis. CONCLUSIONSChanges in pVO2 of +0.35 and -0.61 mL/kg/min were associated with a small but perceptible clinical improvement and worsening, respectively, in patients with oHCM. Applying this newly defined threshold resulted in excellent differentiation of treatment effect in a clinical trial. These novel data provide a measure of clarity to patients and clinicians regarding the interpretation of changes in pVO2 following therapeutic interventions, with potential impact on HCM management strategies and future clinical trials. Clinical Trial RegistrationSEQUOIA-HCM (NCT05186818; https://clinicaltrials.gov/study/NCT05186818?term=sequoia-hcm&rank=1); MAPLE-HCM (NCT05767346; https://clinicaltrials.gov/study/NCT05767346?term=maple-hcm&rank=1) Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIUsing pooled data from over 440 patients with symptomatic obstructive hypertrophic cardiomyopathy enrolled in two phase 3 clinical trials, we define, for the first time, the minimally important difference for peak oxygen uptake (pVO2) and ventilatory efficiency (VE/VCO2) using patient-anchored and distribution-based methodologies. C_LIO_LIA change in pVO2 of +0.35 mL/kg/min and a change in VE/VCO2 of -1.15 represent the minimal thresholds associated with patient-perceived clinical improvement. C_LIO_LIResponder analyses using these thresholds demonstrated robust differentiation between aficamten and placebo/metoprolol, with an odds ratio exceeding 3 for achieving a meaningful improvement in pVO2. C_LI What Are the Clinical Implications?O_LIThese newly defined thresholds bridge the gap between statistically significant changes in cardiopulmonary exercise testing measures and clinically meaningful benefit as perceived by patients with obstructive hypertrophic cardiomyopathy. C_LIO_LIClinicians can use these benchmarks to contextualize individual patient responses to medical therapy, informing shared decision-making regarding treatment continuation or modification. C_LIO_LIThese data provide a standardized, patient-centered framework for designing and interpreting primary end points in future hypertrophic cardiomyopathy clinical trials. C_LI