Circulation: Heart Failure

BackgroundDespite 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. ObjectivesTo evaluate whether the addition of GLP-1RAs to optimized GDMT is associated with improved clinical outcomes in patients with HFrEF (NYHA class II-IV). MethodsWe 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. ResultsIn 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. ConclusionsAmong 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.

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.

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.

Background: Heart failure (HF) is a major contributor to inpatient hospital utilization, with persistently high 30-day readmission rates. Existing prediction tools are frequently restricted to primary-diagnosis HF admissions, potentially excluding clinically relevant HF-related hospitalizations. Objectives: To develop and validate risk prediction models using machine learning (ML)-based risk prediction models to predict 30-day readmissions among patients with HF using the Kansas Health Information Network, a statewide health information exchange. Methods: This retrospective cohort study analyzed HF hospitalizations using predictors including demographics, comorbidities, laboratory results, medications, clinical quality metrics for diabetes and kidney disease management, and prior healthcare utilization. Five ML models, including regularized logistic regression, random forest, extreme gradient boosting, categorical boosting, and deep neural network, were trained using stratified 5-fold cross-validation. Model performance was evaluated on an independent test set using the area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), misclassification rate (MCR), and Brier score. Results: Among 2,734 HF patients, the 30-day readmission rate was 27%. The XGBoost model achieved the best discrimination (AUROC=0.75; AUPRC=0.58; MCR=0.21). Patients in the highest-risk decile had a positive predictive value of 76%, accounted for approximately one-third of all 30-day readmissions, and had a 3.3-fold enrichment compared with baseline risk. The key predictors included prior hospital utilization, diabetes and kidney disease management indicators, and comorbidity burden. Conclusions: Risk stratification using routinely collected clinical data identified a subgroup at elevated risk for 30-day readmission. These findings support the potential role of data-driven risk prediction to inform targeted transitional care.

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

BackgroundPatients 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. MethodsWe 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 (VO2peak). ResultsBaseline plasma IL-1Ra levels were 380 [290 to 1046] pg/mL. On-treatment IL-1Ra levels were significantly higher in the patients treated with anakinra vs. placebo (3,994 [3,372 to 5,000] pg/mL vs. 492 [304 to 1370] pg/mL, 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 VO2peak values (P>0.05). ConclusionsPatients 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 (VO2peak).

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.

BackgroundChagas cardiomyopathy remains a major cause of heart failure (HF) in endemic regions and is increasingly recognized globally, yet data on in-hospital outcomes are limited. Objective: To assess whether Chagas disease is associated with higher in-hospital mortality among patients hospitalized with HF. MethodsWe analyzed a nationwide administrative database from the Brazilian Unified Health System (DATASUS/SIHSUS), including adults hospitalized with HF between April 2017 and August 2021. HF was identified using ICD-10 code I50.x and Chagas disease using B57.x. The primary outcome was in-hospital mortality, evaluated using multivariable Cox models. Results: Among 910,128 HF hospitalizations, 1,082 (0.12%) were associated with Chagas disease. Patients with Chagas were younger but had a more complex clinical profile and higher resource use. In-hospital mortality was higher in the Chagas group (25% vs 12%; p<0.001). After adjustment, Chagas disease remained independently associated with mortality (HR 1.54; 95% CI 1.35-1.75; p<0.001). ConclusionsIn this large real-world cohort, Chagas disease was associated with higher in-hospital mortality and greater healthcare utilization. These findings reinforce the high-risk nature of Chagas cardiomyopathy and point to the need for more targeted treatment strategies. What is the clinical question being addressed?Chagas cardiomyopathy is a major cause of heart failure in endemic regions and an emerging global health problem, yet real-world data on in-hospital outcomes remain limited. Is Chagas disease associated with higher in-hospital mortality? What is the main finding?Chagas disease was independently associated with a 54% higher risk of in-hospital mortality in a large real-world cohort.

AimsAssessment 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 resultsFrom 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. ConclusionIn 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: Red cell distribution width (RDW), a readily available hematological parameter reflecting erythrocyte size heterogeneity, has been increasingly recognized as a prognostic marker in congestive heart failure (CHF), with elevated levels independently associated with adverse outcomes. However, RDW-derived composite indices-particularly the RDW-to-platelet ratio (RPR) and RDW-to-hemoglobin ratio (RHR), which integrate inflammatory, hemostatic, and oxygen-delivery pathways-remain largely unexplored in CHF populations. Whether these indices provide incremental prognostic value beyond RDW alone in critically ill patients with CHF has not been established. Methods: This retrospective cohort study included 30,409 participants from the MIMIC-IV and eICU-CRD databases. Multivariable logistic regression, restricted cubic spline (RCS) analysis, and subgroup analyses were employed to evaluate the associations between RDW, RDW-derived indices (RPR and RHR), and in-hospital mortality in patients with congestive heart failure. Results: Based on a pooled cohort of 30,409 patients with CHF from the MIMIC-IV and multi-center eICU-CRD databases (15,983 and 14,426, respectively), 16,295 (53.6%) were male and 14,114 were female, with a median age of 71.7 years. The mean RDW was 16.0 {+/-} 2.5, and the overall in-hospital mortality rate was 12.6%. Higher RDW quintiles were associated with progressively increased in-hospital mortality. In the fully adjusted model, RDW, RPR, and RHR were all significantly associated with increased in-hospital mortality, with adjusted odds ratios (ORs) of 2.46 (95% CI: 2.17-2.79) for RDW, 1.55 (95% CI: 1.38-1.73) for RPR, and 2.43 (95% CI: 2.09-2.82) for RHR. Sensitivity analyses using restricted cubic splines demonstrated that the association between RDW and RHR with in-hospital mortality was linear (P for nonlinearity > 0.05), whereas that for RPR exhibited a non-linear pattern (P = 0.02 for non-linearity). Conclusions. Elevated RDW, RPR, and RHR were independently associated with increased in-hospital mortality in patients with congestive heart failure. Notably, RPR exhibited a non-linear threshold association with in-hospital mortality.

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.

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.

BackgroundProgression 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. ObjectiveTo evaluate real-world CE of acoramidis versus tafamidis in newly treated patients with ATTR-CM. MethodsRetrospective 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. ResultsAfter 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). ConclusionsIn 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: Treatment response in heart failure with reduced ejection fraction (HFrEF) is assessed predominantly through left ventricular (LV) functional recovery, while longitudinal changes in left atrial (LA) hemodynamic burden remain underexplored. The LA stiffness index (LASI), derived from E/e' and LA reservoir strain, integrates LV filling pressure and LA compliance. Objectives: We investigated longitudinal trajectories of LASI and their prognostic implications in HFrEF treated with angiotensin receptor-neprilysin inhibitor (ARNI)-based therapy. Methods: From the multicenter STRATS-HF-ARNI registry, 1,039 patients with HFrEF who underwent serial echocardiography at baseline and one-year follow-up were classified into four LASI trajectory patterns dichotomized at the cohort median (1.22): persistently compliant (Group A, 46.8%), reverse remodeling (B, 28.5%), progressive stiffening (C, 3.2%), and persistently stiff (D, 21.6%). Results: On multivariable Cox regression, Group D was independently associated with elevated risks of all-cause mortality (adjusted hazard ratio [aHR] 2.68, 95% CI 1.57-4.59), cardiovascular mortality (aHR 4.36, 1.97-9.64), and HF hospitalization (aHR 3.83, 2.22-6.60), whereas Group B showed outcomes comparable to Group A. One-year LASI progression independently predicted all three outcomes. LASI elevation at one year predicted adverse outcomes even among patients with recovered LV function, and LASI trajectory classification provided incremental prognostic discrimination beyond conventional diastolic and strain parameters. Among sinus-rhythm patients (n=786), Group C exhibited the highest risk of new-onset atrial fibrillation. Conclusions: In HFrEF treated with ARNI-based therapy, LASI trajectories identify distinct prognostic phenotypes. Persistent LA stiffness confers adverse outcomes independent of LV recovery, and serial LASI assessment may enhance risk stratification beyond LV-centric metrics.

Diastolic heart failure (HF) in primary cardiomyopathy is under-recognized and often diagnosed late, particularly in children. While recent studies have advanced understanding of HF with preserved ejection fraction in older adults, the prevalence, outcomes and molecular drivers of diastolic HF in pediatric and young adult cardiomyopathy remain poorly defined, where disease is typically driven by primary myocardial disease rather than acquired co-morbidities. The Canadian Cardiomyopathy Collaborative (C3) was assembled to leverage three of Canadas leading pediatric and adult cardiomyopathy biobank registries. Its flagship initiative, Artificial Intelligence to Model Diastolic Heart Failure (AID-HF), aims to integrate deep phenotyping - including comprehensive diastolic function assessment - with genomics, lipidomics and proteomics and apply machine learning to identify biological and clinical signatures that drive cardiac function and outcomes in cardiomyopathy. Harmonized phenotyping and multiomics protocols across registries will create a uniquely integrated national data resource and enable the goals of AID-HF i.e., earlier diagnosis and new therapeutic targets for diastolic HF in cardiomyopathy.

Background World Symposium on Pulmonary Hypertension (WSPH) Group 2 pulmonary hypertension (PH) is a clinically integrated phenotype attributed to left heart disease, whereas pre- versus post-capillary classification is operationalized primarily by pulmonary capillary wedge pressure (PCWP). Although current recommendations emphasize contextual interpretation and provocative testing for intermediate PCWP values, the relationship between PCWP-based classification and underlying phenotype has not been systematically evaluated. We aim to quantify phenotype-hemodynamic discordance across the PCWP spectrum and evaluate a staged physiology-guided framework incorporating inhaled nitric oxide (iNO), ventricular geometry, and provocative testing. Methods We studied 1,032 participants from the NHLBI-sponsored PVDOMICS cohort with multidisciplinary adjudicated phenotypes integrating clinical, imaging, physiologic, and hemodynamic data. Stage-specific PCWP thresholds classified pre- versus post-capillary physiology at rest, during iNO, and during provocation (fluid challenge or invasive cardiopulmonary exercise testing [iCPET]). Echocardiographic right ventricular-to-left ventricular (RV/LV) ratio was evaluated as a marker of ventricular interdependence. Restricted cubic spline and staged concordance analyses defined certainty-based PCWP ranges and incremental diagnostic yield. Results Adjudicated Group 2 phenotype was present in 37.0% of participants. Resting PCWP demonstrated good discrimination (AUC 0.86), but substantial bidirectional phenotype-hemodynamic discordance persisted across intermediate PCWP ranges. At a resting PCWP of 12 mmHg, 25% of participants classified as pre-capillary had adjudicated Group 2 PH, whereas at 18 mmHg, 35% classified as post-capillary remained discordant non-Group 2. Concordance did not approach 90% until PCWP values were <9 mmHg or >24 mmHg. Dynamic testing incrementally improved concordance within these overlap zones. Nearly half of adjudicated Group 2 PH participants (46.5%) were not identified by resting PCWP alone; incorporation of iNO and provocative testing increased cumulative Group 2 identification by 63.4% and improved sensitivity from 79.9% to 83.7%. Model discrimination improved from an AUC of 0.863 to 0.908 (likelihood-ratio P<0.001). iNO increased PCWP in discordant Pre/G2 participants, unmasking latent left-sided limitation, while lowering PCWP in discordant Post/NonG2 participants, consistent with ventricular interdependence. RV/LV ratio [&ge;]0.94 reduced discordant Post/NonG2 classification by 70.5%, and incorporation of PCWP/cardiac output slope improved physiologic specificity during exercise. Conclusions Group 2 PH is a dynamic, load-dependent phenotype inadequately characterized by resting PCWP alone. Intermediate PCWP values represent continuous probabilities of bidirectional discordance rather than discrete diagnostic states. A staged physiology-guided approach integrating iNO, ventricular geometry, and provocative testing improves concordance between hemodynamic classification and clinically integrated phenotype assignment.

Abstract Background: Heart Failure is a complex clinical syndrome of growing public health concern in sub-Saharan Africa, yet the data from Sierra Leone are absent. The aim of the study is to characterise the clinical profile, etiological and temporal trends of hospitalised HF patients at Choithrams Memorial Hospital (CMH), Freetown, Sierra Leone, to confirm specific management strategies. Methods: This single-center, retrospective observational cohort study analysed data on HF patients (>18years) admitted at the CMH between January 2021 to 31 December 2025. The clinical definition of HF was based on the Framingham criteria and the European Society of Cardiology (ESC) guidelines , including standard echocardiographic parameters. All variables, including patients demographics, HF. phenotype, aetiology, medical history and hospital outcomes were extracted from the digital record. Non-parameteric tests, multivariable logistic regression to identify variables associated with etiology, Wilcoxon rank-sum test to compare groups and Kruskal-Wallis test to analyse trends over time were utilised. Result: A total of 765 patients were included in the study, with a median age of 53 years (IQR 42-61) and male predominance of 55.3%. Patients with recurrent HF (60.9%) were more common than those with de novo HF (39.1%), were older (54 years vs 53 years), had a higher comorbidity burden (34% vs 4%, p < 0.001), and presented with a cold-wet hemodynamic profile (18.4% vs 8.4%, p < 0.001). HFrEF (61.3%) was the most predominant phenotype, though HFpEF increased with age. Dilated Cardiomyopathy (37.0%), Hypertensive Heart Disease (31.2%) and Valvular Heart Failure (17.1%) were the leading etiologies, while ischemic heart disease (6.3%) was relatively uncommon. A majority of the patients were referred (77.9%), and 50.8% presented with NYHA IV. The strongest independent predictor for HF was hypertensive heart disease [AOR = 17.81; C.I 95%: (3.13-48.76), p <0.001]. An analysis of the trends in etiologies and demographics over the five-year period demonstrated no significant changes (all p-values > 0.05 for age, sex, aetiology, and most comorbidities). Conclusion: HF affects the younger adult population in Sierra Leone and is mainly caused by DCM and HHD. The late case presentations, the high prevalence of recurrent HF, and the associated high burden of comorbidities emphasize an urgent need to develop and implement improved strategies for the prevention, early detection, and long-term management of HF within Sierra Leone's healthcare system.

Background: Cardiogenic shock (CS) remains associated with high short-term mortality despite contemporary advances in care. The association between institutional cardiac capability and outcomes?particularly among transferred patients and after accounting for clinical instability?remains incompletely defined. Objectives: To evaluate the association between hierarchical hospital cardiac capability and in-hospital mortality using a latent measure of acute physiologic severity. Methods: Using the National Inpatient Sample (2016?2022), hospitals were classified into five hierarchical tiers ranging from non-PCI (Tier 1) to heart transplant/durable LVAD centers (Tier 5). Generalized structural equation modeling (GSEM) assessed the relationship between hospital tier and mortality. A latent "Acute Severity" construct?comprising cardiac arrest, acute kidney and liver injury, and mechanical ventilation?was incorporated to model the effects of clinical instability Results: Among an estimated 1,177,180 CS hospitalizations, most occurred at cardiac surgical and transplant/LVAD centers. Crude mortality declined stepwise from non-PCI hospitals (64.5%) to transplant/LVAD centers (36.5%). After adjustment, higher hospital tier was independently associated with lower mortality (Tier 2 OR 0.43 [95% CI 0.38?0.48]; Tier 3 OR 0.37 [0.32?0.43]; Tier 4 OR 0.33 [0.30?0.38]; Tier 5 OR 0.35 [0.31?0.40]). Although transfer-in status was associated with increased mortality (OR 1.39 [1.33?1.46]), this association was attenuated at cardiac surgical and transplant/LVAD centers, consistent with a mitigation of transfer associated risk. Conclusions: Higher hospital cardiac capability is independently associated with lower mortality in CS. Advanced centers are associated with mitigation transfer-associated risk, supporting regionalized hub-and-spoke systems with early referral to high-capability centers.

Tricuspid regurgitation and pulmonary artery systolic pressure may contribute to post-operative morbidity and mortality in liver transplantation. Previous studies suggest that a high Model for End-Stage Liver Disease score may influence the relationship between tricuspid regurgitation and post-operative mortality. Adult patients undergoing liver transplantation workup between 2010 and 2023 were included in this retrospective observational cohort study. Patients with significant portopulmonary hypertension were excluded. Transthoracic echocardiograms were completed pre-transplant and patients were followed up for one year post-operatively. 1031 patients (median MELD score 17, IQR 12-23) underwent transthoracic echocardiography for liver transplantation workup, of whom 708 underwent successful transplantation. Mild or greater tricuspid regurgitation did not predict 1-year mortality in the overall population (HR 1.79 (95% CI 0.78-4.11), p=0.19). Among patients with MELD scores [&ge;]20, mild or greater tricuspid regurgitation was a significant predictor of 1-year mortality (7 (12.7%) vs 9 (3.8%), p=0.01) (HR 3.46 (1.30-10.32), p=0.02). Tricuspid regurgitation in patients with high MELD scores was associated with a trend towards an increased risk of 30-day major adverse cardiovascular events (9 (16.4)% vs 46 (8.1%), p=0.06), driven predominantly by rates of post-operative heart failure (12.7% vs 3.8%, HR 3.66 (95%CI 1.30-10.32), p=0.01). Elevated pulmonary artery systolic pressure was associated with prolonged hospital stay (30 days (14-46) vs 15 days (11-29), p=0.01). Our study confirms that mild or greater tricuspid regurgitation is a significant predictor of 1-year mortality in patients with high MELD scores undergoing liver transplantation. Tricuspid regurgitation severity should be considered during pre-liver transplantation risk stratification.