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.

BackgroundLeft ventricular reverse remodeling (LVRR) is a surrogate marker of treatment response in heart failure with reduced ejection fraction (HFrEF), usually observed within 24 months. Some patients experience LVRR beyond this period, but its prognostic significance remains unclear. MethodsWe retrospectively analyzed symptomatic HFrEF patients with left ventricular ejection fraction (LVEF) [&le;]40%. All patients underwent echocardiography at baseline and at two follow-up points: 6-24 months (Follow-up 1) and 24-78 months (Follow-up 2). LVRR was defined as an LVEF increase [&ge;]10% to >40% and classified as Early (at Follow-up 1) or Late (at Follow-up 2). The Simple-GDMT Score was used to assess guideline-directed medical therapy (GDMT). The primary outcome was a composite of all-cause death or HF hospitalization, evaluated from Follow-up 2 onward. ResultsOf 213 patients, 84 (39.4%) achieved Early LVRR, 25 (11.7%) Late LVRR, and 104 (48.8%) showed no LVRR. The primary endpoint was lower in both Early and Late LVRR groups compared with the No-LVRR group (vs Early; p < 0.001, vs Late; p = 0.015). The Simple-GDMT Score increased over time in all groups, but trajectories differed, with a gradual up-titration only in the Late LVRR group. In Cox models, Late LVRR was independently associated with a lower risk of the composite outcome compared with the No-LVRR group. ConclusionsBoth early- and late-onset LVRR were associated with improved prognosis compared with no LVRR. Even delayed remodeling carried prognostic value, underscoring the importance of long-term follow-up in HFrEF management. (245/250 words) Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LIThis study demonstrates that late-onset LVRR, occurring beyond 24 months, is associated with favorable prognosis in HFrEF, extending its prognostic relevance across a broader timeframe and multiple etiologies. C_LIO_LIIn patients with late LVRR, reverse remodeling was seen alongside gradual GDMT intensification, suggesting that delayed titration may have contributed. C_LI What are the Clinical Implications?O_LIEarly initiation and optimization of GDMT is ideal, yet even patients with initially inadequate or delayed therapy should still undergo intensification, as this can promote reverse remodeling and improve outcomes. C_LIO_LISuch patients should not be excluded from aggressive management; timely escalation of therapy remains essential to achieving survival benefit. C_LI

AimTo evaluate whether initiation of cardiac rehabilitation (CR) within 6 weeks improves long-term outcomes of patients with acute heart failure (HF). MethodsPatients with acute HF who participated in an HF disease management program from January 2019 to July 2022 were prospectively enrolled. Eligible patients were divided into two groups: early CR (and continued home-based CR during the follow-up period) and non-CR. The primary outcome was all-cause mortality. Secondary outcomes were rehospitalisation for recurrent HF and changes in 12-item Kansas City Cardiomyopathy Questionnaire scores from baseline to 6 months and 1 year. A post-hoc analysis stratified by lysyl oxidase-like 2 (LOXL2) levels assessed CR benefits for patients with cardiac fibrosis. ResultsOf 162 patients, 34 received early CR. The non-CR group was older (median age: 58.5 vs. 53.0 years, p=0.022) and had higher N-terminal pro-B-type natriuretic peptide levels (4552.5 vs. 1275.0 pg/mL, p=0.002). Propensity score matching yielded 33 patients per group. Over 2.85 years, the early CR group had lower all-cause mortality (0 vs. 87.16 events per 1000 patient-years, rate difference: -0.087 [95% confidence interval {CI}: -0.143 to -0.031], p=0.002). Patients with LOXL2 >200 pg/mL benefited the most (0 vs. 172.3 events per 1000 patient-years, rate difference: -0.172 [95% CI: -0.299 to -0.046], p=0.008). ConclusionEarly post-discharge exercise-based CR was associated with reduced all-cause mortality in patients with acute HF. Patients with more severe cardiac fibrosis, indicated by higher LOXL2 levels, derived greater benefits from the CR program. Large-scale trials are needed to validate these findings. Trial registrationThe study protocol was registered at ClinicalTrials.gov (identifier: NCT03782337). Lay summaryO_LIEarly exercise after discharge for patients with acute heart failure is feasible, and early cardiac rehabilitation with nearly 3 years of follow-up is associated with a reduction in all-cause mortality without significant risks. C_LIO_LIFurthermore, for patients with severe cardiac fibrosis, cardiac rehabilitation can result in an even greater reduction in all-cause mortality. C_LI Based on our findings, cardiac rehabilitation and exercise recommendations should be initiated early after discharge in patients with acute heart failure, particularly those with cardiac fibrosis.

BackgroundReal-world evidence shows alarmingly suboptimal utilization of GDMT in HFrEF. One of the barriers of GDMT implementation appears to be concerns about the potential development of drug-related adverse events (AEs), particularly in high-risk patients. This study aimed to evaluate whether advanced HFrEF patients can be up-titrated safely and whether advanced HFrEF predisposes to the occurrence of putatively drug-related AEs. MethodsA total of 373 HFrEF patients from our prospective HF registry were analyzed for HF drug utilization and target dosages (TDs) at baseline, 2 months, and 12 months. Successful up-titration and AEs were evaluated for different stages of HF reflected by NT-proBNP (<1000pg/ml, 1000-2000pg/ml, >2000pg/ml). ResultsA stepwise increase in HF medications could be observed for all drug classes during follow-up. At 12 months 73%, 75%, 62%, 86% and 45% of patients received [&ge;]90% of TDs of beta-blockers (BB), renin-angiotensin system inhibitors (RASi), mineralocorticoid receptor antagonists (MRA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and triple-therapy, respectively. Predictors of successful up-titration in logistic regression were baseline HF-drug TDs, eGFR, and potassium, but not NT-proBNP or age. The development of AEs was rare, with hyperkalemia as the most common event (34% at 12 months). AEs were comparable in all stages of HF. However, development of hyperkalemia was more frequent in patients with higher NT-proBNP and also accounted for most cases for incomplete up-titration. ConclusionsThis study suggests that with dedicated protocols and frequent visits GDMT can be successfully implemented across all stages of HFrEF, including patients with highest NT-proBNP levels who probably profit the most. CLINICAL PERSPECTIVEO_ST_ABSWhat is new?C_ST_ABSO_LIGDMT up-titration is feasible even in advanced HFrEF patients, with this study demonstrating that [&ge;]50% target doses for all HF medications can be achieved in about 90% of patients within 12 months through high-intensity care and frequent follow-up visits. C_LIO_LIAdverse events during up-titration are rare, even in high-risk patients, and the most notable AE, hyperkalemia, can be effectively managed in most cases without discontinuing therapy. C_LI What are the clinical implications?O_LIThis study demonstrates that GDMT up-titration is achievable even in advanced HFrEF, challenging the notion that medication intolerance should be part of the definition of advanced HF. C_LIO_LIPracticing physicians should pursue GDMT up-titration for all HFrEF patients, as AEs are manageable, and its potential benefit to stabilize disease progression and improve outcomes far outweigh the risks. C_LIO_LIThe lack of consensus on when to halt up-titration or define true intolerance, combined with limited evidence on GDMT efficacy or futility in advanced HF, underscores the need for further research to optimize treatment in this high-risk group. C_LI

BackgroundMultimorbidity is common among patients with heart failure (HF) and contributes to poor prognosis; however, the influence of age group and sex differences on the prevalence and outcomes of multimorbidity remains unclear. MethodsThis multicenter retrospective study included 3,004 hospitalized patients with HF. Multimorbidity was defined as the presence of two or more comorbidities and was quantified for stratification of comorbidity burden using the age-adjusted Charlson Comorbidity Index (CCI). Patients were dichotomized into high-and low-CCI groups based on the median CCI and were evaluated for prognosis using a composite endpoint of all-cause death or HF readmission. ResultsMultimorbidity increased with age but declined slightly in individuals aged > 85 years. And sex differences were observed, with males demonstrating a steeper increase in multimorbidity prevalence than females. Event-free survival rates were lower in the high-CCI group (hazard ratio [HR], 1.786; 95% confidence interval [CI], 1.483-2.151), consistent across sexes (males: HR, 1.927; 95% CI, 1.520-2.443; females: HR, 1.581; 95% CI, 1.171-2.135). Among individuals aged [&ge;]75 years with a high CCI, males had a stronger association with events than females (HR, 1.334; 95% CI, 1.031-1.727). ConclusionsIn individuals with HF, sex differences were evident in the prevalence of multimorbidity by age group and were associated with prognosis in older populations with a high comorbidity burden. Recognizing these differences is essential for tailoring HF management strategies to improve outcomes in individuals with multimorbid HF. Clinical trial registrationURL: https://www.umin.ac.jp/ctr; unique identifier: UMIN000054854 Clinical perspective What Is New?O_LIThis multicenter study demonstrated that age-dependent sex differences exist in both the prevalence and prognostic impact of multimorbidity among Japanese individuals with heart failure. C_LIO_LIA three-way interaction analysis (age x sex x comorbidity burden) utilizing restricted cubic splines revealed that, among individuals with a high comorbidity burden, sex-related prognostic differences became increasingly pronounced with age, with older males exhibiting a higher risk than females. C_LI What Are the Clinical Implications?O_LIIncorporating age-and sex-specific risk assessments based on comorbidity burden may enhance individualized management strategies and improve clinical outcomes in individuals with heart failure, particularly in older adults with multiple comorbidities. C_LI

BackgroundKidney dysfunction is highly prevalent in heart failure with preserved ejection fraction (HFpEF). It poses therapeutic challenges and is associated with worse clinical outcomes. Obesity is increasingly recognized as a key factor in HFpEF pathogenesis, yet its impact on kidney function remains unclear. MethodsWe conducted a retrospective analysis using data from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Obesity was examined using body mass index (BMI), waist circumference (WC) and waist to height ratio (WHtR). The primary outcome was a decline in estimated glomerular filtration rate (eGFR) by >30% from baseline. Single eGFR decline was defined as meeting this threshold with one qualifying follow-up eGFR; persistent eGFR decline was defined by meeting it on two consecutive qualifying eGFR values. Univariable and multivariable Cox proportional hazards regression models were performed, modeling each exposure as a continuous variable and as quartiles. ResultsA total of 1765 patients were included (mean age 72{+/-}10 years, median eGFR of 60.8 [IQR 47.8, 76.1] ml/min/1.73m2) with a median follow up of 3.3 years. There were 690 (39.1%) patients who met the definition of single eGFR>30% decline, and 459 (26%) patients who met the definition of persistent eGFR>30% decline. Compared to the lowest quartile, there was a significantly higher risk of >30% eGFR decline in the highest quartile of BMI (HR=1.26 [95% CI 1.00, 1.60]), WC (HR=1.35 [1.06, 1.71]) and WHtR (HR=1.27 [1.00, 1.61]), with similar trends in continuous analyses. All associations were attenuated and no longer met statistical significance when using the outcome of persistent kidney function decline. ConclusionsObesity is independently associated with declines in kidney function in patients with HFpEF. Associations were similar but attenuated and no longer met statistical significance for persistent declines in kidney function, suggesting that perhaps obesity is a risk factor for fluctuations in eGFR in HFpEF.

BackgroundAcute decompensation is associated with increased mortality in heart failure (HF) patients, though the underlying etiology remains unclear. Extracellular vesicles (EVs) and their cargo may mark specific cardiovascular physiologic states. We hypothesized that EV transcriptomic cargo, including long non-coding RNAs (lncRNAs) and mRNAs, is dynamic from the decompensated to recompensated HF state, reflecting molecular pathways relevant to adverse remodeling. MethodsWe examined differential RNA expression from circulating plasma extracellular RNA in acute HF patients at hospital admission and discharge alongside healthy controls. We leveraged different exRNA carrier isolation methods, publicly available tissue banks, and single nuclear deconvolution of human cardiac tissue to identify cell and compartment specificity of the topmost significantly differentially expressed targets. EV-derived transcript fragments were prioritized by fold change (-1.5 to + 1.5) and significance (<5% false discovery rate), and their expression in EVs was subsequently validated in 182 additional patients (24 control; 86 HFpEF; 72 HFrEF) by qRT-PCR. We finally examined the regulation of EV-derived lncRNA transcripts in human cardiac cellular stress models. ResultsWe identified 138 lncRNAs and 147 mRNAs (present mostly as fragments in EVs) differentially expressed between HF and control. Differentially expressed transcripts between HFrEF vs. control were primarily cardiomyocyte derived, while those between HFpEF vs. control originated from multiple organs and different (non-cardiomyocyte) cell types within the myocardium. We validated 5 lncRNAs and 6 mRNAs to differentiate between HF and control. Of those, 4 lncRNAs (AC092656.1, lnc-CALML5-7, LINC00989, RMRP) were altered by decongestion, with their levels independent of weight changes during hospitalization. Further, these 4 lncRNAs dynamically responded to stress in cardiomyocytes and pericytes in vitro, with a directionality mirroring the acute congested state. ConclusionCirculating EV transcriptome is significantly altered during acute HF, with distinct cell and organ specificity in HFpEF vs. HFrEF consistent with a multi-organ vs. cardiac origin, respectively. Plasma EV-derived lncRNA fragments were more dynamically regulated with acute HF therapy independent of weight change (relative to mRNAs). This dynamicity was further demonstrated with cellular stress in vitro. Prioritizing transcriptional changes in plasma circulating EVs with HF therapy may be a fruitful approach to HF subtype-specific mechanistic discovery. CLINICAL PERSPECTIVEO_ST_ABSWhat is new?C_ST_ABSWe performed extracellular transcriptomic analysis on the plasma of patients with acute decompensated heart failure (HFrEF and HFpEF) before and after decongestive efforts. Long non-coding RNAs (lncRNAs) within extracellular vesicles (EVs) changed dynamically upon decongestion in concordance with changes within human iPSC-derived cardiomyocytes under stress. In acute decompensated HFrEF, EV RNAs are mainly derived from cardiomyocytes, whereas in HFpEF, EV RNAs appear to have broader, non-cardiomyocyte origins. What are the clinical implications?Given their concordance between human expression profiles and dynamic in vitro responses, lncRNAs within EVs during acute HF may provide insight into potential therapeutic targets and mechanistically relevant pathways. These findings provide a "liquid biopsy" support for the burgeoning concept of HFpEF as a systemic disorder extending beyond the heart, as opposed to a more cardiac-focused physiology in HFrEF.

AimsWhile physical frailty is a common feature in heart failure (HF), less is known about how frailty is linked to impaired clinical biomarkers and metabolic dysregulation in HF. MethodsWe recruited 25 patients with HF (67.9 {+/-} 10.0 years) and 29 adults without HF (NonHF) (67.8 {+/-} 11.1 years). Physical frailty was assessed using low physical activity levels with low handgrip strength (HGS) and/or 30-second chair stand test (30CST). Untargeted plasma metabolomic profiling was performed via gas chromatography-mass spectrometry. Statistical analyses were conducted via SPSS and MetaboAnalyst. ResultsHF-Frail (n=25) compared to NonHF-NonFrail (n=18), had lower 6-minute walking distance (386.4 vs. 501.3 meters, P<0.01) and weaker HGS/body mass index (BMI) (1.05 vs. 1.41, P=0.04). HF-Frail compared to NonHF-NonFrail had significantly elevated plasma N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) (241.2 vs. 117.1 pg/ml, P=0.007) and growth differentiation factor-15 (GDF-15) levels (1227.2 vs. 382.5 pg/ml, P<0.01). Agnostic principal component analysis revealed elevated plasma branched chain amino acids and reduced glutamine, methionine and tryptophan in HF-Frail vs. NonHF-NonFrail controls (P<0.05). Compared to HF-NonFrail (n=7), HF-Frail had lower galacturonic acid-1-phosphate, methionine, indole-3-acetamide, pyruvic and malic acid (P<0.05). Significant negative correlations were found between NT-proBNP, tumour necrosis factor-alpha (TNF-), GDF-15, and frailty outcomes (HGS/BMI, 30CST; P<0.05). ConclusionsIn HF, physical frailty is linked to impaired energy and amino acid metabolism, along with elevated inflammation and GDF-15. These findings warrant for longitudinal studies to unravel clinical biomarkers that could serve as therapeutic agents, targeting frailty progression in HF. Lay SummaryThis study investigated the association between physical frailty, clinical biomarkers, and metabolic dysregulation in patients with heart failure (HF), revealing significant impairments in physical performance and metabolic profiles compared to non-frail HF and non-HF controls. O_LIPatients with HF and frailty exhibited reduced 6-minute walk distance and 30-second chair stand repetitions, had weaker handgrip strength, and elevated levels of N-terminal pro-B-type natriuretic peptide and growth differentiation factor-15 compared to non-frail controls (P<0.05). C_LIO_LIMetabolomic analysis showed increased plasma branched-chain amino acids, reduced glutamine and methionine, and altered energy metabolism intermediates (i.e., pyruvic acid) (P<0.05) in HF with frailty, indicating significant metabolic disruptions. C_LI

BackgroundEjection fraction (EF) is a key component of heart failure (HF) classification, including the increasingly codified HF with mildly reduced EF (HFmrEF) category. However, the biologic basis of HFmrEF as an entity distinct from HF with preserved EF (HFpEF) and reduced EF (HFrEF) has not been well characterized. MethodsThe EXSCEL trial randomized participants with type 2 diabetes (T2DM) to once-weekly exenatide (EQW) vs. placebo. For this study, profiling of [~]5000 proteins using the SomaLogic SomaScan platform was performed in baseline and 12-month serum samples from N=1199 participants with prevalent HF at baseline. Principal component analysis (PCA) and ANOVA (FDR p<0.1) were used to determine differences in proteins between three EF groups, as previously curated in EXSCEL (EF>55% [HFpEF], EF 40-55% [HFmrEF], EF<40% [HFrEF]). Cox proportional hazards was used to assess association between baseline levels of significant proteins, and changes in protein level between baseline and 12-month, with time-to-HF hospitalization. Mixed models were used to assess whether significant proteins changed differentially with exenatide vs. placebo therapy. ResultsOf N=1199 EXSCEL participants with prevalent HF, 284 (24%), 704 (59%) and 211 (18%) had HFpEF, HFmrEF and HFrEF, respectively. Eight PCA protein factors and 221 individual proteins within these factors differed significantly across the three EF groups. Levels of the majority of proteins (83%) demonstrated concordance between HFmrEF and HFpEF, but higher levels in HFrEF, predominated by the domain of extracellular matrix regulation, e.g. COL28A1 and tenascin C [TNC]; p<0.0001. Concordance between HFmrEF and HFrEF was observed in a minority of proteins (1%) including MMP-9 (p<0.0001). Biologic pathways of epithelial mesenchymal transition, ECM receptor interaction, complement and coagulation cascades, and cytokine receptor interaction demonstrated enrichment among proteins with the dominant pattern, i.e. HFmrEF-HFpEF concordance. Baseline levels of 208 (94%) of the 221 proteins were associated with time-to-incident HF hospitalization including domains of extracellular matrix (COL28A1, TNC), angiogenesis (ANG2, VEGFa, VEGFd), myocyte stretch (NT-proBNP), and renal function (cystatin-C). Change in levels of 10 of the 221 proteins from baseline to 12 months (including increase in TNC) predicted incident HF hospitalization (p<0.05). Levels of 30 of the 221 significant proteins (including TNC, NT-proBNP, ANG2) were reduced differentially by EQW compared with placebo (interaction p<0.0001). ConclusionsIn this HF substudy of a large clinical trial of people with T2DM, we found that serum levels of most proteins across multiple biologic domains were similar between HFmrEF and HFpEF. HFmrEF may be more biologically similar to HFpEF than HFrEF, and specific related biomarkers may offer unique data on prognosis and pharmacotherapy modification with variability by EF.

BackgroundRight heart failure (RHF) leads to an elevation in central venous pressure and causes hepatic congestion. Apolipoprotein M (ApoM), a hepatocyte-derived lipocalin bound to high-density lipoprotein, transports sphingosine-1-phosphate (S1P), which maintains vascular integrity and modulates inflammation. Although low ApoM predicts adverse outcomes in heart failure (HF), its role in RHF is unclear. We sought to investigate the impact of RHF on circulating ApoM, its prognostic value in RHF mortality, and its functional role in the cardio-hepatic axis. MethodsPatients undergoing right heart catheterization were classified as normal, HF, or RHF. Serum ApoM and S1P were measured by ELISA. Survival was analyzed using Kaplan-Meier and Cox proportional hazards models. Meanwhile, ApoM Tg or WT mice were subjected to pulmonary artery banding (PAB) to induce right ventricular (RV) dysfunction or partial inferior vena cava ligation (pIVCL) to cause hepatic congestion. Cardiac and hepatic pathology were assessed by tissue imaging and molecular analyses. ResultsApoM levels were lowest in RHF patients and inversely correlated with inflammatory markers. Each 0.01 M increase in ApoM was associated with a 6% lower risk of mortality. PAB induced RV dysfunction and reduced serum ApoM in wild-type mice, while ApoM Tg mice showed less severe RV remodeling and improved hepatic congestion. In contrast, ApoM Tg mice subjected to pIVCL showed no significant improvement in liver pathology. ConclusionIn patients with RHF and mice with RV dysfunction, circulating ApoM was reduced. Lower ApoM was independently associated with worse outcomes. Restoring ApoM expression primarily protects the heart and subsequently alleviates liver congestion, underscoring its distinct protective role in the heart-liver axis. Further investigation of the ApoM axis in RHF is warranted. DisclosuresResearch reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number TL1TR002344. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/25342523v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1ad080forg.highwire.dtl.DTLVardef@ec2522org.highwire.dtl.DTLVardef@17a04aforg.highwire.dtl.DTLVardef@1c99db7_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundObesity is common in heart failure with reduced ejection fraction (HFrEF). As anti-obesity treatments advance, understanding how body mass index (BMI) affects outcomes in HFrEF is increasingly important. ObjectiveTo examine whether a BMI >27 kg/m{superscript 2} is linked to higher risks of all-cause mortality, cardiovascular death, and heart failure (HF) hospitalization in HFrEF patients. MethodsThis study included 1,017 clinically stable, medically optimized HFrEF patients from the NorthStar study (2005-2009), followed through 2023 using Danish registries. Outcomes were assessed with Cox models adjusted for prognostic factors. The primary endpoint was all-cause mortality; secondary endpoints included cardiovascular death, HF hospitalization, and a composite of mortality or hospitalization. Subgroup analyses compared BMI categories (<24, 24-27, >27 kg/m{superscript 2}). ResultsPatients with BMI >27 had more diabetes (27.8% vs. 17.7%) and lower NT-proBNP (median 776 vs. 1,163 pg/mL) than those with BMI 24-27, with similar HF etiology. Over a median 8.8 years, 821 patients (80.7%) died, including 444 cardiovascular deaths, and 740 (72.8%) were hospitalized for HF. A BMI of 35 vs. 27 was associated with non-significant increased all-cause mortality (HR 1.18, 95% CI 0.94-1.48) but significantly higher cardiovascular mortality (HR 1.42, 95% CI 1.05-1.92), HF hospitalization (HR 1.33, 95% CI 1.05-1.67), and composite outcome (HR 1.30, 95% CI 1.06-1.60). Subgroup analysis showed higher mortality with BMI >27 vs. 24-27 in ischemic cardiomyopathy (HR 1.31, 95% CI 1.05-1.64), but not in non-ischemic (HR 0.86, 95% CI 0.66-1.12), interaction p=0.015. ConclusionAmong HFrEF patients--especially those with ischemic cardiomyopathy--BMI >27 is associated with worse outcomes, challenging the "obesity-survival paradox" and highlighting the importance of effective weight management.

BackgroundTwo general phenotypes of heart failure (HF) are recognized: HF with reduced ejection fraction (HFrEF) and with preserved EF (HFpEF). To develop HF disease phenotype-specific approaches to define and guide treatment, distinguishing biomarkers are needed. The goal of this study was to utilize quantitative metabolomics on a large, diverse population to replicate and extend existing knowledge of the plasma metabolic signatures in human HF. MethodsQuantitative, targeted LC/MS plasma metabolomics was conducted on 787 samples collected by the Penn Medicine BioBank from subjects with HFrEF (n=219), HFpEF (n=357), and matched non-failing Controls (n=211). A total of 90 metabolites were analyzed, comprising 28 amino acids, 8 organic acids, and 54 acylcarnitines. 733 of these samples were also processed via an OLINK protein panel for proteomic profiling. ResultsConsistent with previous studies, unsaturated forms of medium/long chain acylcarnitines were elevated in the HFrEF group to a greater extent than the HFpEF group compared to Controls. A number of amino acid derivatives, including 1- and 3-methylhistidine, homocitrulline, and symmetric (SDMA) and asymmetric (ADMA) dimethylarginine were elevated in HF, with ADMA elevated uniquely in HFpEF. Plasma branched-chain amino acids (BCAA) were not different across the groups; however, short-chain acylcarnitine species indicative of BCAA catabolism were significantly elevated in both HF groups. The ketone body 3-hydroxybutyrate (3-HBA) and its metabolite C4-OH carnitine were uniquely elevated in the HFrEF group. Linear regression models demonstrated a significant correlation between plasma 3-HBA and NT-proBNP in both forms of HF, stronger in HFrEF. ConclusionsThese results identify plasma signatures that are shared as well as potentially distinguish between HFrEF and HFpEF. Metabolite markers for ketogenic metabolic re-programming in extra-cardiac tissues were identified as unique signatures in the HFrEF group, possibly related to the lipolytic action of increased levels of BNP. Future studies will be necessary to further validate these metabolites as HF biosignatures that may guide phenotype-specific therapeutics and provide insight into the systemic metabolic responses to HFpEF and HFrEF. Clinical Perspective What Is New?O_LI"Real world" targeted metabolomic profiling on wide range of metabolites in a diverse population of patients with HFrEF and HFpEF. C_LIO_LILevels of 3-hydroxybutyrate and its metabolite C4OH-carnitine were uniquely increased in the HFrEF group and correlated with levels of plasma NT-proBNP in both the heart failure groups, indicating the possibility of a heart-adipose-liver axis. C_LIO_LIAsymmetric dimethylarginine, a known inhibitor of nitric oxide synthase, was uniquely upregulated in HFpEF suggesting that there may also be an underlying component of vascular dysregulation contributing to HFpEF pathophysiology. C_LI What Are the Clinical Implications?O_LIThe plasma metabolomic changes seen in the heart failure cohorts support the existing theory of metabolic reprogramming, providing further rationale for the pursuit of therapeutic targets for the treatment of heart failure. C_LIO_LIQuantitative metabolomic profiling shows promise for guiding therapeutic decisions in HFrEF and HFpEF. C_LIO_LIModulation of natriuretic peptides may enhance the delivery of ketone and fatty acids to the "fuel starved" failing heart. C_LI

BackgroundAlthough insulin resistance (IR) is associated with a higher risk of incident heart failure (HF), it is not fully understood whether IR could affect clinical outcomes in patients with established HF. We investigated the relationship between the triglyceride-glucose (TyG) index, a simple surrogate marker for IR, and clinical outcomes in patients with HF with preserved ejection fraction (HFpEF). MethodsThis retrospective analysis from the PURSUIT-HFpEF registry included 917 patients hospitalized for decompensated HFpEF. The TyG index was calculated at discharge as ln(triglyceride [mg/dL] x fasting blood glucose [mg/dL]/2). The primary outcomes were all-cause death and major adverse cardiovascular events (MACEs; a composite of all-cause death, heart failure hospitalization, and stroke). ResultsThe median age of patients was 83 years, 44.7% was male, and 39.2% had diabetes. The median BMI was 21.5 kg/m{superscript 2}, with 20.9% having BMI <18.5 kg/m {superscript 2}. During a median follow-up of 387 days, 168 deaths and 343 MACEs occurred. A stepwise Cox hazard model revealed that higher TyG index was independently associated with lower risk of all-cause death (HR 0.53, 95% CI 0.38-0.75) and MACEs (HR 0.77, 95% CI 0.61-0.97). When patients were divided into quartiles based on TyG index, the incidences of both outcomes were significantly lower in higher TyG quartiles (all-cause death; p=0.0003, MACEs; p=0.007 by log-rank). ConclusionsIn this predominantly elderly, low BMI cohort with established HFpEF, higher TyG index was paradoxically associated with better clinical outcomes. These findings imply a complex relationship between IR and HFpEF outcomes. Clinical Perspective1) What is new?O_LIThe triglyceride-glucose (TyG) index is a novel, easily calculated surrogate marker for insulin resistance (IR) using only serum triglyceride and fasting blood glucose levels. C_LIO_LIA higher TyG index, reflecting greater IR, was paradoxically associated with a lower incidence of all-cause mortality and major adverse cardiovascular events in patients hospitalized with heart failure with preserved ejection fraction (HFpEF) over approximately one year of follow-up. C_LIO_LIThis association remained consistent across various subgroups stratified by age, sex, BMI, diabetes status, and other risk factors. C_LI 2) What are the clinical implications?O_LIA paradoxical relationship between IR and clinical outcomes may exist in predominantly older, low-BMI Japanese patients with established HFpEF. C_LIO_LIThe prognostic impact of IR in established heart failure appears complex and may vary depending on patient characteristics. C_LI

AimsIt remains uncertain which patients would benefit the most from transcatheter edge-to-edge repair (TEER). We aim to investigate the relationship between right ventricular function, as assessed by pressure-strain loops (PSL), and post-TEER clinical improvement. Methods and resultsA total of 48 heart failure with reduced ejection fraction (HFrEF) patients (68{+/-}15 yrs) with moderate-to-severe or severe SMR were enrolled for TEER. Impaired health status (Kansas City Cardiomyopathy Questionnaire Overall Summary Score [KCCQ-OS]) and exercise capacity (6-min walk distance [6MWD]) were evaluated at baseline and during 1-year follow up. Before and right after TEER, myocardial work (MW) metrics were non-invasively evaluated, including global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE). RV GLS, RVGWI, RVGCW, RVGWE were significantly increased after MitraClip treatment (-9.7{+/-}3.8%, 452.4{+/-}112.5 mmHg%, 596.3{+/-}127.5 mmHg% and 85.7{+/-}15.6% before vs -12.5{+/-}3.5%, 589.4{+/-}119.6 mmHg%, 778.8{+/-}135.3 mmHg% and 91.2{+/-}22.4% after MitraClip treatment, p = 0.025, 0.030, 0.025 and 0.037, respectively). The Kaplan-Meier estimates for survival, freedom from HF hospitalization at 12 months were 95.8% and 89.1%. On multivariable linear regression analysis, RVGWI and RVGCW immediate change was independently associated with KCCQ-OS ({bigtriangleup}RVGWI: {beta} = 0.40, P < 0.001; {bigtriangleup}RVGCW: {beta} = 0.39, P =0.003), RVGWI, RVGCW and RVGLS immediate change were independently associated with 6MWD improvement ({bigtriangleup}RVGWI: {beta} = 0.31, P = 0.029; {bigtriangleup}RVGCW: {beta} = 0.30, P = 0.039; {bigtriangleup}RVGLS: {beta} = 0.35, P = 0.041). ConclusionRVMW was significantly increased after MitraClip treatment. And RV reserve function is an important predictor of clinical improvement in HFrEF patients with TEER.

BackgroundLeft ventricular ejection fraction (LVEF) continues to be employed as the principle phenotypic marker for the classification, prognostication, and management of cardiovascular disease. However, expanding evidence identifies similarly important roles for right ventricular ejection fraction (RVEF) across multiple referral cohorts, raising the consideration of bi-ventricular ejection fraction (BiVEF) based phenotyping in broader clinical practice. We assessed the value of cardiovascular magnetic resonance (CMR)-based BiVEF phenotyping versus conventional LVEF-only phenotyping for the prediction of NYHA functional class and future heart failure (HF) outcomes. Methods9,437 consecutively enrolled adult patients clinically referred for CMR were evaluated for NYHA class [&ge;]II at time of imaging and a future composite outcome of HF hospitalization, HF death, and need for cardiac transplantation or LV assist device. ResultsMedian age was 57 years (Q1, Q3 44-66, 62% male). Across all LVEF strata, RVEF<45% was independently associated with NYHA [&ge;]II after comprehensive adjustment for baseline clinical and imaging characteristics. Respective adjusted odds ratios for RVEF <45% versus [&ge;]45% were 2.30 (1.79-2.97), 1.58 (1.13-2.20), and 2.01 (1.44-2.79) for LVEF <40%, 40-50, and >50% categories (p<0.001, =0.007, and <0.001; respectively). Over a median follow-up of 3.9 years, 766 patients (8%) experienced the HF outcome. In a multivariable Fine-Gray model, the respective adjusted HRsub for LVEF <40% and 40-50% were 2.13 (1.64-2.77) and 1.70 (1.33-2.17); p<0.001) relative to LVEF >50%. In this model, RVEF <45% was associated with 1.52 (1.25-1.86) greater hazard for future HF outcome versus RVEF [&ge;]45% (p<0.001). ConclusionsRV contractile health is independently associated with HF symptoms and identifies patients at elevated risk of future HF outcomes. Incremental prognostic value from BiVEF phenotyping is delivered versus LVEF-only phenotyping.

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

AimWe conducted a meta-analysis on the effectiveness of sodium-glucose co-transporter 2 (SGLT2) inhibitors in heart failure (HF) patients with preserved (HFpEF) and reduced (HFrEF) ejection fraction. MethodsA comprehensive search of several databases for placebo-controlled randomised controlled trials of SGLT2 inhibitors from inception to September 30 2022, limited to English language and excluding animal studies, was conducted. The databases included Medline, Scopus, Cochrane Central, and ClinicalTrials.gov. Randomised controlled studies were chosen if they included HF patients and reported at least one of the predetermined outcomes. Hazard ratios (HRs) or risk ratios were pooled together with the appropriate 95% confidence intervals using a random-effect model. Fourteen trials met the inclusion criteria, with 42 409 HF patients participating (N = 21 678 in the SGLT2 inhibitor arms and N = 20 731 in the placebo arms). ResultsSGLT2 inhibitors significantly reduced the composite of HF hospitalisation or cardiovascular death [HR: 0.75 (0.71-0.79); P < 0.001; I2 = 0%], total hospitalisations for heart failure [HR: 0.70 (0.66- 0.75); P < 0.001; I2 = 0%], and reduced the occurrence of cardiovascular death [HR: 0.86 (0.81-0.92); P < 0.001; I2 = 43%]. Sub-group analysis was conducted based on HF status at baseline, EF, diabetes status at baseline, and sex. SGLT2 inhibitors significantly reduced the composite heart failure hospitalisation and cardiovascular death for all the subgroups except for patients with HFpEF at baseline [HR: 0.87 (0.74- 1.03); P = 0.11; I2 = 60%] and no diabetes status at baseline [HR: 0.92 (0.73-1.16); P = 0.50; I2 = 78%]. ConclusionsIn patients with HF, SGLT2 inhibitors may significantly improve clinical outcomes, including all-cause and cardiovascular mortality. In this meta-analysis, SGLT2 inhibitors did not show a reduction in composite heart failure in patients with heart failure with preserved ejection fraction at baseline.

IntroductionCirculating biomarkers play an important role in patients with heart failure (HF) for risk stratification and mechanistic insights. We aimed to examine if a diverse set of biomarkers in the REHAB-HF trial would predict improvement in physical function following a 12-week tailored physical therapy rehabilitation intervention compared to attention control. MethodsThe study population consisted of participants [&ge;]60 years of age who were hospitalized with acute HF and randomized to a subsequent multidomain outpatient physical rehabilitation intervention vs. attention control with outcomes of 12-week functional change including the Short Physical Performance Battery (SPPB) and six-minute walk distance (6MWD). Blood was collected prior to randomization and at 12-weeks for cardiac, renal, and inflammatory biomarkers. Linear trends across progressively higher biomarker values versus improvement in functional outcomes based on treatment assignment were evaluated. Classification and regression trees (CART) were created to estimate optimal biomarker levels associated with differential improvement in the two functional outcomes. ResultsA total of 242 of 349 participants (69%) had baseline biomarkers measured. In an adjusted regression model, higher baseline cardiac troponin (cTn) I and T were associated with greater gains in SPPB and 6MWD respectively with the rehabilitation intervention (P=0.04 and 0.03 for interaction) versus attention control. In the CART analysis of the physical rehabilitation and attention control participants, those with baseline C-reactive protein (CRP) [&ge;]9.9 mg/L and hs-cTnT [&ge;]36 ng/L receiving the rehabilitation intervention had a 129 m (95% CI 78-180m) greater 12-week 6MWD increase vs attention control. In contrast, for participants with CRP<9.9 mg/L there was no significant incremental 6MWD difference (30m, 95% CI -0.5m, 60.2m). For SPPB, a CRP [&ge;]9.9 mg/L and creatinine [&ge;]1.4 mg/dL optimally identified a differential improvement with the rehabilitation intervention versus attention control. The biomarkers (except for creatinine) decreased by 12 weeks post hospitalization but with no differences based on treatment assignment. ConclusionHigher baseline levels of biomarkers of inflammation, cardiac injury, and renal dysfunction identified older adults after a HF hospitalization with the greatest differential improvement in physical function with a rehabilitation intervention. Biomarkers may help clinicians predict the benefits of this treatment. (Funded by the National Institutes of Health and others; REHAB-HF ClinicalTrials.gov number, NCT02196038).

Background and ObjectivesCognitive impairment is prevalent in patients with heart failure with reduced ejection fraction (HFrEF), affecting self-care and outcomes. Novel blood-based biomarkers have emerged as potential diagnostic tools for neurodegeneration. This study aimed to assess neurodegeneration in HFrEF by measuring neurofilament light chain (NfL), total tau (t-tau), amyloid-beta 42 (A{beta}42), and 40 (A{beta}40) in a large, well-characterised cohort. MethodsThe study included 470 HFrEF patients from a biobank-linked prospective registry at the Medical University of Vienna. High-sensitivity single-molecule assays were used for measurement. Unplanned hospitalisations and all-cause death were recorded as outcome parameters. ResultsAll markers, but not the A{beta}42/A{beta}40 ratio, correlated with heart failure (HF) severity, i.e. NTproBNP and NYHA class, comorbidity burden and were significantly associated with all-cause death and HF-hospitalisations [crude HR for 1-log unit increase (95%CI): 4.44 (3.02-6.53), 5.04 (2.97-8-58), 3.90 (2.27-6.72) and 5.14 (2.84-9.32) for all-cause death and 2.48 (1.60-3.85), 3.44 (1.95-6.04), 3.13 (1.84-5.34) and 3.48 (1.93-6.27) for HHF, p<0.001 for all]. These markers remained significant after adjustment in multivariate models including NT-proBNP. NfL and t-tau showed the highest prognostic ability in the receiver operating characteristic analysis [AUC: 0.72, 0.68, 0.66, 0.67 for NfL, t-tau, A{beta}40 and A{beta}42, respectively]. The performance of NfL was comparable to that of NT-proBNP [C-index: 0.70 vs 0.72, p=0.225]. ConclusionsNeurodegeneration is directly interwoven with the progression of HF. Biomarkers, particularly NfL, may help identify patients profiting from detailed neurological workups. Further research is necessary to test if early diagnosis or optimised HFrEF treatment can preserve cognitive function.

BackgroundImpaired energy metabolism in the heart is critical in the development of cardiac hypertrophy and failure. Src-associated in mitosis 68 kDa (Sam68) is a member of the signal transducer and activator of RNA (STAR) protein family, and its role in cardiac energy metabolism is undefined. MethodsWe assessed Sam68 expression in human myopathic and failing hearts. We also generated mice with cardiomyocyte-specific Sam68 deletion or overexpression and subjected them to angiotensin II infusion or transverse aortic constriction (TAC) surgery to induce pathological cardiac hypertrophy. Mechanistic studies were performed using RNA-seq, metabolomics, and immunoprecipitation analyses. ResultsSam68 expression was significantly elevated in cardiomyocytes of human myopathic and failing hearts. Deletion of Sam68 in adult mouse cardiomyocytes prevented angiotensin II- and TAC-induced cardiac hypertrophy. Conversely, AAV9-mediated overexpression of Sam68 in cardiomyocyte exacerbated cardiac hypertrophy and failure. RNA-seq and metabolomic analyses showed that Sam68 deficiency led to a marked downregulation of pyruvate dehydrogenase kinase 4 (PDK4), which was associated with enhanced cardiac glucose oxidation and oxidative phosphorylation. Mechanistically, Sam68 directly interacts with STAT3, promoting its phosphorylation and nuclear translocation via Src signaling, thereby enhancing PDK4 transcription. Pharmacological inhibition of the Sam68-Src interaction using a specific peptidomimetic molecule mitigated pathological cardiac hypertrophy by attenuating STAT3 phosphorylation and restoring glucose oxidation. Additionally, the Sam68/STAT3/PDK4 signaling axis was significantly unregulated in patients with heart failure. ConclusionsOur findings reveal a novel role of Sam68 in regulating cardiac glucose oxidation, highlighting the potential therapeutic targeting of Sam68 for managing cardiac hypertrophy and heart failure. Clinical Perspective What Is New?O_LISam68 (Src-associated-in-mitosis-of-68kDa) expression is upregulated in human failing hearts and in mouse models of cardiac hypertrophy and heart failure. C_LIO_LIDeletion of Sam68 in cardiomyocytes mitigates pressure overload-induced cardiac hypertrophy and dysfunction, while overexpression of Sam68 exacerbates these conditions. C_LIO_LISam68 exacerbates pressure overload-induced cardiac hypertrophy and dysfunction by binding to STAT3, increasing its phosphorylation and nuclear translocation, which ultimately leads to the upregulation of PDK4 and impairment of glucose oxidation. C_LI What Are the Clinical Implications?O_LIUpregulation of the Sam68/STAT3/PDK4 signaling axis in cardiomyocytes is associated with the development of cardiac hypertrophy and heart failure. C_LIO_LIPharmacological inhibition of Sam68 has the potential to improve cardiac energy metabolism, offering new therapeutic options for treating cardiac hypertrophy. C_LIO_LIBy modulating the Sam68/STAT3/PDK4 axis, it may be possible to enhance glucose oxidation and mitigate the progression of heart failure. C_LI