Circulation: Heart Failure

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

Heart failure with preserved ejection fraction (HFpEF) accounts for >50% of all heart failure world-wide and remains a major unmet medical need. The most effective recently approved treatments were first developed for diabetes, suggesting metabolic defects are paramount. Myocardial metabolomics in human HFpEF has identified reduced fatty acid and branched chain amino acid catabolism, but the status of glycolysis is unknown. Here we performed targeted metabolomics and protein analysis of glycolytic pathway enzymes in myocardial biopsies of patients with HFpEF versus HF with reduced ejection fraction (HFrEF0 or non-failing controls. Glucose was increased in HFpEF myocardium, but immediate downstream glycolytic metabolites (glucose-6 phosphate, fructose 1,6 diphosphate), were more reduced in HFpEF than the other groups, as were their associated synthetic enzymes hexokinase and phosphofructokinase. Pyruvate was also reduced in HFpEF versus controls. These changes were either not present or substantially less so in HFrEF. Suppression of proximal glycolysis was also coupled to lower metabolites and proteins in the pentose phosphate pathway but was independent of diabetes or obesity. These findings support marked metabolic inflexibility in HFpEF and identifies very proximal blockade in glucose metabolism. Efforts to improve metabolic use of carbohydrates in HFpEF will likely need to target these proximal glycolytic enzymes.

STUCTURED ABSTRACTO_ST_ABSObjectivesC_ST_ABSWe hypothesized that disruption of pathways downstream of insulin signaling characterize pathological ventricular remodeling and may provide insights into the pathophysiology of heart failure. To test this hypothesis, we examined components of the insulin signaling pathway in tissue explants from human hearts obtained from healthy donors and explants from heart failure patients with and without diabetes, receiving a heart transplant. BackgroundPathologic ventricular remodeling accompanied by hypertrophic growth is a common characteristic of heart failure including in patients with diabetes. The contribution of aberrant insulin signaling in the pathophysiology of diabetes-associated heart failure and, ventricular hypertrophy is incompletely understood. MethodsHearts of twenty non-failing donor participants and thirty-one human cardiac transplant patients were assessed for insulin signaling. Samples were sorted into four groups: non-failing non-obese (NFN), non-failing obese (NFO), failing non-diabetic (FND), and failing diabetic (FDM). Ejection fraction was assessed by echocardiography and clinically relevant systolic dysfunction was defined as left ventricular ejection fraction <50%. A clinical diabetes diagnosis was obtained from chart review. As a proxy measure of prolonged glycemia, plasma fructosamine was determined by colorimetric assay. Insulin signaling, protein phosphorylation, and total protein levels were measured by immunoblot. ResultsWhen all groups were analyzed together, hyperglycemia correlated with increased cardiac size and decreased function. Cardiac size correlated with increased levels of insulin receptor (IRb) and phosphorylated ERK but with decreased levels of phosphorylated Akt and mTOR. IRb and p-Akt correlated with fructosamine, but p-ERK and p-mTOR did not. Cardiac hypertrophy correlated with decreased GLUT1 levels, increased Hexokinase I and repression mitochondrial complexes I, III and IV in concert with activation of AMPK. ConclusionsAltered insulin signaling, characterized by increased IRb content, activation of ERK but repression of Akt and mTOR signaling pathways is present in the end-stage failing human heart. Similar divergence of insulin signaling pathways have been previously described in vascular smooth muscle. CONDENSED ABSTRACTWe hypothesized that disruption of pathways downstream of insulin signaling characterize pathological ventricular remodeling and may provide insights into pathophysiology. To test this hypothesis, we examined components of the insulin signaling pathway in tissue explants from human hearts obtained from healthy donors and explants from heart failure patients with and without diabetes, receiving a heart transplant. We found that altered insulin signaling, characterized by increased IRb content and activation of ERK but repression of Akt and mTOR signaling pathways is present in the end-stage failing human heart. HIGHLIGHTSIn this cross-sectional analysis of end-stage failing human cardiac tissue, hyperglycemia correlated with cardiac dysfunction and increased cardiac hypertrophy. O_LIWhile myocardial insulin resistance may exist in the PI3K-Akt-mTOR pathway in end-stage failing human hearts, ERK signaling is induced, which may contribute to cardiac hypertrophy in a manner that is independent of plasma insulin. C_LIO_LIDifferential activation of branches of insulin signaling in human failing hearts, supports the concept of selective insulin resistance. C_LIO_LIThese findings have implications for the consequences of modulating systemic insulin sensitivity in patients with heart failure. C_LI

Background and AimsSome, but not all, patients with heart failure (HF) develop pulmonary vascular disease (PVD), which contributes to poor prognosis. Mechanisms leading to PVD in HF are poorly understood. Unbiased analysis of transpulmonary gradients may identify mediators of PVD by finding proteins consumed or elaborated across the lungs. Methods21 controls and 160 HFrEF patients underwent pulmonary artery (PA) catheterization with blood sampling from postcapillary (wedged balloon) and precapillary (unwedged) position to obtain transpulmonary gradients. The samples from controls and HF from the highest (Q4, n=40) and lowest quartile (Q1, n=40) of pulmonary vascular resistance (PVR) were analyzed using proteomic proximity extension assay (Olink) of 275 proteins. Venous blood concentrations or transpulmonary gradients were analyzed to identify biomarkers or mediators of PVD. ResultsComparison of Q1 and Q4 of PVR identified Surfactant protein-D (PSP-D) as a marker of PVD. Examination of gradients across the lungs in high PVR HF revealed significant uptake of 18 mediators, mostly associated with inflammation (chemokines, oncostatin-M, MMP9) or with TGF/activin pathway (GDF2/BMP9), and release of 5 mediators, notably IL-6 and IL-33. In contrast, these protein gradients were negligible in controls and low PVR HF patients. ConclusionsThe lungs of patients with HF and high PVR, display abnormal uptake and release of proinflammatory cytokines from IL6/gp130 family (IL6, IL33, Oncostatin-M), along with increased transpulmonary uptake of GDF2/BMP9. The study shows that proteins orchestrating inflammation or pulmonary vessel remodeling in group 1 PH, are also operating in patients with PVD due to HF. Structured graphical abstractO_ST_ABSKey questionC_ST_ABSCan transpulmonary gradients of regulatory peptides, measured by unbiased proteomic assay, provide a hint on mechanisms of increased pulmonary vascular resistance (PVR) in patients with heart failure (HF)? Key findingsIn striking contrast to Controls (n=21) and HF with low PVR (n=40), the lungs of patients with HF and high PVR (n=40) display abnormal release of proinflammatory cytokines (IL6, IL33), along with increased transpulmonary uptake of chemokines, BNP, Oncostatin M and GDF2/BMP9, a key ligand of BMPRII receptor. Take home messageThe study shows that proteins orchestrating inflammation or pulmonary vessel remodeling in group 1 pulmonary hypertension, are also operating in patients with pulmonary vascular disease due to HF. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/25321512v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@6f90c1org.highwire.dtl.DTLVardef@888de6org.highwire.dtl.DTLVardef@11c1823org.highwire.dtl.DTLVardef@174c547_HPS_FORMAT_FIGEXP M_FIG C_FIG

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

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.

AimTo investigate the utility of serum proteins to predict new-onset heart failure (HF), including those with reduced or preserved ejection fraction (HFrEF or HFpEF), with or without the consideration of known HF-associated clinical variables. Methods and resultsThe study included 612 participants with HF events from the prospective population-based AGES-Reykjavik cohort of the elderly (N = 5457), 440 of whom were incident cases, with a median follow-up time of 5.45 years. The incident HF population with echocardiographic data included patients with HFrEF (n = 167) and HFpEF (n = 188). The least absolute shrinkage and selection operator (LASSO) model in conjunction with bootstrap resampling validation (500 replications) were used to select predictor variables based on the analysis of 4782 serum proteins and numerous clinical variables related to HF. In at least 80% of bootstrap replications, a subset of 8 to 13 serum proteins had non-zero coefficients for predicting all incident HF, HFpEF, or HFrEF separately. We used C-statistics to assess the goodness of fit when modeling a prognostic risk score for incident HF. In the null model, which did not take age, sex or clinical variables into account, 13 proteins combined had a C-index of 0.80 for all incident HF, whereas for incident HFpEF and HFrEF, the C-index for a subset of 8 or 10 protein predictors combined was 0.78 and 0.80, respectively. The concordance gain for each set of protein predictors was also investigated in the context of the approved biomarker NPPB as well as a number of clinical variables such as Framingham risk score components and calcium in the coronary artery and thoracic aorta. We show that these proteins improve prediction of future HF events even when a large number of HF-associated clinical variables are not included in the model. ConclusionA small number of circulating proteins were found to accurately predict new-onset HF when no demographic or other information was included, and they also improved the prediction when the main known biomarker NPPB and many HF-associated clinical risk factors of the condition were taken into account.

BackgroundRight ventricular failure (RVF) after left ventricular assist devices (LVAD) is associated with significant morbidity and mortality and identifying patients at risk for severe RVF is an important clinical goal. Current risk prediction models were not developed in contemporary LVAD populations and have limited clinical applicability. ObjectivesTo evaluate whether the Model for End Stage Liver Disease - eXcluding INR (MELD-XI) can predict severe RVF after HeartMate 3 (HM3) implantation. MethodsWe retrospectively analyzed all adult patients who received HM3 LVAD as initial implantation at two academic medical centers. We assessed whether MELD-XI is an independent risk factor for severe RVF in multivariate analysis and compared the predictive accuracy of MELD-XI with previously published risk scores. We also investigated the relationship between MELD-XI and markers of right ventricular function and whether MELD-XI was associated with death or pump exchange at 1-year follow-up. ResultsOur study included a total of 246 patients, of which 74 (30%) experienced severe RVF. After adjusting for relevant covariables, MELD-XI was independently associated with severe RVF (OR 1.18, CI 1.09-1.29, p<0.001) and performed similarly to the EUROMACS and Michigan RVF risk scores. In addition, MELD-XI was not reflective of traditional echocardiographic or hemodynamic measures of right ventricular function. Finally, MELD-XI [&ge;] 14 predicted worse in-hospital mortality. ConclusionsAmong patients undergoing HM3 implantation, MELD-XI is independently associated with an increased risk of RVF and in-hospital mortality.

BackgroundSystemic chronic inflammation plays a role in the pathophysiology of both heart failure with preserved ejection fraction (HFpEF) and metabolic dysfunction-associated fatty liver disease (MAFLD). AimThis study aimed to investigate whether serum high-sensitivity C-reactive protein (hs-CRP) levels were associated with the future risk of heart failure (HF) hospitalization in patients with MAFLD and a normal left ventricular ejection fraction (LVEF). MethodsThe study enrolled consecutive individuals with MAFLD and normal LVEF who underwent coronary angiography for suspected coronary heart disease. The study population was subdivided into non-HF, pre-HFpEF, and HFpEF groups at baseline. The study outcome was the first hospitalization for HF. ResultsIn 10,019 middle-aged individuals (mean age 63.3{+/-}10.6 years; 38.5% female), the prevalence rates of HFpEF and pre-HFpEF were 34.2% and 34.5%, with a median serum hs-CRP level of 4.5 mg/L (IQR: 1.9-10 mg/L) and 5.0 mg/L (IQR: 2.1-10.1 mg/L), respectively. Serum hs-CRP levels were significantly higher in the pre-HFpEF and HFpEF groups than in the non-HF group. HF hospitalizations occurred in 1942 (19.4%) patients over a median of 3.2 years, with rates of 3.7% in non-HF, 20.8% in pre-HFpEF, and 32.1% in HFpEF, respectively. Cox regression analyses showed that patients in the highest hs-CRP level quartile had a [~]4.5-fold increased risk of being hospitalized for HF compared to those in the lowest hs-CRP level quartile (adjusted-Hazard Ratio 4.42, 95% CI 3.72-5.25). ConclusionsThere was a high prevalence of baseline pre-HFpEF and HFpEF in subjects with MAFLD. There was an increased risk of HF hospitalization in those with elevated hs-CRP levels.

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.

Heart failure (HF) remains a major cause of morbidity and mortality worldwide, with limited treatment options. Heart transplantation is an end stage option but limited by donor availability. Left-ventricular assist device (LVAD) implantation serves as a bridging strategy for patients awaiting a transplant. Intriguingly, LVAD support (typically for 6-12 months before heart transplantation) is often associated with some level of improvement in cardiac function and histology. In rare cases, LVAD support can improve cardiac function sufficiently to avoid heart transplantation after LVAD removal. The underlying mechanisms of this improvement in cardiac function are not understood. Here, we provide evidence that the improvement in cardiac function post-LVAD is associated with a reduction in fibrosis and an increase in capillary density. This heart failure recovery (HFR) is also associated with an angiogenic cell fate transition. We observed a distinct pro-angiogenic phenotype of cardiac non-myocytes isolated from post-LVAD hearts. Single-nuclei RNA sequencing of pre- and post-LVAD cardiac tissue reveals a fibroblast subtype that undergoes mesenchymal to endothelial transition (MEndoT), potentially facilitating HFR. In a murine model of HFR, lineage tracing studies confirm that MEndoT is associated with the increase in capillary density and perfusion during HFR. In summary, our results support the new concept that HFR is associated with a reduction in interstitial cardiac fibrosis, an increase in capillary density and perfusion, that is due in part to an angiogenic cell fate transition. Our work represents a shift in the conceptual framework regarding mechanisms of HFR, and a new therapeutic avenue for exploration.

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.

Mechanisms underlying the cardiovascular-kidney-metabolic (CKM) syndrome are unknown, although key small molecule metabolites may be involved. Bulk and spatial metabolomics identified adenine to be upregulated and specifically enriched in coronary blood vessels in hearts from patients with diabetes and left ventricular hypertrophy. Single nucleus gene expression studies revealed that endothelial methylthioadenosine phosphorylase (MTAP) was increased in human hearts with hypertrophic cardiomyopathy. The urine adenine/creatinine ratio in patients was predictive of incident heart failure with preserved ejection fraction. Heart adenine and MTAP gene expression was increased in a 2-hit mouse model of hypertrophic heart disease and in a model of diastolic dysfunction with diabetes. Inhibition of MTAP blocked adenine accumulation in the heart, restored heart dysfunction in mice with type 2 diabetes and prevented ischemic heart damage in a rat model of myocardial infarction. Mechanistically, adenine-induced impaired mitophagy was reversed by reduction of mTOR. These studies indicate that endogenous adenine is in a causal pathway for heart failure and ischemic heart disease in the context of CKM syndrome.

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

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

Dilated cardiomyopathy (DCM), an incurable disease of the cardiomyocyte terminating in systolic heart failure (HFrEF), is prevalent, causes hospitalization and is associated with increased mortality. Despite evidence of immune activation in DCM, anti-inflammatory interventions so far did not prove to alter the course of this disease. Here we show that myeloperoxidase (MPO), the principal heme peroxidase expressed by polymorphonuclear neutrophils (PMN) and monocytes, critically contributes to HFrEF in DCM. Muscle LIM protein (MLP) deficient mice, which spontaneously develop DCM, display increased circulating PMN counts and augmented levels of vessel-immobilized MPO. Genetic ablation and pharmacological inhibition of MPO resulted in enhanced nitric oxide (NO) bioavailability of systemic conductance and resistance vessels, and subsequently restoration of systolic left ventricular (LV) function, whereas infusion of MPO worsened systolic LV function. When patients diagnosed for DCM were treated with an orally available MPO inhibitor, systolic LV function increased, natriuretic peptides declined, and functional status improved. Impairment of endothelial NO bioavailability by release of leukocyte-derived MPO evolves as a disease-aggravating mechanism in DCM. MPO inhibition profoundly improved ventricular function by lowering systemic vascular resistance and thus holds promise as a novel and complementary treatment strategy for patients with DCM.

BackgroundLeft ventricular ejection fraction (LVEF) has well-known limitations including modest reproducibility, load dependence, and representation of the percentage change in left ventricular (LV) volume rather than myocardial contractility. We aimed to assess the prognostic value of systolic blood pressure: indexed left ventricular end-systolic volume ratio, or cardiac contractility index (CCI). MethodsWe conducted a prospective cohort study in 728 unselected individuals newly diagnosed with chronic heart failure. We divided patients into tertiles of LVEF and CCI, and also divided those with heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) by the median value of CCI (4.43mmHg/ml/m2) into four groups. Mortality rates for CCI and LVEF as continuous variables were assessed using unadjusted and adjusted Poisson regression models. ResultsThere was a modest, positive correlation between LVEF and CCI (r=0.70 [0.66-0.74], R2 0.49; p<0.0001), although the latter was distributed widely for any given value of LVEF, especially for those with HFpEF. We observed distinct clinical characteristics across tertiles of both LVEF and CCI, with an inverse relationship with conventional markers of risk including N-terminal B-type natriuretic peptide (p<0.001 in both comparisons). There was a clear relationship between tertiles of CCI and all-cause mortality risk, which was less evident when patients were divided by LVEF. When modelled as continuous variables there was a curvi-linear relationship between all-cause mortality rates and CCI, but the relationship between LVEF and mortality risk was more complex, with no clear association across a wide range from 25-55%. In models including relevant covariates, the association between LVEF and mortality was no longer evident except for those with LVEF 60% (relative to 50%) but remained evident for all specified values of CCI. Patients with HFpEF and CCI below the median value had an all-cause mortality risk [~]40% higher than those with CCI above median (p<0.001), similar to those with HFrEF. ConclusionsCCI is a non-invasive, relatively afterload independent measure left ventricular contractility which provided additional prognostic information beyond conventional assessment by LVEF. Furthermore, CCI was able to reclassify around a third of patients with HFpEF, and these patients had distinct characteristics and a worse prognosis. Clinical perspective Whats new?O_LIIn an unselected population with chronic heart failure, cardiac contractility index (CCI) provided better prognostic accuracy than left ventricular ejection fraction. C_LIO_LICCI was able to reclassify around a third of patients with a preserved ejection fraction who had evidence of reduced left ventricular contractility, and these patients had distinct characteristics and all-cause mortality risk similar to those with a reduced ejection fraction. C_LI What are the clinical implications?O_LICCI is a simple, relatively afterload independent measure of left ventricular contractility, which utilises data already part of a standard echocardiographic assessment. C_LIO_LIThe identification of subtle or concomitant systolic dysfunction in heart failure with a preserved ejection fraction may help better define risk and refine the phenotypic classification of this heterogenous group. C_LI

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.

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.