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Aims: Reverse ventricular remodelling, defined as a decrease in left ventricular end-systolic volume indexed to body surface area (LVESVI) or an increase in left ventricular ejection fraction (LVEF), is associated with improved clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, the underlying pathophysiological mechanisms remain unclear., Methods and Results: We evaluated paired core-lab assessed echocardiograms and measurements of 92 biomarkers at baseline and 8 months thereafter in 419 participants with HFrEF. Reverse ventricular remodelling was defined as a >5% LVEF increase or >15% LVESVI relative decrease between baseline and 8 months. We evaluated the association between baseline biomarkers and their changes with reverse ventricular remodelling in the prospectively randomized controlled VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) trial. Of 419 patients (median age 66 [interquartile range 57-74] years, 27.4% women), 206 (49.2%) had reverse ventricular remodelling (either a 5% LVEF increase or a 15% LVESVI decrease). There were no differences in baseline biomarker concentrations between patients with versus those without reverse ventricular remodelling on follow-up. However, in patients with reverse ventricular remodelling there were significant decreases in biomarkers relating to inflammation and cardiac metabolism; particularly the tumour necrosis factor superfamily member 13B (ratio 0.82, 95% confidence interval [CI] 0.77-0.88), growth differentiation factor-15 (ratio 0.74, 95% CI 0.66-0.84), and insulin-like growth factor binding protein 7 (ratio 0.80, 95% CI 0.73-0.88)., Conclusions: Reverse ventricular remodelling in patients with HFrEF is associated with a decrease of biomarkers related to inflammation and cardiac metabolism., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The relationship of serial NT-proBNP (N-terminal pro-B-type natriuretic peptide) measurements with changes in cardiac features and outcomes in heart failure (HF) remains incompletely understood. We determined whether common clinical covariates impact these relationships., Methods and Results: In 2 nationwide observational populations with HF, the relationship of serial NT-proBNP measurements with serial echocardiographic parameters and outcomes was analyzed, further stratified by HF with reduced versus preserved left ventricular ejection fraction, inpatient versus outpatient enrollment, age, obesity, chronic kidney disease, atrial fibrillation, and attainment of ≥50% guideline-recommended doses of renin-angiotensin system inhibitors and β-blockers. Among 1911 patients (mean±SD age, 65.1±13.4 years; 26.6% women; 62% inpatient and 38% outpatient), NT-proBNP declined overall, with more rapid declines among inpatients, those with obesity, those with atrial fibrillation, and those attaining ≥50% guideline-recommended doses. Each doubling of NT-proBNP was associated with increases in left ventricular volume (by 6.1 mL), E/e' (transmitral to mitral annular early diastolic velocity ratio) (by 1.4 points), left atrial volume (by 3.6 mL), and reduced left ventricular ejection fraction (by -2.1%). The effect sizes of these associations were lower among patients with HF with preserved ejection fraction, atrial fibrillation, or advanced age ( P interaction <0.001). A landmark analysis identified that an SD increase in NT-proBNP over 6 months was associated with a 27% increase in the risk of the composite event of HF hospitalization or all-cause death between 6 months and 2 years (adjusted hazard ratio, 1.27 [95% CI, 1.15-1.40]; P <0.001)., Conclusions: The relationships between NT-proBNP and structural/functional remodeling differed by age, presence of atrial fibrillation, and HF phenotypes. The association of increased NT-proBNP with increased risk of adverse outcomes was consistent in all subgroups.

Aim: Pathophysiological differences between patients with heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction (EF) remain unclear. Therefore we used a phenomics approach, integrating selected proteomics data with patient characteristics and cardiac structural and functional parameters, to get insight into differential pathophysiological mechanisms and identify potential treatment targets., Methods and Results: We report data from a representative subcohort of the prospective Singapore Heart Failure Outcomes and Phenotypes (SHOP), including patients with HFrEF (EF <40%, n = 217), HFpEF (EF ≥50%, n = 213), and age- and sex-matched controls without HF (n = 216). We measured 92 biomarkers using a proximity extension assay and assessed cardiac structure and function in all participants using echocardiography. We used multi-block projection to latent structure analysis to integrate clinical, echocardiographic, and biomarker variables. Candidate biomarker targets were cross-referenced with small-molecule and drug databases. The total cohort had a median age of 65 years (interquartile range 60-71), and 50% were women. Protein profiles strongly discriminated patients with HFrEF (area under the curve [AUC] = 0.89) and HFpEF (AUC = 0.94) from controls. Phenomics analyses identified unique druggable inflammatory markers in HFpEF from the tumour necrosis factor receptor superfamily (TNFRSF), which were positively associated with hypertension, diabetes, and increased posterior and relative wall thickness. In HFrEF, interleukin (IL)-8 and IL-6 were possible targets related to lower EF and worsening renal function., Conclusion: We identified pathophysiological mechanisms related to increased cardiac wall thickness parameters and potentially druggable inflammatory markers from the TNFRSF in HFpEF., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: The aims of this study were to compare the characteristics of patients with and without diabetes and to use network analyses to compare biomarker profiles and associated pathways in patients with diabetes compared with those without diabetes, which might offer new avenues for potential therapeutic targets., Background: Diabetes adversely affects clinical outcomes and complicates treatment in patients with heart failure (HF). A clear understanding of the pathophysiological processes associated with type 2 diabetes in HF is lacking., Methods: Network and pathway over-representation analyses were performed to identify unique pathological pathways in patients with and without diabetes using 92 biomarkers from different pathophysiological domains measured in plasma samples from 1,572 patients with HF (31% with diabetes) with reduced ejection fraction (left ventricular ejection fraction <40%). The results were validated in an independent cohort of 729 patients (30% with diabetes)., Results: Biomarker profiles were first compared between patients with HF with and without diabetes. Patients with diabetes showed higher levels of galectin-4, growth differentiation factor 15, and fatty acid binding protein 4 and lower levels of paraoxonase 3. Network analyses were then performed, revealing that epidermal growth factor receptor and galectin-3 were the most prominent connecting proteins. Translation of these networks to biologic pathways revealed that diabetes was associated with inflammatory response and neutrophil degranulation. Diabetes conferred worse outcomes after correction for an established risk model (hazard ratio: 1.20; 95% confidence interval: 1.01 to 1.42)., Conclusions: Concomitant diabetes in patients with HF with reduced ejection fraction is associated with distinct pathophysiological pathways related to inflammation, protein phosphorylation, and neutrophil degranulation. These data support the evaluation of anti-inflammatory therapeutic approaches, epidermal growth factor receptor in particular, for patients with HF and diabetes., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: In this study, the authors used biomarker profiles to characterize differences between patients with acute heart failure with a midrange ejection fraction (HFmrEF) and compare them with patients with a reduced (heart failure with a reduced ejection fraction [HFrEF]) and preserved (heart failure with a preserved ejection fraction [HFpEF]) ejection fraction., Background: Limited data are available on biomarker profiles in acute HFmrEF., Methods: A panel of 37 biomarkers from different pathophysiological domains (e.g., myocardial stretch, inflammation, angiogenesis, oxidative stress, hematopoiesis) were measured at admission and after 24 h in 843 acute heart failure patients from the PROTECT trial. HFpEF was defined as left ventricular ejection fraction (LVEF) of ≥50% (n = 108), HFrEF as LVEF of <40% (n = 607), and HFmrEF as LVEF of 40% to 49% (n = 128)., Results: Hemoglobin and brain natriuretic peptide levels (300 pg/ml [HFpEF]; 397 pg/ml [HFmrEF]; 521 pg/ml [HFrEF]; p trend  <0.001) showed an upward trend with decreasing LVEF. Network analysis showed that in HFrEF interactions between biomarkers were mostly related to cardiac stretch, whereas in HFpEF, biomarker interactions were mostly related to inflammation. In HFmrEF, biomarker interactions were both related to inflammation and cardiac stretch. In HFpEF and HFmrEF (but not in HFrEF), remodeling markers at admission and changes in levels of inflammatory markers across the first 24 h were predictive for all-cause mortality and rehospitalization at 60 days (p interaction  <0.05)., Conclusions: Biomarker profiles in patients with acute HFrEF were mainly related to cardiac stretch and in HFpEF related to inflammation. Patients with HFmrEF showed an intermediate biomarker profile with biomarker interactions between both cardiac stretch and inflammation markers. (PROTECT-1: A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function; NCT00328692)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Young patients (<50years) exhibit specific characteristics in chronic heart failure (HF), but their phenotype in acute heart failure (AHF) is not well described., Methods and Results: 2033 patients of the PROTECT trial were divided into two groups: young patients (≤50years) and older patients (>50years). Biomarkers from different pathophysiological domains were available in 1266 patients. Patients were compared with regard to clinical characteristics, biomarker profiles, and in-hospital (worsening renal function [WRF] and decongestion) and post-discharge (180-day survival) outcome. Young patients (n=121) were mostly men, had fewer comorbidities with better renal function, and more often had a reduced ejection fraction. At admission, young patients were more likely to have jugular venous distension, but less rales and dyspnea compared with older patients. During hospitalization, young patients received higher loop diuretic doses and were decongested earlier than older patients. WRF occurred less frequently in young patients (5.9% vs. 13.3%, p=0.020) and they were more often discharged alive. At 180days, the mortality of young patients was lower than that of the older patients (9.9% vs. 18.1, p=0.021). Biomarker levels indicative of inflammation and renal damage were lower in the young, although they exhibited higher BNP levels than older patients., Conclusions: Despite use of higher diuretic doses, young patients with AHF less often developed WRF during hospitalization and had better outcomes than older patients. Differences in biomarker levels between the age groups suggest distinct underlying pathophysiologies. https://clinicaltrials.gov numbers NCT00328692 and NCT00354458., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

This article explores the use of biomarkers and echocardiography in preventing heart failure. The authors conducted a study to examine the proteomic profiles associated with left atrial volume and how they are affected by spironolactone. They discovered that certain biomarkers, such as MMP-2, IGFBP-2, and NT-proBNP, were significantly linked to left atrial volume. Spironolactone was found to reduce levels of MMP-2 and NT-proBNP, regardless of the initial left atrial volume. The study suggests that screening high-risk patients for diastolic dysfunction, indicated by left atrial enlargement, could be beneficial, and biomarkers could aid in selecting patients for spironolactone treatment. The use of AI-supported ultrasound devices at primary care level could facilitate screening. The article also discusses the potential integration of biomarkers, AI, and point-of-care echocardiography for screening high-risk populations for heart failure. Personalized treatment based on biomarker selection could improve the effectiveness and cost-efficiency of heart failure screening and treatment strategies. The study's findings provide further evidence of the link between fibrosis and diastolic dysfunction in high-risk patients. The article also discloses the authors' conflict of interest. [Extracted from the article]

Aims: Renal dysfunction is one of the most critical risk factors for developing heart failure (HF). However, the association between repeated measures of renal function and incident HF remains unclear. Therefore, this study investigated the longitudinal trajectories of urinary albumin excretion (UAE) and serum creatinine and their association with new‐onset HF and all‐cause mortality. Methods and results: Using group‐based trajectory analysis, we estimated trajectories of UAE and serum creatinine in 6881 participants from the Prevention of Renal and Vascular End‐stage Disease (PREVEND) study and their association with new‐onset HF and all‐cause death during the 11‐years of follow‐up. Most participants had stable low UAE or serum creatinine. Participants with persistently higher UAE or serum creatinine were older, more often men, and more often had comorbidities, such as diabetes, a previous myocardial infarction or dyslipidaemia. Participants with persistently high UAE had a higher risk of new‐onset HF or all‐cause mortality, whereas stable serum creatinine trajectories showed a linear association for new‐onset HF and no association with all‐cause mortality. Conclusion: Our population‐based study identified different but often stable longitudinal patterns of UAE and serum creatinine. Patients with persistently worse renal function, such as higher UAE or serum creatinine, were at a higher risk of HF or mortality. [ABSTRACT FROM AUTHOR]

Aims The exploration of novel immunomodulatory interventions to improve outcome in heart failure (HF) is hampered by the complexity/redundancies of inflammatory pathways, which remain poorly understood. We thus aimed to investigate the associations between the activation of diverse immune processes and outcomes in patients with HF. Methods and results We measured 355 biomarkers in 2022 patients with worsening HF and an independent validation cohort (n  = 1691) (BIOSTAT-CHF index and validation cohorts), and classified them according to their functions into biological processes based on the gene ontology classification. Principal component analyses were used to extract weighted scores per process. We investigated the association of these processes with all-cause mortality at 2-year follow-up. The contribution of each biomarker to the weighted score(s) of the processes was used to identify potential therapeutic targets. Mean age was 69 (±12.0) years and 537 (27%) patients were women. We identified 64 unique overrepresented immune-related processes representing 188 of 355 biomarkers. Of these processes, 19 were associated with all-cause mortality (10 positively and 9 negatively). Increased activation of ' T-cell costimulation ' and ' response to interferon-gamma/positive regulation of interferon-gamma production ' showed the most consistent positive and negative associations with all-cause mortality, respectively, after external validation. Within T-cell costimulation , inducible costimulator ligand, CD28, CD70, and tumour necrosis factor superfamily member-14 were identified as potential therapeutic targets. Conclusions We demonstrate the divergent protective and harmful effects of different immune processes in HF and suggest novel therapeutic targets. These findings constitute a rich knowledge base for informing future studies of inflammation in HF. [ABSTRACT FROM AUTHOR]

Aims: Elevated concentrations of growth differentiation factor 15 (GDF‐15) in patients with heart failure (HF) have been consistently associated with worse clinical outcomes, but what disease mechanisms high GDF‐15 concentrations represent remains unclear. Here, we aim to identify activated pathophysiological pathways related to elevated GDF‐15 expression in patients with HF. Methods and results: In 2279 patients with HF, we measured circulating levels of 363 biomarkers. Then, we performed a pathway over‐representation analysis to identify key biological pathways between patients in the highest and lowest GDF‐15 concentration quartiles. Data were validated in an independent cohort of 1705 patients with HF. In both cohorts, the strongest up‐regulated biomarkers in those with high GDF‐15 were fibroblast growth factor 23 (FGF‐23), death receptor 5 (TRAIL‐R2), WNT1‐inducible signalling pathway protein 1 (WISP‐1), tumour necrosis factor receptor superfamily member 11a (TNFRSF11A), leucocyte immunoglobulin‐like receptor subfamily B member 4 (LILRB4), and trefoil factor 3 (TFF3). Pathway over‐representation analysis revealed that high GDF‐15 patients had increased activity of pathways related to inflammatory processes, notably positive regulation of chemokine production; response to interleukin‐6; tumour necrosis factor and death receptor activity; and positive regulation of T‐cell differentiation and inflammatory response. Furthermore, we found pathways involved in regulation of insulin‐like growth factor (IGF) receptor signalling and regulatory pathways of tissue, bones, and branching structures. GDF‐15 quartiles significantly predicted all‐cause mortality and HF hospitalization. Conclusion: Patients with HF and high plasma concentrations of GDF‐15 are characterized by increased activation of inflammatory pathways and pathways related to IGF‐1 regulation and bone/tissue remodelling. [ABSTRACT FROM AUTHOR]

Aims: The lack of effective therapies for patients with heart failure with preserved ejection fraction (HFpEF) is often ascribed to the heterogeneity of patients with HFpEF. We aimed to identify distinct pathophysiologic clusters of HFpEF based on circulating biomarkers. Methods and results: We performed an unsupervised cluster analysis using 363 biomarkers from 429 patients with HFpEF. Relative differences in expression profiles of the biomarkers between clusters were assessed and used for pathway over‐representation analyses. We identified four distinct patient subgroups based on their biomarker profiles: cluster 1 with the highest prevalence of diabetes mellitus and renal disease; cluster 2 with oldest age and frequent age‐related comorbidities; cluster 3 with youngest age, largest body size, least symptoms and lowest N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) levels; and cluster 4 with highest prevalence of ischaemic aetiology, smoking and chronic lung disease, most symptoms, as well as highest NT‐proBNP and troponin levels. Over a median follow‐up of 21 months, the occurrence of death or heart failure hospitalization was highest in clusters 1 and 4 (62.1% and 62.8%, respectively) and lowest in cluster 3 (25.6%). Pathway over‐representation analyses revealed that the biomarker profile of patients in cluster 1 was associated with activation of inflammatory pathways while the biomarker profile of patients in cluster 4 was specifically associated with pathways implicated in cell proliferation regulation and cell survival. Conclusion: Unsupervised cluster analysis based on biomarker profiles identified mutually exclusive subgroups of patients with HFpEF with distinct biomarker profiles, clinical characteristics and outcomes, suggesting different underlying pathophysiological pathways. [ABSTRACT FROM AUTHOR]

Background: A systemic proinflammatory state has been hypothesized to mediate the association between comorbidities and abnormal cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). We conducted a proteomic analysis to investigate this paradigm.Methods: In 228 patients with HFpEF from the multicenter PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction), 248 unique circulating proteins were quantified by a multiplex immunoassay (Olink) and used to recapitulate systemic inflammation. In a deductive approach, we performed principal component analysis to summarize 47 proteins known a priori to be involved in inflammation. In an inductive approach, we performed unbiased weighted coexpression network analyses of all 248 proteins to identify clusters of proteins that overrepresented inflammatory pathways. We defined comorbidity burden as the sum of 8 common HFpEF comorbidities. We used multivariable linear regression and statistical mediation analyses to determine whether and to what extent inflammation mediates the association of comorbidity burden with abnormal cardiac structure/function in HFpEF. We also externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without heart failure.Results: Comorbidity burden was associated with abnormal cardiac structure/function and with principal components/clusters of inflammation proteins. Systemic inflammation was also associated with increased mitral E velocity, E/e' ratio, and tricuspid regurgitation velocity; and worse right ventricular function (tricuspid annular plane systolic excursion and right ventricular free wall strain). Inflammation mediated the association between comorbidity burden and mitral E velocity (proportion mediated 19%-35%), E/e' ratio (18%-29%), tricuspid regurgitation velocity (27%-41%), and tricuspid annular plane systolic excursion (13%) (P<0.05 for all), but not right ventricular free wall strain. TNFR1 (tumor necrosis factor receptor 1), UPAR (urokinase plasminogen activator receptor), IGFBP7 (insulin-like growth factor binding protein 7), and GDF-15 (growth differentiation factor-15) were the top individual proteins that mediated the relationship between comorbidity burden and echocardiographic parameters. In the validation cohort, inflammation was upregulated in HFpEF cases versus controls, and the most prominent inflammation protein cluster identified in PROMIS-HFpEF was also present in HFpEF cases (but not controls) in the validation cohort.Conclusions: Proteins involved in inflammation form a conserved network in HFpEF across 2 independent cohorts and may mediate the association between comorbidity burden and echocardiographic indicators of worse hemodynamics and right ventricular dysfunction. These findings support the comorbidity-inflammation paradigm in HFpEF. [ABSTRACT FROM AUTHOR]

Aims: Cathepsin D is a ubiquitous lysosomal protease that is primarily secreted due to oxidative stress. The role of circulating cathepsin D in heart failure (HF) is unknown. The aim of this study is to determine the association between circulating cathepsin D levels and clinical outcomes in patients with HF and to investigate the biological settings that induce the release of cathepsin D in HF. Methods and results: Cathepsin D levels were studied in 2174 patients with HF from the BIOSTAT‐CHF index study. Results were validated in 1700 HF patients from the BIOSTAT‐CHF validation cohort. The primary combined outcome was all‐cause mortality and/or HF hospitalizations. Human pluripotent stem cell‐derived cardiomyocytes were subjected to hypoxic, pro‐inflammatory signalling and stretch conditions. Additionally, cathepsin D expression was inhibited by targeted short hairpin RNAs (shRNA). Higher levels of cathepsin D were independently associated with diabetes mellitus, renal failure and higher levels of interleukin‐6 and N‐terminal pro‐B‐type natriuretic peptide (P < 0.001 for all). Cathepsin D levels were independently associated with the primary combined outcome [hazard ratio (HR) per standard deviation (SD): 1.12; 95% confidence interval (CI) 1.02–1.23], which was validated in an independent cohort (HR per SD: 1.23, 95% CI 1.09–1.40). In vitro experiments demonstrated that human stem cell‐derived cardiomyocytes released cathepsin D and troponin T in response to mechanical stretch. ShRNA‐mediated silencing of cathepsin D resulted in increased necrosis, abrogated autophagy, increased stress‐induced metabolism, and increased release of troponin T from human stem cell‐derived cardiomyocytes under stress. Conclusions: Circulating cathepsin D levels are associated with HF severity and poorer outcome, and reduced levels of cathepsin D may have detrimental effects with therapeutic potential in HF. [ABSTRACT FROM AUTHOR]

Background: Chemo- and radiotherapy for breast cancer (BC) can lead to cardiotoxicity even years after the initial treatment. The pathophysiology behind these late cardiac effects is poorly understood. Therefore, we studied a large panel of biomarkers from different pathophysiological domains in long-term BC survivors, and compared these to matched controls.Methods and Results: In total 91 biomarkers were measured in 688 subjects: 342 BC survivors stratified either to treatment with chemotherapy ± radiotherapy (n = 170) or radiotherapy alone (n = 172) and matched controls. Mean age was 59 ± 9 years and 65 ± 8 years for women treated with chemotherapy ± radiotherapy and radiotherapy alone, respectively, with a mean time since treatment of 11 ± 5.5 years. No biomarkers were differentially expressed in survivors treated with radiotherapy alone vs. controls (P for all >0.1). In sharp contrast, a total of 19 biomarkers were elevated, relative to controls, in BC survivors treated with chemotherapy ± radiotherapy after correction for multiple comparisons (P <0.05 for all). Network analysis revealed upregulation of pathways relating to collagen degradation and activation of matrix metalloproteinases. Furthermore, several inflammatory biomarkers including growth differentiation factor 15, monocyte chemoattractant protein 1, chemokine (C-X-C motif) ligand 16, tumour necrosis factor super family member 13b and proprotein convertase subtilisin/kexin type 9, elevated in survivors treated with chemotherapy, showed an independent association with lower left ventricular ejection fraction.Conclusion: Breast cancer survivors treated with chemotherapy ± radiotherapy show a distinct biomarker profile associated with mild cardiac dysfunction even 10 years after treatment. These results suggest that an ongoing pro-inflammatory state and activation of matrix metalloproteinases following initial treatment with chemotherapy might play a role in the observed cardiac dysfunction in late BC survivors. [ABSTRACT FROM AUTHOR]

Aims: Heart failure is traditionally classified by left ventricular ejection fraction (LVEF), rather than by left ventricular (LV) geometry, with guideline-recommended therapies in heart failure with reduced ejection fraction (HFrEF) but not heart failure with preserved ejection fraction (HFpEF). Most patients with HFrEF have eccentric LV hypertrophy, but some have concentric LV hypertrophy. We aimed to compare clinical characteristics, biomarker patterns, and response to treatment of patients with HFrEF and eccentric vs. concentric LV hypertrophy.Methods and Results: We performed a retrospective post-hoc analysis including 1015 patients with HFrEF (LVEF <40%) from the multinational observational BIOSTAT-CHF study. LV geometry was classified using two-dimensional echocardiography. Network analysis of 92 biomarkers was used to investigate pathophysiologic pathways. Concentric LV hypertrophy was present in 142 (14%) patients, who were on average older and more likely hypertensive compared to those with eccentric LV hypertrophy. Network analysis revealed that N-terminal pro-B-type natriuretic peptide was an important hub in eccentric hypertrophy, whereas in concentric hypertrophy, tumour necrosis factor receptor 1, urokinase plasminogen activator surface receptor, paraoxonase and P-selectin were central hubs. Up-titration of beta-blockers was associated with a mortality benefit in HFrEF with eccentric but not concentric LV hypertrophy (P-value for interaction ≤0.001). For angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, the hazard ratio for mortality was higher in concentric hypertrophy, but the interaction was not significant.Conclusion: Patients with HFrEF with concentric hypertrophy have a clinical and biomarker phenotype that is distinctly different from those with eccentric hypertrophy. Patients with concentric hypertrophy may not experience similar benefit from up.-titration of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta-blockers compared to patients with eccentric hypertrophy. [ABSTRACT FROM AUTHOR]

Background: Information on the pathophysiological differences between heart failure with reduced ejection fraction (HFrEF) versus heart failure with preserved ejection fraction (HFpEF) is needed OBJECTIVES: The purpose of this study was to establish biological pathways specifically related to HFrEF and HFpEF.Methods: The authors performed a network analysis to identify unique biomarker correlations in HFrEF and HFpEF using 92 biomarkers from different pathophysiological domains in a cohort of 1,544 heart failure (HF) patients. Data were independently validated in 804 patients with HF. Networks were enriched with existing knowledge on protein-protein interactions and translated into biological pathways uniquely related to HFrEF, HF with a midrange ejection fraction, and HFpEF.Results: In the index cohort (mean age 74 years; 34% female), 718 (47%) patients had HFrEF (left ventricular ejection fraction [LVEF] <40%) and 431 (27%) patients had HFpEF (LVEF ≥50%). A total of 8 (12%) correlations were unique for HFrEF and 6 (9%) were unique to HFpEF. Central proteins in HFrEF were N-terminal B-type natriuretic peptide, growth differentiation factor-15, interleukin-1 receptor type 1, and activating transcription factor 2, while central proteins in HFpEF were integrin subunit beta-2 and catenin beta-1. Biological pathways in HFrEF were related to DNA binding transcription factor activity, cellular protein metabolism, and regulation of nitric oxide biosynthesis. Unique pathways in patients with HFpEF were related to cytokine response, extracellular matrix organization, and inflammation. Biological pathways of patients with HF with a midrange ejection fraction were in between HFrEF and HFpEF.Conclusions: Network analysis showed that biomarker profiles specific for HFrEF are related to cellular proliferation and metabolism, whereas biomarker profiles specific for HFpEF are related to inflammation and extracellular matrix reorganization. (The BIOlogy Study to TAilored Treatment in Chronic Heart Failure [BIOSTAT-CHF]; EudraCT 2010-020808-29). [ABSTRACT FROM AUTHOR]