Proteomic profiling in heart failure with preserved ejection fraction
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Ailiman Mahemuti
PROVIDER: PXD053164 | iProX | Fri Jun 14 00:00:00 GMT+01:00 2024
REPOSITORIES: iProX
Publications
Identification of noval diagnostic biomarker for HFpEF based on proteomics and machine learning.
Abudurexiti Muyashaer M Aimaier Salamaiti S Wupuer Nuerdun N Duan Dongqin D Abudouwayiti Aihaidan A Nuermaimaiti Meiheriayi M Mahemuti Ailiman A
Proteome science 20250408 1
<h4>Background</h4>Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome that currently lacks effective biomarkers for early diagnosis and treatment. This study seeks to identify new potential biomarkers for HFpEF using proteomics and machine learning.<h4>Methods</h4>Plasma samples were collected from 20 patients newly diagnosed age, sex, BMI matched HFpEF and 20 healthy controls (HCs). Proteomic analysis was performed using liquid chromatography-tandem mass spectrometry ( ...[more]
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Project description:Background: Heart failure with preserved ejection fraction (HFpEF) constitutes more than half of all heart failure but has few effective therapies. Recent human myocardial transcriptomics and metabolomics have revealed major differences between HFpEF, HF with reduced EF (HFrEF), and controls. How this translates at the protein level is currently unknown. Methods: Myocardial tissue from patients with HFpEF and non-failing donor controls was analyzed by data-dependent (DDA, n=10 HFpEF, n=9 controls) and data-independent (DIA, n=44 HFpEF, n=5 controls) mass spectrometry-based proteomics. Previously reported myocardial proteomic data from end-stage HFrEF and controls were also used. Differential protein expression analysis, machine learning and pathway enrichment were integrated with clinical characteristics and myocardial transcriptomics. Results: DDA-MS proteomics identified 88 significantly upregulated and 248 down-regulated proteins in HFpEF vs controls, out of 1996 identified proteins. Principal component analysis of DDA-MS proteomics found HFpEF was separated into 2 sub-groups: one being similar to controls the other quite disparate. Top proteins contributing to the separation of HFpEF subgroups were enriched in actin/myosin binding, regulation of DNA replication/repair, transcription, and translation. Downregulated proteins in HFpEF vs controls were enriched in pathways related to ribosome structure, transmembrane transporters, metabolic enzymes, and oxidative phosphorylation (OxPhos) proteins. Enriched pathways for proteins upregulated in HFpEF related to actin and phospholipid binding, growth factor signaling, kinase regulation, and glycolysis. Ingenuity pathway analysis predicted downregulation of protein translation, mitochondrial function, and glucose and fat metabolism in HFpEF. OxPhos gene (increased) versus protein (decreased) expression was discordant in HFpEF. The second DIA proteomic analysis also yielded two HFpEF sub-groups; the one most different from controls also having reduced OxPhos and protein translation pathways. A higher proportion of these patients also had severe obesity. Conclusions: Integrative proteomics, transcriptomics, and pathway analysis supports a translational defect particularly involving mitochondrial, ribosomal and protein translation proteins in HFpEF. Patients with more distinct proteomic signatures from control were more often very obese. The results support therapeutic efforts targeting metabolism, mitochondrial function, and protein translation in this subgroup.
2025-04-11 | PXD060431 | Pride
Project description:Heart failure with preserved ejection fraction (HFpEF) accounts for ~50% of all heart failure cases. HFpEF is a heterogeneous condition with poorly understood molecular mechanisms related to different forms including acute and chronic HFpEF. Here, we utilised plasma samples collected from patients with different forms of HFpEF to identify unique molecular mechanisms and pathways. We performed unbiased, comprehensive proteomic analyses of 31 gender- and BMI-matched plasma samples from patients with acute HFpEF (n=8), chronic HFpEF (n=9) and hypertrophic cardiomyopathy (HCM; n=14). We identified leucine-rich alpha-2-glycoprotein 1 (LRG1) as an aberrant protein across all three forms of HFpEF. We reported perturbations in signalling pathways in HFpEF mainly driven by complement/coagulation/protease and extracellular matrix (ECM) proteins, highlighting the haemostatic disturbances, notably platelet degranulation caused by systematically elevated platelet cytosolic Ca2+. We provided a publicly available online application (https://hao-chen-uts-99171821.shinyapps.io/HFpEF-Proteomics/) of our findings.
2023-03-11 | PXD024012 | Pride
Project description:BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of heart failure patients. Clinically, HFpEF prevalence show age and gender biases. Although the majority of HFpEF patients are elderly, there is an emergence of young HFpEF patients. A better understanding of the underlying pathogenic mechanism is urgently needed. Here, we aimed to determine the role of aging in the pathogenesis of HFpEF. METHODS AND RESULTS: HFpEF dietary regimen (HFD + L-NAME) was used to induce HFpEF in wildtype and telomerase RNA knockout mice (mTRG2 and mTRG3), an aging murine model. First, both male and female animals develop HFpEF equally. Second, cardiac wall thickening preceded diastolic dysfunction in all HFpEF animals. Third, accelerated HFpEF onset was observed in mTRG2 (at 6-weeks) and mTRG3 (at 4-weeks) compared to wildtype (8-weeks). Fourth, we demonstrate that mitochondrial respiration transitioned from compensatory state (normal basal yet loss of maximal respiratory capacity) to dysfunction (loss of both basal and maximal respiratory capacity) in a p53 dosage dependent manner. Last, using myocardial-specific p53 knockout animals, we demonstrate that p53 is necessary for the development of HFpEF. CONCLUSIONS: Here we demonstrate that p53 activation is critical for the pathogenesis of HFpEF. We show that short telomere animals exhibit a basal level of p53 activation, mitochondria upregulate mtDNA encoded genes as a mean to compensate for blocked mitochondrial biogenesis, and loss of myocardial p53 prevents HFpEF upon HFD + L-NAME challenge.
2022-07-06 | GSE195482 | GEO
Project description:Background: We previously showed in a rat model of heart failure with preserved ejection fraction (HFpEF) that transcutaneous vagus nerve stimulation (tVNS) reduced cardiac fibrosis and inflammation. However, macrophage-mediated mechanisms through which tVNS rescues cardiac function remain poorly understood. Methods: We induced HFpEF in 8-week-old mice by a combination of a high-fat diet and L-NAME for 5 weeks followed by 4 weeks of tVNS or sham stimulation. At this time, we analyzed cardiac function by echocardiography and immune cell numbers by single cell RNA sequencing and flow cytometry. Results: Our data demonstrate that HFpEF mice exhibited diastolic dysfunction, left ventricular hypertrophy and fibrosis, consistent with HFpEF, and that tVNS significantly improved HFpEF severity. Analysis of merged single cell RNA sequencing data from control, HFpEF + sham, and HFpEF + tVNS mice showed that HFpEF was associated with accumulation of Spp1 expressing CCR2+ cardiac resident macrophages (CRM). Further, treatment with tVNS reduced the number of CCR2+ CRM and the expression of Spp1, while also inducing the expression of Igf1 in Timd4+/Lyve1+/Folr2+ (TLF+) and MHC2+ CRM. Global deletion of Spp1 or blockade of CCR2+ CRM recruitment improved HFpEF, whereas TLF+/MHC2+ specific deletion of Igf1 reversed the protective effect of tVNS on HFpEF. The benefits of tVNS were also abolished in the setting of disrupted acetylcholine (ACh)/α7 neuronal ACh receptor (α7nAChR) signaling, either via pharmacological inhibition of α7nAChR or choline acetyltransferase deletion in CD4⁺ T cells. Conclusion: Collectively, our data indicate that tVNS improves HFpEF by reducing Spp1 expressing CCR2+ CRM and inducing expression of pro-reparative Igf1 in TLF+/MHC2+ CRM. These effects are mediated through cholinergic signaling, highlighting a neuroimmune pathway in HFpEF.
2025-07-23 | GSE295382 | GEO
Project description:Heart failure with preserved ejection fraction (HFpEF) is a leading cause of morbidity and mortality worldwide; nonetheless, effective therapies remain elusive. In Western populations, HFpEF is typically obesity-related, whereas in Asia it frequently develops in non-obese patients with hypertension and underlying mechanisms are poorly defined. Here, analysis of two Japanese hospital cohorts revealed that obesity and metabolic comorbidities are uncommon in HFpEF, while sympathetic overactivation and hypertension predominated. To model this condition, we combined isoproterenol (ISO)–induced sympathetic activation with L-arginine methyl ester (L-NAME)-induced endothelial dysfunction, establishing the first non-obese HFpEF mouse model. These mice exhibited hallmark HFpEF features, whereas ISO alone caused hypertensive heart disease (HHD) without HFpEF, indicating that a "second hit" is essential for HFpEF progression. HFpEF mice showed expansion and reprogramming of cardiac macrophages to Pla2g7⁺ phenotypes and fibroblast activation via PDGF signaling, as loss of Timd4⁺ resident macrophages impaired cardiomyocyte energetics due to diminished BMP signaling. These outcomes drove maladaptive remodeling and inflammation, which precedes HFpEF onset. Notably, inhibition of the inflammatory mediator ANGPTL2 attenuated cardiac inflammation and prevented HFpEF progression. Our findings identify hypertensive stress-induced macrophage reprogramming as a central mechanism of non-obese HFpEF and highlight cardiac inflammation as a promising therapeutic target.
2026-07-27 | GSE308210 | GEO
Project description:Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust pre-clinical mouse models of human HFpEF. We have developed a novel “2-hit” mouse model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57Bl6/NJ mice fed a high fat diet for at least 10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse Renin1d. Control mice, HFD only, Renin only and HFD-Renin (aka “HFpEF”) littermates underwent a battery of cardiac and extracardiac phenotyping. HFD-Renin mice demonstrated obesity and insulin resistance, a 2-3-fold increase in circulating renin levels and resulted in 30-40% increase in LVH hypertrophy, preserved systolic function, and diastolic dysfunction indicated by altered E/e’, IVRT, and strain measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. The transcriptomic and metabolomic signature of HFpEF indicates upregulation of fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to human HFpEF data. Treatment of these mice with the sodium-glucose cotransporter 2 inhibitor empagliflozin, a powerful but incompletely understood HFpEF therapy, showed improvement in exercise tolerance, left heart enlargement, and insulin homeostasis. The HFD-Renin mouse model recapitulates many critical features of human HFpEF and allows for dissection of how individual pathogenic drivers contribute to cardiac and peripheral metabolic changes. Multiple HFpEF models will also allow for orthogonal studies and increase validity in pre-clinical research efforts.
2025-01-01 | GSE269053 | GEO
Project description:Cardiometabolic heart failure with preserved ejection fraction (cHFpEF) is highly prevalent and associated with a poor outcome. Pathological gene expressions in heart failure are accompanied by changes in active histone marks without major alterations in DNA methylation. Whether chromatin modifications participate to obesity-induced HFpEF is largely unknown. We will investigate whether chromatin marks participate to obesity-induced HFpEF in vivo.
2025-06-05 | GSE289265 | GEO
Project description:Inflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 (Angptl4) next to basement membrane compounds, such as collagen IV (Col4a1). Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNFɑ with estimated fibroblast target genes including Col4a1 and Angptl4. Treatment with recombinant ANGPTL4 ameliorated the murine HFpEF phenotype and diastolic dysfunction by reducing collagen IV deposition from fibroblasts in vivo and in vitro. In line, ANGPTL4, was elevated in plasma samples of HFpEF patients and particularly high levels associated with a preserved global longitudinal strain. Taken together, our study provides a comprehensive characterization of molecular fibroblast activation patterns in murine HFpEF, as well as the identification of Angiopoietin-like 4 as central mechanistic regulator with protective effects.
2024-08-28 | GSE275031 | GEO
Project description:Heart failure with preserved ejection fraction (HFpEF) is characterised by a distinct but poorly understood in skeletal muscle pathology. In a rat model ZSF1, we identify impaired myonuclear accretion as a mechanism for ablated myofiber growth in HFpEF following resistance exercise intervention. Muscle vascular or mitochondrial dysfunction, or impaired protein synthesis signalling, do not appear as primary limiting mechanisms, and cardiac therapies do not attenuate skeletal muscle pathology. However, we identify that acute caloric restriction rejuvenates myofiber growth in HFpEF during resistance exercise intervention.
2025-01-19 | E-MTAB-12494 | biostudies-arrayexpress
Project description:Heart failure with preserved ejection fraction (HFpEF) is a serious health problem with limited treatment options. This study is designed to investigate the protective function of exercise training in regulating heart failure with preserved ejection fraction (HFpEF).
2025-12-31 | GSE212839 | GEO