Dataset Information

Systemic Pathogenesis of Different Phenotypes of Heart Failure with Preserved Ejection Fraction.

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Matthew Padula

LAB HEAD: Lana McClements

PROVIDER: PXD024012 | Pride | 2023-03-11

REPOSITORIES: Pride

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Publications

Systemic Biomarkers and Unique Pathways in Different Phenotypes of Heart Failure with Preserved Ejection Fraction.

Chen Hao H Tesic Milorad M Nikolic Valentina N VN Pavlovic Milan M Vucic Rada M RM Spasic Ana A Jovanovic Hristina H Jovanovic Ivana I Town Stephanie E L SEL Padula Matthew P MP McClements Lana L

Biomolecules 20221004 10

Heart failure with preserved ejection fraction (HFpEF) accounts for around 50% of all heart failure cases. It is a heterogeneous condition with poorly understood pathogenesis. Here, we aimed to identify unique pathogenic mechanisms in acute and chronic HFpEF and hypertrophic cardiomyopathy (HCM). We performed unbiased, comprehensive proteomic analyses of plasma samples from gender- and BMI-matched patients with acute HFpEF (n = 8), chronic HFpEF (n = 9) and HCM (n = 14) usin ...[more]

PMID: 36291628

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Project description:Hypertension in pregnancy is the leading cause of morbidity and mortality in pregnancy, affecting up to 10% of all gestations1. Hypertensive disorders of pregnancy include chronic hypertension, gestational hypertension, eclampsia and pre-eclampsia, all of which increase the risk of complications in both mothers and babies during gestation. Preeclampsia, in particular, is characterised by the new-onset of gestational hypertension in the presence of proteinuria or other organ damage. It affects 5-7% of pregnancies and causes approximately 76,000 maternal deaths and 500,000 foetal deaths worldwide each year2. The classification of preeclampsia has been evolving over the last decade. In 2013, American College of Obstetricians and Gynecologists (ACOG) and International Society for the Study of Hypertension in Pregnancy (ISSHP) in the absence of proteinuria included other symptoms/features including liver dysfunction, thrombocytopenia, cerebrovascular events or foetal growth restriction (FGR) in the diagnosis of preeclampsia 1,3,4. Despite the fact that preeclampsia is a multifactorial and heterogeneous disorder, it is now widely accepted that preeclampsia is stratified depending on the time of onset into: i) early-onset PE (EOPE) manifested before 34 weeks of gestation, and ii) late-onset PE (LOPE) manifested from 34 weeks of gestation. Although EOPE and LOPE share the same diagnostic criteria, these two phenotypes of preeclampsia lead to different outcomes. EOPE is commonly associated with FGR, abnormal uterine artery Doppler often leading to preterm birth and higher risk of post-pregnancy morbidities5,6. On the other hand, LOPE appears to be a less severe disorder, often with normal or slightly increased uterine resistance index and a low rate of FGR6,7. Distinct delineation between EOPE and LOPE is still not well understood, with most patients with preeclampsia presenting elements of both pathologies proposing a clinical spectrum for preeclampsia. The lack of untargeted discovery studies involving ‘omics’ analyses has impeded understanding of the molecular differences between these two phenotypes of preeclampsia. Notably, a study from 20058 utilised a proteomics approach using urine samples from a cohort of pregnant women with EOPE and healthy controls, however the differences between EOPE and LOPE were not elucidated. Another more recent bioinformatics study, identified overlapping pathogenic mechanisms between preeclampsia, hypertension and heart disease but could not stratify between EOPE and LOPE due to underreported of data related to individual phenotypes9. In this study, we conducted an unbiased, comprehensive proteomics investigation using plasma samples collected from patients with EOPE (n=17) and LOPE (n=11), compared with age- and BMI-matched normotensive controls (n=18). The use of plasma samples is able to better reflect the pathogenesis of EOPE and LOPE as systemic conditions centred by widespread endothelial dysfunction.

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.

Dataset Information

Systemic Pathogenesis of Different Phenotypes of Heart Failure with Preserved Ejection Fraction.

Publications

Systemic Biomarkers and Unique Pathways in Different Phenotypes of Heart Failure with Preserved Ejection Fraction.

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