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A three-tiered integrative analysis of transcriptional data reveals the shared pathways related to heart failure from different aetiologies.

ABSTRACT: Heart failure (HF) is the end stage of most heart disease cases and can be initiated from multiple aetiologies. However, whether the molecular basis of HF has a commonality between different aetiologies has not been elucidated. To address this lack, we performed a three-tiered analysis by integrating transcriptional data and pathway information to explore the commonalities of HF from different aetiologies. First, through differential expression analysis, we obtained 111 genes that were frequently differentially expressed in HF from 11 different aetiologies. Several genes, such as NPPA and NPPB, are early and accurate biomarkers for HF. We also provided candidates for further experimental verification, such as SERPINA3 and STAT4. Then, using gene set enrichment analysis, we successfully identified 19 frequently dysregulated pathways. In particular, we found that pathways related to immune system signalling, the extracellular matrix and metabolism were critical in the development of HF. Finally, we successfully acquired 241 regulatory relationships between 64 transcriptional factors (TFs) and 17 frequently dysregulated pathways by integrating a regulatory network, and some of the identified TFs have already been proven to play important roles in HF. Taken together, the three-tiered analysis of HF provided a systems biology perspective on HF and emphasized the molecular commonality of HF from different aetiologies.

SUBMITTER: Jiang Z

PROVIDER: S-EPMC7417717 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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A three-tiered integrative analysis of transcriptional data reveals the shared pathways related to heart failure from different aetiologies.

Jiang Zhenhong Z Guo Ninghong N Hong Kui K

Journal of cellular and molecular medicine 20200708 16

Heart failure (HF) is the end stage of most heart disease cases and can be initiated from multiple aetiologies. However, whether the molecular basis of HF has a commonality between different aetiologies has not been elucidated. To address this lack, we performed a three-tiered analysis by integrating transcriptional data and pathway information to explore the commonalities of HF from different aetiologies. First, through differential expression analysis, we obtained 111 genes that were frequentl ...[more]

PMID: 32638546

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Project description:BackgroundHeart failure (HF) is the most common potential cause of death, causing a huge health and economic burden all over the world. So far, some impressive progress has been made in the study of pathogenesis. However, the underlying molecular mechanisms leading to this disease remain to be fully elucidated.MethodsThe microarray data sets of GSE76701, GSE21610 and GSE8331 were retrieved from the gene expression comprehensive database (GEO). After merging all microarray data and adjusting batch effects, differentially expressed genes (DEG) were determined. Functional enrichment analysis was performed based on Gene Ontology (GO) resources, Kyoto Encyclopedia of Genes and Genomes (KEGG) resources, gene set enrichment analysis (GSEA), response pathway database and Disease Ontology (DO). Protein protein interaction (PPI) network was constructed using string database. Combined with the above important bioinformatics information, the potential key genes were selected. The comparative toxicological genomics database (CTD) is used to explore the interaction between potential key genes and HF.ResultsWe identified 38 patients with heart failure and 16 normal controls. There were 315 DEGs among HF samples, including 278 up-regulated genes and 37 down-regulated genes. Pathway enrichment analysis showed that most DEGs were significantly enriched in BMP signal pathway, transmembrane receptor protein serine/threonine kinase signal pathway, extracellular matrix, basement membrane, glycosaminoglycan binding, sulfur compound binding and so on. Similarly, GSEA enrichment analysis showed that DEGs were mainly enriched in extracellular matrix and extracellular matrix related proteins. BBS9, CHRD, BMP4, MYH6, NPPA and CCL5 are central genes in PPI networks and modules.ConclusionsThe enrichment pathway of DEGs and GO may reveal the molecular mechanism of HF. Among them, target genes EIF1AY, RPS4Y1, USP9Y, KDM5D, DDX3Y, NPPA, HBB, TSIX, LOC28556 and XIST are expected to become new targets for heart failure. Our findings provide potential biomarkers or therapeutic targets for the further study of heart failure and contribute to the development of advanced prediction, diagnosis and treatment strategies.

Project description:Systolic heart failure (HF) is a complex systemic syndrome that can result from a wide variety of clinical conditions and gene mutations. Despite phenotypic similarities, characterized by ventricular dilatation and reduced contractility, the extent of common and divergent gene expression between different forms of HF remains a matter of intense debate.Using a meta-analysis of 28 experimental (mouse, rat, dog) and human HF microarray studies, we demonstrate that gene expression changes are characterized by a coordinated and reciprocal regulation of major metabolic and signaling pathways. In response to a wide variety of stressors in animal models of HF, including ischemia, pressure overload, tachypacing, chronic isoproterenol infusion, Chagas disease, and transgenic mouse models, major metabolic pathways are invariably downregulated, whereas cell signaling pathways are upregulated. In contrast to this uniform transcriptional pattern that recapitulates a fetal gene expression program in experimental animal models of HF, human HF microarray studies displayed a greater heterogeneity, with some studies even showing upregulation of metabolic and downregulation of signaling pathways in end-stage human hearts. These discrepant results between animal and human studies are due to a number of factors, prominently cardiac disease and variable exposure to cold cardioplegic solution in nonfailing human samples, which can downregulate transcripts involved in oxidative phosphorylation (OXPHOS), thus mimicking gene expression patterns observed in failing samples. Additionally, ?-blockers and ACE inhibitor use in end-stage human HF was associated with higher levels of myocardial OXPHOS transcripts, thus partially reversing the fetal gene expression pattern. In human failing samples, downregulation of metabolism was associated with hemodynamic markers of disease severity.Irrespective of the etiology, gene expression in failing myocardium is characterized by downregulation of metabolic transcripts and concomitant upregulation of cell signaling pathways. Gene expression changes along this metabolic-signaling axis in mammalian myocardium are a consistent feature in the heterogeneous transcriptional response observed in phenotypically similar models of HF.

Project description:AimsLittle is known regarding acute heart failure (AHF) clinical characteristics and its hospital outcome in Latin America. This study sought to assess the prevalence of, and identify differences among, in-hospital outcomes in patients hospitalized for AHF who were stratified by clinical phenotype at a hospital in Latin America.Methods and resultsThis is a retrospective cohort study of patients with AHF who were hospitalized in the coronary care unit of a Latin American teaching hospital from January 2006 to December 2018. Cox regression analysis was used to identify predictors of mortality. Of 21 042 patients admitted, 7759 (36.6%) had AHF. Their median age was 62 years, and 35% were women. De novo heart failure was seen in 39.4% of patients. Most common was AHF-associated acute coronary syndromes (ACS-HF) in 43.0%, decompensated heart failure (DHF) in 33.7%, hypertensive heart failure (HT-HF) in 11.8%, and cardiogenic shock (CS) in 5.2%. Pulmonary oedema (PO) (3.3%) and right heart failure (RHF) (3.0%) were least frequent. Coronary artery disease was the most frequent aetiology in 56.5% of patients, valvular heart disease in 22.4%, and cardiomyopathies in 12.3%. Other less frequent aetiology included adult congenital heart disease (2.5%), lung diseases (2.1%), acute aortic syndromes (1.4%), pericardial diseases (0.8%), and intracardiac tumours (0.3%). Aetiology could not be established in 1.6% of patients. Before admission, patients with worsening chronic heart failure and reduced ejection fraction were treated with renin-angiotensin system blockers (60.4%), beta-blockers (42.5%), or spironolactone (34.4%). The percentages of patients given in-hospital management with intravenous diuretics, vasodilators, inotropes, and vasopressors were 81.2%, 33.4%, 18.9%, and 20.4%, respectively. The overall in-hospital mortality was 17.9% (71.3%, 43.9%, 23.8%, 14.9%, 13.6%, and 10.1% for CS, PO, RHF, DHF, ACS-HF, and HT-HF, respectively; P < 0.0001). Multivariate analysis revealed that PO (hazard ratio [HR] 2.68, 95% confidence interval [CI] 1.73-4.14, P < 0.0001) and CS (HR 3.37, 95% CI 2.12-5.35, P < 0.0001) were independent predictors of in-hospital mortality. Use of intravenous diuretics was linked to reduction of in-hospital mortality (HR 0.70, 95% CI 0.59-0.59, P < 0.0001). By contrast, increased in-hospital mortality was associated with the use of intravenous inotrope or vasopressor (HR 1.49, 95% CI 1.27-1.76 and HR 2.91, 95% CI 2.41-3.51, P < 0.0001, respectively).ConclusionsReal-world evidence from a university hospital in Latin America shows that the high mortality among patients with AHF may depend, among other factors, on patients' AHF clinical phenotypes. The clinical characteristics and aetiologies of AHF appear to differ between these data from Mexico and those from European and US registries.

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A three-tiered integrative analysis of transcriptional data reveals the shared pathways related to heart failure from different aetiologies.

Publications

A three-tiered integrative analysis of transcriptional data reveals the shared pathways related to heart failure from different aetiologies.

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