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BMC Genomics. 2018 Nov 12;19(1):812. doi: 10.1186/s12864-018-5213-9.

Transcriptome analysis of human heart failure reveals dysregulated cell adhesion in dilated cardiomyopathy and activated immune pathways in ischemic heart failure.

Author information

1
Human Medical Genetics and Genomics, University of Colorado, Aurora, CO, USA.
2
Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado, Aurora, CO, USA.
3
Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplant, University of Colorado, Aurora, CO, USA.
4
Department of Statistics, E. & J. Gallo, Modesto, CA, USA.
5
Department of Cardiothoracic Surgery, University of Colorado Hospital, Aurora, CO, USA.
6
Division of Cardiology, Department of Medicine, University of Colorado, Aurora, CO, USA.
7
Human Medical Genetics and Genomics, University of Colorado, Aurora, CO, USA. matthew.taylor@ucdenver.edu.
8
Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado, Aurora, CO, USA. matthew.taylor@ucdenver.edu.

Abstract

BACKGROUND:

Current heart failure (HF) treatment is based on targeting symptoms and left ventricle dysfunction severity, relying on a common HF pathway paradigm to justify common treatments for HF patients. This common strategy may belie an incomplete understanding of heterogeneous underlying mechanisms and could be a barrier to more precise treatments. We hypothesized we could use RNA-sequencing (RNA-seq) in human heart tissue to delineate HF etiology-specific gene expression signatures.

RESULTS:

RNA-seq from 64 human left ventricular samples: 37 dilated (DCM), 13 ischemic (ICM), and 14 non-failing (NF). Using a multi-analytic approach including covariate adjustment for age and sex, differentially expressed genes (DEGs) were identified characterizing HF and disease-specific expression. Pathway analysis investigated enrichment for biologically relevant pathways and functions. DCM vs NF and ICM vs NF had shared HF-DEGs that were enriched for the fetal gene program and mitochondrial dysfunction. DCM-specific DEGs were enriched for cell-cell and cell-matrix adhesion pathways. ICM-specific DEGs were enriched for cytoskeletal and immune pathway activation. Using the ICM and DCM DEG signatures from our data we were able to correctly classify the phenotypes of 24/31 ICM and 32/36 DCM samples from publicly available replication datasets.

CONCLUSIONS:

Our results demonstrate the commonality of mitochondrial dysfunction in end-stage HF but more importantly reveal key etiology-specific signatures. Dysfunctional cell-cell and cell-matrix adhesion signatures typified DCM whereas signals related to immune and fibrotic responses were seen in ICM. These findings suggest that transcriptome signatures may distinguish end-stage heart failure, shedding light on underlying biological differences between ICM and DCM.

KEYWORDS:

Cardiomyopathy; Gene expression; Heart failure; RNA-seq; Transcriptome

PMID:
30419824
PMCID:
PMC6233272
DOI:
10.1186/s12864-018-5213-9
[Indexed for MEDLINE]
Free PMC Article

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