Integrative Analysis of Bulk and Single-Cell RNA Sequencing Data Reveals Cell Types Involved in Heart Failure.

Xin Shi,Jieyuan Xue,Yi Li,Feng Liang,Han-Wen Ni,Zhaohua Cai,Ben He,Xia Wang,Li Zhang,Ling-Hong Shen,Tao Huang

doi:10.3389/fbioe.2021.779225

Abstract

Owing to the high mortality rates of heart failure (HF), a more detailed description of the HF becomes extremely urgent. Since the pathogenesis of HF remain elusive, a thorough identification of the genetic factors will provide novel insights into the molecular basis of this cardiac dysfunction. In our research, we performed publicly available transcriptome profiling datasets, including non-failure (NF), dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) hearts tissues. Through principal component analysis (PCA), gene differential expression analysis, gene set enrichment analysis (GSEA), and gene Set Variation Analysis (GSVA), we figured out the candidate genes noticeably altered in HF, the specific biomarkers of endothelial cell (EC) and cardiac fibrosis, then validated the differences of the inflammation-related cell adhesion molecules (CAMs), extracellular matrix (ECM) genes, and immune responses. Taken together, our results suggested the EC and fibroblast could be activated in response to HF. DCM and ICM had both commonality and specificity in the pathogenesis of HF. Higher inflammation in ICM might related to autocrine CCL3/CCL4-CCR5 interaction induced chemokine signaling activation. Furthermore, the activities of neutrophil and macrophage were higher in ICM than DCM. These findings identified features of the landscape of previously underestimated cellular, transcriptomic heterogeneity between ICM and DCM.

Highlights

Heart failure (HF) is a chronic, progressive syndrome with high mortality and mobility, and affects approximately over 37.7 million patients worldwide (Ziaeian and Fonarow, 2016)
To identify and characterize the cell types in the human left ventricle (LV), we collected two single-cell RNA sequencing datasets of left ventricle provided by earlier study (Han et al, 2020)
Marker genes of dendritic cell, M1/2 macrophage, neutrophil, and smooth muscle cell were enriched within the upregulated genes in ischemic cardiomyopathy (ICM) (Figure 2C, adjusted p-value < 0.05). These results indicated that dilated cardiomyopathy (DCM) and ICM had both similarity and specificity in the pathogenesis of heart failure based on these disease-related cell types

Summary

Introduction

Heart failure (HF) is a chronic, progressive syndrome with high mortality and mobility, and affects approximately over 37.7 million patients worldwide (Ziaeian and Fonarow, 2016). Complex biological processes are involved in the pathogenesis of HF, and cardiac abnormalities often lead to heart dysfunction. Liu et al(Liu et al, 2015) collected and analyzed left ventricle issues from six individuals including one ISCH patient, two dilated cardiomyopathy (DCM) patients and three controls as training sets to reveal genetic signatures of HF using RNA-seq and microarray data, which were further validated by a larger cohort with 313 individuals with HF or non-failing (NF). (Sweet et al, 2018) utilized RNA-seq and pathway analysis to reveal the heterogeneous gene signatures and disease-specific mechanisms in 64 explanted human hearts, which consisted of 37 DCM patients, ICM patients, and NF controls. Liu et al(Liu et al, 2015) collected and analyzed left ventricle issues from six individuals including one ISCH patient, two dilated cardiomyopathy (DCM) patients and three controls as training sets to reveal genetic signatures of HF using RNA-seq and microarray data, which were further validated by a larger cohort with 313 individuals with HF or non-failing (NF). (Sweet et al, 2018) utilized RNA-seq and pathway analysis to reveal the heterogeneous gene signatures and disease-specific mechanisms in 64 explanted human hearts, which consisted of 37 DCM patients, ICM patients, and NF controls. (Vigil-Garcia et al, 2020) applied cardiomyocyte-specific transcriptomic analysis to detect a specific gene set involved in the process of pathological cardiac remodeling related to HF, and they explained the alternations precisely, which occurred during the transition from hypertrophic towards failing cardiomyocytes

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