Bioinformatics and Immune Infiltration Analyses Reveal the Key Pathway and Immune Cells in the Pathogenesis of Hypertrophic Cardiomyopathy.

Si Zhang,Xu-Zhe Zhang,Xiang Cheng,Ting-Ting Tang

doi:10.3389/fcvm.2021.696321

Abstract

Objective: This study was designed to identify the key pathway and immune cells for hypertrophic cardiomyopathy (HCM) via bioinformatics analyses of public datasets and evaluate the significance of immune infiltration in the pathogenesis of HCM.Methods: Expressional profiling from two public datasets (GSE36961 and GSE141910) of human HCM and healthy control cardiac tissues was obtained from the GEO database. After data preprocessing, differentially expressed genes (DEGs) were then screened between HCM and healthy control cardiac tissues in parallel. Gene Ontology, pathway functional enrichment, and gene set enrichment analysis were performed using DAVID and GSEA application. The compositional patterns of immune and stromal cells in HCM and control cardiac tissues were estimated based on the merged data using xCell. Protein–protein interaction (PPI) network and module analyses were constructed by STRING and Cytoscape applications. Gender-based expressional differences analyses were also conducted to explore gender differences in HCM. GSE130036 and clinical samples were used for verification analyses.Results: A total of 310 DEGs were identified. Upregulated DEGs were mainly enriched in “adhesion” and “apoptotic process” in the biological process. As for the downregulated DEGs, “inflammatory response,” “innate immune response,” “phagosome,” and “JAK-STAT signaling pathway” were highly enriched. Immune infiltration analyses suggested that the scores of macrophages, monocytes, DC, Th1, Treg, and plasma cells in the HCM group were significantly decreased, while CD8+ T cells, basophils, fibroblasts, and platelets were significantly enriched. Module analyses revealed that STAT3, as the hub genes in HCM together with LYVE1+CD163+ macrophages, may play a key role in the pathogenesis of HCM while there were no obvious gender differences in the HCM samples from selected datasets. Verification analyses performed on GSE130036 and clinical samples showed a strong positive correlation (Spearman correlation = 0.7646) and a good co-localization relationship between LYVE1 and CD163, suggesting the potential function of LYVE1+CD163+ macrophages in maintaining the homeostasis of cardiac tissue.Conclusion: STAT3-related pathway and CD163+LYVE1+ macrophages were identified as the potential key pathway and immune cells in HCM and may serve as interesting targets for further in-depth research.

Highlights

Hypertrophic cardiomyopathy (HCM), as a complex genetic heterogeneous disease, is one of the main causes of sudden cardiac death in young adults [1]
The HCM samples of the above two datasets came from the ventricular septum of patients with obstructive symptoms that require surgical intervention and the left ventricle of patients with heart failure, both of which represent the period when pharmacological treatment cannot control the symptoms of HCM, while the control samples were derived from unused healthy donated hearts; we considered these two datasets to be comparable
We examined whether gender differences would affect the expression of CD163 and LYVE1 in cardiac tissues of HCM patients

Summary

Introduction

Hypertrophic cardiomyopathy (HCM), as a complex genetic heterogeneous disease, is one of the main causes of sudden cardiac death in young adults [1]. Regarded as a genetic disease, there is still a gap in how to fully understand the contribution of sarcomere gene mutation in the overall pathophysiological mechanism and clinical process of HCM. From the mechanism point of view, cardiac hypertrophy, as a pathological stimulus, will, in turn, cause inflammatory signal transduction and immune cell activation, thereby affecting heart function [7]. It is still unclear whether this process will be independent or coordinated with the main pathogenic sarcomere mutation genes and interfere with the clinical course and prognosis of HCM patients. More extensive identification of key pathways and non-sarcomeric mutationrelated pathophysiological mechanisms in HCM is very necessary and urgent

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Discussion

Conclusion