Development and verification of the nomogram for the diagnosis of the gene of dilated cardiomyopathy


DCM is most common in middle-aged people and has been around for more than 10 years. It is characterized by hypertrophy of the left or right ventricle or bilateral ventricles, accompanied by myocardial hypertrophy. Decreased ventricular systolic function, with or without congestive heart failure. Ventricular or atrial arrhythmia is more common. And death can occur at any stage of the disease. Currently, dilated cardiomyopathy is diagnosed by the method of exclusion, i.e. excluding other specific causes of cardiac enlargement and heart failure, and diagnosis based on clinical manifestations and auxiliary examinations1. It is difficult to prevent DCM due to the unclear mechanism. Therefore, early diagnosis of DCM will improve the prognosis and quality of life of DCM patients. With the development of genomics, it has been widely used to predict disease susceptibility, drug response, and early diagnosis of disease.4. In this study, 333 differentially expressed genes were identified by analyzing the GSE141910 microarray, and then 197 genes significantly related to DCM were obtained using WGCNA. Among the genes obtained from WGCNA, RGS, FKBP5, STAT4, MYH6, COL9A1 and other genes have been confirmed to be associated with the progression of DCM17,18,19,20,21. Additionally, ACE inhibitors have been widely studied in the treatment of DCM.

We observed that the expression of NPPA and NPPB is elevated. The ventricular hypertrophy of DCM patients and reduced myocardial systolic function force the atria and cardiomyocytes to express and release ANP and BNP, thereby exerting diuretic, vasodilatory and immunosuppressive effects. But interestingly, we also found increased expression of ACE and ATGR2, which antagonizes the function of ANP to relax blood vessels. Among them, the overexpression of ATGR2 may be the main cause why DCM forces the heart to remodel, fibroblasts are the main cell type, and ATGR2 is the main inducer of this cell.22. Additionally, Yan et al. showed that ATGR2 is upregulated in ventricular myocytes and its expression is tightly linked to phosphorylated protein levels of PKC-α, PKC-β and p70S6 kinase, which promotes the development of dilated cardiomyopathy and heart failure in vivo23. There is also evidence that DCM is closely linked to immunity. Dysregulation of the cellular and humoral immune system should go hand in hand with the development of DCM. Infiltration of lymphocytes and monocytes and increased expression of cell adhesion molecules are often found in DCM patients. The production of autoantibodies and the corresponding side effects have also been widely discussed.24,25,26. Nakayama et al. confirmed that increased myocardial immune activation was positively correlated with poor DCM prognosis, and that CD163-specific M2 macrophages were closely linked to ventricular DCM remodeling27. The important cause of DCM also includes a genetic predisposition. About 20-35% of DCM cases are reported as a family inheritance28. Zhao et al. by sequencing revealed that 7 genetic mutations, including MYH6, are closely linked to the pathogenesis of DCM18.

Subsequently, we performed enrichment analysis of these DCM-related genes and explored their potential mechanisms in DCM. Among them, BP and CC are mainly enriched in extracellular matrix or structure related to cardiac fibrosis, transport or regulation of different ions, regulation of renin-angiotensin and related immune response and regulation . In MF, in addition to the structural components of the extracellular matrix, there are also G protein-coupled receptors and CXCR chemokine receptors. G-protein-coupled receptors are the largest family of cell membrane surface receptors in the human body, which are closely linked to the occurrence of diseases such as cancer, heart disease, diabetes and Alzheimer’s disease. . Among them, autoantibodies against G-protein-coupled β1-adrenergic receptors and M2-cholinergic receptors are specifically expressed in DCM patients and are involved in the pathological and physiological functions of DCM.29. Similarly, CXCR chemokine receptors are also a subfamily of G protein-coupled receptors, and this family of receptors is linked to cardiac fibrosis. In patients with DCM and end-stage heart failure, there is a close relationship between persistent atrial fibrillation and extracellular remodeling. In atrial fibrosis and atrial fibrillation, biochemical mediators that play a central role include angiotensin II, CTGF, PDGF, and TGF-β. The interaction of cytokines and cytokine receptors is also enriched in KEGG, which mediates and initiates cellular signal transduction. Cytokines exert their biological effects by binding to corresponding cytokine receptors on the cell surface. According to their structure and signal transduction pathway, cytokine receptors have been divided into different families or superfamilies, such as cytokine receptor type I, cytokine receptor type II, tumor necrosis factor receptor and chemotactic cytokine receptor. As confirmed by Ohtsuka, the increase in serum VEGF and IL-13 may be closely related to changes in the structure of DCM myocardial tissue.30. Chen et al. found that the TNF-α (G-308A) gene polymorphism may be related to DCM sensitivity31. This evidence has clarified the mechanism underlying the physiological and pathological development of DCM.

Additionally, we conducted a series of analyzes to identify 7 hub genes in the DCM. Among them, ATGR2 induces cardiac fibroblasts to remodel the DCM heart and promote the development of mental retardation22.23. While CXCL9, CXCL10, and CXCL11 belong to the chemokine family, CX3CR1, ADORA3, and SAA1 have not been reported in dilated cardiomyopathy, and more research is needed. Finally, we constructed a nomogram to predict the incidence of DCM based on the expression levels of these 7 genes, and performed multiple verifications, which not only confirmed its good predictive performance, but also revealed its wide applicability. It can help clinicians and patients diagnose DCM as early as possible and perform timely interventions to achieve better prognosis and improve patients’ quality of life.


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