Jing Yuan

The heterogeneous subtypes in dilated cardiomyopathy (DCM) are poorly characterized, thus posing challenges to risk stratification. This study aimed to establish a DCM subtype framework based on metabolic and immunoinflammatory factors. DCM subtypes were identified using unsupervised clustering based on the expression patterns of metabolism-related genes in the left ventricular myocardium of 89 DCM patients. By comparing metabolic pathways, clinical characteristics, immune cell infiltration, inflammatory responses, and immunotherapy efficacy between the subtypes, key metabolic genes were identified through correlation analysis and validated at both bulk and single-cell levels. The alterations in gene expression were verified using the DCM mouse model. Molecular docking was performed to assess the binding affinity between the target protein and potential therapeutic small molecules. Two subtypes were identified; subtypes 1 and 2 were characterized by increased amino acid metabolism and decreased glucose and energy-related metabolisms, respectively. Subtype 2 displayed worse left ventricular structure and function, higher levels of immune and inflammatory activity, and a more favorable response to immunotherapy. The integrative analysis identified DHRS7C as a key regulator of glucose/energy metabolism; its expression was inversely correlated with left ventricular impairment. The DCM mice showed downregulated DHRS7C expression, which positively correlated with cardiac dysfunction. Additionally, molecular docking identified 17beta-estradiol as a potential therapeutic agent targeting DHRS7C. This study suggested two heterogeneous DCM subtypes with different metabolic and immunoinflammatory profiles. Furthermore, DHRS7C was inversely correlated with DCM indices and could be targeted by 17beta-estradiol.

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Objective Qiliqiangxin (QLQX) capsule- a traditional Chinese medicine used for treating heart failure (HF), can modulate inflammatory cytokines in rats with myocardial infarction. However, its immune-regulating effect on dilated cardiomyopathy (DCM) remains unknown. The aim of this study was to investigate whether QLQX has a unique regulatory role in the imbalance of pro- and anti-inflammatory cytokines in patients with DCM. Methods The QLQX-DCM is a randomized- double-blind trial conducted at 24 tertiary hospitals in China. A total of 345 patients with newly diagnosed virus-induced DCM were randomly assigned to receive QLQX capsules or placebo while receiving optimal medical therapy for HF. The primary endpoints were changes in plasma inflammatory cytokines and improvements in left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDd) over the 12-month treatment. Results At the 12-month follow-up, the levels of IFN-γ, IL-17, TNF-α, and IL-4 decreased significantly, while the level of IL-10 increased in both groups compared with baselines (all PP<0.001). Additionally, compared with placebo, QLQX treatment also reduced all-cause mortality and rehospitalization rates by 2.17% and 2.28%, respectively, but the difference was not statistically significant. Conclusion QLQX has the potential to alleviate the imbalance of inflammatory cytokines in patients with DCM, potentially leading to further improvements in cardiac function when combined with anti-HF standard medications.

Background: Systemic lupus erythematosus (SLE) is frequently accompanied by various complications, with cardiovascular diseases being particularly concerning due to their high mortality rate. Although there is clinical evidence suggesting a potential correlation between SLE and heart failure (HF), the underlying shared mechanism is not fully understood. Therefore, it is imperative to explore the potential mechanisms and shared therapeutic targets between SLE and HF.Methods: The SLE and HF datasets were downloaded from the NCBI Gene Expression Omnibus database. Differentially expressed genes (DEGs) in both SLE and HF were performed using “limma” R package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genes (KEGG) analyses were conducted to analyze the enriched functions and pathways of DEGs in both SLE and HF datasets. Protein–Protein Interaction network (PPI) and the molecular complex detection (MCODE) plugins in the Cytoscape software were performed to identify the shared hub genes between SLE and HF datasets. R package “limma” was utilized to validate the expression of hub genes based on SLE (GSE122459) and HF (GSE196656) datasets. CIBERSORT algorithm was utilized to analyze the immune cell infiltration of SLE and HF samples based on SLE (GSE112087) and HF (GSE116250) datasets. A weighted gene co-expression network analysis (WGCNA) network was established to further validate the hub genes based on HF dataset (GSE116250). Molecular biology techniques were conducted to validate the hub genes.Results: 999 shared DGEs were identified between SLE and HF datasets, which were mainly enriched in pathways related to Th17 cell differentiation. 5 shared hub genes among the common DGEs between SLE and HF datasets were screened and validated, including HSP90AB1, NEDD8, RPLP0, UBB, and UBC. Additionally, 5 hub genes were identified in the central part of the MEbrown module, showing the strongest correlation with dilated cardiomyopathy. HSP90AB1 and UBC were upregulated in failing hearts compared to non-failing hearts, while UBB, NEDD8, and RPLP0 did not show significant changes.Conclusion: HSP90AB1 and UBC are closely related to the co-pathogenesis of SLE and HF mediated by immune cell infiltration. They serve as promising molecular markers and potential therapeutic targets for the treatment of SLE combined with HF.

Myocardial infarction (MI) is the leading cause of premature death. The death of cardiomyocytes (CMs) and the dysfunction of the remaining viable CMs are the main pathological factors contributing to heart failure (HF) following MI. This study aims to determine the transcriptional profile of CMs and investigate the heterogeneity among CMs under hypoxic conditions. Single-cell atlases of the heart in both the sham and MI groups were developed using single-cell data (GSE214611) downloaded from Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/). The heterogeneity among CMs was explored through various analyses including enrichment, pseudo time, and intercellular communication analysis. The marker gene of C5 was identified using differential expression analysis (DEA). Real-time polymerase chain reaction (RT-PCR), bulk RNA-sequencing dataset analysis, western blotting, immunohistochemical and immunofluorescence staining, Mito-Tracker staining, TUNEL staining, and flow cytometry analysis were conducted to validate the impact of the marker gene on mitochondrial function and cell apoptosis of CMs under hypoxic conditions. We identified a cell subcluster named C5 that exhibited a close association with mitochondrial malfunction and cellular apoptosis characteristics, and identified Slc25a4 as a significant biomarker of C5. Furthermore, our findings indicated that the expression of Slc25a4 was increased in failing hearts, and the downregulation of Slc25a4 improved mitochondrial function and reduced cell apoptosis. Our study significantly identified a distinct subcluster of CMs that exhibited strong associations with ventricular remodeling following MI. Slc25a4 served as the hub gene for C5, highlighting its significant potential as a novel therapeutic target for MI.

Objective: To elucidate the bidirectional correlation of sarcopenia with coronary heart disease (CHD), as well as to investigate the mediating role of cardiometabolic factors and inflammatory biomarkers, a bidirectional two-sample, two-step Mendelian randomization (MR) study was conducted. Methods: Summary statistics were obtained from genome-wide association studies (GWAS). In our bidirectional two-sample MR, genetic variants associated with sarcopenia-related traits and CHD were instrumented for the estimation of bidirectional correlations. Besides, genetic variants associated with thirteen cardiometabolic factors and six inflammatory biomarkers were selected for further mediation analyses. To confirm the consistency of the results, several sensitivity analyses were carried out. Results: Genetically predicted higher appendicular lean mass (OR = 0.835, 95% CI: 0.790–0.882), left hand grip strength (OR = 0.703, 95% CI: 0.569–0.869), right hand grip strength (OR = 0.685, 95% CI: 0.555–0.844), and walking pace (OR = 0.321, 95% CI: 0.191–0.539) reduced CHD risk, while genetic predisposition to CHD did not affect any of the sarcopenia-related traits. Seven mediators were identified for the effects of appendicular lean mass on CHD, including waist-to-hip ratio, hip circumference, systolic blood pressure, low-density lipoprotein cholesterol, total cholesterol, triglycerides, and fasting insulin. The mediation proportion ranged from 10.23% for triglycerides to 35.08% for hip circumference. Hip circumference was found to mediate the relationships between both left (mediation proportion: 24.61%) and right-hand grip strength (24.14%) and CHD, and the link between walking pace and CHD was partially mediated by waist-to-hip ratio (31.15%) and body mass index (26.66%). Conclusion: Our results showed that higher appendicular lean mass, hand grip strength, and walking pace reduced CHD risk, but the causal relationship was not bidirectional. Several mediators were found to mediate the causal pathways between sarcopenia-related traits and CHD, and intervention of these factors may be helpful in terms of CHD prevention in sarcopenia patients.

Background. Coronary artery disease (CAD) is a complex disease and the leading cause of death worldwide. It is caused by genetic and environmental factors or their interactions. Candidate gene association studies are an important genetic strategy for the study of complex diseases, and multiple variants of inflammatory cytokines have been found to be associated with CAD using this method. Interleukin-5 (IL-5) is an important inflammatory immune response factor that plays a role in a various inflammatory disease. Clinical tests and animal experiments indicated that IL-5 is involved in CAD development, but the exact mechanisms are unclear. This study investigated the genetic relationship between the single nucleotide polymorphisms (SNPs) in IL5 and CAD. Materials and Methods. Based on the Chinese Han population, we collected 1,824 patients with CAD and 1,920 control subjects and performed a two-stage case-control association analysis for three SNPs in IL5 (rs2057687, rs78546665, and rs2069812) using the high resolution melt (HRM) technology. Logistic regression analyses were applied to adjust for traditional risk factors for CAD and to perform haplotype and gene interaction analyses. Multiple linear regression analyses were used to study relationships between the selected SNPs and serum lipid levels. Results. In this study, two-stage case-control association analysis revealed that the allele and genotype frequency distributions of the three IL5 SNPs were not statistically significant between the case and control groups. In addition, none of the IL5 haplotypes were associated with CAD. Further stratified analyses were conducted by sex, age, hypertension, and disease status, respectively, and the results revealed that the rs2057687 and rs2069812 of IL5 were associated with CAD in the male group ( , OR, 0.77 (95% CI, 0.62-0.97); , OR, 0.82 (95% CI, 0.70-0.97), respectively); the rs2057687 and rs78546665 of IL5 were associated with late-onset CAD ( , OR, 0.78 (95% CI, 0.62-0.99); , OR, 1.46 (95% CI, 1.02-1.53), respectively); the rs2069812 of IL5 was associated with CAD in the hypertension group ( , OR, 0.84 (95% CI, 0.71-0.99)); and none of the SNPs in IL5 were associated with different CAD states (anatomical CAD and clinical CAD). In addition, the association between SNPs and the serum lipid levels indicated that rs78546665 was positively correlated with triglyceride levels ( ). Finally, SNP-SNP interaction analyses revealed that interactions of rs2057687 and rs2069812 were associated with CAD ( , OR, 0.77 (95% CI, 0.13-4.68)). Conclusion. This study suggested that the common variants of IL5 might play a role in CAD by affecting the risk factors for CAD and through SNP-SNP interactions, which provides a new target for specific treatment of CAD patients and a theoretical basis for personalized medicine.