Table_7_Integrated whole-genome gene expression analysis reveals an atlas of dynamic immune landscapes after myocardial infarction.XLSX

IntroductionMyocardial infarction (MI) is a deadly medical condition leading to irreversible damage to the inflicted cardiac tissue. Elevated inflammatory response marks the severity of MI and is associated with the development of heart failure (HF), a long-term adverse outcome of MI. However, the efficacy of anti-inflammatory therapies for MI remains controversial. Deciphering the dynamic transcriptional signatures in peripheral blood mononuclear cells (PBMCs) is a viable and translatable route to better understand post-MI inflammation, which may help guide post-MI anti-inflammatory treatments.
MethodsIn this work, integrated whole-genome gene expression analysis was performed to explore dynamic immune landscapes associated with MI.
ResultsGSEA and GSVA showed that pathways involved in the inflammatory response and metabolic reprogramming were significantly enriched in PBMCs from MI patients. Based on leukocyte profiles generated by xCell algorithm, the relative abundance of monocytes and neutrophils was significantly increased in PBMCs from MI patients and had positive correlations with typical inflammation-associated transcripts. Mfuzz clustering revealed temporal gene expression profiles of PBMCs during the 6-month post-MI follow-up. Analysis of DEGs and gene sets indicated that PBMCs from HF group were characterized by elevated and lasting expression of genes implicated in inflammation and coagulation. Consensus clustering generated 4 metabolic subtypes of PBMCs with molecular heterogeneity in HF patients.
DiscussionIn summary, integrated whole-genome gene expression analysis here outlines a transcriptomic framework that may improve the understanding of dynamic signatures present in PBMCs, as well as the heterogeneity of PBMCs in MI patients with or without long-term clinical outcome of HF. Moreover, the work here uncovers the diversity and heterogeneity of PBMCs from HF patients, providing novel bioinformatic evidence supporting the mechanistic implications of metabolic reprogramming and mitochondrial dysfunction in the post-MI inflammation and HF. Therefore, our work here supports the notion that individualized anti-inflammatory therapies are needed to improve the clinical management of post-MI patients.

引言
心肌梗死（Myocardial infarction, MI）是一种致命的疾病，可导致受累心肌组织发生不可逆损伤。炎症反应升高是心肌梗死严重程度的标志性特征，且与心力衰竭（heart failure, HF）的发生相关——后者是心肌梗死的长期不良结局。然而，针对心肌梗死的抗炎治疗疗效仍存在争议。解析外周血单个核细胞（peripheral blood mononuclear cells, PBMCs）的动态转录特征，是深入理解心梗后炎症状态的可行且可转化的途径，或可为心梗后抗炎治疗提供指导。
方法
本研究通过整合全基因组基因表达分析，探究与心肌梗死相关的动态免疫图谱。
结果
基因集富集分析（Gene Set Enrichment Analysis, GSEA）与基因集变异分析（Gene Set Variation Analysis, GSVA）结果显示，心肌梗死患者外周血单个核细胞中显著富集了炎症反应与代谢重编程相关通路。基于xCell算法生成的白细胞谱，心肌梗死患者外周血单个核细胞中单核细胞与中性粒细胞的相对丰度显著升高，且与典型炎症相关转录本呈正相关。Mfuzz聚类分析揭示了心梗后6个月随访期间外周血单个核细胞的时序基因表达谱。对差异表达基因（Differentially Expressed Genes, DEGs）与基因集的分析表明，心力衰竭组患者的外周血单个核细胞以涉及炎症与凝血过程的基因表达升高且持续为特征。一致性聚类将心力衰竭患者的外周血单个核细胞分为4种具有分子异质性的代谢亚型。
讨论
综上，本研究中的整合全基因组基因表达分析构建了一个转录组学框架，可增进我们对心肌梗死患者（伴或不伴长期心力衰竭临床结局）外周血单个核细胞动态特征及异质性的理解。此外，本研究揭示了心力衰竭患者外周血单个核细胞的多样性与异质性，为心梗后炎症与心力衰竭中代谢重编程及线粒体功能障碍的机制意义提供了新的生物信息学证据。因此，本研究支持这一观点：需采用个体化抗炎治疗以优化心肌梗死患者的临床管理。