Integrated multi-omics profiling of the early post-infarct heart reveals a hub gene network associated with...

The early inflammatory phase (EIP, 0-72 h) post-acute myocardial infarction (AMI) is a critical determinant of cardiac repair and clinical outcomes. However, a comprehensive understanding of the regulatory gene networks and cellular interactions that govern this decisive period remains incomplete. This study aimed to define the key transcriptional programs and immune dynamics during the EIP of AMI.

We performed an integrated analysis of time-series bulk RNA-sequencing (RNA-seq) datasets (GSE206281, GSE153494) from murine myocardium post-ischemia. Single-cell RNA-seq (scRNA-seq) data (GSE163129, GSE163465) from cardiac immune cells were analyzed to characterize cellular heterogeneity and intercellular communication. A multi-modal framework combining inflammatory progression scoring with weighted gene co-expression network analysis (WGCNA) was applied to identify critical modules. Hub genes were pinpointed through protein-protein interaction network analysis and intersection with inflammation-related genes (IRGs). Their association with immune infiltration was assessed, and expression was validated in an external dataset, a murine AMI model, and a human peripheral blood cohort (GSE60993).

Temporal analysis identified 160 dynamically regulated genes post-AMI, prominently enriched in myeloid leukocyte activation and extracellular matrix organization. scRNA-seq revealed a remodeled immune landscape at day 3, characterized by increased proportions of macrophages, monocytes, and neutrophils, alongside enhanced intercellular signaling via pathways such as MIF and GALECTIN. Network analysis distilled a core set of seven inflammation-associated hub genes (Grn, Igf1, Il18, Itgb2, Ncf2, Ncf4, Spp1). These genes showed cell-type-specific expression patterns in myeloid subsets, correlated positively with myeloid cell infiltration in bulk tissue, and were significantly upregulated in the murine AMI model. Exploratory single-gene ROC analyses in a human peripheral blood cohort suggested preliminary differential expression trends for some hub genes (e.g., Spp1, Ncf4), but the very limited sample size precluded reliable construction of a multi-gene model and renders these findings strictly hypothesis-generating.

This study delineates a high-resolution map of transcriptional and cellular dynamics during the EIP of AMI, revealing a coordinated network of inflammatory mediators linked to early myeloid cell recruitment and activation. The identified seven-candidate hub genes represents a prioritized set of candidates for future investigation into diagnostic biomarkers and therapeutic strategies targeting the early inflammatory window.