Aim To reveal the mechanism of cross-species ischemic heart failure from the perspective of spatial and gene co-expression networks. Methods GSE210374 and GSE57338 high-throughput sequencing datas were retrieved from the national center for biotechnology information gene expression database (NCBI-GEO), and R language software packages was used to analyze and screen differentially expressed genes (DEG) in different myocardial regions of myocardial infarction rats, as well as DEG of myocardial samples from patients with ischemic heart failure and healthy controls, and the regional expression of common genes was analyzed. Weighted gene co-expression network analysis (WGCNA) was used to screen the genes related to myocardial infarction and to carry out enrichment analysis, protein-protein interaction network (PPI) was constructed to screen core genes (HG). Results A total of 4 835 differentially expressed genes were screened out in myocardial infarction rats and normal controls, and 51 differentially expressed genes were screened out in ischemic heart failure patients and normal control samples, which revealed representative gene sets in the left ventricular myocardial infarction area (I area), border area (BZ area), and remote area (R area) after myocardial infarction. Spatial expression analysis revealed that there were 20 co-expressed genes in each myocardial region, 16 of which were expressed in all three regions, the number of genes specifically expressed in I, BZ and R regions were 2,0 and 2, respectively. Enrichment analysis showed that the functions of co-expressed genes were different in different region. The I and BZ regions were related to collagen fiber assembly, stress-induced cardiomyocyte hypertrophy, down-regulation of c-Jun amino terminal kinase (JNK signal) and cell proliferation, and complement signaling pathways; The I and R regions were enriched in the binding of Wnt and collagen; As a non-ischemic distal R region, the co-expressed genes were significantly enriched in the extracellular matrix for functions such as compressive resistance, cytolysis and inhibition of T cell proliferation. Furthermore, it was worth noting that the products of co-expressed genes in the three regions were mostly located in the extracellular space and extracellular matrix, suggesting that there may be active cellular secretion and interaction regulation. Further PPI analysis suggested that asporin (ASPN) , osteoglycin (OGN) and collagentype ⅩⅣ alpha chain (COL14A1) gene might be the core genes of the mechanism mentioned above. Conclusions The common mechanism of ischemic heart failure in rats and human involves multiple signaling pathways such as complement and coagulation cascade signaling and Wnt; which may be closely related to cell apoptosis mediated by extracellular matrix and exosomes; ASPN, OGN, and COL14A1 may be the core genes. This work is expected to provide spatial and pathway reference for the selection of intervention targets and pathway in the transformation research related to ischemic heart failure.