Myocardial gene expression in patients with myocardial infarction

Abstract

Abstract Funding Acknowledgements Type of funding sources: None. Introduction. Myocardial infarction (MI) and following heart failure (HF) have various clinical scenarios. However, despite the clinical heterogeneity, the management of MI lacks effective personalized approaches. The response to ischemic injury in the infarct zone and remote myocardium has a definite spatio-temporal sequence and underlies the mechanism of adverse cardiac remodeling. Understanding its myocardial biology remains unclear due to insufficiency of heart tissue molecular and genetic analysis. Although animal models play an important role in data accumulation, they failure to reflect all the compounds of response to ischemic injury and following HF syndrome. Purpose. The purpose of the study was to investigate myocardial expression profile in the infarct zone in comparison to remote myocardium in patients with MI. Methods. The study included 4 patients with fatal MI type 1. All patients died within 48 hours of MI. The post-mortem examination was performed according to country policy. In each case, we obtained myocardial samples from the infarct zone and remote myocardium. Genome-wide gene-level expression was assessed by microarray analysis. We used transcriptome analysis software to analyze and visualize global expression patterns of genes. The analysis included normalization process. Differentially expressed genes (DEGs) were defined as gene-level fold change <-2 or >2 and adjusted P-value of <0.05. Results. We studied expression of 21448 genes. A total of 1785 DEGs, including 1692 up-regulated genes and 93 down-regulated genes in the infarct zone, were identified (Figure 1). According to the fold change, the first 10 up-regulated genes were TNFSF10 (TRAIL), SUCLA2, NAE1, PDCL3, OSBPL5, FCGR2C, SELE, CEP63, ST3GAL3, C4orf3. Fold changes for TNFSF10 (TRAIL), SUCLA2, and NAE1 were 19.83 (p = 0.049), 10.68 (p = 0.048), and 10.24 (p = 0.008), respectively. These 3 up-regulated genes were enriched in apoptotic signaling pathways, immune response, angiogenesis, inflammation, tricarboxylic acid cycle, and protein binding. Conclusions. We performed myocardial transcriptomic analysis in patients with MI. DEG analysis clearly distinguishes the infarct zone and remote myocardium. Genes overexpressed in the infarct zone included TNFSF10 (TRAIL), SUCLA2, NAE1. TNFSF10 (TRAIL) regulates vasodilation, angiogenesis, and inflammation. TNFSF10 (TRAIL) regulated effects could be both protective and harmful in ischemic heart disease. The enzyme encoded by SUCLA2 is active in tissues that require a large amount of energy, such as those of the heart, brain, and muscle. Overexpression of NAE1 causes apoptosis through deregulation of NEDD8 conjugation. It is known that the protein encoded by NAE1 binds to the beta-amyloid precursor protein, and it is thought to play a role in the pathogenesis of Alzheimer"s disease. Thus, our pilot study emphasized the potential of translational approach and identified targets to consider for precision diagnostics and therapeutics. Abstract Figure. С1: infarct zone; C2: remote myocardium