The most important limitation for accurate investigation of the pathophysiology of AMI is the necessity for heart tissue sample [8, 9]. Transcriptome technologies have provided new opportunities to discover disease-specific mechanisms which were distinguishable and may offer diagnostic and prognostic value [10,11,12,13,14,15,16,17,18]. In this paper, we compared the two transcriptome profiles: AMI patients versus healthy controls, admission, discharge, and 6 months after AMI patients versus with the controls (not the healthy group), with the aims to identify potential cardiac ischemia-related biomarkers and revealed the anticipated modulation networks and pathways that correlate with AMI development.
AMI patients versus healthy controls
We retained the 243 overlap between differentially expressed genes in AMI and control group in three cases, which were functionally enriched for inflammation, immune response pathways in AMI patients compared to matched, healthy controls. These findings are consistent with previous studies which also demonstrated the increased gene levels for immune response, inflammation and apoptosis pathways, raising the possibility of relationship between myocardial pathological procedure and inflammatory transcriptional changes in circulating cells. Indeed, targeted gene studies by measuring directly the inflammatory mRNA profile of leucocytes in multigene system, supporting the hypothesis that an inflammatory response involving leucocytes contributed to the pathogenesis of myocardial infarction [19]. For another, as in the modulation of leukocyte transcriptional machinery, the analyses of changes in blood leukocyte gene expression patterns reveals that the human blood leukocyte response to transient dysregulation and modulation of translational machinery, providing further evidence that myocardial ischemia results in transcriptional gene expression changes in the peripheral blood [20, 21].
The complexity of the dataset was reduced by lowing non-significant probe sets using WGCNA method, the most significant module was generated in each case. We found only three overlapping genes between the pink module of the GSE48060 group, the midnightblue module of the GSE66360 group and the brown module of the GSE60993 group. These three genes were FGFBP2, GFOD1 and MLC1. This finding implied the AMI pathogeny was associated with an increased expression of genes involved in the intravascular lesions, immunological responses and brain-derived factor regulatory system, suggesting a potential use of FGFBP2, GFOD1 and MLC1 as gene expression biomarkers for very early stages of AMI.
We then selected the co-expression module that showed great significance to analyze biological functions, these analyses associated inflammation and immune response pathway including natural killer cell mediated cytotoxicity, graft-versus-host disease, allograft rejection, antigen processing and presentation and Cytokine-cytokine receptor interaction with pathological changes following ischemic cardiac injury. These findings provide evidence that profiling of circulating cells in patients is capable of identifying distinct, biologically relevant gene expression changes and modulated networks and pathways. It’s worth mentioning that functional analysis of these differential gene sets revealed the enrichment of Type I diabetes mellitus and Autoimmune thyroid disease pathways. The subclinical hypothyroidism (associated with reduced systolic function, an atherogenic lipid profile, diastolic hypertension, and inflammatory condition) and hyperthyroidism (related to a mild decreased of coronary reserve, and an increased risk of supraventricular arrhythmias, hypercoagulable state) have recently been documented as clinical entities with negative effects on the cardiovascular system [22, 23]. Thus, mild forms of thyroid hormones disorders, often leads to the similar changes in cardiac function and gene expression, even small variations of the thyroid hormone within the physiological range may cause the adverse cardiovascular development. This supports the utility of large-scale gene expression analysis of the blood transcriptome at initial diagnosis of AMI for identification of relevant mechanisms of disease.
Admission, discharge, and 6 months after AMI patients versus with the controls
Numerous studies found significant roles of PBMCs in the systemic and regional inflammatory responses associated with remodeling in AMI [24, 25]. Thus, activation of the PBMCs, which reflects the magnitude of inflammation, could be linked to the progression of AMI patients.
The prognosis of patients after acute coronary syndrome (ACS) largely depends on the extent of myocardial damage during the acute phase. In this study, two gene expression profiling in PBMCs—GSE59867 and GSE62646 were downloaded to identify biologically relevant transcripts significantly altered through the AMI follow-up. Next, we performed four comparison: admission versus control, discharge versus control, admission versus 6 month and discharge versus 6 month group, respectively (Fig. 4). Notably, most differentially expressed genes were common in admission versus control and discharge versus control group, with maximum differentially expressed genes in admission versus 6 month and discharge versus 6 month group respectively, which is the same in the pathway analysis (Fig. 5).
These indicating that these gene expression profile modification may be responsible for the functional change during the recovery from AMI. Consistent with pathological changes following ischemic cardiac injury, the top five pathways enriched in the comparison of admission or discharge versus control group were associated with inflammation and immune response, which is also consistent with the previous results in the first section. Interestingly, possibly duo to the pharmacological intervention and myocardial function recovery, the comparison of admission or discharge versus 6 month were functional enriched in metabolic pathways and neurological disease. One possibility is that neurosecretion was involved in a protective systemic response to the development of the cardiac insufficiency in the face of partial or total occlusion of the coronary artery. Previous studies [26] have demonstrated that tyrosine kinase receptor B (TrkB)—a high-affinity receptor for brain-derived neurotrophic factor protects endothelial integrity during atherogenesis and plays a previously unknown protective role in the development of CAD. Also, the long term activation of autonomic nervous system may increase the risk of atherosclerosis, myocardial infarction or sudden death [27, 28].