The present study revealed that four genes were significantly changed between the HF and non-HF patients and all showed a predictive ability of the long-term HF, including CD28, CXCR5, FOS, IL2RA. In addition, functional enrichment analysis showed immune system process was enriched in the process of HF, including lymphocyte proliferation, T cell proliferation, lymphocyte proliferation, and IL-17 signaling pathway. These newly-observed biomarkers could complement current biomarkers for predicting the long-term HF in AMI patients and provide novel insights for the rationale of the development of HF.
CD28 is known as a co-stimulator of T cell which plays an important role in inflammation[17, 18]. As we know, inflammation is involved in congestive heart failure[19]. Huan Wang et al indicated that CD28/B7 deficiency hindered activated effector T-cell accumulation, inhibited myocardial inflammation, and thus reduced the development of congestive heart failure[17]. Nadine Gladow ea al showed that CD28 combined with CD4 + T cells inhibited myocardial healing. In additon, anti-CD28 antibody treatment may be a potentially approach to improving the prognostic outcomes of MI[20].
CXCR5 is the chemokine receptor of CXCL13 and expressed on mature B cells and follicular T helper (Tfh) cells; it regulates homeostatic lymphoid cell trafficking and homing to B cell follicles within secondary lymphoid organs [21, 22]. Combined with members of lymphotoxin/tumor necrosis factor family, CXCR5 and its ligand CXCL13 play an important role in the development and maintenance of secondary lymphoid organs. It has been reported that CXCR5-deficient mice show impaired B cell follicle development [22, 23]. Heinrichs M et al [24] reported that compared with wild-type controls, mice treated with a neutralizing CXCL13-specific antibody or CXCR5-deficient mice displayed decreased post-MI B cells infiltration. Recent reports have uncovered that B cells and antibodies can affect inflammation and remodeling secondary to myocardial infarction [24]. The study of Waehre A et al revealed that after three weeks of aortic banding, mice with knockout of the CXCR5 (CXCR5(-/-) showed obvious left ventricular dilation compared with wild type mice. And patients with HF had an elevated levels of CXCR5 in myocardium [25].
A previous study, involved in CXCR5 expression in thrombus matters obtained from plaque rupture during myocardial infarction, discovered strong immunostaining of CXCR5 in the above thrombus matters in patients with ST elevation MI and unstable carotid lesion. Additionally, the levels of CXCR5 increased in monocytes when certain matters released from thrombin-activated platelets [26]. Another report showed that at the seven days after MI, matrix metalloproteinases 12 inhibitor (MMP-12i) lengthened the upregulation of CXCR5 [27]. Consequently, activation of immune response played a vital role during MI and HF, such as provoking adverse cardiac remodeling and left ventricular disorder.
As for FOS, the activity of miR-146a directly targeting at Fos was explored by Xavier Palomer et al. Overexpression of miR-146a led to a reduction in Fos mRNA and protein expression. MMP-9 activity was suppressed by the downregulation of the Fos-AP-1 pathway induced by miR-146a. And upregulation of MMP-9 protein level was associated closely with heart failure[28]. Yongliang Xue et al elucidated that anti-fibrotic effect of miR-29b-3p on cardiac fibrosis was partly induced by targrting FOS[29]. In summary, the FOS gene is involved with cardiac fibrosis and heart failure.
IL2RA is the alpha-chain of the IL-2 receptor and expressed on immune and non-immune cells with different proportions[30]. From the study of Elena de Dios ea al, we obtained that high expression of CD25 and CD69 and related immune checkpoints was associated with a better short and long period cardiac structure and function in patients of post ST-elevation myocardial infarction [31].
Several reports have shown that immune cells play a negative role in myocardial injury[32–34]. Especially, monocytes and macrophages within the infarcted heart can lead to harmful imflammatory responses and drive left ventricular adverse remodeling as well as heart failure[33, 35–36]. From our study, we can observed that resting NK cells were significantly upregulated in HF patients than non-HF patients. Our report broadens the mechanism of the post-AMI heart failure from a novel perpective.
The limitations of our study should be acknowledged. Firstly, the sample size in this study was comparatively small and thus the results of the analysis may be biased by population differences. Secondly, the results were all obtained by bioinformatics analysis; therefore it is required to validate these biomarkers in wet experiments. Thirdly, the CIBERSORT algorithm had its own inevitable limitations. For instance, CIBERSORT may be inclined to systematically underestimate or overestimate certain cell types even though a relatively lower estimation bias was demonstrated as compared with other similar methods [16].