The value of miRNA-29b in the diagnosis of myocardial infarction and the evaluation of cardiac function after myocardial infarction

Introduction

According to the World Health Organization, cardiovascular diseases (CVDs) account for approximately 30% of all deaths worldwide. Among CVDs, myocardial infarction (MI) is a critical cause of increased morbidity and mortality of CVD (1). After MI, cardiomyocytes in the ischemic region die, causing irreversible damage to cardiac structure and function. This increases the mortality of patients with MI in the acute phase, and the long-term complications also seriously reduce the quality of life of patients. Therefore, preserving viable myocardium and maintaining cardiac function have become the focus of clinical treatment of MI in recent years.

In the preliminary work for this study, bioinformatics techniques were used to identify potential key genes through a comparison of MI tissue and normal tissue, and enrichment and pathway analyses were performed (2). The critical role of miRNA-29b in the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway in MI was verified through public datasets and cell and animal experiments. miRNA-29b appears to act as a negative regulator in the context of MI by inhibiting the activation of the PI3K/mTOR signaling pathway. Because microRNAs (RNAs) exhibit remarkable stability in vivo, can be readily detected in the blood, and can be released via paracrine signaling by necrotic cardiomyocytes, they may serve as effective biomarkers for monitoring MI. In this study, we aimed to assess the expression of miRNA-29b in patients with MI and to clarify its effect on cardiac function after infarction. We present this article in accordance with the STROBE reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-561/rc).

Methods

Participants

This prospective study enrolled a total of 106 patients with acute myocardial infarction (AMI) admitted to the Department of Cardiology of Hebei General Hospital from January 2023 to July 2024. Patients were enrolled within 24 hours after the onset of MI. The inclusion criteria were as follows: (I) a diagnosis of AMI according to American Heart Association criteria (3), persistent chest pain lasting >30 minutes; and (II) a more than twofold increase in the level of cardiac troponin T (cTnT) or other cardiac enzymes above the upper limit of normal. Meanwhile, the exclusion criteria were as follows: (I) patients with other CVDs and the (II) presence of severe abnormal liver and kidney function (alanine aminotransferase or aspartate aminotransferase >3 times the upper limit of normal; creatinine >3 times the upper limit of normal). Thirty healthy individuals who received physical examination during the same period were selected as the control group. Demographic and clinical characteristics (including gender, age, body mass index, comorbidities, medication use, etc.) of the enrolled population were collected. Complete clinical data were available, and signed informed consent was obtained from all participants.

Experimental methods

Quantification of serum miRNA-29b expression

The level of miRNA-29b was determined via real-time quantitative polymerase chain reaction (RT-qPCR). Fasting elbow venous blood (5 mL) was collected from all participants; for the patients with AMI, the blood was obtained within 24 hours after MI; for the control group, blood was obtained on the morning of the physical examination. TRIzol reagent was used to extract total RNA in serum, and RT-qPCR was used to detect the expression of miRNA-29b.

Measurement of myocardial enzymes

The 5 mL of fasting peripheral venous blood collected from the participants was centrifuged at 3,400 ×g for 10 min for serum collection. The levels of cTnT and creatine kinase-MB (CK-MB) were measured with an automatic biochemical analyzer (Beckman Coulter AU5821, Brea, CA, USA).

Measurement of VEGF and TNF-α

After the serum was separated and collected, the levels of VEGF and TNF-α were detected via double-antibody sandwich enzyme-linked immunosorbent assay with reagents purchased from Shanghai Taikang Biotechnology Co., Ltd. (Shanghai, China).

Echocardiography

Transthoracic echocardiography was performed with an EPIQ 7C color Doppler ultrasound diagnostic instrument (Philips Healthcare, Amsterdam, the Netherland), equipped with a phase-control array electronic sector cardiac probe (model S5-1) at a frequency of 1–5 MHz. The patients were in the left and supine positions, breathing calmly, and the examination was performed on the left side of the parasternal. The measured parameters included left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-diastolic diameter (LVEDd), left ventricular end-systolic diameter (LVEDs), and left ventricular posterior wall thickness at end-diastole (LVPWd) and end-systole (LVPWs). According to the results of LVEF, patients with AMI were divided into in an abnormal cardiac function (ACF) group (LVEF <50%; n=50) and a normal cardiac function (NCF) group (LVEF ≥50%; n=56). Echocardiography was performed 2 weeks after the MI. All participants were examined via echocardiography by two ultrasound physicians at an associate senior position or higher. All measurements were averaged over three consecutive cardiac cycles.

Ethical considerations

The study protocol was approved by the Institutional Ethics Committee of Hebei General Hospital (No. 2024-365). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. All participants were provided with a detailed explanation of the study’s purpose and procedures. Written informed consent, confirming voluntary participation, was obtained from all subjects. Patient confidentiality was strictly maintained, and personal information was kept secure. All identifying details were omitted from reports and publications.

Statistical analysis

SPSS 22.0 software (IBM Corp., Armonk, NY, USA) was used for statistical analysis. The Shapiro-Wilk test was used to test the normal distribution, and the Levene test was used to test the homogeneity of variance. The Wilcoxon rank-sum test was used for nonparametric testing. If the data had a normal distribution and there was a homogeneity of variance between two groups, a t-test was used to compare the means of two samples. The rank-sum test was applied for data with a nonnormal distribution and uneven variance. Pearson correlation analysis was applied to determine the correlation between variables. P<0.05 was considered statistically significant. The receiver operating characteristic (ROC) curve was used to analyze the value of miRNA-29b in diagnosing MI and postinfarction cardiac dysfunction.

Results

Baseline characteristics

Among the patients with AMI treated at Hebei General Hospital, 120 patients who met the inclusion criteria were selected. After exclusion of cases with incomplete data or failed follow-up, 106 patients were finally included in this study. Additionally, 30 healthy patients were enrolled in the control group (Figure 1). The baseline information (Table 1) included age, gender, body mass index, and other general conditions, while the clinical parameters included the levels of alanine aminotransferase, aspartate aminotransferase, cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, creatinine, fasting blood glucose, glycosylated hemoglobin, and other indicators. There was no significant difference in baseline demographic between the AMI and control groups except for low-density lipoprotein cholesterol and fasting blood glucose (P<0.001 for both).

Figure 1 Flowchart of the enrollment and grouping of the study participants. AMI, acute myocardial infarction; ECHO, echocardiography; LVEF, left ventricular ejection fraction.

Comparison of serum miRNA-29b expression

The relative expression of serum miRNA-29b in the AMI group was 0.31±0.16, which was significantly lower than that in the control group (0.73±0.40; P<0.01). Among patients with AMI, the expression was also significantly lower in the ACF group (0.24±0.15) than in the NCF group (0.39±0.14; P<0.01) (Figure 2).

Figure 2 Comparison of serum miRNA-29b expression levels in the different groups. **, P<0.01. ACF, abnormal cardiac function group; AMI, acute myocardial infarction; NCF, normal cardiac function group.

Comparison of myocardial enzymes, VEGF, and TNF-α between the AMI and control groups

The levels of serum myocardial enzymes cTnT and CK-MB and the expression of VEGF and TNF-α in the AMI group were significantly higher than those in the control group (P<0.01) (Table 2).

Comparison of myocardial enzyme, VEGF, and TNF-α levels between the NCF and ACF groups

The serum levels of myocardial enzymes cTnT and CK-MB and the expression of VEGF and TNF-α in the ACF group were significantly higher than those in the NCF group (P<0.01) (Table 3).

Comparison of echocardiographic parameters between the AMI and control groups

Compared with the LVEDd and LVEDs in the control group, those in the AMI group were significantly higher (P<0.01). There was no significant difference in LVPWd or LVPWs.

Compared with the LVEF and LVFS in the control group, those in the AMI group were significantly lower, and the difference was statistically significant (P<0.01) (Table 4).

Comparison of echocardiographic parameters between the NCF group and ACF group

Compared with the NCF group, the ACF group had a higher LVEDd and LVEDs but a lower LVPWd (P<0.01). There was no significant difference in LVPWs.

Compared with the LVEF and LVFS in the NCF group, those in the ACF group were significantly lower (P<0.01) (Table 5; Figure 3).

Figure 3 Echocardiography in a patient with acute myocardial infarction. (A) Echocardiography of the NCF group. (B) Echocardiography of the ACF group. ACF, abnormal cardiac function group; ASE, American Society of Echocardiography; EDV, end diastolic volume; EF, ejection fraction; ESV, end systolic volume; FS, fractional shortening; IVS, interventricular septum; LVEF, left ventricular ejection fraction; LVFS, left ventricular fractional shortening; LVIDs, left ventricular end-systolic diameter; LVIDd, left ventricular end-diastolic diameter; LV MASSd, left ventricular mass; LVPW, left ventricular posterior wall; LVPWTd, left ventricular posterior wall thickness at end-diastole; LVSV, left ventricular stroke volume; NCF, normal cardiac function group; SV, stroke volume.

Correlations between serum miRNA-29b level and clinical parameters

miRNA-29b was positively correlated with LVEF [r=0.608; P<0.001; 95% confidence interval (CI): 0.494–0.701] and LVFS (r=0.583; P<0.001; 95% CI: 0.448–0.702). However, it was negatively correlated with cTnT (r=–0.687; P<0.001; 95% CI: –0.769 to –0.610), CK-MB (r=–0.626; P<0.001; 95% CI: –0.744 to –0.488), VEGF (r=–0.581; P<0.001; 95% CI: –0.708 to –0.422), TNF-α (r=–0.527; P<0.001; 95% CI: –0.658 to –0.369), LVEDd (r=–0.451; P<0.001; 95% CI: –0.578 to –0.284), and LVEDs (r=–0.462; P<0.001; 95% CI: –0.593 to –0.330) (Figure 4).

Figure 4 Correlation analysis between miRNA-29b and cardiac function indexes. (A) Correlation between miRNA-29b and LVEF. (B) Correlation between miRNA-29b and LVFS. (C) Correlation between miRNA-29b and cTnT. (D) Correlation between miRNA-29b and CK-MB. (E) Correlation between miRNA-29b and VEGF. (F) Correlation between miRNA-29b and TNF-α. (G) Correlation between miRNA-29b and LVEDd. (H) Correlation between miRNA-29b and LVEDs. CK-MB, creatine kinase isoenzyme; CI, confidence interval; cTnT, cardiac troponin; LVEDd, left ventricular end-diastolic diameter; LVEDs, left ventricular end-systolic diameter; LVEF, left ventricular ejection fraction; LVFS, left ventricular fractional shortening; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.

Diagnostic value of serum miRNA-29b for AMI

ROC curve analysis showed that the sensitivity of miRNA-29b in the diagnosis of AMI was 95.5%, the specificity was 66.1%, and the area under the curve (AUC) was 0.853; the cutoff threshold was 0.375 (95% CI: 0.767–0.939) (Figure 5).

Figure 5 ROC. (A) The ROC curve was used to analyze the diagnostic value of miRNA-29b for myocardial infarction. ROC curve analysis showed that at a cutoff of 0.375, the sensitivity of miRNA-29b in the diagnosis of MI was 95.5%, the specificity was 66.1%, and the area under the curve was 0.853. (B) The ROC curve was used to analyze the diagnostic value of miRNA-29b for cardiac dysfunction. ROC curve analysis showed that at a cutoff of 0.245, the sensitivity of miRNA-29b in the diagnosis of cardiac dysfunction was 84.0%, the specificity was 76.7%, and the area under the curve was 0.797. ROC, receiver operating curve.

Diagnostic value of serum miRNA-29b for cardiac dysfunction in patients with AMI

ROC curve analysis showed that the sensitivity of miRNA-29b in the diagnosis of cardiac dysfunction was 84.0%, the specificity was 76.7%, and the AUC was 0.797; the cutoff threshold was 0.245 (95% CI: 0.673–0.920) (Figure 5).

Discussion

AMI is a serious coronary artery disease caused by the acute occlusion of the coronary artery. About 50% of deaths due to AMI occur before the hospital can be reached. Although hospital reperfusion therapy is used to restore blood supply to the occluded coronary artery, the damage of ischemia and hypoxia to the myocardium in the infarcted area is permanent. About half of the patients who survive MI are readmitted due to heart failure within 1 year after reperfusion therapy. This is a long-term injury caused by a series of pathological processes such as impaired cardiac signal transduction and myocardial remodeling involving viable cardiomyocytes in the late stage of MI. Cardiac remodeling begins as an adaptive mechanism for maintaining cardiac function, but serious complications such as cardiac fibrosis, dilated cardiomyopathy, and development of heart failure occur at a later stage.

Endogenous miRNAs play an important role in a variety of CVDs (4,5). The function of transporters and endothelial cells and the establishment of collateral circulation and myocardial remodeling are all regulated by miRNA after MI. Bostjancic et al. examined the myocardial tissue at the infarct site of patients with MI and found that the expression of 77 miRNAs was dysregulated, among which 47 miRNAs changed within 1 week after MI and 30 changed within 4 weeks after MI (6). The changes of miRNA levels are closely related to the development and prognosis of MI. At present, the laboratory diagnosis of MI includes cTnT and CK-MB, among other indicators. Although these biomarkers can inform a diagnosis in the early stage of the disease, serum markers with higher sensitivity and specificity, especially novel markers that can reflect the prognosis of patients, are being urgently sought. miR-29 family members can be detected in cardiovascular tissues, endothelial cells (7-9), aortic tissues (10), myocardial cells, and other parts and exert regulatory activity (11,12). One study showed that the expression of miRNA-29b in the myocardium is 4- and 8-fold higher than that of miR-29a and miR-29c, respectively (13). miRNA-29b not only has good cardiac specificity but is also relatively stable in blood (14-16). Therefore, we aimed to determine whether miRNA-29b can be used as a biological indicator for the diagnosis of MI and the evaluation of cardiac function.

miRNA-29b affects angiogenesis and cardiac fibrosis by regulating biological pathways and signal transduction factors (17). Tang et al. found that the overexpression of miRNA-29b-3p reduced the cell proliferation and angiogenesis ability of endothelial cells by inhibiting VEGF expression (18). In our basic experiments confirmed that miRNA-29b reduced neovascularization and promoted myocardial fibrosis after MI by inhibiting the PI3K/mTOR/HIF-1α/VEGF signaling pathway. In this study, the expression of miRNA-29b was significantly decreased in the AMI group, and the expression of miRNA-29b in the ACF group was lower than that in the NCF group. Moreover, there was a significant correlation between the level of miRNA-29b and VEGF expression. These results suggest that miRNA-29b is involved in the occurrence of MI and in the regulation of angiogenesis. The serum level of miRNA-29b in the AMI group was lower than that in the control group, which may be due to the difference in the distribution of miRNA-29b in myocardial tissue and blood in the disease state.

Additionally, it has been confirmed that miRNA-29b regulates cardiac fibrosis after MI by directly binding to the target genes of collagen (19). In our study, the ACF group, as compared to the NCF group, had a lower expression of serum miRNA-29b, myocardial contractility, and LVEF and LVFS. As the level of miRNA-29b decreased in patients with MI, LVEF also gradually decreased, suggesting that miRNA-29b is related to the severity of MI. The differences in cardiac function between the groups may be related to the differing degrees to which miRNA-29b mediated cardiac fibrosis. LVPWd varied between the AMI subgroups. According to echocardiography, there was a decrease in left ventricular systolic function and a thinning of left ventricular posterior wall in the ACF group, while there was no significant difference in cardiac systolic function or ventricular wall structure in the NCF group. Thus there was no significant difference between the NCF group and the control group. It has been reported that miRNA-29b aggravates vascular endothelial injury in vivo, accelerates myocardial cell apoptosis and cardiac remodeling, and consequently increases the severity of MI (20). The ROC curve also showed that the expression level of miRNA-29b was closely related to MI and postinfarction cardiac function, demonstrating a high diagnostic value for AMI and cardiac insufficiency.

TNF-α is a pleiotropic inflammatory cytokine that promotes the inflammatory response of coronary atherosclerosis and is also a risk factor for coronary artery disease, with circulating TNF-α levels being associated with an increased risk of recurrent MI (21-23). Cardiac insufficiency and coronary restenosis after MI are also closely related to the high expression of TNF-α (24,25). Consistent with previous studies, the expression of TNF-α in the AMI group was significantly higher than that in the control group, and TNF-α in the ACF group was also significantly higher than that in the NCF group. VEGF can stimulate angiogenesis and myocardial perfusion and has anti-inflammatory activity. It can be continuously released to the lesion site to reduce the inflammatory response and plays an important role in the body’s anti-inflammatory response (26-28). The level of VEGF in the ACF group was lower than that in the NCF group, indicating that low levels of VEGF may reduce neovascularization and aggravate inflammation, resulting in the reduction of cardiac function. Therefore, we hypothesize that TNF-α and VEGF are also involved in the regulatory network of miRNA-29b and jointly affect the development and outcome of MI.

Certain limitations to this study should be noted. We examined the expression of miRNA-29b in blood and did not observe the expression level of miRNA-29b in the myocardium or the effect of miRNA-29b on angiogenesis and fibrosis in the myocardium after infarction. In future studies, these aspects will be explored in depth.

Conclusions

miRNA-29b aggravates the pathological process of MI by affecting signaling pathways. miRNA-29b is differentially expressed in patients with MI, and the expression level is correlated with myocardial enzymes, inflammatory indicators, and cardiac function. These findings suggest that miRNA-29b is an important regulator in the pathogenesis of MI, which can assist in the diagnosis of AMI and cardiac insufficiency and may be used as an biomarker to predict long-term complications.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-561/rc

Data Sharing Statement: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-561/dss

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-561/prf

Funding: This study was supported by the Government-Funded Clinical Medicine Outstanding Talent Training Project of Hebei Province in 2021 (No. 2021046).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-561/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and approved by the Ethics Committee of Hebei General Hospital (No. 2024-365). Informed consent was obtained from all eligible patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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