Abstract
Objective: This study was conducted to investigate the feasibility of using the serum homocysteine (Hcy), C-reactive protein (CRP), and cystatin C (Cys-C) levels to evaluate the conditions and prognoses of acute myocardial infarction (AMI) patients. Methods: One hundred and twenty patients with AMI were enrolled as an observation group (the AMI group). Eighty patients with stable angina pectoris were included in a control group (the SA group). Eighty healthy volunteers were enrolled as a healthy control group (the NCHD group). The AMI patients were divided into groups of >20 (n = 32), 10-20 (n = 45) and <10 (n = 43) according to their APACHE-II scores. The groups were divided into a death group (n = 23) and a survival group (n = 97) according to the patients’ 1-year follow-up outcomes. The differences in the serum Hcy, CRP, and Cys-C levels among the different groups, and the correlations between the serum levels were calculated. Results: The serum Hcy, CRP, and Cys-C levels in the AMI group were significantly higher than they were in the SA and NCHD groups (P<0.05), and the serum levels in the APACHE-II score >20 group were significantly higher than the serum levels in the 10-20 group. The dead group exhibited higher serum Hcy, CRP, and Cys-C levels than the survival group (P<0.05), and our Spearman’s correlation analysis showed that the serum Hcy, CRP and Cys-C levels were positively correlated with the APACHE II scores (r = 0.9157, r = 0.8519, r = 0.8598, P<0.001). The area under curve of Hcy, CRP, and Cys-C for the AMI diagnoses were 0.9638 (95% CI: 0.9183-1.000), 0.8125 (95% CI: 0.6652-0.9598), and 0.7515 (95% CI: 0.5847-0.9184), respectively. Conclusion: Serum Hcy, CRP, and Cys-C levels can reflect the severity of the patients’ conditions.
Keywords: Hcy, CRP, Cys-C, disease prognosis, analysis, feasibility investigation
Introduction
With the development of the domestic economy, residents’ dietary habits and lifestyles have undergone great changes. The incidence rate of cardiovascular diseases has increased significantly. Acute myocardial infarction (AMI) is a kind of myocardial necrosis caused by acute or persistent coronary ischemia and hypoxia [1]. Patients with AMI usually have severe and long-lasting retrosternal pain that can be appropriately relieved with rest or nitrate drugs. Clinical trials show increased myocardial enzyme activity and progressive ECG changes [2,3]. Some patients may experience arrhythmia, shock, or heart failure, which may threaten patients’ lives and health. Data show that AMI is currently the leading cause of death worldwide. There are 500,000 AMI cases each year in China, and its mortality rate has ranked first since 2014 [4,5].
Clinical practice has found that patients with AMI in critical condition often suffer from myocardial necrotizing disease due to continuous severe ischemia and hypoxia. Most patients have poor prognosis due to impaired cardiac function, and some patients have a higher chance of sudden death or recurrence. At the same time, due to the rapid development of AMI, it is clinically recommended to carry out active monitoring and prognostic analysis for patients, followed by targeted interventions to reduce the recurrence and mortality [6,7].
Hcy is an important metabolic intermediate in the human body, and it is also a diagnostic index for cardiovascular disease. A study has found that Hcy levels can be used as an independent risk factor for atherosclerosis, and when an individual’s serum Hcy level increases by 5 μmol/L, the risk of stroke increases by 59% [8]. CRP is a non-specific inflammation marker, and the CRP level is dramatically increased when an individual is exposed to infection or tissue damage. Clinical practice has shown that CRP is directly involved in inflammation and cardiovascular diseases such as atherosclerosis and is the strongest predictor and risk factor for cardiovascular disease [9]. Cys-C, a protein encoded by the CST3 gene, is clinically used as a biomarker of renal function, but recent studies have indicated that Cys-C is also useful in predicting the occurrence or worsening of cardiovascular disease [10,11]. The present study was conducted to investigate the application value of the above serum indices in the diagnosis and prognosis analysis of AMI patients, so as to provide a clinical reference for relieving the clinical symptoms of AMI patients.
Materials and methods
General information
One hundred and twenty patients with AMI treated in the Affiliated Hospital of Chengde Medical University from January 2016 to January 2019 were placed in the observation group (the AMI group). Another 80 patients with stable angina treated in our hospital during the same period were enrolled as the case control group (the SA group), and 80 healthy individuals were placed in the healthy control group (the NCHD group).
Inclusion criteria: (1) The patients in the AMI group all met the AMI diagnostic criteria [12], (2) Patients with a clear consciousness and good compliance, (3) Patients with complete medical records, and (4) Patients ≤70 years old. The present study was approved by the hospital ethics committee. The patients or their families signed the informed consent form.
Exclusion criteria: (1) Patients with psychiatric disorders, (2) Patients with other serious underlying physical disorders, (3) Patients with uncontrolled cardiac arrhythmia, (4) Patients with decompensated heart failure, (5) Patients with poor treatment compliance, (6) Patients with malignant tumors, (7) Patients with severe hepatic or renal insufficiency, (8) Patients with autoimmune diseases, (9) Pregnant or lactating women, and (10) Patients with hematologic disorders or chronic gastrointestinal disorders that may affect their serum factor levels.
Withdrawal criteria: (1) Patients who developed diseases or illnesses that interfered with the results, (2) Patients who voluntarily withdrew during the study, (3) Patients who lost contact with the research team.
Intervention method
Blood sample collection and testing
All the subjects were instructed to fast from 22:00, and 5 ml of peripheral elbow vein blood was drawn from each at 6:00-7:00 a.m. the next morning. The samples were treated with anticoagulant (heparin anticoagulation) and left for 30 min, followed by centrifugation at 3000 r/min for 15 min. The upper plasma was poured into heparin anticoagulant tubes, and stored at -80°C. The Hcy, CRP, and Cys-C levels were measured using enzyme-linked immunosorbent assays (ELISA), and all the kits used were purchased from Siemens AG. The measurement procedures were carried out strictly in accordance with the kits’ instructions. The average value of each index was taken as the final result after three consecutive tests.
Grouping of the patients
The APACHE II score is a general measure of disease severity based on current physiologic measurements, age and previous health conditions. APACHE II score = acute physiology score + age points + chronic health points. Minimum score = 0; maximum score = 71. Increased scores are associated with an increased risk of hospital death. According to their APACHE II scores, 120 patients in the AMI group were divided into the score of >20 group (n = 32), the 10-20 group (n = 45) and the <10 group (n = 43). After a 1-year follow-up, the patients were divided into death (n = 23) and survival groups (n = 97) according to their clinical outcomes.
Observation indicators
Comparison of the differences in the serological parameters
The serum Hcy, CRP, and Cys-C levels were compared among the patients in the AMI, SA, and NCHD groups, among the APACHE II score of >20, 10-20, and <10 groups, and between the death and survival groups.
Correlation between the serological parameters and the APACHE II scores
Spearman’s correlation analysis was used to investigate the relationship between the serologic parameters and the APACHE II scores.
The value of the serological indices for the diagnosis of AMI
The ROC curves of the serum Hcy, CRP, and Cys-C levels for the diagnosis of AMI were each drawn, and the areas under the curves (AUC) for Hcy, CRP, and Cys-C were calculated, and the diagnostic values of Hcy, CRP, and Cys-C for AMI were analyzed.
Statistical methods
SPSS 22.0 was used for the data analysis. If the data conformed to a normal distribution, the count data were expressed as [n (%)], and the differences between groups were examined using Chi-square tests, while the measurement data were expressed as the (mean ± standard deviation) and compared using t tests. F tests were used to compare the differences among multiple groups, and Spearman rank correlation coefficient was used for the correlation analysis. P<0.05 was considered statistically significant [13].
Results
Comparison of the differences in the baseline data
There were no significant differences among the three groups in terms of their gender ratios, mean ages, mean weights, or underlying diseases (P>0.05), so they were comparable (Table 1).
Table 1.
Comparison of the baseline data (x̅ ± s)/[n (%)]
| Clinical information | AMI Group (n = 120) | SA group (n = 80) | NCHD group (n = 80) | F | P | |
|---|---|---|---|---|---|---|
| Gender | Male | 71 | 45 | 50 | 0.547 | 0.362 |
| Female | 49 | 35 | 30 | |||
| Average age (years) | 44.59±3.22 | 45.19±2.98 | 44.28±3.01 | 0.036 | 0.987 | |
| Average weight (kg) | 63.29±3.41 | 64.11±2.98 | 64.33±3.22 | 0.066 | 0.917 | |
| History of hypertension | Yes | 20 | 13 | 15 | 0.445 | 0.298 |
| No | 100 | 67 | 65 | |||
| History of diabetes | Yes | 23 | 15 | 10 | 0.591 | 0.322 |
| No | 97 | 65 | 70 | |||
Comparison of the serological parameters of the patients in the AMI, SA, and NCHD groups
There were significant differences in the levels of the serological indices among the three groups (P<0.05). The Hcy, CRP, and Cys-C levels in the AMI group were higher than the corresponding levels in the SA and NCHD groups (P<0.05), and the levels of the above indices in the SA group were higher than they were in the NCHD group (P<0.05) (Figure 1).
Figure 1.
Comparison of the serological indexes among the AMI, SA, and NCHD groups. The Hcy, CRP, and Cys-C levels in the AMI group were significantly higher than the corresponding levels in the SA and NCHD groups (P<0.05), and the above indices in the SA group were significantly higher than they were in the NCHD group. * represents a significant difference of the same index between groups, P<0.05.
Comparison of the serological parameters in patients with different APACHE II scores
The patients’ Hcy, CRP, and Cys-C levels in the APACHE II score >20 group were significantly higher than those of the patients in the 10-20 and <10 groups, but the patients in the 10-20 group had higher levels of the above indices than the patients in the <10 group (P<0.05) (Figure 2).
Figure 2.
Comparison of the differences in the serological indices among the patients with different APACHE II scores. The Hcy, CRP, and Cys-C levels in the APACHE II >20 group were significantly higher than they were in the 10-20 and <10 groups, and the Hcy, CRP, and Cys-C levels in the 10-20 group were significantly higher than they were in the <10 group. * represents a significant difference in the same index between groups, P<0.05.
Comparison of the serological parameters in the patients with different clinical outcomes
The patients in the death group had significantly higher Hcy, CRP, and Cys-C levels than the patients in the survival group (P<0.05) (Figure 3).
Figure 3.
Comparison of the differences in the serological parameters among the patients with different clinical outcomes. The Hcy, CRP, and Cys-C levels in the death group were significantly higher than the corresponding levels in the survival group. # represents a significant difference in the same index between groups, P<0.05.
Correlation analysis of the serological parameters with the APACHE II scores
A significant positive relationship was found between the Hcy, CRP, and Cys-C levels and the APACHE II scores (r = 0.9157, r = 0.8519, r = 0.8598, P<0.001) (Figure 4).
Figure 4.
A correlation analysis of the serological parameters with the APACHE II scores. The Hcy (A), CRP (B), and Cys-C (C) levels showed significant positive associations with the APACHE II scores (r = 0.9157, r = 0.8519, r = 0.8598, P<0.001).
The value of the serological indices in the diagnosis of AMI
The AUCs of Hcy, CRP and Cys-C for the diagnosis of AMI were 0.9638, 0.8125, and 0.7515, and the 95% CI were 0.9183-1.000, 0.6652-0.9598, and 0.5847-0.9184, respectively (P<0.05), suggesting that the above indicators have a high value in the diagnosis of AMI (Figure 5).
Figure 5.
The value of the serological parameters for diagnosing AMI. The AUCs of Hcy, CRP, and Cys-C for diagnosing AMI were 0.9638, 0.8125, and 0.7515, and the 95% CIs were 0.9183-1.000, 0.6652-0.9598, and 0.5847-0.9184, respectively (P<0.05).
The sensitivity of the serological parameters for the diagnosis of AMI
The sensitivity, specificity, and accuracy of the serum Hcy, CRP, and Cys-C levels for the diagnosis of AMI were 89.28%, 78.89%, 73.22%, 91.72%, 78.28%, 70.77%, 90.17%, 67.67%, and 87.12%, respectively, with only small differences among the groups (P>0.05) (Table 2).
Table 2.
Analysis of the sensitivity, specificity and accuracy
| Indices | Sensitivity | Specificity | Accuracy |
|---|---|---|---|
| Hcy | 89.28% | 78.89% | 73.22% |
| CRP | 91.72% | 78.28% | 70.77% |
| Cys-C | 90.17% | 67.67% | 87.12% |
| F | 1.221 | 0.989 | 0.782 |
| P | >0.01 | >0.05 | >0.05 |
Discussion
AMI is a serious cardiovascular disease with a high mortality rate. Under the influence of lifestyles, social aging, and changes in dietary structure, the prevalence of AMI is on the rise worldwide, posing a serious threat to human health [14,15]. Due to the rapid onset and poor prognosis of AMI, most patients will still have adverse consequences such as reduced cardiopulmonary function, decreased exercise tolerance, as well as self-care ability after timely interventions. Therefore, appropriate interventions are recommended to improve the patients’ quality of life [16].
In this study, the differences in the serum Hcy, CRP, and Cys-C levels in AMI patients with different courses of the disease and different prognoses were explored by setting up different groups. The results showed that the Hcy, CRP and Cys-C levels in the SA group were significantly higher than the corresponding levels in the NCHD group, suggesting that with the aggravation of the disease condition, the serum factor levels of the patients showed significant changes. A comparative study of 66 AMI patients showed that the serum Hcy, hs-CRP and Cys-C levels of AMI patients were significantly higher than the levels in healthy individuals, and these levels showed a positive correlation with each other, suggesting that they can be used in the assessment of AMI patients’ conditions [17]. The current monitoring measures for AMI mainly rely on ECG, laboratory tests, etc. Among them, the interpretation of the ECG results depends on the physicians’ experience, and the cardiac dysfunction may lead to large errors in the ECG results, so it is not recommended to use ECG as the only means of diagnosing and identifying AMI [18,19]. Laboratory tests have the advantages of speed, good repeatability, and high accuracy, and they are also commonly used in clinical practice. Hcy is a reactive vascular injury amino acid and one of the important metabolic intermediates of the human body. The abnormal elevation of Hcy is closely associated with the occurrence of cardiovascular diseases, which have been clinically regarded as an independent risk factor for atherosclerotic lesions [20]. The mechanisms of Hcy that have been demonstrated as an independent risk factor for cardiovascular disease may be as follows: (1) Hcy promotes the generation of oxygen free radicals , and its elevated level will damage vascular endothelial cells, (2) Hcy can affect the process of apoptosis in vascular endothelial cells and inhibit the growth of vascular endothelial cells, (3) Hcy can regulate the body’s lipid metabolism and promote lipid peroxidation, which in turn accelerates the oxidation of LDL, (4) Hcy accelerates platelet aggregation and adhesion and induces thrombosis [21]. CRP is an acute phase response protein synthesized by hepatocytes, mostly present in the form of glycoprotein in the blood. CRP levels are extremely low in healthy people but can rise sharply when an individual has an infection or tissue damage. The abnormal elevation of serum CRP levels may be related to cardiovascular rupture, and a study has found that CRP levels are positively correlated with the incidence of sudden cardiac death [22]. CRP has been confirmed to be closely related to individual tissue damage and inflammation. AMI is characterized by cell apoptosis which will stimulate the body to secrete a large amount of CRP. Therefore, the CRP level is closely related to the disease condition, so it is also evidenced in the index differences among patients with different APACHE II scores. It has been demonstrated that Cys-C participates in the homeostasis of extracellular matrix production and degradation by regulating the protease activity of Hcy. Cys-C can also affect cellular phagocytosis and chemotaxis, so it is involved in the inflammatory process, and this has also been demonstrated by the differences in serum blood parameters among AMI patients with varying disease stages [23,24].
Hcy, CRP, and Cys-C levels are positively associated with the APACHE II scale scores. A retrospective study on AMI patients showed that the BNP, Hcy, and hs-CRP levels in AMI patients were significantly correlated with the disease condition and could be considered indicators for the assessment of the conditions of AMI patients, and the results also showed that the Hcy, cTnT, and PCT levels were correlated with the prognostic index scores (SIRS) of AMI patients, which confirms the association between the serological indicators and the prognosis [25]. The AUCs of Hcy, CRP, and Cys-C for the diagnosis of AMI were 0.9638, 0.8125, and 0.7515 respectively, indicating that the serological indices have a good diagnostic value for AMI. A study pointed out that the more severe the inflammatory response in the initial stage of AMI patients, the longer the duration of the disease, and the greater the possibility of later worsening. The higher the level of Hcy, the worse the patient’s prognosis and the higher the probability of stroke and myocardial infarction [26].
In summary, the serum Hcy, CRP, and Cys-C levels are valuable for assessing AMI patients’ conditions and prognoses and indicating the severity of the patients’ conditions. However, the small sample size and the short-term follow-up may still limit the accuracy of the experimental results, and further large-scale prospective studies are yet to be carried out.
Acknowledgements
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Disclosure of conflict of interest
None.
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