The expression and prognostic value of ischemia modified albumin (IMA), red blood cell distribution width (RDW), and lipoprotein (LP) in patients with diabetes mellitus complicated with coronary heart disease

Introduction

Diabetes melltus (DM) is a group of lifelong metabolic diseases characterized by chronic blood glucose elevation which can be caused by multiple factors. Oxidative stress resulting from long-term hyperglycemia can aggravate arteriosclerosis and cause various complications (1). Coronary heart disease (CHD) is a significant complication for diabetic patients with a high-risk of death. With the increasing incidence of diabetic patients complicated with CHD, the search for prognostic biochemical indicators with significant sensitivity and specificity has become a major clinical focus.

Ischemia modified albumin (IMA) is a novel and effective ischemic marker (2). Many studies have shown that IMA can sensitively reflect myocardial ischemia and can be used in the early diagnosis of acute coronary syndromes. This has great significance for patient risk stratification and treatment guidance (3). Malondialdehyde and advanced oxidation protein products can be considered better than IMA in the evaluation of diabetes progression, but malondialdehyde is more useful as a diagnostic indicator to detect vascular complications. Hemoglobin measurement is of greater value than the oxidative stress markers in the prediction of vascular complications (4). The red blood cell distribution width (RDW) is a parameter that reflects the physical heterogeneity of red blood cells. Recently, studies have revealed that RDW can be used for early risk stratification of CHD patients and is an important predictor for acute cardiovascular events (5). RDW values are found to be increased in the diabetic coronary artery disease population. Higher RDW values are related to more extensive and complex coronary lesions in patients with DM (6). Diabetic patients with high-coronary artery calcium scores and significant coronary artery disease have higher RDW (7). Elevated serum lipoprotein is a significant risk factor; and the risk of CHD appears to increase with increasing serum lipoprotein concentrations (8). Lipoproteins (LPs) are spherical particles composed of a hydrophobic core rich in sterol lipids and triglycerides, and a shell composed of proteins, phospholipids, and cholesterol (9). LPs play an important role in the packaging and storage of extracellular lipids as well as in molecular transportation and metabolism. It has been shown that abnormal LP metabolism is closely related to the occurrence of diabetes, arteriosclerosis, and other diseases (10). Both low-molecular-weight lipoprotein and low relative lymphocyte concentration are significant and independent risk factors for coronary heart disease and that the combination thereof more strongly predicts coronary heart disease in patients with type 2 diabetes mellitus (11). Glycation of high-density lipoprotein exerts a deleterious effect on the development of cardiovascular complications in diabetes (12). Therefore, this study investigated the levels and prognostic value of IMA and LPs, and the RDW in patients with DM complicated with CHD with the aim of providing an effective biomarker for clinical application. We present the following article in accordance with the STARD reporting checklist (available at http://dx.doi.org/10.21037/apm-21-425).

Methods

General information

A total of 95 patients with DM who were diagnosed and treated in our hospital from January 2018 to January 2019 were retrospectively studied. There were 61 patients with DM complicated with CHD (designated group A) and 34 patients with DM and no CHD complications (designated group B). All patientsagreed to participate in this study and signed an informed consent form. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China (No. 20171212). The inclusion criteria were as follows: (I) patients diagnosed with DM according to the criteria of the Chinese Guidelines for Diabetes Prevention and Treatment (13); and (II) patients with CHD confirmed by coronary angiography showing greater than 50% coronary artery stenosis. The following patients were excluded from the study: (I) patients with severe or active infectious diseases; (II) patients with insufficiencies of the liver and/or kidneys; (III) patients with malignant tumors; and (IV) patients with severe hematological diseases. A total of 45 patients without DM who underwent physical examination in our hospital during the same period were included as the control group. All relevant clinical data were true and complete for all study subjects, and there were no differences in the general patient characteristics such as age, gender, and body mass index (BMI) among the three groups (Table 1).

Table 1 A comparison of the general patient characteristics
Full table

Study method

All patients with DM complicated with CHD underwent percutaneous coronary intervention (PCI), and the levels of IMA, LP, and RDW were compared among the three groups. The occurrence of cardiovascular events in DM patients complicated with CHD after PCI treatment was analyzed. The receiver operating characteristic (ROC) curve was used to analyze the predictive values of IMA, LP, and RDW for cardiovascular events in DM patients complicated with CHD. Multivariate logistic regression analysis was used to assess the risk factors associated with cardiovascular events in DM patients complicated with CHD after PCI treatment.

The cardiovascular events defined in this study included hypotension during hospitalization, malignant arrhythmia, cardiac function Killip ≥III, cardiogenic death, and recurrent myocardial infarction.

Observation indicators

• IMA test: at admission, 5 mL of venous blood was collected and centrifuged at 1,000 rpm for 10 minutes. The supernatant (400 µL) was collected and the IMA content was measured using an enzyme-linked immunosorbent assay (ELISA) kit according to the manufacturer’s instructions (Cusabio, Maryland, USA). An IMA level ≤65 U/mL was defined as a normal value.
• LP test: fasting venous blood (5 mL) was collected from all patients on the morning of the second day after admission (the day of the physical examination). The blood was centrifuged to separate the serum and LP levels were assessed using an immunoturbidimetric kit (Shanghai Zhicheng Biotechnology Co., Ltd., Shanghai, China) and the Roche ModularP800 automatic biochemical analyzer. A LP measurement of <300 mg/L was considered a normal value.
• RDW test: fasting venous blood (5 mL) was collected from all patients on the morning of the second day after admission and the RDW was determined using an automatic blood cell analyzer. A RDW range between 11% and 16% was considered normal.

Statistical analysis

SPSS 20.0 statistical software was used for data analysis. Measurement data were expressed as mean ± standard deviation (x¯±s) and assessed using the F/t-test. Counting data were expressed in percentages (%) and the χ² test was used for comparison. The ROC curve was used to analyze the predictive value of IMA, LP, and RDW for cardiovascular events in patients with DM complicated by CHD. The relevant factors affecting the incidence of cardiovascular events were analyzed by logistic regression and α=0.05 was considered significant.

Results

The levels of IMA, LP, and RDW in the three groups of patients

The levels of IMA, LP, and RDW were significantly higher in groups A and B compared to the control group (P<0.05), with the levels significantly higher in group A compared to group B (P<0.05; Table 2).

Table 2 A comparison of the levels of ischemia modified albumin, lipoprotein, and red blood cell distribution width in the 3 groups of patients (x¯±s)
Full table

The occurrence of cardiovascular events in diabetes mellitus patients complicated with chronic heart disease after PCI treatment

A total of 28 cardiovascular events occurred in 61 DM patients complicated with CHD after PCI treatment, that is an incidence rate of 45.90%. The adverse cardiovascular events included 9 cases of hypotension during hospitalization, 10 cases of malignant arrhythmia, 4 cases of cardiac function Killip ≥III, 2 cases of cardiac deaths, and 3 cases of recurrent myocardial infarction.

The predictive value of IMA, LP, and RDW for cardiovascular events in diabetes mellitus patients complicated by chronic heart disease after PCI treatment

The levels of IMA, LP, and RDW were higher in patients who suffered a cardiovascular event compared to patients in the non-cardiovascular event group (P<0.05; Table 3).

Table 3 A comparison of the levels of ischemia modified albumin, lipoprotein, and red blood cell distribution width in patients with and without an adverse cardiovascular event (x¯±s)
Full table

The ROC curve was used to analyze the predictive values of IMA, LP, RDW, and the combined detection of all three factors on the occurrence of cardiovascular events in DM patients complicated by CHD after PCI treatment. The area under the curve for each predictive indicator and their combined detection was 0.910, 0.774, 0.846, and 0.995, respectively, where the combined detection achieved the best predictive performance (Figure 1).

Figure 1 A comparison of the area under the curve for the prediction of cardiovascular events in diabetes mellitus patients complicated with coronary heart disease. The predictive values of IMA, LP, RDWand the combination of all three factors is shown. IMA, ischemia modified albumin; LP, lipoprotein; RDW, red blood cell distribution width; ROC, receiver operating characteristic.

Single-factor analysis of the cardiovascular events in diabetes mellitus patients complicated by chronic heart disease after PCI treatment

Gender, age, BMI, history of hypertension, and history of smoking did not significantly affect the incidence of cardiovascular events (P>0.05). However, patients with an abnormal level of blood lipids, blood creatinine, IMA, LP, or RDW showed a significantly poorer prognosis, with increased incidences of cardiovascular events (P<0.05; Table 4).

Table 4 Single-factor analysis of cardiovascular events in diabetes mellitus patients complicated by chronic heart disease after percutaneous coronary intervention treatment
Full table

An analysis of the factors affecting cardiovascular events in diabetes mellitus patients complicated by chronic heart disease after PCI treatment

Analyses with unconditional multivariate logistic regression models revealed that abnormal levels of blood creatinine, IMA, LP, and RDW were all independent risk factors for cardiovascular events in DM patients complicated with CHD after PCI treatment (P<0.05; Table 5).

Table 5 Multi-factorial analysis of cardiovascular events in diabetes mellitus patients complicated by chronic heart disease after percutaneous coronary intervention treatment
Full table

Discussion

Abnormal glucose metabolism increases the morbidity and mortality of cardiovascular diseases. In fact, 46% of all newly diagnosed DM patients are complicated with CHD (14) and the National Cholesterol Education Program III considers DM and CHD to be “equal risk diseases” (15). PCI treatment is one of the mainstream methods for patients with DM complicated with CHD and is widely used in clinical practice. However, such patients often have severe coronary atherosclerosis and calcification, which can impede the efficacy of clinical treatments. Therefore, it is of great importance to target both the prevention and treatment of DM and CHD.

The levels and prognostic value of IMA in diabetes mellitus patients complicated by chronic heart disease

At present, the early diagnosis of CHD mainly relies on medical history, echocardiography, and coronary computed tomography (CT). However, the inclusion of these factors for the early prediction of vascular disease lacks sensitivity and specificity (16). IMA is formed when the body undergoes ischemia and the amino acid sequence of serum albumin is destroyed by free radicals and other substances resulting in changes in the binding capacity of albumin with transition metals. Thus, IMA has become a novel marker of myocardial ischemia (2,17). Previous studies compared the IMA levels in DM patients without CHD, DM patients with stable angina, and DM patients with acute CHD. They found that the IMA levels were highest in DM patients with acute CHD, suggesting that human serum IMA is an important biochemical indicator for the early diagnosis of clinical CHD, and can be used to detect and evaluate the severity of disease, as well as for prognosis and treatment (18,19). These results support the findings of our current study.

Further analysis of the risk factors that affect the occurrence of cardiovascular events in patients with DM complicated with CHD after PCI treatment found that abnormal IMA levels is one of the high-risk factors, suggesting that elevated IMA levels are closely related to the occurrence of cardiovascular events. Therefore, clinical management should focus on serum IMA testing in patients with DM complicated with CHD to accurately evaluate the progress of the disease and improve prognosis for patients.

The levels and prognostic value of RDW in diabetes mellitus patients complicated by chronic heart disease

Metabolic diseases generally involve the chronic inflammation process, and patients with DM typically have higher levels of chronic inflammation and oxidative stress (19). RDW can reflect the uniformity of red blood cells and is often used in the differential diagnosis of anemia. Recent studies have found that high levels of RDW can reflect potential inflammatory conditions. Some studies suggested that inflammatory responses can increase RDW by weakening iron metabolism, inhibiting the survival of erythropoietin, and shortening the lifespan of red blood cells (20,21). In DM patients, the RDW level is related to the occurrence of microvascular and macrovascular diseases and is one of the clinical indicators for evaluating vascular complications. The results of this study demosntrated that RDW levels were significantly higher in patients with DM complicated with CHD and in patients with poor prognosis after treatment (P<0.05), which is consistent with previous studies (22). RDW values are found to be increased in the diabetic coronary artery disease population. Higher RDW values are related to more extensive and complex coronary lesions in patients with DM (6). Diabetic patients with high-coronary artery calcium scores and significant coronary artery disease have higher RDW (7). Elevated serum lipoprotein is a significant risk factor; and the risk of CHD appears to increase with increasing serum lipoprotein concentrations (8). These results suggested that a high RDW value is positively correlated with coronary artery disease, and can be used as a predictor for vascular complications in patients with DM. Since RDW is easy to detect, economical, and repeatable, it is of high value in the clinical setting.

Furthermore, the results of the unconditional multivariate logistic regression analysis revealed that abnormal levels of RDW affected the occurrence of cardiovascular events in patients with DM complicated by CHD after PCI treatment (P<0.05). This suggested that RDW may be useful in assessing the prognosis of patients with DM complicated by CHD. It is possible that the increase in RDW reduces the deformability of red blood cells, resulting in obstruction of the microcirculation. This can lead to an increase in peripheral blood resistance which is related to the severity of coronary artery disease (23,24).

The levels and prognostic value of LP in diabetes mellitus patients complicated by chronic heart disease

LPs are composed of proteins and lipids, and can cause thrombosis and arteriosclerosis. LPs can cause atherosclerosis via several different mechanisms including: (I) inhibition of the tissue plasminogen activator; (II) enhancing the inhibition of plasmin by α2-antiplasmin; (III) competing with plasmin for binding to fibrin although it has no plasmin-like activity; (IV) enhancing the adhesion between monocytes and endothelial cells; and (V) binding to the plasminogen receptor on endothelial cells and promoting the transformation of macrophages into foam cells (25-27). Both low-molecular-weight lipoprotein and low relative lymphocyte concentration are significant and independent risk factors for coronary heart disease and that the combination thereof more strongly predicts coronary heart disease in patients with type 2 diabetes mellitus (11). Glycation of high-density lipoprotein exerts a deleterious effect on the development of cardiovascular complications in diabetes (12). This current study demonstrated that DM patients complicated with CHD had significantly higher levels of LP compared to patients without CHD and healthy people (P<0.05). The multi-factor analysis showed that abnormal LP levels can affect the occurrence of cardiovascular events in DM patients complicated with CHD after PCI treatment (P<0.05), suggesting that LP levels can be used to assess the severity of CHD complicated with DM, and guide prognosis and treatment. In addition, the ROC curve showed that the combined detection of IMA, LP, and RDW achieved the highest predictive value for the occurrence of cardiovascular events in DM patients complicated by CHD after PCI treatment. This is consistent with previous studies (28). Therefore, the combined detection of IMA, LP and RDW can improve the predictive value of cardiovascular events in DM patients complicated with CHD after PCI treatment.

The unconditional multivariate logistic regression analysis showed that an abnormal level of blood creatinine was a risk factor for the occurrence of cardiovascular events in DM patients complicated with CHD after PCI treatment (P<0.05). Serum levels of creatinine can reflect glomerular filtration capacity, and abnormal renal function is often associated with a more serious state of arteriosclerosis (29). Therefore, DM patients complicated with CHD may need to control blood creatinine levels and repair renal function prior to PCI treatment to improve the clinical outcome.

In summary, the levels of IMA, RDW, and LP are significantly elevated in DM patients complicated with CHD. Abnormal levels of IMA, LP, and RDW are independent risk factors that affect cardiovascular events in DM patients complicated with CHD after PCI treatment and the combined detection of all three indicators may be an effective means for predicting the prognosis of such patients.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at http://dx.doi.org/10.21037/apm-21-425

Data Sharing Statement: Available at http://dx.doi.org/10.21037/apm-21-425

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/apm-21-425). 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 approved by the Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China (No. 20171212). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). All patients agreed to participate in this study and signed an informed consent form.

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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(English Language Editor: J. Teoh)