Introduction
Coronary artery disease (CAD) is one of the most common causes of death worldwide, and it is responsible for more than twice the number of deaths due to cancer [
1,
2]. Acute coronary syndrome (ACS) is caused due to the rupture of atherosclerotic plaques and complete or incomplete thrombosis of the coronary arteries, which is the main part of CAD [
3]. Retinol-binding protein-4 (RBP-4) is a novel adipokine or hepatocytic cytokine, and its high serum levels have been associated with insulin resistance and obesity. In fact, elevated RBP-4 levels were found to be a new risk factor for cardiovascular disease [
4‐
7]. Recently, non-traditional lipid profiles have attracted the attention of researchers, and it has been seen that the lipoprotein combine index (LCI) is higher in CAD patients than non-CAD patients. However, it is still controversial whether LCI can be established as a new risk predictor for ACS and further research is needed to clarify this [
8‐
10]. Previous studies have reported that RBP-4 is an HDL-associated protein and it is correlated with adverse lipid profiles [
11,
12]. In this study, we hypothesized that RBP-4 + LCI is a better diagnostic predictor of ACS than RBP-4 and LCI alone.
Discussion
In this cross-sectional study, we discovered that a combination of the RBP-4 level and the LCI value can be used to diagnose ACS and found that RBP-4 + LCI was a novel independent risk factor for ACS. The main findings of this study are as follows: First, per ROC curve analysis, the AUC of the LCI + RBP-4 group was higher than the AUC of the individual LCI and RBP-4 groups, and this indicated that the accuracy of ACS diagnosis using combined RBP-4 + LCI values was higher than the accuracy of RBP-4 or LCI alone. Second, RBP-4 ≥4 ng/ml, LCI ≥16 and LCI ≥16 + RBP-4 ≥4 ng/ml were all new independent risk factors of ACS besides the classical risk factors of CAD. Interestingly, the risk associated with LCI ≥16 + RBP-4 ≥4 ng/ml was higher than the risk of LCI ≥16 or RBP-4 ≥4 ng/ml alone. Third, the risk of RBP-4 ≥4 ng/ml for the occurrence of lesion 2 vessels is highest, while the risk of LCI ≥16 for the occurrence of 1 lesion vessel is highest. There is growing evidence supporting that the presence and severity of the cardiovascular disease can be detected using certain biomarkers and components of the lipid profile. However, to our knowledge, this is the first study that has reported the association among LCI ≥16, RBP and ACS [
14‐
16].
There is increasing data strongly supporting the fact that the serum level of RBP-4 is associated with cardiovascular disease as well as adverse cardiovascular outcomes [
17,
18]. Liu et al. [
19] conducted a cross-sectional and prospective study, which reported that the level of RBP-4 is significantly associated with the complexity of coronary lesion in patients with ACS. A cross-sectional study by Lambadiari et al. [
20] found that RBP-4 is a strong predictor of CAD, and independently correlated its levels with CAD severity. Both these conclusions are consistent with our results. Additionally, our findings also extend the reports of these previous studies by showing that the level of RBP-4 showed an upward trend with the increase in the number of lesions in the vessels, and the risk of RBP-4 ≥4 ng/ml for occurrence of 2 vessels lesion was the highest compared to 1 or ≥3 vessels lesion group. Recent studies have demonstrated that RBP-4 contributes to inflammatory injury of cardiomyocytes through Toll-like receptor 4 activation and myeloid differentiation through the primary response gene 88 (MyD88) pathway [
21]. Additionally, pathophysiological mechanism of insulin resistance, type 2 diabetes, and endothelial dysfunction occurs through extracellular signal-regulated kinase activity [
7,
22,
23].
The patients with ACS had higher levels of TC, TG, LDL-C and lower level of HDL-C than those in the control group in previous studies [
24,
25]. There is evidence indicating that TC, TG, LDL-C and HDL-C levels could be used as risk markers of cardiovascular disease with a strong correlation with coronary atherosclerosis [
16,
26,
27]. However, the HDL-C levels had no statistical difference between the two groups in our study.TG-rich lipoproteins, TG, and LDL-C play roles in promoting inflammation, thrombosis, and insulin resistance, which are related to the formation, development and vulnerability of coronary plaque [
28‐
30]. In addition to participating in reverse cholesterol transport, HDL-C also has antioxidant, anti-inflammatory, and anti-atherosclerotic effect [
31]. Previous studies have shown that the ratios of TG/HDL-C, TC/HDL-C, LDL-C/HDL-C are significantly associated with insulin resistance [
32]. Further, the ratio of TG/HDL-C is related to the severity of CAD and can be used as a significant predictor of ACS in young adults, while non-HDL-C/TC is a new marker to assess the severity of coronary artery lesions and cardiovascular outcomes [
26,
33]. Although Wu et al. [
10] proposed the importance of LCI value, they did not report LCI as a significant risk predictor of CAD. However, our study has clearly shown that LCI can be used as a risk factor for ACS, and the risk associated with it was similar to the risk of hypertension and diabetes mellitus.
In the past few decades, a large number of studies have been conducted to understand the pathogenesis, clinical prevention and treatment of cardiovascular diseases. Studies have also confirmed that adipose tissues such as epicardial adipose tissue, pericardial adipose tissue, and thoracic adipose tissue secrete adipocytokines such as adiponectin, tumor necrosis factor-α (TNF-α), and omentin-1. Moreover, the clinical risk factors such as diabetes, hypertension, dyslipidemia are strongly linked with the pathophysiological mechanisms of CAD [
14,
34‐
38]. Although these efforts have improved the screening, diagnosis, treatment, and prognosis of CAD, the prevalence of CAD remains high and it is still one of the major health issues in the world. ACS remains to be the most common cause of death worldwide, and the mortality due to ACS continues to rise [
39]. Previous studies have focused on the unilateral effects of adipocytokines or clinical risk factors or adipose tissue on CAD. In this study, we have shown that when the levels adipocytokines such as RBP-4 were combined with clinical markers related to the diagnosis of ACS, the diagnostic accuracy of the combined indicator was higher than that of the single indicator, and the risk associated with the combined indicator was higher than the single indicator. In addition, we have also found that the numbers of stenotic vessels increased with increase in risk factors such as risk of hypertension, diabetes mellitus, smoking and history of MI. These findings might help in further promoting the diagnosis, prevention, and treatment of ACS.
In this study, the risk of LCI ≥16 for the occurrence of 1 lesion vessel was surprisingly higher than the risk of occurrence of 2 or ≥3 lesion vessels. We searched Medline by “lipoprotein combine index” and got three literatures only. A cross- sectional study found that LCI correlated with the atherosclerotic vascular disease better than serum lipid parameters [
40]. Stephen et al. found that LCI was a predictive indicator of CAD [
10,
41]. However, no literatures above were correlated with LCI and the numbers of stenotic coronary arteries. We are so sorry that the true mechanisms of LCI in coronary artery lesions is still unclear. Therefore, further researches are needed to tell the whole story then.
This study had some limitations. First, the sample size is relatively small, and as a result, there might be a selection bias. Second, as this is a single-center study, all inpatients were enrolled from one hospital within a specific period of time. Hence, a multi-regional and multi-ethnic study with a large sample size is needed in the future. Third, our study only explored the combined effects of RBP-4 and LCI on ACS, and the role of other adipocytokines and clinical risk factors along with these factors need to be further explored.
In conclusion, increase of the RBP-4 and LCI values were found to be independent risk factors for ACS, and the risk associated with the combined rise of LCI and RBP-4 was higher than the risk of LCI or RBP-4 alone. Therefore, combined tests assessing the LCI and RBP-4 values might be a potential diagnostic marker for ACS. However, as a single-center pilot study with a small sample size, the conclusions may have some limitations indeed. Our team will do more research work on ACS territory in the future clinical practice.
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