Background
Cardiovascular disease (CVD) is a leading cause of early death and disability around the world [
1]. Earlier identification of high CVD-risk individuals is of vital importance to reduce the mortality associated with CVD. Carotid artery intima-media thickness (CA-IMT) serves as one of the key markers for CVD in different populations [
2,
3]. In addition, plaque composition and its instability in the carotid arteries is closely related to the risk for CVD [
4,
5]. Early detection of vulnerable plaques is deemed to be an important factor in the prevention of CVD. Carotid ultrasonography is the major imaging modality for evaluating carotid wall thickness and providing information on plaque composition [
6]. However, it is not a routine test for annual health check-up, especially in rural area. Thereby, exploration of potential biomarkers related to CA-IMT and carotid atherosclerotic plaque might be an alternative way to predict CVD in early stage.
Low–density lipoprotein cholesterol (LDL-C) is a well-studied risk factor of CVD [
7,
8]. While growing evidence has challenged the conventional view of LDL-C, as a large part of patients with normal plasma LDL-C levels still experienced CV events [
9]. LDL consists of seven subclasses (LDL 1—LDL 7), LDL 1 and 2 are defined as larger-buoyant LDL, and LDL 3 to 7 are defined as small-dense (sd) LDLs according to their size and density [
10]. Notably, sdLDL-C is thought to be more atherogenic. Evaluated level of sdLDL-C has been reported to be correlated with an increased risk of CVD, and sdLDL-C is considered to be a more suitable predictor for cardiovascular disease outcomes than total LDL-C level [
11]. More studies trend to evaluate the treatment effect on the changes in sdLDL-C level other than total LDL-C level [
12,
13]. Since evidence showed that patients who took lipid-lowering drugs and reached the set LDL-C level were still at risk of cardiovascular and cerebrovascular events [
13,
14]. Previous studies related to the sdLDL-C mainly focused on the patients who have experienced cardiovascular and cerebrovascular events [
15,
16]. For instance, studies have shown that sdLDL-C is an independent risk factor for IMT in acute ischemic stroke [
17], as well as for unstable plaques in acute cerebral infarction (ACI) patients [
18]. While, atherosclerosis progresses silently. By the time symptoms do arise, it’s usually advanced and serious. sdLDL-C has been found playing a role in the plaque progression. The levels of sdLDL-C are positively correlated with the severity of carotid stenosis in cerebral infarction patients [
19]. And cholesterol in the dense LDL fractions was found significantly affect carotid plaque cellular composition in patients with severe carotid artery stenosis [
20]. However, study related to the association of sdLDL-C with CA-IMT and carotid plaque in individuals with clinically silent atherosclerosis are relatively sparse.
According to the report on cardiovascular disease in China, 40% of deaths in the Chinese population were due to CVD [
21]. This study investigated the relationship of sdLDL-C to CA-IMT and carotid plaque in Chinese general population, especially explore the association of sdLDL-C with carotid plaque (CAP) stability in the subjects with abnormal IMT via a rapid, quantitative method for LDL subfractionation assay. Whether sdLDL-C could be an independent risk factor for individuals with subclinical atherosclerosis was also evaluated.
Discussion
CVD is giving a heavy burden to the patients and society worldwide. Population screening to find cases with asymptomatic atherosclerosis is one of the effective ways to reduce cardiovascular mortality and morbidity. Although, LDL-C level has been considered to be a useful marker to predict CVD. Increasingly evidence showed that a portion of the population with CVD has normal LDL-C [
28]. Thus, current research began to focus on exploring better lipid biomarkers for CVD. For instance, proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease, was found playing a crucial role in the regulation of plasma LDL-C concentration by inducing LDL receptor degradation [
29]. In addition, lipoprotein(a) [Lp(a)] is another established CVD risk factor, and LDL-C contains a contribution from the cholesterol in Lp(a). Previous study indicates that it has causal association with atherosclerosis due to the proatherogenic LDL-like properties and the prothrombotic plasminogen-like activity of apolipoprotein(a) [apo(a)] [
30]. Meanwhile, according to available evidence, sdLDL-C levels have been considered as a potential marker for monitoring CVD and early diagnosis of atherosclerosis [
31]. As yet, studies investigating the relationship between asymptomatic atherosclerosis and levels of sdLDL-C are relatively sparse.
In this retrospective study, we reported that sdLDL-C levels were significantly higher in subjects with abnormal IMT (IMT > 1 mm), compared with control group (IMT ≤ 1 mm). And sdLDL-C levels were significantly positively correlated with IMT value and presence of carotid plaque in the subjects with abnormal IMT. In addition, the results suggested that sdLDL-C may contribute to unstable plaque. Notably, sdLDL-C was an independent risk factor of the occurrence of CAP in the Chinese subjects with abnormal IMT.
Despite great effort on the diagnosis and treatment of symptomatic atherosclerosis, screening methods for early detection and treatment of asymptomatic coronary artery disease are still a challenge. CA-IMT and plaques measured by ultrasound are key indicators for carotid atherosclerosis [
32]. Nevertheless, carotid ultrasonographic examination is not a routine test for annual health check-up, especially in rural area with limited health care systems. The polyacrylamide gel (PAG) based system of the electrophoretic separation of human plasma lipoproteins enables quick identification and quantitative assessment of the atherogenic lipoproteins, especially the small dense LDL-C. In the present study, we used this FDA-cleared method to analyze the plasma sdLDL-C levels. We found that sdLDL-C positively associated with IMT value and presence of carotid plaque in the subjects with abnormal IMT. And through multivariable regression analysis, sdLDL-C was an independent risk factor of the occurrence of CAP. Our findings indicated that sdLDL-C detected by LipoPrint system could be an alternative way to identify individuals with subclinical atherosclerosis.
LDL cholesterol is a significant risk factor for the development of CVD by evidence from observational studies and clinical trials [
33‐
35]. However, it is worth noting that there are no significant differences in LDL-C level between abnormal IMT group and control group, and LDL-C has no significant correlation with presence of CAP in this study. These results may provide evidence to support previous studies that a relatively high proportion of individuals with normal LDL-C level still develop CVD [
9,
36]. In stark contrast, sdLDL has been considered to have more atherogenic effect than other LDL particles due to its increased susceptibility to oxidation, high endothelial permeability, and decreased hepatic LDL receptor affinity [
36,
37]. Previous studies demonstrate that sdLDL-C is a new risk factor for cardiovascular events [
11,
15,
16,
38]. For instance, one previous study suggested that sdLDL-C concentrations were a better marker for assessment of coronary heart disease (CHD) than total LDL-C [
39]. In another study, elevated sdLDL-C concentrations, but not total sdLDL particle concentrations, were reported to be a significant marker of CHD risk in nondiabetic individuals [
40]. Moreover, it has been demonstrated that sdLDL-C could predict the CHD risk even in patients considered to be at low cardiovascular risk based on their LDL-C levels in a large prospective study including 11,419 individuals [
38]. Meanwhile, a study on the correlation between sdLDL-C and CA-IMT in a healthy Chinese population showed that CA-IMT was significantly associated with sdLDL-C, even being adjusted by traditional CVD risk factors such as higher age, male sex, and other traditional CVD risk factors [
41]. These studies combined with our findings indicate that sdLDL-C has an important role in the early development of atherosclerosis, and sdLDL-C could be an additional marker for heart disease early screening in the health check-up. Furthermore, reducing the cholesterol content of LDL-C has been the mainstay of atherosclerosis prevention, but accumulating evidence shows that patients who are treated with lipid-lowering medications and reached a targeted LDL-C level are still at risk of mortality and recurrent cardiovascular and cerebrovascular events [
9,
36]. Previous studies and our results imply that not only the total LDL-C level, but also the sdLDL-C levels should be drew attention in the prevention and treatment for CVD.
Carotid ultrasound is a widely-used imaging technique for the assessment of cardiovascular. However, given that the price of ultrasound assay is not cheap compared with blood routine test, and the measurement needs to be performed by a trained and experienced ultrasound technologist. Normally, it is not a routine test for annual health check-up, especially in the low-income rural areas. Moreover, patients should be positioned lying face-up on an examination table for ultrasound, which may limit the results for those with respiratory disease unable to lie flat or those with arthritis incapable of rotating the head. The plasma sdLDL-C assessment is performed by the LipoPrint system. It is easy and simple to handle by technologist in accordance with the manufacturer's instructions. And it is accurate and relatively inexpensive compared to other established methods [
42], In addition, it has population-reference values from a normal population as defined by NCEP ATP III guidelines for desirable lipid levels. Combined the results of this study with other previous evidences, sdLDL-C assay may be an alternative way to the asymptomatic atherosclerosis screening, especially for those in areas that lack medical resources.
ertain limitations apply to the present study. First, this was a single-centred, retrospective study. Only Han Chinese in the Kaifeng area were involved in this study. Secondary, the effect of other risk factors such as smoking, drinking, and family history of CVD were not considered in this study. Third, due to the lack of data on sdLDL-C and CVD outcome at follow-up, the results of our study only reflect the relationship of sdLDL-C to IMT and CAP in individuals with abnormal IMT. Further prospective study may better uncover the role of sdLDL on the CVD occurrence in the individuals with clinically silent atherosclerosis.
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