In this study, we report that patients with a high sdLDL-C were more likely to be have a high risk of CV events in Chinese patients with ACS undergoing PCI. This higher risk remained significant in patients regardless of diabetes status, LDL-C and TG levels. To our knowledge, our study is the first large-scale trial estimating the association between sdLDL-C and the risk of CV events in patients with ACS undergoing PCI. Actually, there may be no significant increase in LDL-C levels in some patients with diabetes or metabolic syndrome［23-24］. Therefore, it is clinically valuable to measure sdLDL-C for estimating the risk of CV events in patients with ACS undergoing PCI for its highly atherogenic properties. Overall, sd-LDL-C was favorable for distinguishing patients with high risk of CV events beyond LDL-C level.
There are several observational studies reported the associations between sdLDL-C and subclinical atherosclerosis［13,25-26］, or CAD［11-12,27］. In a small prospective study, an increase of sdLDL-C was shown to predict intima media thickness (IMT) and insulin resistance［28］. Results from a trial with 816 patients without diabetes or CVD showed sdLDL-C can independently predict arterial stiffness progression［29］. Moreover, several studies have indicated that sdLDL-C was independently associated with the progression of carotid atherosclerosis［13,25-26］. The Suita Study followed 2,034 general urban Japanese residents for an average of 11 years and have suggested that the highest quartile of sdLDL-C level was associsated with a 3.3-fold higher risk of incident CHD compared with the lowest quartile (95% CI, 1.3‒8.2)［30］. The Multi-Ethnic Study of Atherosclerosis, which included 4387 USA patients and followed up for an average of 8.5 year, demonstrated that adjusted hazard ratios for incident CHD between extreme quartile of sdLDL-C was 2.4［11］. The ARIC study, which included 11,419 patients and followed up for 11-year, demonstrated that sdLDL-C was associated with incident CHD［31］. And the association remained significant regardless of LDL-C levels in these studies. Meanwhile, Duran EK et al. also indicated that sdLDL-C affected atherogenesis independently of LDL-C and hs-CRP［32］, which was consistent with results of the above mentioned research. Furthermore, sdLDL-C predicted the CHD risk not only in patients at high cardiovascular risk［12］, but also at low cardiovascular risk according to LDL-C values［31］, therefore providing additional value for better risk assessment.
In addition, several studies reported the association between sdLDL-C and coronary stenosis severity or prognosis in patients with CAD. Koba S et al. recruited 482 stable CHD patients and 389 patients without CHD and indicated sdLDL-C level was more efficacious in predicting coronary severity［33］. A cohort study from china suggested that increased sdLDL-C were associated with higher risk of CV events in patients with diabetes and stable CAD［14］. Therefore, the current study might provide valuable further information on the relationship of sdLDL-C and CV events in patients with ACS undergoing PCI.
Also, several studies have shown sdLDL-C was closely related to stroke［26］. A cross-sectional study included a total of 754 acute ischemic stroke (AIS) patients indicated that sdLDL-C levels was an independent predictor of NIHSS scores and the severity of cerebral artery calcification［34］. A study enrolled 530 elderly patients hospitalized within 48 h after stroke suggested high sdLDL-C were associated with a greater risk for ischemic stroke［35］. Another study recruited 355 AIS and 171 non-AIS patients and found that elevated sdLDL-C was associated with a higher incidence of AIS［36］.
In this study, we also report that sdLDL-C was associations with increased risk of CV events regardless of diabetes status, which seems to be not very consistent with previous study. The Multi-Ethnic Study of Atherosclerosis demonstrated that elevated sdLDL-C was an independent risk factors for CHD only in non-diabetic patients but not in diabetes patients［11］. A cohort study from china indicated that elevated sdLDL-C was associated with greater risk of CV events in DM patients with stable CAD but not non-diabetic patients［14］. There were several limits for these studies. First, TG had a strong relationship with sdLDL-C［9］, which means the inclusion of both variables in the final multivariable regression model may bias the results. Second, the small sample size in the subgroup may explain the overall positive results but negative in subgroup analysis in these studies. Therefore, the negative result should not be used as a definite conclusion. Actually diabetic and non-diabetic patients accounted for almost half of the patients in the final analysis in our study, which means that our research may come up with positive results. In another study, the relationship between sdLDL-C and CHD was significant regardless of diabetes ststus, which was consistent with our study［12］. Moreover, patients with DM was likely to have smaller LDL［37］. sdLDL-C had strong association with metabolic syndrome［38］, insulin resistance［9,39］and subclinical diabetes status［40］.
The multiple characteristics of sdLDL-C, including greater propensity for endothelial penetration, lower affinity with LDL receptors, longer time in circulation and greater susceptibility to desialylation, glycation and oxidation, played an important role in the atherosclerosis［31］. Krychtiuk et al. showed that sdLDL-C was associated with an increase of non-classical monocytes (NCM; CD14+CD16++) and a decrease of classical monocytes (CM; CD14++CD16-) ［41］. In a prospective study within the Women’s Health Study, sdLDL-C was a strong risk factor for MI but not peripheral artery disease (PAD), which indicated that elevated sdLDL-C may be relevant to instability and vulnerability plaque rather than the more stable plaque［32］. Compared with LDL-C, sdLDL-C are more vulnerable to oxidative and easily engulfed by macrophages［42-43］, which strongly correlated with plaque instability in coronary［44］and carotid artery disease［45-46］.
This study has several limitations to consider. First, our results may be affected by residual confounding in this observational study. Second, there may be a significant decrease in sdDL-C in patients with AMI, but our study still found a close relationship between preoperative sdLDL-C concentration and prognosis. In addition, we collected blood samples immediate after admission to reducing the effect on sdLDL-C. Third, time-dependent analysis was not available for only once measurement of sdLDL-C at baseline. Fourth, unable to obtain follow-up information of medical treatments may bias the results. Finally, current research findings may not be generalizable to other ethnic groups because the participants in our study were only Chinese. Therefore, our findings should be confirmed in other ethnic populations.