This study revealed that the TC/HDL-C, RC/HDL-C, LDL-C/HDL-C, non-HDL-C/HDL-C, apo B/HDL-C, and apo B/apo A-I ratios were significantly correlated with ICAS. Moreover, ROC analyses revealed that lipid ratios were better than lipid levels alone for predicting ICAS. The apo B/apo A-I ratio had a higher predictive value than that of other variables. This is the first study to present these relationships in a Chinese population.
The correlation between the apo B/apo A-I ratio and ICAS was established in a Korean population by Park and colleagues. They demonstrated that a higher apo B/apo A-I ratio could be a discriminator for ICAS rather than ECAS [9]. Sun et al [11] found that apoB/AI ratio could be an independent factor for risk stratification of ICAS in both stroke patients and non-stroke controls, which is similar to the results of this study. Moreover, this ratio has also been shown to be superior to other ratios for the identification of coronary artery lesions in a Chinese population and coronary disease in a Swedish population [13, 21]. Thus, the apo B/apo A-I ratio is considered to be an excellent surrogate for the prediction of vascular disease risk. Nevertheless, few studies have focused on the apo B/HDL-C ratio. Maki and colleagues demonstrated that the apo B/apo A-I ratio can be a predictor of CIMT progression in vascular walls[22]. Biswas et al.[23] demonstrated that this ratio correlated well with the risk of coronary heart disease among Indian populations. Atherosclerosis is one of the main contributory indicator for coronary heart disease [24, 25]. Hence, the apo B/HDL-C ratio has been proposed to be a marker of atherosclerosis.
This study also identified the important predictive abilities of the apo B/HDL-C and apo B/apo A-I ratios for ICAS rather than ECAS. This phenomenon could be explained by the greater effect on antioxidant enzymes in ICAS than in ECAS [26]. In an experimental study, dyslipidemic mice were characterized by increased oxidation of apoB in the blood and impaired HDL-associated antioxidative defense[27]. Moreover, apoA-I is considered a marker of antioxidant and anti-inflammatory properties [28], and is closely associated with the patients with pre-existing ischemic stroke [29]. Thus, this deficit in antioxidant protection might be the pathomechanism of ischemic stroke in ICAS in patients with high apoB/apoA-I ratios [29].
As the crucial lipoprotein in intermediate-density lipoprotein (IDL), very low-density lipoprotein (VLDL), as well as LDL and apo B, can reflect the potential atherogenic lipoprotein particles in lipid metabolism [30]. Conversely, apo A-I is the main component in HDL-C, which has anti-atherogenic and anti-inflammatory potential [31]. HDL-C can reverse cholesterol transport. Apo A-I and HDL-C have valuable antioxidant capacities. Therefore, the apo B/HDL-C and apo B/apo A-I ratios can more comprehensively reflect atherogenicity and lower antioxidant capacity.
Non-HDL-C integrates multiple types of cholesterol, including IDL, LDL, VLDL, and lipoprotein (a) and can be determined simply by calculation (TC level minus the HDL-C level) [17]. Because of the protective role of HDL-C against cardiovascular diseases, non-HDL-C has an atherogenic effect in the circulation. This association between non-HDL-C and ICAS has been confirmed in a Chinese population [6]. However, the diagnostic ability of the non-HDL-C/HDL-C ratio for ICAS has not been investigated. Moreover, the non-HDL-C/HDL-C ratio possesses good predictive ability for some diseases. This ratio is more useful than the apo B/apo A-I ratio for identifying the metabolic syndrome in a Korean population. In addition, a large retrospective study demonstrated a positive correlation between insulin resistance and C-reactive protein levels [32]. Among individuals with obesity and insulin resistance syndromes, lower HDL-C and higher non-HDL-C levels demonstrated associations with coronary heart disease in regression models [33]. Moreover, non-HDL-C/HDL-C ratio is a strong indicator for predicting carotid atherosclerotic plaque in middle-aged postmenopausal women [34]. Besides, for the prediction of risk of cardiovascular diseases, this ratio is similar to the apo B/apo A-I ratio for DM patients [35]. Compared with traditional lipid variables, this ratio is more suitable for the estimation of arterial stiffness in a Chinese population [36]. In this study, the non-HDL-C/HDL-C ratio was associated with a two-fold risk of ICAS. Therefore, control of this ratio may be important for ICAS risk. The results of the TC/HDL-C ratio were similar to those of the non-HDL-C/HDL-C ratio.
RC comprises the TG-rich lipoproteins IDL, VLDL, and chylomicrons [18]. RC is regarded as a causal indicator of cardiovascular diseases [37, 38]. The diagnostic values of RC and the RC/HDL-C ratio have been identified simultaneously in Chinese patients with peri-procedural myocardial injury [39]. The RC/HDL-C ratio appears to be a useful tool for assessing the risk of ICAS. Compared with other important lipid ratios, only the RC/HDL-C ratio showed a slight association with ICAS in this study. The exact mechanism of action is not clear, but low-grade inflammation caused by RC could be one reason for this association. Subsequently, RC could enter vascular walls by infiltrating the endothelial barrier, and lead to the formation of foam cells by upregulating the expression of scavenger receptors [40].
Study strengths and limitations
This study had several strengths. First, this study not only verified the data of other studies, but it also clarified the specific diagnostic value of lipid ratios upon ICAS. This study found that lipid ratios were better than routinely used lipid concentrations for predicting ICAS. Second, ROC curves indicated that the diagnostic ability of the apo B/apo A-I ratio surpassed those of all other ratios tested. This ratio was determined to be the best marker for ICAS risk. The lipid ratios indicated the balance between anti-atherogenic and pro-atherogenic mechanisms. The combined effects of lipid ratios could be more valuable than lipid levels alone. Third, this study suggested that lipid ratios had better predictive values than those of lipid levels alone for identifying ICAS risk. Finally, sex-based differences were examined regarding the predictive accuracy of lipid profiles. The apo B/apo A-I ratio had the highest AUC value for men, and the apo B/HDL-C ratio displayed the highest AUC value for women. One interpretation is that estrogen may exert an effect on lipid profiles, but the exact cause is not known, and further investigation is needed.
This study had five main limitations. First, data from a relatively small hospital-based population cannot be generalized to larger populations. Second, given the cross-sectional design and a relatively small cohort of patients with symptomatic ischemic stroke, a causal relationship between lipid ratios and ICAS could not be accurately ascertained. Third, this study focused on a Chinese population, therefore, the conclusions cannot be extrapolated to different ethnic groups. Fourth, cerebral atherosclerotic stenosis was evaluated using DSA and CTA. These methods have a high degree of accuracy for evaluating the severity of stenosis but are less accurate for cerebral atherosclerotic stenosis. Fifth, the absence of data such as insulin resistance, inflammatory indicators, menopausal status, the use of hypolipidemic drugs or anti-hypertensives drugs, apo CIII, apo-E, lipoprotein(a), and dietary habits may have a potential influence on outcomes.