In this sample of large rural residents, the nontraditional lipid profiles were all positively related to the risk of PAD in hypertension participants in China. The restricted cubic spline indicated that the relationship of the four nontraditional lipid indices with PAD was linear. Moreover, the findings suggested that the TC/HDL-C and LDL-C/HDL-C ratios were better early predictors of PAD risk than other nontraditional lipid indices.
To date, the relationship between nontraditional lipid indices and arteriosclerotic cardiovascular disease (ASCVD) has not been comprehensively examined. Lee et al. [11] performed a prospective study of 107 participants with type 2 diabetes in Taiwan and found that TC/HDL-C showed an inverse trend in changing in the ABI (β = −0.212, 95% CI: −0.043-−0.001). Another post hoc data analysis from a randomized controlled trial of 1599 community-based elderly participants reported that the TC/HDL-C ratio (per SD increment, OR: 1.31; 95% CI: 1.14-1.49), non-HDL-C level (OR: 1.15; 95% CI: 1.01-1.31) and LDL-C/HDL-C ratio (OR: 1.25; 95% CI: 1.10-1.43) were significantly correlated with PAD [12]. Moreover, another population-based study of the elderly in rural China also observed a significant association between the LDL-C/HDL-C ratio and PAD (highest compared with the lowest tertile; OR: 2.56; 95% CI, 1.37 to 4.81) [20]. Additionally, Ridker et al. [21] and Pradhan et al. [22] separately reported the results concerning the association between the TC/HDL-C ratio and PAD in male physicians and female health professionals in the United States. Both studies yielded the same results that the TC/HDL-C ratio was significantly associated with PAD. However, Tongdee et al. found that the TC/HDL-C, TG/HDL-C and LDL-C/HDL-C ratios failed to predict early subclinical atherosclerosis in perimenopausal/menopausal women [23]. A cross-sectional survey [24] based on 2982 elderly Beijing residents found that the TG/HDL-C ratio was not associated with a low ABI (ABI ≤ 0.9) (highest compared with the lowest quartile; OR: 1.64; 95% CI, 0.88 to 3.07; P ≥ 0.05). This study also showed that the trends of the association between the TC/HDL-C ratio and the risk of PAD were nonlinear. The PAD risk was almost identical on the left side of inflexion and then increased linearly when the TC/HDL-C ratio ≥ 3. However, no studies have assessed the association between nontraditional lipid profiles and PAD in hypertensive populations.
Previous studies did not find that the linear relationship, to some extent, may be attributed to differences in patient characteristics, tHcy levels, or adjustment of confounders. First, the participants in the present study had hypertension, and the study by Lee et al. included only participants with type 2 diabetes. Hypertension may exhibit heterogeneity, and different diseases have different injury saturation point. Second, the lipid levels are significantly different based on region and diet, and the baseline lipid levels may impact the levels of lipid ratios and the prevalence of PAD. The high-carbohydrate diets of Chinese populations may contribute to hypertriglyceridemia, and the standard Western high-fat diets are more likely to induce hypercholesterolemia [25]. The present study was performed in a population with high-carbohydrate diets, and the studies of Ridker et al. and Pradhan et al. were undertaken in regions with the standard high-fat diets. Indeed, obvious geographical differences in PAD incidence also exist in China [26]. The present study was performed in the inland areas of the south, but the studies of Liang et al. and Zhan et al. were conducted in northern areas, while the study by Chi et al. was performed in the coastal areas. Third, the mean baseline tHcy was 18.0 μmol/L in the present study, much higher than normal levels. High tHcy could causes disorders of lipid metabolism and further atherosclerotic disease [27, 28]. Therefore, the association between nontraditional lipid profiles and PAD in a group of low tHcy concentrations cannot be examined. Overall, the current studies are just hypothesis-generating, and further investigations are necessary to consolidate the results of this study.
The exact mechanisms by which the nontraditional lipid indices could predict the risk of PAD were unclear, but using nontraditional lipid indices to predict PAD is biologically plausible. First, significant alterations in nontraditional lipid profiles, which are likely the result of dyslipidaemia in the early stages of PAD, may be characterized as a state of miniaturized low-density lipoprotein particle (LDL-P), and decreased high-density lipoprotein particle (HDL-P). The TC/HDL-C ratio, as a manifestation of atherogenic particle load, was associated with LDL-P, and the particle differences in low-density lipoprotein (LDL) may be attributed to a source of residual risk of cardiovascular events and a unique lipoprotein signature for PAD [29, 30]. In addition, previous studies showed that an elevated serum TG/HDL-C ratio independently predicted a decrease in LDL-P size [31]. Previous studies showed that small dense LDL (sdLDL) promoted pro-atherogenic modifications with the characteristics of incremental flux into the arterial intima, prolonged circulation time and reduced LDL receptor affinity [32, 33]. Moreover, the TC/HDL-C and TG/HDL-C ratios may reflect a decrease in mature large-size HDL-P, which is related to anti-atherosclerosis [25, 34, 35]. Non-HDL-C is a recognized risk factor for ASCVD because of its containment all of the atherogenic lipoproteins, and an epidemiological survey showed that non-HDL-C was a stronger lipid parameter of atherogenesis than LDL-C [15]. Overall, the TC/HDL-C, TG/HDL-C and non-HDL-C ratios indirectly suggest early PAD risk by reflecting the size and density of LDL-P, HDL-P and other atherosclerotic factors, such as chylomicron, very-low density lipoprotein (VLDL), and intermediate density lipoprotein (IDL), which are all closely related to CVD. Second, the TC/HDL-C and TG/HDL-C ratios were strongly related to insulin resistance, whereas insulin resistance was closely related to the development of PAD [36-38]. Third, most participants (98.7%) in the present study had hyperhomocysteinaemia (HHcy, defined as tHcy ≥ 10 µmol/L) simultaneously, and HHcy may reflect the clinical significance of nontraditional lipid indices by mediating the changes in blood lipid levels and increased adverse effects of lipids on atherosclerosis. In addition to reducing the apolipoprotein A-I composite, HHcy also reduces the high-density lipoprotein (HDL) content in circulation via the promotion of HDL-C clearance [28, 39]. Furthermore, elevated LDL levels in patients with HHcy could be more likely to produce atherosclerotic disease [40, 41]. Therefore, the LDL-C/HDL-C ratio may be a good indicator for identifying the risk of early atherosclerosis, and it can replace the standard lipid profile in the HHcy population. Because a lot of studies have come to the same conclusion that nontraditional lipid profiles would better represent the potential atherosclerotic evolution, using nontraditional lipid profiles to assess the risk of atherosclerotic diseases is reasonable.
Study strengths and limitations
This study is currently the largest study to assess the association between nontraditional lipid profiles and the risk of PAD in hypertension patients. Nevertheless, several potential limitations of this study are noteworthy. First, this study was a cross-sectional study, which makes it difficult to explain the causal relationship between non-traditional lipid profiles and PAD. Second, the study population comprised rural hypertensive patients in southern China, and the study subjects were over 18 years old. Therefore, these results cannot be generalized to other age groups, regions, or types of diseases.