To the best of our knowledge, the present study is the first to demonstrate the effects of age, gender, and menopausal status on the sdLDL-C and sdLDL-C/LDL-C ratio. The age-related sdLDL-C trends showed roughly an increasing phase, followed by a decreasing phase in men and a plateaued phase in middle-aged women. The age-related sdLDL-C trend in men, but not in women, was similar to traditional lipid cholesterol profiles. The reason for this gender difference might be related to the mechanism of hypertriglyceridemia in postmenopausal women, which induced small LDL particles.18–20 There were age or gender-related differences in the ability to generate sdLDL-C from LDL-C. This ability in men was higher than that in women for all age groups or standardized groups, which is identical to the fact that atherosclerosis is more common in men than in women, considering sdLDL-C is a highly atherogenic factor.
Our study showed three important results. First, age showed partial correlation trends with sdLDL-C levels and sdLDL-C/LDL-C ratio and non-linear trends between age and sdLDL-C and sdLDL-C/LDL-C ratio were found in both men and women. Therefore, using the sdLDL-C and sdLDL-C/LDL-C ratio, the definition of CVD risk assessment and the adaption of the lipid-lowering therapy should fully consider age-related trends and gender differences.
Second, menopausal status was an additional determinant of increasing sdLDL-C and sdLDL-C/LDL-C ratio. SdLDLs are regulated through multiple and complex mechanisms regarding excess adiposity, free fatty acids, apo-lipoproteins, and action of lipoprotein lipase activity and cholesterol ester transfer protein for lipoproteins.12,16,17 In postmenopausal women, the decrease of plasma estrogen levels plays a significant role in reducing the clearance of LDL particles via LDL receptor and increasing TG and the number of smaller LDL particles.21 This hormone change was related to the process of regulating sdLDL-C but there was little evidence available on the association between menopausal status and sdLDL-C or sdLDL-C/LDL-C ratio in a real-world, population setting.22 Our results showed that sdLDL-C in postmenopausal women was 0.8 or 3.9 mg / dL higher than men or premenopausal women in the standardized analysis.
Finally, the relationships between age-related trends in sdLDL-C and sdLDL-C/LDL-C ratio and gender were different from traditional lipid factors, such as LDL-C. The crossover of LDL-C for the genders occurred in middle-aged patients. On the contrary, the crossover of sdLDL-C occurred between 70–74 years and the sdLDL-C/LDL-C ratio did not occur. Rather than LDL-C, the results of the sdLDL-C and sdLDL-C/LDL-C ratio might reflect the fact that, for all age groups, men have more susceptible to CVD than women, even with the narrowing gap of risk for CVD in postmenopausal women.23
Our findings suggest that a subgroup-specific approach is required to develop efficient cardiovascular disease prevention strategies using the sdLDL-C and sdLDL-C/LDL-C ratio.
Our study has several limitations. First, age-related trends and levels of traditional lipid factors were almost similar to National Health and Nutrition Survey in Japan and our age-related trends of these factors were also similar to the trends of the Korean and Chinese Singaporeans population.14,15 But the trends of the US population or healthy Caucasian24,25 were not similar. Especially in healthy Caucasian patients aged ≥ 70 years, the trends for TC, LDL-C, and nonHDL-C differed from our observed trends and continuously increased. Although our results could not identify the mechanism, there might be racial differences. Therefore, it is unclear whether our results of sdLDL-C would be valid for these populations. Second, compared with mean lipid levels of the Korean population from KNHANES, Japanese men showed higher mean TC, LDL-C, and HDL levels (TC 199 mg / dL; LDL-C 115 mg / dL; HDL-C 56 mg / dL) compared to Korean men (TC 183 mg / dL; LDL-C 106 mg / dL; HDL 50 mg / dL), and Japanese women also showed higher mean levels (TC 212 mg / dL; LDL-C 124 mg / dL; HDL-C 64 mg / dL) than Korean women (TC 188 mg / dL; LDL-C 111 mg / dL; HDL-C 55 mg / dL). The reason for the difference in the lipoprotein profile between Japanese and Korean populations might be due to genetics and environmental factors. It is also unknown whether these factors might affect sdLDL-C levels and sdLDL-C/LDL-C ratio because sdLDLs are regulated through complex mechanisms. Third, we did not control for the effects of genetic factors, mental stress, diet, life activity, and socioeconomic status, which might be associated with changes in lipid metabolism.26,27,28