CAD is one of the leading causes of morbidity and mortality worldwide. Despite best efforts, available therapies protect only 30–40% of individuals at risk . Thus, it is important to investigate new predictors of CAD to help protect against and provide a new treatment for CAD. A possible relationship between HHcy and CAD was first suggested by Wilcken and Wilcken in 1976 . Since then, more data from various epidemiological investigations and laboratory studies have demonstrated that an increased concentration of serum Hcy was considered to be an independent risk factor for CVD. A meta-analysis showed that an increase of 5 µmol/L in plasma homocysteine level enhances the risk of CVD by 1.6- to 1.8-fold, which is similar to the risk seen with an increase of 20 mg/ dL (0.52 mmol/L) in cholesterol concentration . However, the mechanism for this risk remains unclear. It is well known that serum lipid levels are the most important risk factors for CAD. In the present study, perhaps due to the effects of lipid-lowering drugs, there were no significant increases in the levels of serum TC, TGs, LDL-C, or ApoB in CAD patients, but the serum HDL-C and ApoAI were lower in the CAD patients. We also found that serum Hcy was higher in CAD patients. Therefore, we speculate that HHcy may affect the occurrence of CAD by affecting the blood lipid profile, especially HDL-C and ApoAI.
In the present research, statistical analysis was performed between normal Hcy and HHcy groups according to whether the serum homocysteine concentration was greater than 15 µmol/L. The levels of serum TC, LDL-C and ApoB in control subjects with HHcy and the levels of serum HDL-C and ApoAI in CAD subjects with HHcy were significantly lower than those of individuals with normal Hcy (P for all < 0.05). There were also some invaluable clinical observations that demonstrate the possible link between Hcy and lipid metabolism pathways. Most research findings suggest that Hcy is significantly and negatively correlated with HDL-C and ApoAI in CAD or community-based populations. HDL and ApoAI exert anti-atherogenic effects by transporting cholesterol from cells into peripheral tissues , reducing oxidative stress and suppressing inflammatory pathways . Low ApoAI (HDL-C) levels are a risk factor for atherosclerosis. Recent animal and in vitro cell studies have also demonstrated that Hcy suppresses hepatic ApoAI expression via the peroxisome proliferator-activated receptor α (PPARα)-ApoAI pathway . Moreover, Hcy could decrease the transcription of ApoAI by stimulating nuclear factor κB (NF-κB) and ApoAI regulatory protein-1 (ARP-1)  and enhancing HDL cholesterol clearance . These increased Hcy levels may impair cardiovascular function via the inhibition of ApoAI expression and the impairment of its antioxidant capacity . In the present study, although the subjects enrolled in this study had been treated with statins prior to angiography, it is well known that the effect of statins on blood lipids is mainly reflected by lower TC and LDL-C levels and less on HDL-C and ApoAI levels. The negative correlation between HHcy and HDL-C and ApoAI was confirmed by multivariate regression analysis, which suggests that serum Hcy may promote CAD by disturbing HDL (ApoAI) metabolism.
The interaction between Hcy and serum TC, TGs and LDL-C has been explored in some small sample clinical observation studies. Durdi et al. reported that in 126 myocardial infarction patients, Hcy was positively correlated with LDL-C levels . In 300 Indian subjects with proven CAD, Hcy was found to be positively associated with TGs and very low-density lipoprotein cholesterol (VLDL-C) . In northern Chinese subjects, the prevalence of HHcy in the combined hyperlipidemia group was reported to be significantly higher than that in the control group, with an OR of 3.339 . There are also two community-based studies that incorporated large samples in China; Momin M et al. showed that HHcy was independently associated with hypertriglyceridemia , and Qin YY et al. showed that HHcy was related to high concentrations of TC, TGs, and LDL-C . However, not all prior studies have found correlations between HHcy and lipid profiles [36, 37]. Importantly, the most recent data, including 18297 US adults from the Very Large Database of Lipids (VLDL-21), indicate that, in unadjusted analysis, levels of LDL-C and non-HDL-C were lower, whereas levels of TGs and VLDL-C were higher in the highest Hcy quartile, but after adjusting for confounders, the associations disappeared . In the present study, we found that the levels of serum TC, LDL-C and ApoB in the HHcy group were significantly lower than those in the normal Hcy group in a population treated with lipid-lowering therapy, which appears to suggest that Hcy is associated with lipid parameters in the protection against atherosclerosis in these populations. To explain these contradictions, it must be noted that information on lipid-lowering medication, one of the most important confounders, was uncertain in our study and the VLDL-21 study. Perhaps it is very interesting to explore why individuals with HHcy who are taking lipid-lowering drugs have healthier blood lipid profiles. However, we lack information about the dose and treatment course of lipid-lowering drugs and the baseline lipid level before treatment. The effect of the interaction between HHcy and lipid-lowering drugs on blood lipids needs further research to clarify. Therefore, it is difficult to determine whether HHcy promotes atherosclerosis or protects against atherosclerosis by evaluating indicators such as TC, LDL and ApoB that are greatly affected by lipid-lowering drugs.
Nontraditional lipid profiles, including TC/HDL-C, LDL/HDL-C, TG/HDL-C and ApoB/AI, have been found to be independent indicators of vascular risk with greater predictive value than isolated lipid levels. Our current study aimed to evaluate whether HHcy is associated with promoting atherosclerosis or protecting against atherosclerotic lipid profiles by evaluating the lipid ratio. The present study showed that different trends in Hcy affect the ratio of TC/HDL-C and LDL-C/HDL-C between the CAD and controls (P for interaction < 0.05). In the controls, HHcy was associated with a decreased trend in the ratio of TC/HDL-C (normal Hcy: 4.11 ± 1.03 vs HHcy: 4.05 ± 1.11; P = 0.481) and LDL/HDL-C (normal Hcy: 2.52 ± 0.80 vs HHcy: 2.45 ± 0.85; P = 0.303). However, CAD patients with HHcy had a significantly higher ratio of TC/HDL-C (normal Hcy: 4.10 ± 1.32 vs HHcy: 4.43 ± 2.60; P = 0.025) and higher LDL/HDL-C (normal Hcy: 2.48 ± 1.07 vs HHcy: 2.65 ± 1.36; P = 0.045) than normal Hcy patients. The importance of TC/HDL-C and LDL/HDL-C was highlighted in some large studies; Ridker PM showed that the use of either the ratio of TC/HDL-C or that of LDL/HDL-C is superior to the use of TC or LDL-C alone . Arsenault BJ et al. observed that among apparently healthy men and women in a cohort representative of a contemporary Western population, the TC/HDL-C ratio was more strongly associated with the risk of future CHD than LDL-C; they also found that at any LDL-C level, individuals with an elevated TC/HDL-C ratio were still at an increased risk of developing CAD . Therefore, these findings suggest that HHcy may play an important role in the atherogenic lipid profile in patients with CAD. In people taking lipid-lowering drugs, the ratio of blood lipids is more suitable for assessing the effect of HHcy on CAD.