In this observational study that included young patients who were ≤ 35 years of age, we found that HHCY was significantly associated with the presence of ACS, which was independent of traditional risk factors. In addition, HHCY had a strong correlation with the severity of coronary artery stenosis.
Due to the changes in lifestyle, especially the increased obesity rates and reduced physical activity, the onset age for CAD has been gradually decreasing [16]. A previous study showed that nearly 4–10% of patients with AMI were younger than 45 years old [17]. In contrast, the prevalence of AMI among young patients (< 35 years old) in China has more than doubled over a decade [18], which caused serious consequences for families and society. Compared with older patients, younger ones may have different coronary risk factor profiles. Results from a review identified male gender, current smoking status, alcohol consumption, diabetes, hypertension, dyslipidemia, psychosocial factors, sedentary lifestyle, obesity, and family history of premature MI as the leading causes of ACS in most young patients [19]. In the current study, we narrowed the age range of young participants to 18–35 years to determine the association between HHCY and ACS. Our results showed that very young ACS patients were more likely to have HHCY.
Studies performed over the last two decades identified HHCY as a crucial promoter for atherosclerotic vascular disease. There is a great controversy on the association between HHCY and the incidence of CAD, and whether it is casual, since lowering HCY levels in patients with CAD has not shown any benefit [3]. Nevertheless, many observational studies found that HHCY, which acts as an essential marker, is strongly associated with CAD and major adverse cardiac events (MACE) (death, reinfarction, restenosis) after PCI [4]; however, most of these studies were conducted in older people. Despite the increasing population of young ACS and the growing proportion of sudden death among these patients, there is limited evidence on the effect of HHCY on the risk of ACS in very young patients. Additionally, the results of few available researches were conflicting; a case-control study carried out among patients aged < 40 years showed a positive correlation between HHCY and CAD occurrence [20], while another study showed no difference of serum HCY level between healthy controls and young AMI patients aged ≤ 35 years [21]. Thus, we conducted this large-scale observational study, which revealed that the very young patients with ACS had higher HCY level than non-CAD participants [16.55 (11.93–29.68) vs. 12.50 (9.71–17.42), P < 0.001], and HHCY was identified as an independent predictor associated with the presence of ACS (OR, 4.393; 95% CI, 3.171–6.087; P < 0.001).
The relationship between HCY and the severity of coronary artery stenosis has been investigated by several studies before. Still, the current study is the only one conducted among the young ACS population. The results of this study showed a positive correlation between HHCY and angiographic severity expressed by Gensini Score. Li et al [22] studied 667 middle-aged and elderly CAD patients who underwent drug-eluting stent implantation and reported that patients with HHCY had a higher stenosis degree, as indicated by elevated SYNTAX scores. In their study, Shenoy et al [23] suggested that serum HCY level was significantly correlated with the Gensini Score of CAD patients (r = 0.443), which was consistent with our data. However, the sample size in a study conducted by Shenoy et al [23] was smaller, and the participants of Li et al [22] and Shenoy et al [23] study were much older compared with ours. In addition, Li and colleagues [22] also showed that the number of coronary artery target vessels in the HHCY group was obviously higher, and patients with high HCY levels had a higher proportion of coronary lesions. Another study involving HCY levels and premature CAD (56.1 ± 6.2 years of age) in 2019 [24] showed that the HCY levels were significantly higher in patients with multi-vessel disease. These findings were in agreement with the current study on the association between HHCY and the number of lesion vessels. Nonetheless, their participants were older than the participants in the present study. Moreover, we found young ACS patients with HHCY had decreased value of LVEF, which might be due to the relatively high prevalence of AMI in patients with higher HCY.
Many possible mechanisms have been reported as relevant for the association between HCY and CAD. A recent review [25] showed that HCY had a vast array of toxic effects on the vasculature, including impairing endothelial function by reducing the production of nitric oxide (NO), inducing vascular remodeling and vessel stiffening by increasing the synthesis of smooth muscle cells (SMC) as well as elevating adventitial inflammation, which might lead to the development of atherosclerosis. This review [25] also hypothesized that besides serum HCY, tissue-bound HCY and the incorporation of HCY into proteins could also stress the toxic effects of HCY on the vasculature. In their study, Yun et al. [26] indicated the enhancement of arterial stiffness in HHCY might be attributed to HCY-related LDL atherogenesis, such as small LDL particle size and its oxidative modification. Bianca et al [27] suggested that HCY exerted a prothrombotic effect by enhancing platelet aggregation. Also, several studies showed that HHCY might enhance the adverse effects of CAD risk factors such as essential hypertension, smoking, dyslipidemia, and diabetes mellitus [28–31]. These were probably related to the formation and progression of CAD in young adults.
Although traditional risk factors have a vital role in the development of cardiovascular disease, only 50% of these diseases could be explained by classical factors, which is why non-traditional risk factors have drawn more attention. The clinical significance of this article is to identify that HHCY played an important role in the occurrence and progression of ACS, which increased awareness of the importance of the HCY level among patients ≤ 35 years of age. Since excessive weight, current smoker status, alcohol and caffeine intake, and insufficient vitamin B and folic acid levels could increase HCY concentration, very young patients should adhere to a healthy lifestyle so as to maintain HCY levels within the normal range.