Acute coronary syndrome (ACS) has become a significant public health problem and the leading cause of morbidity and mortality in the entire world as well in China [1]. Although ACS primarily occurs in older people, the incidence of ACS has been gradually increasing among younger Chinese individuals aged ≤ 45 years [2]. Several traditional risk factors for coronary artery disease (CAD), which include current smoking status, elevated body mass index (BMI), and a family history of premature acute myocardial infarction (AMI), have been associated with younger age [3]. In addition, non-traditional risk factors, such as hyperhomocysteinemia (HHCY), have also been suggested as novel markers for CAD and are supposed to be added to Framingham Risk Factors (FRFs) to boost their predictive value [4, 5]. In an observational study conducted in elderly patients undergoing coronary angiography (CAG), the elevation of homocysteine (HCY) level was closely associated with severity of coronary artery stenosis [6]; still, the impact of HHCY on ACS in young adults has not drawn much attention among research community due to the relatively low prevalence of ACS among young adults.

Since general HHCY prevalence has increased over the last two decades in China [7], as well as prevalence among young individuals, the aim of the current study was to analyze the association between HHCY and ACS, including the presence and the severity of coronary artery stenosis among young adults who are 35 years of age and younger.

In this observational study that included young patients who were ≤ 35 years of age, HHCY was found to be 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 lifestyle changes, especially the increased obesity and reduced physical activity, the onset age for CAD has been gradually decreasing [17]. A previous study showed that nearly 4–10% of AMI patients were younger than 45 years old [18]. In contrast, the prevalence of AMI among young patients (< 35 years old) in China has doubled over a decade [19], causing 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 [20]. In the current study, the age range of young participants were narrowed to 18–35 years to determine the association between HHCY and ACS. The results showed that 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 [4]. Nevertheless, many observational studies found that HHCY, which acted as an important marker, was strongly associated with CAD and major adverse cardiac events (MACE) (death, reinfarction, restenosis) after PCI [5]; 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 young adults. Additionally, the results of a few available studies were conflicting. A case–control study carried out among patients aged < 40 years showed a positive correlation between HHCY and CAD occurrence [21]. In comparison, another study showed no difference of serum HCY level between healthy controls and young AMI patients aged ≤ 35 years [22]. Thus, this large-scale observational study was conducted, which revealed that 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, 4.561; 95% CI, 3.288–6.327; P < 0.001).

Except for HHCY and other conventional risk factors, the present study found eGFR was also associated with ACS among young adults (OR, 1.014; 95% CI, 1.006–1.022; P < 0.001). This result was consistent with the study of Sasso et al. [23], which suggested a liner correlation between eGFR and cardiovascular events. But Sasso et al. study was conducted in DM patients who were much older. In addition, eGFR was decreased in patients with HHCY in the study, while the prevalence of DM was identified to be lower, which was unexpected. A study involving 3056 middle-aged and elderly patients with CAD or Heart valve disease suggested there was no correlation between DM and plasma HCY concentrations [24]. Glowinska et al. [25] investigated new atherosclerosis risk factors in diabetic children and adolescents, and found diabetic patients had lower concentrations of HCY compared with healthy subjects, but with no statistical significance. Giannattasio and colleagues [26] showed young adults with type 1 diabetes mellitus without microvascular complications had significant lower HCY levels and obvious higher vitamin B12 concentrations compared with controls. Furthermore, previous study indicated plasma HCY levels in young individuals at increased risk of type 2 diabetes mellitus were associated with subtle differences in GFR, but not with insulin resistance [27]. In this study, due to the young age and exclusion of lower eGFR in the participants, eGFR of most patients were in a normal range, which may partially affect the correlation between HHCY and DM. Since plasma HCY levels are determined by genetic and nutritional factors, the association of HHCY and DM in young ACS patients need more in-depth research.

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. [28] 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. [29] suggested that serum HCY level was significantly correlated with the Gensini Score of CAD patients (r = 0.443), which was consistent with this study. However, the sample size in the study conducted by Shenoy et al. [29] was smaller, and the participants of Li et al. [28] and Shenoy et al. [29] study were much older. In addition, Li et al. [28] 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 [30] showed that the HCY levels were significantly higher in patients with multi-vessel disease. These findings were consistent 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. In this study, decreased value of LVEF was found in young ACS patients with HHCY, 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 [31] 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 [31] also hypothesized that besides serum HCY, tissue-bound HCY and the incorporation of HCY into proteins could cause toxicity to the vasculature. In their study, Yun et al. [32] 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. [33] suggested that HCY exerted a prothrombotic effect by enhancing platelet aggregation. Several studies also showed that HHCY might enhance the adverse effects of CAD risk factors such as essential hypertension, smoking, dyslipidemia, and diabetes mellitus [34‐37]. These were probably related to the formation and progression of CAD in young adults. Furthermore, some pathophysiological mechanisms of acute coronary damage are often not taken into consideration which, although relevant, we do not yet know adequately [38, 39].

Although traditional risk factors have a vital role developing 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 plays 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, young adults should adhere to a healthy lifestyle so as to maintain HCY levels within the normal range.

HHCY is significantly associated with the presence of ACS and the severity of coronary artery stenosis in young adults ≤ 35 years of age.