In up to a mean of 36 ± 14 months of follow-up, three main results were found in the current study. First, the mortality rate and MACE rate were significantly lower in the low homocysteine group than in the high homocysteine group. Second, the univariate Cox proportional hazards analysis, the MACE rates were significantly associated with age and plasma HCY levels ≥ 15 µmol/L. However, while after adjusting for age, gender, hypertension, diabetes mellitus, hyperlipidemia, serum creatinine, HCY levels ≥ 15 µmol/L, creatinine, history of PCI, number of stents per lesion, smoking, alcoholic history, and BMI, only age remained as a statistically significant predictor for long-term cardiovascular outcomes, with a HR of 1.97 (95% CI: 1.14–3.39, p = 0.014).Finally, in Kaplan–Meier analysis, there was a significant difference in the MACE-free survival rate between the two groups (log-rank test; p = 0.037).
Many studies have now shown that hyperhomocysteinemia is an independent risk factor for coronary and cerebrovascular disease. In recent years some studies have also tried to explore the relationship between homocysteine and prognosis in coronary arteries. A study from the institutional registry of Cardiovascular Atherosclerosis and Percutaneous TrAnsluminal Interventions (CAPTAIN) enrolled 1,307 patients with documented CAD undergone PCI with bare metal stents from July 2003 to December 2014. All of the patients were divided into two groups according to fasting plasma HCY levels: group Ⅰ (883 patients, <12 µmol/L) and group II (424 patients, ≥ 12 µmol/L). After a mean follow-up period of 58 ± 41 months, the group II patients had a higher MACE rate (33.3% vs. 25.6%, p = 0.005) .Elevated HCY levels (≥ 12 µmol/L) were independently associated with an increased risk of long-term cardiovascular events in patients after coronary bare metal stent implantation.[13]In our study, mortality and MACE were higher in the group with high homocysteine levels compared to the group with normal homocysteine levels. However, their study focused on metal stents, while all of our patients received second-generation drug-eluting stents, which may also have contributed to our different results. Hcy is a sulfur-containing amino acid produced by the metabolism of methionine. It is now thought to contribute to atherosclerotic plaque formation and adverse cardiovascular events through a variety of mechanisms and adverse cardiovascular events.[14] However, the pathophysiological mechanisms were not fully understood. Basic studies have shown that high homocysteine significantly stimulates the proliferation of cultured human and porcine smooth muscle cells, while inhibiting the growth of cultured endothelial cells. Vascular injury stimulates smooth muscle proliferation, which is further enhanced by homocysteine in a dose-dependent manner.[15] Hcy is a prothrombotic disorder that may lead to oxidative endothelial damage and impair endogenous fibrinolysis.[16]In addition, Hcy also has a diastolic response to small vessels (especially in non-nitric oxide-mediated pathways), which predisposes to rupture of vulnerable plaques, leading to the progression of atherosclerosis and ultimately to atherosclerotic events. This can lead to the rupture of vulnerable plaques, leading to the progression of atherosclerosis and ultimately to cardiovascular events.[17] The extent of the association between acute myocardial infarction (AMI) and hyperhomocysteine remains unknown. In a prospective study of a Chinese population, researchers measured plasma Hcy levels in 178 patients with ST-segment elevation AMI treated with primary PCI, and ultimately found that elevated homocysteine concentrations were a significant risk factor for advanced diffuse coronary atherosclerosis in Chinese patients with acute myocardial infarction treated with primary PCI.[18]
However, in many trials of Hcy-lowering treatments, such as vitamin B12 and folic acid supplements, there were no beneficial effects on cardiovascular disease prevention.[19–22] Therefore, vitamin B12 and folic acid supplements were not included in our study protocol.It is generally believed that infarct-related in-stent restenosis is one of the most important prognostic factors for patients with ACS after PCI, and it is also one of the major difficulties in the treatment of ACS. [23]Most studies have evaluated the effect of elevated Hcy levels on restenosis after PCI, and few studies have evaluated mortality in patients with CAD after PCI by baseline plasma Hcy levels[19, 24, 25]. Few studies have assessed mortality in patients with myocardial infarction after PCI by baseline plasma Hcy levels, especially in non-ST-segment elevation myocardial infarction.[26] However, the effect of homocysteine on restenosis is controversial, the present study provides evidence that elevated plasma Hcy levels have a negative impact on long-term survival in patients with PCI and that patients with elevated Hcy levels (≥ 15 mmol/L) had significantly higher mortality than those with low levels (< 15 mmol/L), after adjusting for other factors that may affect the prognosis of PCI. However regarding hyperhomocysteine and stent restenosis, a meta-analysis that included 4340 participants showed that although there was no clear association between higher Hcy levels and restenosis after stenting, higher Hcy levels appeared to increase the risk of restenosis after coronary angioplasty and increased the risk of all-cause mortality, MACE, and cardiac death after PCI.[10] J. Guo’s study about the correlation between Hcy and ISR severity found a positive correlation between homocysteine and the severity of restenosis after PCI. In addition, ROC curve analysis showed that serum Hcy level could be used as a predictive biomarker of ISR severity after PCI.[11] A number of other studies have been conducted in support of a better prognostic correlation between interventions to lower blood Hcy levels (folic acid, vitamin B6, and vitamin B12) after PCI in patients with hyperhomocysteinemia and after PCI. For example, Schnyder et al.[27] conducted a study enrolled 553 patients undergoing angioplasty and found that the primary adverse cardiac event composite endpoint was significantly lower in the intervention group than in the non-intervention group. However, some studies of the effect of elevated Hcy on PCI outcomes have reached negative conclusions; A study by Ebbing et al.[28] included 3096 patients after PCI and found no prognostic impact of Hcy after a median follow-up of 38 months. In addition, another small study by Genser et al.[29] followed 292 patients who successfully underwent PCI. At six-month follow-up, stent restenosis was not associated with Hcy levels.At six months of follow-up, stent restenosis was not associated with Hcy levels.
For increased cardiac mortality in patients with hyperhomocysteinemia, a study comparing the relationship between hyperhomocysteinaemia and short-term prognosis in patients with acute myocardial infarction. Eighty-five patients were divided into two groups based on plasma Hcy levels. Gender, hypertension, diabetes mellitus, hyperlipidaemia, time from onset of symptoms to percutaneous coronary intervention, homocysteine, creatine kinase isoforms, and the incidence of 30-day adverse events were compared between the two groups. The overall incidence of adverse cardiovascular events was found to be significantly higher in the plasma Hcy group than in the comparison group, but the incidence of postprocedural angina and reinfarction was similar in all groups. They therefore concluded that elevated total plasma Hcy levels in patients with acute myocardial infarction undergoing percutaneous coronary intervention may be associated with short-term prognosis. Although this is similar to the results of our study, the short duration of this study and had a small sample size, which may have been affected by patient selection bias.[30] Similar trials have demonstrated that elevated Hcy levels in patients with AMI are independent of other risk factors and are associated with a higher incidence of coronary events.[31] The present study is in agreement with the results of most studies that high Hcy can exacerbate coronary artery disease and that serum Hcy levels had an important prognostic value for the long-term prognosis of patients with NSTEMI.
This study had several limitations. First, homocysteine metabolism is also influenced by diet, and we were unable to adjust for individual differences. Second, the methylenetetrahydrofolate reductase (MTHFR) enzyme, folate, vitamin B6, and vitamin B12 are required for the metabolism of homocysteine to methionine or cysteine. However, the MTHFR C677T gene has a polymorphism associated with hyperhomocysteinaemia.[32–34] In our study protocol, we did not routinely measure serum folate, vitamin B12 and gene polymorphisms, which resulted in no way to understand the interaction between them in terms of risk of cardiovascular events. Third, our sample size was small, which may have led to trial bias. Therefore, we need to further increase the sample size for inclusion in the future, as well as extend the follow-up time. Finally, we did not consider the effect of drugs on homocysteine.
In conclusion, serum Hcy level is an independent risk factor for adverse cardiovascular events after PCI in patients with NSTEMI.