Homocysteine multiplies risks of adverse outcomes in premature myocardial infarction: synergistic effects with obesity and inflammation
J Gao, J Y Liu, Y H Wang, C P Li, Z H Cui, Y LiuAbstract
Background
Premature myocardial infarction(PMI) patients face significant residual risk linked to metabolic inflammation and thrombosis. While homocysteine (Hcy) contributes to these processes, its synergistic effect with other metabolic risk factors on the long-term prognosis of PMI patients has not yet been established.
Purpose
To evaluate the independent prognostic value of Hcy on long-term MACE and to investigate its synergistic effects with metabolic and inflammatory risk factors.
Methods
We conducted a prospective cohort research of 1,220 consecutive PMI patients underwent percutaneous coronary intervention(PCI) (men ≤45 years, women ≤55 years) from January 2017 to December 2024. Baseline plasma Hcy was measured and categorized as either high (≥15 µmol/L) or normal (<15 µmol/L). The primary endpoint was major adverse cardiovascular events (MACE), including cardiac death, rehospitalization for severe heart failure, non-fatal myocardial infarction, ischemic stroke, readmission for unstable angina, and target lesion revascularization. Independent and synergistic associations were evaluated using multivariable Cox models and joint effect analysis.
Results
136 patients (11.1%) experienced MACE over a median follow-up of 582 days. High Hcy continued to be independently linked to MACE after multivariable correction(aHR=2.72; 95%CI 1.87–3.95, P<0.001). This risk was amplified by coexisting cardiometabolic factors, increasing from a 3-to 4-fold higher risk when combined with high D-Dimer, Lp(a), or hs-CRP (aHRs 3.13-4.12), to a 6.5-fold higher risk with obesity (aHR=6.54; 95%CI 3.01-14.20, P<0.001) compared to patients with normal Hcy and normal BMI.In three-way interaction analyses, the combination of high Hcy, obesity, and elevated D-Dimer(D-Dimer>0.5mg/L) conferred a nearly 10-fold higher risk (aHR=9.91;95%CI 3.68–26.66,P<0.001), while the triad of high Hcy, obesity, and high hs-CRP(hs-CRP >2 mg/L) was associated with a 17.5-fold higher risk (aHR=17.51;95% CI 2.28–134.52,P=0.006).
Conclusions
In PMI patients , elevated homocysteine is an independent predictor of long-term MACE. Importantly, Hcy is a powerful "risk multiplier," increasing the negative consequences of inflammation and obesity.Our results give a clear justification for a significant upgrade in secondary prevention strategy and mechanism-driven nutritional therapies.