Elevated homocysteine associated with higher cardiovascular risk in young patients with myocardial infarction: the role of metabolic phenotypes

Background: Premature myocardial infarction (PMI) is increasingly recognized as a metabolic disease, driven by a cluster of dysregulations including insulin resistance and central obesity. While homocysteine (Hcy)-an intermediate of one-carbon metabolism-is implicated in these atherothrombotic processes, its synergistic effect with coexisting cardiometabolic risk factors for the long-term prognosis of PMI patients remains unclear. Methods: We conducted a prospective cohort study of 1,220 consecutive PMI patients who underwent percutaneous coronary intervention (PCI) (men ≤45 years, women ≤55 years) at Tianjin Chest Hospital from January 2017 to December 2024. Plasma Hcy was measured at baseline and classified as 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. Multivariable Cox models and joint effect analyses were used to assess independent and synergistic associations. Results: Over a median follow-up of 582 days, 136 patients (11.1%) experienced MACE. After multivariable adjustment, high Hcy remained independently associated with MACE (aHR=2.72; 95% CI 1.87-3.95, P<0.001). This risk was higher when cardiometabolic factors coexisted, increasing from a 3.1-to 4.1-fold higher risk when combined with high D-Dimer, high-normal blood pressure, Lp(a), or hs-CRP (aHRs 3.13-4.12), to a 6.5-fold higher risk with coexisting obesity (aHR=6.54; 95% CI 3.01-14.20, P<0.001) compared to patients with normal Hcy and normal BMI. In the exploratory three-way 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). Conclusion: Elevated plasma Hcy is an independent predictor of MACE in PMI patients and may be used to identify subgroups at particularly high risk. This effect is more pronounced in individuals who are obese or have other adverse metabolic characteristics.