Association between homocysteine levels and mortality in CVD: a cohort study based on NHANES database

Cardiovascular disease (CVD) is a major global health concern with increasing incident cases and deaths. Homocysteine (Hcy) has been investigated for its potential association with CVD, researchers have debated the extent to which Hcy should be considered a risk factor for cardiovascular diseases, as only 50% of CVD can be explained by classical risk factors.

We conducted a prospective cohort study using NHANES 1999-2006 data, analyzing 1,739 US patients aged at least 30 with CVD. Cox proportional hazards regression and restricted cubic splines were used to examine the relationship between Hcy levels and mortality, adjusting for covariates.

A total of 1,739 participants with cardiovascular disease (CVD) were enrolled, with a median follow-up period of 126 months. Among them, 1,194 participants died, including 501 deaths due to cardiovascular causes. After adjusting for covariates, the hazard ratios (HR) and 95% confidence intervals (CI) for CVD mortality at different levels of homocysteine (Hcy) (T1 (< 9.3), T2 (9.3-12.5), T3 (> 12.5)) were 1.26 (0.92, 1.73) (T2), and 1.69 (1.14, 2.51) (T3) (P for trend = 0.0086). The HR and 95% CI for all-cause mortality at different levels of Hcy were 1.22 (1.05, 1.42) (T2) and 1.64 (1.29, 2.09) (T3) (P for trend < 0.0001). Elevated Hcy levels were associated with increased risks of all-cause mortality and CVD deaths, even at levels below the conventional threshold. The nonlinear relationship was observed, with inflection points at 14.5 µmol/L for all-cause mortality and 14.6 µmol/L for CVD mortality. Subgroup analyses revealed interactions with age, serum vitamin B12, and smoking.

Our study supports the notion that elevated Hcy levels are associated with higher all-cause and CVD mortality risks in CVD participants. The impact of Hcy on health outcomes can be observed at lower concentrations than previously thought.