The association between mitochondrial metabolite methylmalonic acid and long-term mortality risk in patients with coronary heart disease: a prospective cohort study

Background: Methylmalonic acid (MMA) has been associated with mitochondrial dysfunction and oxidative stress, independent of cobalamin deficiency. However, whether MMA predicts mortality risk in patients with coronary heart disease (CHD) was unknown. This study aims to investigate the relationship between baseline MMA levels and all-cause and cardiovascular mortality risk in adults diagnosed with CHD. Methods Overall, 1775 individuals with CHD and MMA measurement were included from the US National Health and Nutrition Examination Survey (NHANES) and followed up until 31 December 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CI for the association of MMA with all-cause and cause-specific mortality. Results During a mean follow-up of 9.64 years, 980 patients died. Serum MMA had a dose-responsed association with increased mortality risk according to spline curve fitting. Compared to the participants in the bottom tertile of MMA, those in the top quartile had a HR (95%CI) of 1.70 (1.31–2.20) for all-cause mortality, and 2.00 (1.39–2.89) for cardiovascular mortality (both p trend < 0.001) after full adjustment for demographics, lifestyle, clinical and laboratorial variables, and cardiovascular medications. The associations were particularly stronger among participants with diabetes or normal cobalamin (both p for interaction ≤ 0.019). MMA also had a better performance in predicting long-term mortality than traditional cardiovascular biomarkers. Conclusion MMA accumulation was associated with increased risks of all-cause and cardiovascular mortality in patients diagnosed with CHD. Lowering MMA maybe a promising target in the prevention of premature death due to CHD.