Effect of Mitochondria‐Derived Methylmalonic Acid on Progress and Mortality Risk in US Adults With Cardiovascular‐Kidney‐Metabolic Syndrome

Background Methylmalonic acid (MMA) is regarded a biomarker of aging, oxidative stress, and mitochondrial dysfunction, which are also pathophysiological mechanisms that underlying cardiovascular‐kidney‐metabolic (CKM) syndrome. Nevertheless, the relationship between MMA per se and CKM remains unclear. Methods This prospective cohort study was based on data from the National Health and Nutrition Examination Survey (1999–2018). Multinomial logistic regression was conducted to evaluate the relationship between MMA and CKM stages. Hazard ratios (HRs) and 96% CI for the association between MMA and mortality were calculated using the multivariable Cox regression model. The mediating role of MMA on the association between cardiometabolic biomarkers and mortality was estimating using mediation analysis. Results The cohort included 14 581 participants with CKM (median age, 55.0 [interquartile range, 41.0–69.0] years; 52.4% male). MMA showed a significant association with CKM stages (odds ratio, 3.73 [95% CI, 3.47–4.01]) after adjustment for multivariate covariates. During the median follow‐up of 102 months (interquartile range, 76–202), 3738 deaths occurred. Compared with participants in the lowest MMA quartile, those in the highest MMA quartile had HRs of 2.03 (95% CI, 1.78–2.30) for all‐cause death mortality, 2.31 (95% CI, 1.81–2.95) for cardiovascular mortality, and 1.92 (95% CI, 1.65–2.23) for noncardiovascular mortality, consistent with results in the CKM stage 1 to 2 and 3 to 4 groups. Furthermore, MMA mediated the association between several cardiometabolic biomarkers, such as physical activity, frailty, Life’s Simole 7 score, and estimated glomerular filtration rate levels, and mortality outcomes in the population with CKM. Conclusions Mitochondria‐derived MMA may serve as a valuable biomarker for evaluating CKM progression and mortality risk in individuals with CKM.