Effect of Mitochondria-Derived Methylmalonic Acid on Progress and Mortality Risk in US Adults With
Hongyu Liu1,2, Shuang Wu3,4, Bi Huang2,5
1Department of Cardiovascular Medicine, The Second Affiliated Hospital, School of Basic Sciences, Jiangxi Medical College Nanchang University Nanchang Jiangxi People's Republic of China.
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.
Insights
Methylmalonic acid (MMA) is linked to cardiovascular-kidney-metabolic (CKM) syndrome progression and increased mortality risk. Higher MMA levels correlate with advanced CKM stages and higher death rates, suggesting MMA as a key biomarker.
Area of Science:
- Biochemistry
- Gerontology
- Cardiology
Background:
- Methylmalonic acid (MMA) is a known biomarker for aging, oxidative stress, and mitochondrial dysfunction.
- These pathophysiological mechanisms are also central to cardiovascular-kidney-metabolic (CKM) syndrome.
- The direct association between MMA and CKM syndrome, however, remains incompletely understood.
Purpose of the Study:
- To investigate the relationship between methylmalonic acid (MMA) levels and the progression of cardiovascular-kidney-metabolic (CKM) syndrome.
- To evaluate the association between MMA and mortality risk in individuals with CKM syndrome.
- To explore the mediating role of MMA in the link between cardiometabolic biomarkers and mortality.
Main Methods:
- Utilized prospective cohort data from the National Health and Nutrition Examination Survey (1999-2018) including 14,581 participants with CKM.
- Employed multinomial logistic regression to assess MMA's association with CKM stages.
- Applied multivariable Cox regression and mediation analysis to determine MMA's impact on mortality and its mediating role.
Main Results:
- MMA showed a significant association with CKM stages (OR, 3.73).
- Elevated MMA levels (highest quartile) were linked to increased all-cause (HR, 2.03), cardiovascular (HR, 2.31), and noncardiovascular mortality (HR, 1.92) compared to the lowest quartile.
- MMA was found to mediate the association between cardiometabolic factors (physical activity, frailty, Life's Simple 7 score, eGFR) and mortality in the CKM population.
Conclusions:
- Mitochondria-derived MMA is a valuable biomarker for assessing CKM syndrome progression.
- MMA levels can help evaluate mortality risk in individuals diagnosed with CKM syndrome.
- Further research into MMA's role may inform targeted interventions for CKM syndrome management.
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