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Mitochondria-derived methylmalonic acid, a surrogate biomarker of mitochondrial dysfunction and oxidative stress, predicts all-cause and cardiovascular mortality in the general population.

ABSTRACT: BACKGROUND:Inherited methylmalonic acidemia is characterized by mitochondrial dysfunction, oxidative stress, and damage of mitochondria-rich organs in children. It is unclear whether methylmalonic acid (MMA) is related to poor prognosis in adults. The study aims to investigate the associations of MMA with all-cause and cause-specific mortality in the general population. METHODS:Overall, 23,437 adults from the US National Health and Nutrition Examination Survey (NHANES) were enrolled. NHANES 1999-2004 and 2011-2014 were separately used as primary and validation subsets (median follow-up 13.5 and 2.8 years, respectively). Circulating MMA was measured with gas chromatography/mass spectrophotometry. Hazard ratios (HR) were estimated using weighted Cox regression models. RESULTS:During 163,632 person-years of follow-up in NHANES 1999-2004, 3019 deaths occurred. Compared with participants with MMA <120 nmol/L, those with MMA?250 nmol/L had increased all-cause and cardiovascular mortality in the multivariable-adjusted model [HR(95%CI), 1.62 (1.43-1.84) and 1.66 (1.22-2.27), respectively]. The association was especially significant among participants with normal cobalamin. MMA remained an independent predictor of all-cause mortality occurring whether within 5-year, 5-10 years, or beyond 10-year of follow-up (each p for trend?0.007). That association was repeatable in NHANES 2011-2014. Moreover, baseline MMA improved reclassi?cation for 10-year mortality in patients with cardiovascular disease (net reclassification index 0.239, integrated discrimination improvement 0.022), overmatched established cardiovascular biomarkers C-reactive protein or homocysteine. CONCLUSIONS:Circulating level of mitochondrial-derived MMA is strongly associated with elevated all-cause and cardiovascular mortality. Our results support MMA as a surrogate biomarker of mitochondrial dysfunction to predict poor prognosis in adults. The biological mechanisms under cardiovascular disease warrant further investigation.

SUBMITTER: Wang S

PROVIDER: S-EPMC7554255 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Mitochondria-derived methylmalonic acid, a surrogate biomarker of mitochondrial dysfunction and oxidative stress, predicts all-cause and cardiovascular mortality in the general population.

Wang Shanjie S Liu Yige Y Liu Jinxin J Tian Wei W Zhang Xiaoyuan X Cai Hengxuan H Fang Shaohong S Yu Bo B

Redox biology 20200930

<h4>Background</h4>Inherited methylmalonic acidemia is characterized by mitochondrial dysfunction, oxidative stress, and damage of mitochondria-rich organs in children. It is unclear whether methylmalonic acid (MMA) is related to poor prognosis in adults. The study aims to investigate the associations of MMA with all-cause and cause-specific mortality in the general population.<h4>Methods</h4>Overall, 23,437 adults from the US National Health and Nutrition Examination Survey (NHANES) were enroll ...[more]

PMID: 33035815

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Project description:Methylmalonic acidaemia (MMA) has been reported to be associated with cardiovascular involvement, especially for the combined type with homocystinuria. We have screened 80 control subjects and 99 MMA patients (23 isolated type and 76 combined type) using electrocardiograph and echocardiography. 32 cases (34%) of ECG changes were found including sinus tachycardia (n = 11), prolonged QTc interval (n = 1), I-degree atrioventricular block (n = 1), left axis deviation (n = 5) and T wave change (n = 14). By echocardiography, 8 cases of congenital heart disease were found in 4 combined MMA patients (5.3%) including ventricular septal defect (n = 2), atrial septal defect (n = 3), patent ductus arteriosus (n = 1) and coronary artery-pulmonary artery fistula (n =2). Pulmonary hypertension (n = 2) and hypertrophic cardiomyopathy (n = 1) in combined subtype were also noted. Moreover, echocardiographic parameters were analyzed by multiple regression to clarify the influence of different subtypes on cardiac function. It was found that the left ventricular mass index (LVMI) was significantly reduced only in combined subtype [R = -3.0, 95%CI (-5.4, -0.5), P = 0.017]. For left ventricle, the mitral E' velocity was significantly reduced [isolated type: R = -1.8, 95%CI (-3.3, -0.4), P = 0.016; combined type: R = -2.5, 95%CI (-3.5, -1.5), P < 0.001], the global longitudinal strain (GLS) was the same [isolated type: R = -1.4, 95%CI (-2.3, -0.4), P = 0.007; Combined type: R = -1.1, 95%CI (-1.8, -0.4), P = 0.001], suggesting weakened left ventricular diastolic and systolic functions in both subtypes. For right ventricle, only in combined subtype, the tricuspid E' velocity was significantly reduced [R = -1.4, 95%CI (-2.6, -0.2), P = 0.021], and the tricuspid annular plane systolic excursion (TAPSE) was the same [R = -1.3, 95%CI (-2.3, -0.3), P=0.013], suggesting impaired right ventricular systolic and diastolic function. In conclusion, isolated and combined types showed different pattern of cardiac dysfunction, specifically the former only affected the left ventricle while the latter affected both ventricles. And it is necessary to perform echocardiographic screening and follow up in both MMA subtypes.

Dataset Information

Mitochondria-derived methylmalonic acid, a surrogate biomarker of mitochondrial dysfunction and oxidative stress, predicts all-cause and cardiovascular mortality in the general population.

Publications

Mitochondria-derived methylmalonic acid, a surrogate biomarker of mitochondrial dysfunction and oxidative stress, predicts all-cause and cardiovascular mortality in the general population.

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