Plasma methylmalonic acid predicts risk of acute myocardial infarction and mortality in patients with coronary heart disease: A prospective 2‐cohort study

• Published in: Journal of internal medicine 2023-04, Vol.293 (4), p.508-519
• Main Authors: Dhar, Indu, Lysne, Vegard, Ulvik, Arve, Svingen, Gard F. T., Pedersen, Eva R., Bjørnestad, Espen Ø., Olsen, Thomas, Borsholm, Robert, Laupsa‐Borge, Johnny, Ueland, Per M., Tell, Grethe S., Berge, Rolf K., Mellgren, Gunnar, Bønaa, Kaare H., Nygård, Ottar K
• Format: Article
• Language: English
• Subjects: Aged; Angiography; biological markers; Biomarkers; Cardiovascular disease; Cardiovascular diseases; Cohort analysis; Cohort Studies; Confidence intervals; Coronary artery disease; Coronary Disease; coronary heart disease; Energy metabolism; Estimates; Female; Heart attacks; Heart diseases; Humans; Methylmalonic Acid; Mitochondria; Mortality; Myocardial Infarction; Older people; Oxidative metabolism; Oxidative stress; Plasma; Prospective Studies; Risk; Risk Factors; Vitamin B12; Vitamin deficiency
• ISSN: 0954-6820; 1365-2796
• DOI: 10.1111/joim.13610

Background Elevated plasma methylmalonic acid (MMA) is reported in patients with established coronary heart disease (CHD) and is considered a marker of vitamin B12 deficiency. Moreover, MMA‐dependent reactions have been linked to alterations in mitochondrial energy metabolism and oxidative stress, key features in the pathophysiology of cardiovascular diseases (CVDs). Objectives We examined whether plasma MMA prospectively predicted the long‐term risk of acute myocardial infarction (AMI) and mortality. Methods and results Using Cox modeling, we estimated hazard ratios (HRs) for endpoints according to per 1‐SD increment of log‐transformed plasma MMA in two independent populations: the Western Norway Coronary Angiography Cohort (WECAC) (patients evaluated for CHD; n = 4137) and the Norwegian Vitamin Trial (NORVIT) (patients hospitalized with AMI; n = 3525). In WECAC and NORVIT, 12.8% and 18.0% experienced an AMI, whereas 21.8% and 19.9% died, of whom 45.5% and 60.3% from CVD‐related causes during follow‐up (range 3–11 years), respectively. In WECAC, age‐ and gender‐adjusted HRs (95% confidence interval) were 1.18 (1.09–1.28), 1.25 (1.18–1.33), and 1.28 (1.17–1.40) for future AMI, total mortality, and CVD mortality, respectively. Corresponding risk estimates were 1.19 (1.10–1.28), 1.22 (1.14–1.31), and 1.30 (1.19–1.42) in NORVIT. These estimates were only slightly attenuated after multivariable adjustments. Across both cohorts, the MMA‐risk association was stronger in older adults, women, and non‐smokers. Conclusions Elevated MMA was associated with an increased risk of AMI and mortality in patients with suspected or verified CHD.