Should We Measure Asymmetric Dimethylarginine in Patients with Coronary Artery Disease?

In this issue of Clinical Chemistry , Meinitzer et al. (1) present data from The Ludwigshafen Risk and Cardiovascular Health Study in which they assess asymmetric dimethylarginine (ADMA) as a cardiovascular biomarker in 3238 patients. Coronary angiography identified 2543 patients with coronary artery disease as well as 695 persons without significant disease. Study participants were followed for more than 5 years. The major finding of the study was that plasma ADMA was an independent predictor of total and cardiovascular mortality.ADMA is a naturally occurring amino acid that has the interesting property of competitively inhibiting the activity of nitric oxide synthase (NOS). ADMA is produced by methylation of arginine residues in intracellular proteins via protein arginine N -methyltransferases (PRMT). When these proteins are hydrolyzed, ADMA is released. ADMA is excreted in the urine, and, not surprisingly, plasma ADMA is increased in patients with end-stage renal disease (2). Parenthetically, patients with renal disease have an increased risk of cardiovascular morbidity and mortality, and in these patients plasma ADMA concentrations carry prognostic information (3). The primary route of ADMA clearance, however, is by enzymatic degradation (Fig. 1⇓ ). Dimethylamine dimethylaminohydrolase (DDAH) converts ADMA to citrulline and dimethylamine. By regulating plasma and tissue concentrations of ADMA, DDAH protects NOS activity. Compelling evidence for the critical role of DDAH as an NOS regulator was demonstrated by studies of the transgenic DDAH mouse. These animals manifest increased DDAH activity, decreased plasma ADMA concentrations, increased plasma and urinary nitrogen oxides, and decreased vascular resistance, presumably attributable to increased NO (4). Figure 1. Biochemical pathways for generation, elimination, …