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Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery diseaseSchnabel R, Blankenberg S, Lubos E, et al. Circ Res 2005; 97:e53-9Reviewer: KW Tim Park, MD
Introduction: Nitric oxide (NO), synthesized in the endothelium from L-arginine, plays a crucial role not only in the regulation of vascular tone, but also in reduction of adhesion molecule expression, leukocyte adhesion, and proinflammatory cytokines, contributing a protective function against atherosclerosis. Under certain stress conditions, the endothelium also generates methylated amino acids, such as asymmetric dimethylarginine (ADMA), which out-competes with L-arginine to inhibit endothelial nitric oxide synthase and lead to endothelial dysfunction. Evidence is emerging that circulating levels of ADMA may be elevated in patients with cardiovascular risk factors and renal failure. In this study, the authors examined the hypothesis that circulating levels of ADMA are independently associated with future cardiovascular events and compared them with traditional risk factors and new biomarkers such as C-reactive protein and B-type natriuretic peptide. Methods: Between 1999 and 2004, of 1908 patients who underwent coronary angiography at the authors' institutions, 1874 patients who had at least one stenosis > 30% and who did not have significant valvular heart disease, surgery or trauma within the previous month, known cardiomyopathy, known cancer, febrile conditions or use of oral anticoagulant therapy within the previous four months were enrolled. Their demographic and comorbidities were noted and baseline measurements of ADMA, C-reactive protein, and B-type natriuretic peptide were obtained. The patients were followed for a median of 2.6 years (maximum 5.0 years), with the primary end-point of death from cardiovascular causes or nonfatal myocardial infarction and secondary end-points of noncardiovascular deaths and stroke. Characteristics of those reached the primary endpoint and those who did not were compared by t-test, χ2 test, or Wilcoxon rank-sum test as appropriate. Patients were also grouped according to tertile values of ADMA and their outcome was compared. Results: The mean age of the study participants was 61.0 ± 9.8 years and 79.1% were male. The mean ADMA level was 0.68 μmole/L with a 25th/75th interquartile range of 0.53/0.74 ?mol/L. The baseline ADMA level of ADMA was significantly higher among those who reached the primary endpoint than those who did not (0.70 vs. 0.63 μmol/L, P < 0.001). No correlation was observed between ADMA levels and C-reactive protein, B-type natriuretic peptide, or any lipid level (HDL, LDL, and triglyceride). Each SD increase in ADMA levels was associated with a hazard ratio of 1.27 (95% confidence interval, 1.09 to 1.48, P = 0.003) for cardiovascular death and 1.16 (95% confidence interval, 1.01 to 1.35, P = 0.049) for any cardiovascular event, but not a statistically significant increase in non-cardiovascular deaths or stroke. When the baseline ADMA levels were divided into tertiles (< 0.57 μmol/L, 0.57 - 0.7 μmol/L, and > 0.7 μmol/L), the unadjusted cardiovascular event rate increased in a stepwise fashion, with individuals in the upper third revealing a 2.48-fold increase (95% confidence interval, 1.52 to 4.06) in cardiovascular risk compared with those in the lowest third. In multivariate analyses including all biomarkers as well as other potential cardiovascular confounders, ADMA (hazard ratio 1.90; 95% confidence interval, 1.28 to 2.82) and B-type natriuretic peptide (hazard ratio 1.96; 95% confidence interval, 1.28 to 3.0) had the strongest predictive value. Discussion and Comments: The study demonstrates that circulating levels of ADMA constitute an independent risk factor of future cardiovascular events in a large cohort of patients with coronary artery disease. The study corroborates previous studies that showed a correlation of ADMA levels with the occurrence of acute coronary syndrome (Valkonen VP et al. Lancet 2001; 358:2127-8) and with adverse outcome after percutaneous coronary intervention (Lu TM et al. Eur Heart J 2003; 24:1912-9). This study is notable in that ADMA is a significant predictive factor, even when controlled for B-type natriuretic peptide, an indicator of myocyte stretch, and C-reactive protein, a measure of the inflammatory burden in atherosclerosis. In vitro experiments with cultured endothelial cells demonstrate that exposure of these cells to a proatherogenic factor such as glucose, homocysteine, and low-density lipoprotein stimulates the L-arginine methylating enzyme and inhibits demethylating enzymes by means of reactive oxygen species (Lin KY et al. Circulation 2002; 106:987-92; Stuhlniger MC et al. Circulation 2001; 104:2569-75; Boger RH et al. Circ Res 2000; 87:99-105). This results in increased intracellular and extracellular ADMA concentrations and,subsequently, in decreased endothelial NO production and endothelial dysfunction. Increased ADMA production and impairment of NO synthesis may provide a common mechanism whereby many of the proatherogenic factors contribute to clinically relevant cardiovascular risk. In patients with renal disease, ADMA accumulates because of impaired excretion and metabolism. However, ADMA provides risk information that is at least in part independent of renal function, since elevated ADMA levels have been reported to contribute to cardiovascular events and mortality even in patients with renal failure (Zoccali C et al. Lancet 2001; 358:2113-7; Tarnow L et al. Diabetes Care 2004; 27:765-9). Finally, ADMA levels may be useful to indicate a therapeutic response. In small clinical trials, ADMA levels were shown to decrease in response to treatment with angiotensin converting enzyme inhibitors, angiotensin receptor blockers, statins, antioxidants, or antidiabetic medications (Sydow K et al. Atheroscler Suppl 2003; 4:41-51). Table of Contents:
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