The role of asymmetric dimethylarginine and arginine in the failing heart and its vasculature

Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands.
European Journal of Heart Failure (Impact Factor: 6.53). 10/2010; 12(12):1274-81. DOI: 10.1093/eurjhf/hfq158
Source: PubMed


Nitric oxide (NO) is formed from arginine by the enzyme nitric oxide synthase (NOS). Asymmetric dimethylarginine (ADMA) can inhibit NO production by competing with arginine for NOS binding. Therefore, the net amount of NO might be indicated by the arginine/ADMA ratio. In turn, arginine can be metabolized by the enzyme arginase, and ADMA by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). While ADMA has been implicated as a cardiovascular risk factor, arginine supplementation has been indicated as a treatment in cardiac diseases. This review discusses the roles of ADMA and arginine in the failing heart and its vasculature. Furthermore, it proposes nutritional therapies to improve NO availability.

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    • "NO, produced by the oxidation of L-arginine (Arg) by NO synthase (NOS), promotes many beneficial effects in the vasculature , including vasodilatation, enhanced fibrinolysis and inhibition of multiple atherothrombotic processes such as platelet aggregation, leucocyte adhesion and smooth muscle cell proliferation . Some authors have proposed oxidative stress and NO pathway derangements as potential determinants of postoperative adverse events such as cardiopulmonary bypass (CPB)-related complications [1] and vein graft failure [2] or atrial fibrillation [3], since they play a significant role in cardiovascular diseases such as atherosclerosis, coronary artery disease, diabetes and heart failure [4] [5]. "
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    ABSTRACT: We investigated whether oxidative stress and the arginine/nitric oxide pathway differ in control subjects and in adult patients who are candidates for the three most common cardiac surgical operations: coronary bypass surgery, aortic valve replacement for calcific non-rheumatic aortic stenosis or mitral valve repair for degenerative mitral insufficiency. In this prospective observational study, we studied 165 consecutive patients undergoing surgery from January to June 2011 (coronary bypass surgery, n = 63; aortic valve replacement for calcific non-rheumatic aortic stenosis, n = 51; mitral valve repair for degenerative mitral insufficiency, n = 51). Thirty-three healthy subjects with cardiovascular risk factors similar to surgery patients were also studied (Controls). Oxidative stress (the ratio of reduced and oxidized glutathione and urinary isoprostane), antioxidants (alpha- and gamma tocopherol) and factors involved in nitric oxide synthesis (arginine, symmetric and asymmetric dimethylarginine) were measured before surgery. Analysis of variance general linear models and principal component analysis were used for statistical analysis. Surgical patients had increased levels of oxidative stress and decreased levels of antioxidants. Increased levels of nitric oxide inhibitor asymmetric dimethylarginine were detected in surgical candidates, suggesting arginine/nitric oxide pathway impairment. Concerning the differences among surgical procedures, higher oxidative stress and a major imbalance of the ratio between substrate and inhibitors of nitric oxide synthesis were evidenced in patients who were candidates for mitral valve repair with respect to coronary bypass surgery patients and patients with calcific non-rheumatic aortic stenosis. Patients undergoing cardiac surgery have increased oxidative stress and a trend towards an impaired arginine/nitric oxide pathway with respect to Controls. Patients affected by mitral valve regurgitation show more pronounced perturbations in these pathways. The clinical implications of these findings need to be investigated.
    Interactive Cardiovascular and Thoracic Surgery 09/2013; 17(6). DOI:10.1093/icvts/ivt386 · 1.16 Impact Factor
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    • "Nitric oxide is formed from the amino acid arginine by the enzyme nitric oxide synthase (NOS) [12]. ADMA is the most potent endogenous nitric oxide synthase (NOS) inhibitor [21], [22] and acts by competing with arginine for NOS binding [12]. "
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    ABSTRACT: Chronic heart failure is an important cause for morbidity and mortality in adults with congenital heart disease (ACHD). While NT-proBNP is an established biomarker for heart failure of non-congenital origin, its value in ACHD has limitations. Asymmetrical dimethylarginine (ADMA) correlates with disease severity and independently predicts adverse clinical events in heart failure of non-congenital origin. Its role in ACHD has not been investigated. In 102 patients ADMA and NT-proBNP were measured and related to NYHA class, systemic ventricular function and parameters of cardiopulmonary exercise testing. In contrast to NT-proBNP ADMA differentiated between NYHA classes I-III. Both, ADMA and NT-proBNP showed a good correlation with parameters of cardiopulmonary exercise testing with comparable receiver-operating characteristic curves for identifying patients with severely limited cardiopulmonary exercise capacity. ADMA seems to be a better biomarker than NT-proBNP for the assessment of NYHA class and as a good as NT-proBNP for the estimation of maximum exercise capacity in adults with congenital heart disease. Its use in clinical routine should be evaluated.
    PLoS ONE 03/2012; 7(3):e33795. DOI:10.1371/journal.pone.0033795 · 3.23 Impact Factor
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    • "However, the actions of NO can be disturbed by elevated levels of the NO synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), a condition reported in patients with failing hearts [7]. Moreover, ADMA has been indicated as marker of circulatory function and as predictor of outcome in patients with cardiac dysfunction [7,8]. As NO availability might be reflected by the ratio between substrate (arginine) and inhibitor (ADMA), the negative effects of ADMA might be relieved by supplementation of arginine. "
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    ABSTRACT: Background Malnutrition is very common in patients undergoing cardiac surgery. Malnutrition can change myocardial substrate utilization which can induce adverse effects on myocardial metabolism and function. We aim to investigate the hypothesis that there is a disturbed amino acids profile in the cardiac surgical patient which can be normalized by (par)enteral nutrition before, during and after surgery, subsequently improving cardiomyocyte structure, cardiac perfusion and glucose metabolism. Methods/Design This randomized controlled intervention study investigates the effect of uninterrupted perioperative (par)enteral nutrition on cardiac function in 48 patients undergoing coronary artery bypass grafting. Patients are given enteral nutrition (n = 16) or parenteral nutrition (n = 16), at least two days before, during, and two days after coronary artery bypass grafting, or are treated according to the standard guidelines (control) (n = 16). We will illustrate the effect of (par)enteral nutrition on differences in concentrations of amino acids and asymmetric dimethylarginine and in activity of dimethylarginine dimethylaminohydrolase and arginase in cardiac tissue and blood plasma. In addition, cardiomyocyte structure by histological, immuno-histochemical and ultrastructural analysis will be compared between the (par)enteral and control group. Furthermore, differences in cardiac perfusion and global left ventricular function and glucose metabolism, and their changes after coronary artery bypass grafting are evaluated by electrocardiography-gated myocardial perfusion scintigraphy and 18F-fluorodeoxy-glucose positron emission tomography respectively. Finally, fat free mass is measured before and after intervention with bioelectrical impedance spectrometry in order to evaluate nutritional status. Trial registration Netherlands Trial Register (NTR): NTR2183
    Journal of Cardiothoracic Surgery 03/2011; 6(1):36. DOI:10.1186/1749-8090-6-36 · 1.03 Impact Factor
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