Elevated Levels of Asymmetric Dimethylarginine in Chronic Heart Failure: A Pathophysiologic Link Between Oxygen Radical Load and Impaired Vasodilator Capacity and the Therapeutic Effect of Allopurinol

Abstract

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide-dependent vasodilation. In 113 patients with chronic heart failure (CHF) and 26 controls, ADMA level was studied in relation to peripheral blood flow and vasodilator capacity. Further, the effects of allopurinol on concentrations of reactive oxygen species (ROS) and ADMA and peripheral vasodilator capacity were tested in a double-blind design. ADMA level was found to be elevated in CHF patients as compared with controls and increased in parallel with New York Heart Association (NYHA) class and exercise capacity (all P < 0.0001). The level of ADMA predicted resting blood flow (P < 0.05) and postischemic vasodilator capacity (P < 0.001). Sixty eight patients died during the follow-up period. The level of ADMA predicted survival after multivariable adjustment (P = 0.04). Allopurinol reduced uric acid (UA) concentration (P < 0.001) and decreased ROS concentration (allantoin, P < 0.01). Allopurinol lowered ADMA concentration (P = 0.02); postischemic vasodilation as well as endothelium-dependent vasodilation (both P < 0.05) improved. ADMA may be a pathophysiologic factor that is modulated by ROS accumulation and contributes to impaired vascular regulation in CHF.

Xanthine Oxidase and Uric Acid in Cardiovascular Disease: Clinical Impact and Therapeutic Options

“…[50][51][52] An indirect effect of allopurinol on regulation of vascular tone via interaction with asymmetric dimethylarginine has been observed. 53 In addition, multiple other pathophysiologic features in CVD were shown to be improved after XO inhibition (Table 1). From those proof-of-concept studies, further evidence has emerged that indeed XO activity rather than UA may be viewed as the true therapeutic target.…”

Nitric Oxide-Mediated Coronary Flow Regulation in Patients with Coronary Artery Disease: Recent Advances

“…46 The level of ADMA is suggested to predict survival in patients with chronic heart failure. 47 The plasma ADMA levels were higher in patients with typical exertional angina, positive exercise test, and normal coronary arteries diagnosed as cardiac syndrome X than in the control group, whereas plasma L-arginine levels were similar in both groups; patients with abnormal myocardial tissue perfusion had increased plasma ADMA levels compared with those with normal tissue perfusion. 48 In the patients with cardiac syndrome X, increased plasma ADMA levels may be associated with impaired myocardial tissue perfusion.…”

“…In patients with chronic heart failure, allopurinol lowered ROS and ADMA concentrations and improved postischemic vasodilatation and endothelium-dependent vasodilatation. 47 Recent studies by Noman et al 93 on patients with chronic stable angina showed that high-dose (600 mg/d) alloprinol increased the mean time to ST depression, median total exercise time, and the time to chest pain from the baseline. Alloprinol seems to be a useful, inexpensive, welltolerated, and safe anti-ischemic drug for patients with chronic stable angina.…”

Allopurinol, is the Next General Drug for Chronic Heart Failure? A Review Based on 19 Clinical Trials

“…Among the patients undergoing treatments with allopurinol, the levels of plasma Malondialdehyde (MDA), extracellular superoxide dismutase (ecSOD) activity, allantoin, appeared to significantly reduced [18,19,21]. Furthermore, biomarkers of adaptive heart remodeling, Matrix metalloproteinases (MMPs) and Tissue inhibitors of metalloproteinases (TIMMPs), were evaluated without notable changes [15,18].…”

“…Completely different from above, endothelial function improvement benefited from allopurinol attracted great attention to itself, that 9 clinical trials chose it as an end-point was an evidence [11,14,16,18,[19][20][21][22]. Among these studies, endothelial function was directly evaluated by Forearm blood flow (FBF) or Flow-mediated dilation (FMD).…”