Abstract 3749: Plasma Asymmetric Dimethylarginine (ADMA) is Elevated in CHF: Endogenous NO-Inhibition Relates to Clinical Status and to Impaired Vasodilator Capacity.
Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, has been shown to impair in a dose-dependent relationship the regulation of NO mediated vasodilator capacity. Endothelial dysfunction, impaired peripheral blood flow and vasodilator capacity are characteristic findings in chronic heart failure (CHF). The significance of ADMA in CHF in relation to clinical characteristics and to peripheral hemodynamic parameters has not been studied in detail. In 113 stable CHF patients (age 63±12y [mean±SD], NYHA 2.3±0.9, ischemic etiology 66%; peak VO2 18.7±6.2 mL/kg/min) in comparison to healthy controls (n=26) of similar age, ADMA, symmetric dimethylarginine (SDMA), and arginine were assessed by HPLC-mass spectrometry. Forearm resting and postischemic peak blood flow (BF) - an estimate of vasodilator capacity- were measured by occlusion plethysmography (n=83). ADMA was elevated in CHF patients compared to controls (588±91 vs 510±63 nmol/L, p<0.0001), SDMA was also elevated in CHF (855±331 vs 641 ±283 nmol/L; p<0.01) but Arginine was not different (p>0.2). ADMA elevation in CHF occurred independently of etiology (ischemic vs non-ischemic: 595±90 vs 572±92 nmol/L, p=0.18) and increased stepwise in parallel to NYHA class (I:525±54, II:583±90, III:600±92, IV:640±93 nmol/L; ANOVA p<0.0001). In univariate regression analysis, ADMA predicted resting BF (r=0.23, p<0.05) and peak BF (r=0.37, p>0.001). ADMA was further related to age (r=0.25, p<0.01), peak VO2 (r=0.40, p<0.0001), symptom-limited exercise time (r= 0.29), uric acid (r=0.33, both p<0.01), creatinine (r=0.2), and mean blood pressure (r=0.19, both p<0.05), but was not related to body mass index and LVEF. In multivariate regression analysis, ADMA predicted peak BF independently of age, renal function and peak VO2 (r=0.5, p<0.001).
Conclusion: ADMA plasma levels are abnormally elevated in CHF patients. This elevation occurs independently of etiology and in parallel to severity of CHF. ADMA -potentially via NO dependent regulation -predicts peripheral blood flow and vasodilator capacity in CHF, independently of age, renal and cardiovascular function. ADMA may therefore be a mediator of peripheral hemodynamic characteristics within CHF pathophysiology.