Peripheral arterial disease (PAD) is associated with major cardiovascular morbidity and mortality. Abnormalities in nitric oxide metabolism due to excess of the NO synthase inhibitor asymmetric dimethylarginine (ADMA) may be pathogenic in PAD. We explored the association between ADMA levels and markers of atherosclerosis, function, and prognosis.
Methods and Results
133 patients with symptomatic PAD were enrolled. Ankle brachial index (ABI), walking time, vascular function measures (arterial compliance and flow-mediated vasodilatation) and plasma ADMA level were assessed for each patient at baseline. ADMA correlated inversely with ABI (r = −0.238, p=0.003) and walking time (r = −0.255, p = 0.001), independent of other vascular risk factors. We followed up 125 (94%) of our 133 initial subjects with baseline measurements (mean 35 months). Subjects with ADMA levels in the highest quartile (>0.84 μmol/L) showed significantly greater occurrence of MACE compared to those with ADMA levels in the lower 3 quartiles (p = 0.001). Cox proportional-hazards regression analysis revealed that ADMA was a significant predictor of MACE, independent of other risk factors including age, gender, blood pressure, smoking history, diabetes and ABI (Hazard ratio = 5.1, p<0.001). Measures of vascular function, such as compliance, FMVD and blood pressure, as well as markers of PAD severity, including ABI and walking time, were not predictive.
Circulating levels of ADMA correlate independently with measures of disease severity and major adverse cardiovascular events. Agents that target this pathway may be useful for this patient population.