Background-L-Arginine is the precursor of endothelium-derived nitric oxide, an endogenous vasodilator. L-Arginine supplementation improves vascular reactivity and functional capacity in peripheral arterial disease (PAD) in small, short-term studies. We aimed to determine the effects of long-term administration of L-arginine on vascular reactivity and functional capacity in patients with PAD. Methods and Results-The Nitric Oxide in Peripheral Arterial Insufficiency (NO-PAIN) study was a randomized clinical trial of oral L-arginine (3 g/d) versus placebo for 6 months in 133 subjects with intermittent claudication due to PAD in a single-center setting. The primary end point was the change at 6 months in the absolute claudication distance as assessed by the Skinner-Gardner treadmill protocol. L-Arginine supplementation significantly increased plasma L-arginine levels. However, measures of nitric oxide availability (including flow-mediated vasodilation, vascular compliance, plasma and urinary nitrogen oxides, and plasma citrulline formation) were reduced or not improved compared with placebo. Although absolute claudication distance improved in both L-arginine-and placebo-treated patients, the improvement in the L-arginine-treated group was significantly less than that in the placebo group (28.3% versus 11.5%; Pϭ0.024). Conclusions-In patients with PAD, long-term administration of L-arginine does not increase nitric oxide synthesis or improve vascular reactivity. Furthermore, the expected placebo effect observed in studies of functional capacity was attenuated in the L-arginine-treated group. As opposed to its short-term administration, long-term administration of L-arginine is not useful in patients with intermittent claudication and PAD.

Background-Peripheral arterial disease (PAD) is common but commonly unrecognized. Improved recognition of PAD is needed. We used high-throughput proteomic profiling to find PAD-associated biomarkers. Methods and Results-Plasma was collected from PAD patients (ankle brachial index of Ͻ0.90; nϭ45) and subjects with risk factors but without PAD (nϭ43). Plasma was analyzed with surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to quantify 1619 protein peaks. The peak intensity of a 12-kDa protein was higher in PAD patients. Western blot analyses and immunoaffinity studies confirmed that this protein was ␤2-microglobulin (B2M). In a validation study, B2M was measured by ELISA in plasma in age-and gender-matched PAD (nϭ20) and non-PAD (nϭ20) subjects. Finally, we studied a larger cohort of subjects (nϭ237) referred for coronary angiography but without known PAD. Plasma B2M levels were higher in PAD patients than in non-PAD patients with coronary artery disease. Plasma B2M correlated with ankle brachial index and functional capacity. Independent predictors of PAD were diabetes mellitus, age, and the combination of B2M and C-reactive protein level. Conclusions-In PAD patients, circulating B2M is elevated and correlates with the severity of disease independent of other risk factors. These findings might provide a needed biomarker for PAD and new insight into its pathophysiology. Further studies in other populations are needed to confirm the utility of measuring B2M in cardiovascular disease risk assessment.

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improvements in ankle pressures, CBF, and symptoms. 5 Moreover, the approach toward development of novel treatments, such as therapeutic angiogenesis, is Abstract: To the practicing clinician, it seems obvious that limb hemodynamics would be the primary determinant of walking distance. However, other determinants, such as skeletal muscle metabolism, may play a role. Accordingly, in the current study, we examined the relationship between measures of limb hemodynamics and walking capacity in patients with peripheral arterial disease (PAD). We measured toe and ankle pressures for calculation of toe-(TBI) and ankle (ABI)-brachial indices; basal and hyperemic calf blood flow (CBF; by plethysmography); and initial (ICT) and absolute (ACT) claudication time using the Skinner-Gardner protocol. As expected, PAD patients had impaired limb hemodynamics with reduced TBI, ABI and a reduction in ABI post-exercise. However, there was no relationship between any of the hemodynamic variables (including ABI, ABI reduction post-exercise, TBI, baseline or maximal CBF) and walking distance as assessed by ICT or ACT. A subset of PAD patients with an ACT Ͼ750 s (n ϭ 16; 'long claudicators') were compared with a subset of PAD patients with an ACT Ͻ260 s (n ϭ 16; 'short claudicators'). The average ACT in the long claudicants was over fivefold greater than the short claudicators. Surprisingly, there were no differences between the two groups in any of the hemodynamic variables. There was also no relationship between the initial ABI, TBI, toe pressure, baseline or hyperemic CBF, and the improvement in ACT over the 3-month course of the study. This study found little relationship between hemodynamic variables and functional capacity in PAD. Accordingly, to assess the response to therapeutic interventions, exercise performance and functional status need to be directly measured, and cannot be predicted from hemodynamic measurements.