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Objective: Endothelial function is improved by L-arginine (L-arg) supplementation in preclinical and clinical studies of mildly diseased vasculature; however, endothelial function and responsiveness to L-arg in severely diseased arteries is not known. Our objective was to evaluate the acute effects of catheter-directed L-arg delivery in patients with chronic lower extremity ischemia secondary to peripheral arterial disease. Methods: The study enrolled 22 patients (45% male) with peripheral arterial disease (mean age, 62 years) requiring lower extremity angiography. Endothelium-dependent relaxation of patent but atherosclerotic superficial femoral arteries was measured using a combination of intravascular ultrasound (IVUS) imaging and a Doppler FloWire (Volcano Corporation, Rancho Cordova, Calif) during the infusion of incremental acetylcholine (10(-6) to 10(-4) molar concentration) doses. Patients received 50 mg (n = 3), 100 mg (n = 10), or 500 mg (n = 9) L-arg intra-arterially, followed by repeat endothelium-dependent relaxation measurement (limb volumetric flow). IVUS-derived virtual histology of the culprit vessel was also obtained. Endothelium-independent relaxation was measured using a nitroglycerin infusion. Levels of nitrogen oxides and arginine metabolites were measured by chemiluminescence and mass spectrometry, respectively. Results: Patients tolerated limb L-arg infusion well. Serum arginine and ornithine levels increased by 43.6% +/- 13.0% and 23.2% +/- 10.3%, respectively (P <.005), and serum nitrogen oxides increased by 85% (P <.0001) after L-arg infusion. Average vessel area increased by 6.8% +/- 1.3% with L-arg infusion (acetylcholine 10(-4); P <.0001). Limb volumetric flow increased in all patients and was greater with L-arg supplementation by 130.9 +/- 17.6, 136.9 +/- 18.6, and 172.1 +/- 24.8 mL/min, respectively, for each cohort. Maximal effects were seen with L-arg at 100 mg (32.8%). Arterial smooth muscle responsiveness to nitroglycerin was intact in all vessels (endothelium-independent relaxation, 137% +/- 28% volume flow increase). IVUS-derived virtual histology indicated plaque volume was 14 +/- 1.3mm(3)/cm, and plaque stratification revealed a predominantly fibrous morphology (46.4%; necrotic core, 28.4%; calcium, 17.4%; fibrolipid, 6.6%). Plaque morphology did not correlate with L-arg responsiveness. Conclusions: Despite extensive atherosclerosis, endothelial function in diseased lower extremity human arteries can be enhanced by L-arg infusion secondary to increased nitric oxide bioactivity. Further studies of L-arg as a therapeutic modality in patients with endothelial dysie, acute limb ischemia) are warranted.
- 出版日期2017-7
