J Vasc Surg. 2017 Mar 30. pii: S0741-5214(17)30194-5. doi: 10.1016/j.jvs.2016.12.127. [Epub ahead of print]
The LargPAD Trial: Phase IIA evaluation of l-arginine infusion in patients with peripheral arterial disease. Kashyap VS1, Lakin RO2, Campos P2, Allemang M2, Kim A2, Sarac TP3, Hausladen A4, Stamler JS4. Author information 1Division of Vascular Surgery and Endovascular Therapy, University Hospitals Case Medical Center, Cleveland, Ohio. Electronic address: firstname.lastname@example.orgDivision of Vascular Surgery and Endovascular Therapy, University Hospitals Case Medical Center, Cleveland, Ohio.3Divison of Vascular Surgery, Yale School of Medicine, New Haven, Conn.4Institute for Transformative Molecular Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio. Abstract
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 ± 1.3 mm3/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 dysfunction (ie, acute limb ischemia) are warranted.