title: The LargPAD Trial: Phase IIA evaluation of l-arginine infusion in patients with peripheral arterial disease.
abstract: 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.
  
  
  
  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 (10-6to 10-4molar 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Vascular Surgery and Endovascular Therapy, University Hospitals Case Medical Center, Cleveland, Ohio. Electronic address: vikram.kashyap@uhhospitals.org.
authors.forename: Vikram S
authors.initials: VS
authors.lastname: Kashyap
authors.affiliation: Division of Vascular Surgery and Endovascular Therapy, University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Ryan O
authors.initials: RO
authors.lastname: Lakin
authors.affiliation: Division of Vascular Surgery and Endovascular Therapy, University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Patricia
authors.initials: P
authors.lastname: Campos
authors.affiliation: Division of Vascular Surgery and Endovascular Therapy, University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Matthew
authors.initials: M
authors.lastname: Allemang
authors.affiliation: Division of Vascular Surgery and Endovascular Therapy, University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Ann
authors.initials: A
authors.lastname: Kim
authors.affiliation: Divison of Vascular Surgery, Yale School of Medicine, New Haven, Conn.
authors.forename: Timur P
authors.initials: TP
authors.lastname: Sarac
authors.affiliation: Institute for Transformative Molecular Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Alfred
authors.initials: A
authors.lastname: Hausladen
authors.affiliation: Institute for Transformative Molecular Medicine, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Stamler
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage; D000792:Angiography; D001120:Arginine / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D005263:Femoral Artery / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D007261:Infusions, Intra-Arterial; D007511:Ischemia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D035002:Lower Extremity / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D009589:Nitrogen Oxides / Q000097:blood; D005996:Nitroglycerin / Q000008:administration & dosage; D009820:Ohio; D009952:Ornithine / Q000097:blood; D058729:Peripheral Arterial Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D058226:Plaque, Atherosclerotic; D011446:Prospective Studies; D012039:Regional Blood Flow; D013997:Time Factors; D016896:Treatment Outcome; D018616:Ultrasonography, Doppler, Duplex; D018084:Ultrasonography, Interventional; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood
chemical_list: D009589:Nitrogen Oxides; D014665:Vasodilator Agents; D001120:Arginine; D009952:Ornithine; D005996:Nitroglycerin; D000109:Acetylcholine