title: In vivo assessment of endothelial function in human lower extremity arteries.
abstract: OBJECTIVE
  Endothelial function has been measured in preclinical studies in human brachial and coronary arteries but not in lower extremity arteries affected by atherosclerosis. We describe a novel, first-in-man evaluation of endothelial function of the superficial femoral arteries (SFAs) in patients with peripheral arterial disease (PAD).
  
  
  METHODS
  Enrolled were 25 patients with PAD requiring lower extremity angiography. Endothelial-dependent relaxation was measured using intravascular ultrasound (IVUS) imaging and a Doppler flow wire after the infusion of acetylcholine (Ach). IVUS-derived virtual histology of the same vessel was calculated. Endothelial-independent relaxation was measured with an infusion of nitroglycerin (200 μg). Levels of nitric oxide and serum nitric oxide metabolites were determined by laboratory analysis.
  
  
  RESULTS
  Patients (48% male; mean age, 62 years) had a history of hypertension (80%), coronary disease (36%), and diabetes (40%). The mean SFA diameter was 5.2 ± 1 mm (range, 3.2-6.9 mm). Patients tolerated Ach infusion with no adverse events. Endothelial-dependent relaxation increased over baseline for all patients with Ach infusion of 10(-6) to 10(-4). At Ach 10(-4), diameter (0.5%) and area (1.8%) changes in the diseased SFAs were modest and insignificant; however, average peak velocity of blood flow significantly increased 26%, 46%, and 63% with an Ach 10(-6) to 10(-4) infusion. Calculations of limb volumetric flow (68% at Ach 10(-4)) were significantly increased after Ach infusion. Lower extremity nitric oxide levels were slightly lower than systemic venous levels (P = .04). Nitroglycerin infusion indicated normal smooth muscle responsiveness (3% diameter, 9% area, and 116% velocity change over baseline). IVUS-virtual histology plaque stratification indicated predominantly fibrous morphology (46%; necrotic core, 29%; calcium, 18%). Atheroma burden was 14.9 ± 5.5 mm(3)/cm and did not correlate with endothelial responsiveness.
  
  
  CONCLUSIONS
  Endothelial function can be measured directly in human lower extremity arteries at the sites of vascular disease. Despite extensive atherosclerosis, endothelial function is still intact. These data support the application of regional endothelial-specific biologic therapies in patients with PAD.
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.forename: Ryan O
authors.initials: RO
authors.lastname: Lakin
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Feiten
authors.forename: Paul D
authors.initials: PD
authors.lastname: Bishop
authors.forename: Timur P
authors.initials: TP
authors.lastname: Sarac
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage; D000368:Aged; D015415:Biomarkers / Q000097:blood; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000503:physiopathology; D057510:Endovascular Procedures; D005260:Female; D005263:Femoral Artery / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics; D006801:Humans; D007261:Infusions, Intra-Arterial; D035002:Lower Extremity / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood; D005996:Nitroglycerin / Q000008:administration & dosage; D058729:Peripheral Arterial Disease / Q000097:blood / Q000000981:diagnostic imaging* / Q000503:physiopathology / Q000628:therapy; D011237:Predictive Value of Tests; D011379:Prognosis; D011859:Radiography; D012039:Regional Blood Flow; D018608:Ultrasonography, Doppler; D018084:Ultrasonography, Interventional; D014664:Vasodilation; D014665:Vasodilator Agents
chemical_list: D015415:Biomarkers; D014665:Vasodilator Agents; D009569:Nitric Oxide; D005996:Nitroglycerin; D000109:Acetylcholine