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.

Trial registration: ClinicalTrials.gov NCT00848302.

Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Figures

Figure 1

Lower extremity angiogram performed with a IVUS catheter and 0.014” Doppler flow wire. Note that the IVUS probe is at approximately marker 200 and the wire sensor is beyond marker 240.

Figure 2

a. B-mode IVUS image of an artery, depicting the three layers of the arterial wall; b. Border Analysis documenting luminal (light blue) and medial-adventitial (dark blue) borders; c. Virtual Histology is performed using a modified coronary artery algorithm classified by color indicating calcium (white), necrosis (red), and fibrous (green) plaque components

Figure 2

a. B-mode IVUS image of an artery, depicting the three layers of the arterial wall; b. Border Analysis documenting luminal (light blue) and medial-adventitial (dark blue) borders; c. Virtual Histology is performed using a modified coronary artery algorithm classified by color indicating calcium (white), necrosis (red), and fibrous (green) plaque components

Figure 2

a. B-mode IVUS image of an artery, depicting the three layers of the arterial wall; b. Border Analysis documenting luminal (light blue) and medial-adventitial (dark blue) borders; c. Virtual Histology is performed using a modified coronary artery algorithm classified by color indicating calcium (white), necrosis (red), and fibrous (green) plaque components

Figure 3

Average Peak Velocity showed statistically significant increases of 26, 46, and 63% in response to incremental doses of Ach. (P = .0012 by ANOVA)

Figure 4

Percentage change in Limb Volumetric Flow showed statistically significant increases in response to incremental doses of Ach. (P = .0014 by ANOVA)

Figure 5

Lower extremity NOx levels were slightly lower than systemic venous levels (P = .0395).