In vivo assessment of endothelial function in human lower extremity arteries.

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.

Evaluation of peripheral atherosclerosis: a comparative analysis of angiography and intravascular ultrasound imaging.

OBJECTIVE: Angiography remains a critical component for diagnostic imaging and therapeutic intervention in peripheral arterial disease (PAD). The goal of this study was to compare angiography with corresponding intravascular ultrasound (IVUS) imaging of the same vessels in patients with PAD. METHODS: From 2004 to 2008, 93 patients undergoing angiography for PAD were recruited in a prospective observational analysis. At the time of angiography, diseased lower extremities were interrogated using a 10-cm IVUS pullback with registration points. IVUS data were analyzed with radiofrequency techniques for vessel and lumen diameter, plaque volume, plaque composition, and cross-sectional area. Similarly, three vascular surgeons blinded to the IVUS data graded corresponding angiographic images according to vessel diameter, degree of stenosis, degree of calcification, and extent of eccentricity. Statistical analyses of matched IVUS images and angiograms were performed. RESULTS: The distribution of demographic and risk variables were typical for PAD: 54% male, 96% hypertension, 78% hyperlipidemia, 44% diabetic, 87% tobacco history, 65% coronary artery disease, and 10% end-stage renal disease. Symptoms precipitating the angiographic evaluation included claudication (53%), rest pain (18%), and tissue loss (29%). Angiographic and IVUS interpretation were similar for luminal diameters, but external vessel diameter was greater by IVUS imaging (7.0 +/- 0.7 vs 5.2 +/- 0.8 mm, P < .05). The two-dimensional diameter method resulted in a significant correlation for stenosis determination (r = 0.84); however, IVUS determination of vessel area stenosis was greater by 10% (95% confidence interval, 0.3%-21%, P < .05). IVUS imaging indicated that a higher proportion of plaques were concentric. Grading of calcification was moderate to severe in 40% by angiography but in only 7% by IVUS (P < .05). CONCLUSIONS: In the evaluation of PAD, angiography and IVUS imaging provide similar luminal diameters and diameter-reducing stenosis measurements. Determination of overall vessel diameter and interpretation of plaque morphology by angiography are discordant from IVUS-derived data.

Arterial calcification increases in distal arteries in patients with peripheral arterial disease.

The aim of this study was to determine if significant differences in plaque composition exist between the popliteal and tibial vessels in patients with severe peripheral arterial disease (PAD). Forty-four patients with PAD required either above-knee (n = 38), below-knee (n = 5), or through-knee (n = 1) amputation for pedal sepsis/gangrene. The 51 vessels (anterior tibial, n = 9; posterior tibial, n = 10; peroneal, n = 3; popliteal, n = 29) were obtained and underwent intravascular ultrasound (IVUS) evaluation ex vivo within 24 hr of amputation. Sequential IVUS data were obtained at known intervals throughout the vessel length and then analyzed with radiofrequency techniques for quantification of plaque composition, plaque volume, and total vessel volume. Plaque composition was categorized as fibrous, fibro-fatty, necrotic core, and dense calcium. Clinical data were obtained via review of electronic records at the time of amputation. Two-sided t-tests were performed to compare components within each plaque. Results are expressed as mean percentage +/- standard error of the mean. Tibial vessels had more dense calcium within these plaques than popliteal arteries (33.8 +/- 5.6% vs. 10.6 +/- 1.9%, p < 0.001). Consequently, distal vessels had less fibro-fatty and fibrous plaque than popliteal arteries (7.7 +/- 1.4% vs. 13.1 +/- 1.2%, p < 0.005; 42.4 +/- 4.7% vs. 61.4 +/- 2.2%, p < 0.001, respectively). Necrotic core plaque composition was found to be similar when comparing tibial versus popliteal arteries (16.1% vs. 14.9%, p = nonsignificant). Clinical factors including diabetes, hyperlipidemia, and chronic renal insufficiency were not associated with plaque composition differences using a univariate analysis. As we progress distally in the arterial tree of patients with PAD, calcium plaque content increases with decreasing burden of fibro-fatty plaque. Clinical and demographic factors, with the exception of smoking, were not found to be associated with atherosclerotic plaque composition.