Advances in Diagnostic Imaging for Peripheral Arterial Disease

8/6/2019 Advances in Diagnostic Imaging for Peripheral Arterial Disease

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Authors and Disclosures

Gale L Tang1, Jason Chin2 and Melina R Kibbe2

1VA Puget Sound Health Care System, Division of Vascular Surgery, University of

Washington, Seattle, WA, USA

2Division of Vascular Surgery, Northwestern University Feinberg School of Medicine, 676

North St Clair St, Suite 650, Chicago, IL 60611, USA

Advances in Diagnostic Imaging for

Peripheral Arterial Disease

Gale L Tang; Jason Chin; Melina R Kibbe

Posted: 11/16/2010; Expert Rev Cardiovasc Ther. 2010;8(10):1447-1455. 2010 Expert

Reviews Ltd.

Abstract and Introduction

Abstract

Refinements in both noninvasive and invasive imaging techniques have led to

significant improvements in both the diagnosis and treatment of peripheral arterial

disease. Multiple complementary imaging modalities are available for evaluating these

patients. This article reviews the advantages, disadvantages and recent advances in

the commonly used clinical applications of duplex ultrasonography, magnetic

resonance angiography, computed tomographic angiography, digital subtraction

angiography and intravascular ultrasound for arterial imaging in the lower extremities. It

also discusses experimental imaging techniques more recently applied to peripheral

arterial disease such as PET, hyperspectral imaging and molecular imaging ofatherosclerosis. As more is understood about both lesion and patient characteristics

that affect their response to peripheral interventions, clinician selection of the various

imaging modalities as well as different peripheral interventions will allow for more

effective treatment of patients with peripheral arterial disease.

Introduction


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The treatment armamentarium for peripheral arterial disease (PAD) has significantly

changed over the last 20 years with the addition of endovascular therapies to

traditional open bypass procedures. Multiple different endovascular treatment

modalities exist, including balloon angioplasty, cryoplasty, stenting and atherectomy,

including laser, excisional and rotational devices. Preprocedure imaging is increasingly

used to assist in procedural planning, device selection and the determination ofwhether the patient should be treated with an endovascular, open or hybrid approach.

In addition, preprocedure imaging can frequently assist with the minimization of

contrast by allowing a focused endovascular intervention, as well as with the selection

of the safest vascular access site.

Several imaging modalities beyond traditional angiography are available for imaging

the peripheral arterial tree in patients with PAD. These imaging modalities have

evolved and have been refined over time, and have advantages, disadvantages and

contraindications in combination with various patient comorbidities. This article will

focus on the application of duplex ultrasonography, magnetic resonance angiography

(MRA), computed tomographic angiography (CTA), digital subtraction angiography(DSA) and intravascular ultrasound (IVUS) for imaging patients with PAD. The final

section covers some of the current research-based methods of imaging PAD, which

may in the future enter general clinical usage.

Noninvasive Imaging

Duplex Ultrasonography

Duplex ultrasonography has multiple advantages for the assessment of the peripheral

arterial tree. It is the least expensive modality, provides physiologic data in addition toimaging, and can easily be performed in the office as well as in the angiosuite or

operating room, especially with the newer, more portable machines now available. It is

completely noninvasive and does not require the use of potentially nephrotoxic contrast

agents. It has been used successfully as a screening tool to decrease the necessity for

contrast angiography[1] and may also be used as the single preprocedural imaging

modality prior to intervention in approximately 90% of patients (Figure 1).[2,3] The

sensitivity and specificity for the detection and determination of degree of stenosis of

PAD range between 70 and 90%.[4,5]


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monophasic spectral waveform. The calcification interrupts the color flow imaging of

the vessel lumen.

As with all ultrasound applications, this imaging modality requires an experienced

vascular technologist or vascular interventionalist to achieve accurate results. A low-

frequency transducer (23.5 mHz) is used for the proximal aortoiliac segment and ahigh-frequency transducer (510 mHz) is used for the lower extremity. A full

examination (infrarenal aorta to pedal arteries) can be time intensive at up to 2 h per

examination, although this may shortened to 2545 min in very experienced hands.[2]

The predictive value of duplex ultrasound for the tibial vessels is not as good as for the

aortoiliac or femoralpopliteal segments; however, patent tibial vessels are

occasionally visualized by arterial duplex but not by DSA, especially in patients with

critical limb ischemia and multilevel disease.[2,5] The pedal arteries may be visualized

using arterial duplex; however, their superficial course renders them easily compressed

by the transducer, which may affect flow velocities. In addition, it is difficult to assess

the entire pedal arch and the quality of the run-off within the foot.[6] Complex collateral

networks can also pose a challenge to the sonographer and make arterial identificationmore difficult. Arterial duplex may be useful for visualizing arterial wall characteristics

that make a target vessel suitable or not for distal bypass, as well as for determining

whether a plaque is a significant risk for distal embolization during an endovascular

intervention. Last, unlike imaging modalities that primarily detect the luminal size of the

artery (MRA and DSA), arterial duplex can accurately determine the actual arterial size,

including the identification of partially thrombosed peripheral aneurysms.

Bowel gas, leg edema, obesity, skin ulceration, vessel calcification and severe

ischemic pain may be limitations to obtaining an accurate arterial duplex examination.

Bowel gas limiting visualization of the aortoiliac segment can be combated by having

the patient present for the first morning examination after being nil per os after

midnight. Leg edema can sometimes be treated by in-hospital leg elevation with

adequate pain control prior to examination. Multiple projections and the use of SonoCT

(ATL, Philips, WA, USA) can be used to assess even severely calcified vessels.[2]

However, the combination of severe tibial calcification and extremely low-flow states

with peak systolic velocity less than 20 cm/s is most likely to render the examination

nondiagnostic.[2]

During intervention, arterial duplex may be used as a substitute for contrast

angiography to assess whether there has been adequate response to intervention by

demonstrating resolution of a peak systolic velocity ratio more than 2.5 (criteriafrequently used for a >50% stenosis). This may obviate the need for multiplanar

angiographic views and decrease the need for contrast. Arterial duplex can provide

objective evidence of whether a dissection in response to balloon angioplasty is flow

limiting or whether elastic recoil has left a hemodynamically significant stenosis,

thereby requiring placement of a stent. Arterial duplex is commonly used for

postintervention monitoring because of its reliability, repeatability, noninvasive nature

and low cost.


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Recent advances in ultrasound currently used in arterial duplex scanning include the

improved portability of machines, the use of color-flow and power Doppler to detect

patent but extremely low-flow distal vessels, and sonoCT for improved visual resolution

in B-mode imaging. Contrast-enhanced ultrasound has been demonstrated to improve

agreement between arterial duplex scanning and contrast angiography of the tibial

vessels.[7] However, ultrasound contrast agent availability remains extremely limited inthe USA, as there is no US FDA-approved agent. A newer advance involves 3D

ultrasound. The length and changing depth of the peripheral arterial tree may make this

difficult to apply for the entire arterial duplex examination, but it may be useful to

examine focal lesions. An experimental robotic system has been used in phantom

limbs, but clinical applications have not yet been reported.[8]

Computed Tomographic Angiography

The use of CTA for evaluation of the peripheral arterial tree has significantly advanced

with the advent of increased multidetector scanners. Previous fourth-generation and

16-detector scanners had adequate diagnostic accuracy compared with DSA, butproduced images that were significantly limited by calcification in the tibial arteries.

[9,10] These limitations have largely been overcome by the 64-detector scanner, with a

corresponding decrease in scan time, radiation exposure and contrast volume, and

increase in resolution. Current protocols for 64-detector scanners involve a scan time

of 1520 s, a radiation dose of approximately 5 mSev and a contrast volume of 80130

ml of iodinated contrast.[11,12] A delayed peripheral scan may be necessary to obtain

optimal contrast opacification within the tibial vessels, especially in patients with long-

segment upstream occlusions. Sensitivity and specificity to detect a greater than 50%

stenosis or occlusion using CTA are in the 9599% range.[11,12] LightSpeed Volume

CT (VCT; GE Healthcare, WI, USA) is an example of one of the latest innovations with

64-slice computed tomography technology, capturing images from head to toe in as

little as 10 s. VCT is able to provide wide anatomical detail combined with high-

resolution images (Figure 2). Given the speed of image acquisition, this technology will

be especially useful for sick patients who are not able to breath hold for very long, or

for critically ill trauma patients.


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images per examination) generated by MRA. It is important that the imaging volume be

specified to include all vessels of interest, otherwise extra-anatomic bypasses and the

pedal vessels may be accidentally excluded.[15]


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Figure 3. Maximum-intensity projection of a magnetic resonance angiogram

composited image of the peripheral arterial system from the abdomen to the feet

using bolus chase technique and acquired in three stations (abdomen/pelvis,

thigh and calf/foot). The patient has a right common and external iliac artery

occlusion, left external iliac and proximal common femoral artery occlusion, as well as

tibial artery disease. Despite multilevel disease, the tibial-level images are free ofvenous contamination and good run-off into the pedal vessels has been included in the

imaging field.

The major limitations to contrast-enhanced MRA remain cost, length of the examination

and inability of the patient to tolerate the examination. It is the most expensive of the

noninvasive modalities. Severely claustrophobic patients frequently cannot tolerate the

60 min examination even with premedication. Patients with pacemakers, automated

implantable cardioverterdefibrillators, certain types of stent grafts and brain aneurysm

clips are excluded from receiving the examination. In the newer, more powerful magnet

machines (3 T), the manufacturers recommend against studying patients with several

other types of intravascular stents (including some coronary stents). MRA is alsolimited in most centers to patients with glomerular filtration rates more than 3035

ml/min secondary to reports of nephrogenic systemic fibrosis developing in patients

with either end-stage renal disease or declining renal function exposed to gadolinium.

[16,17] The risk is likely greater with certain formulations of gadolinium,[17] although

newer ferrous-based contrast agents may eventually prevent this problem. Last,

metallic artifacts from prior intra-arterial stents preclude evaluation of the stented area.

[15] However, an area undergoing rapid evolution is the development of noncontrast

MRA techniques. Many techniques have been described, including phase contrast

imaging, velocity imaging and ECG-triggered flow-sensitive dephasing, to list a few. It

is clear that these newer techniques hold great promise for the future of MRA imaging,but are currently in the developmental or research phase.

Venous contamination of the tibial-level images can be a problem for MRA, especially

in patients with critical limb ischemia and diabetic foot ulcers.[18] Several newer

techniques can be used to reduce venous contamination and increase the diagnostic

utility of the tibial-level images in selected patients. Tibial images may be acquired first

with a separate contrast bolus; the timing bolus can be omitted using newer software

packages that use real-time bolus monitoring to determine the optimal imaging period

after contrast injection. Time-resolved imaging can be useful both to reduce venous

contamination, as well as to demonstrate whether there is a high-grade stenosis or an

occlusion with retrograde filling of the proximal vessel by collaterals. Time-resolvedimaging can also be used to obtain high-quality pedal vessel imaging.[6,19] Steady-

state MRA, which depends on newer gadolinium contrast agents that have prolonged

intravascular half-life, can also be added to tibial-level imaging to improve the

diagnostic quality.[20]

Newer machines feature higher magnet strength (3 T), which can improve spatial

resolution without requiring increased examination length. The field of view is generally


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smaller than with 1.5 T units; in taller patients, four imaging stations may be required

for the standard abdomen, pelvis and lower extremity run-off views.[21] Dedicated coil

systems for peripheral arterial imaging are available and also increase spatial

resolution.[22] Last, newer contrast agents are being developed that will also improve

distal imaging.[23]

Invasive Imaging

Digital Subtraction Angiography

Digital subtraction angiography remains the gold standard by which other imaging

modalities are compared. However, it is the most costly of imaging strategies, involves

iodinated contrast administration and radiation exposure, is invasive, and may result in

iatrogenic arterial injury[24] or systemic complication. In addition, many patients suffer

discomfort from laying on the flat, hard endotable for the duration of the procedure, or

the need to keep the access site straight for up to 6 h postprocedure. Early ambulation

(2 h postprocedure) may be possible if a vascular closure device is used; however,

some patients may not be candidates for these devices owing to inappropriate access

site location, antegrade access or significant calcification at the access site.[25,26] As

DSA primarily evaluates the arterial lumen, it may significantly underestimate the

presence of plaque in an artery that has undergone outward adaptive remodeling.

Furthermore, the presence of significant eccentric plaque may be undetected without

special views.[27] Poor technique and long segment occlusions may result in difficulty

viewing patent distal vessels, which may be appropriate for distal bypass for limb

salvage.

Carbon dioxide angiography frequently can be helpful in evaluating patients with renalinsufficiency to limit dye load during evaluation of aortoiliac segments down to the level

of the popliteal arteries. Faster frame rates and specialized equipment is required for

carbon dioxide angiography, which may not be available at all institutions. Detailed

tibial- and pedal-level imaging, especially in the face of long segment proximal

occlusions, generally require contrast.[28] Other strategies for limiting contrast dye and

study time include selective injections, omission of the diagnostic portion of the

examination in favor of a limited examination focused on the pathology identified on

preprocedure noninvasive imaging, and selective use of power injectors.

Additional adjuncts such as smaller sheaths, ultrasound-guided access, and the use of

preprocedure noninvasive imaging to select access site (e.g., brachial access to avoidheavily calcified femoral arteries) will likely decrease access site-related complications

such as hematoma, pseudoaneurysm, arteriovenous fistula, dissection and

embolization, and should be utilized frequently.

Intravascular Ultrasound


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There are limited data available regarding the utility of IVUS in peripheral arterial

interventions. It remains questionable whether long-term patency in the infrainguinal

arena can be improved by the use of IVUS during peripheral intervention to the point

where it justifies the additional time spent during the procedure by using another

imaging modality, as well as the US$6001000 additional expense for the IVUS

catheter.[29] Certainly, IVUS can more accurately determine the true arterial diameter,which assists in device size selection, as well as determine whether the stent has been

adequately deployed with good stentarterial wall apposition.[29] Like transcutaneous

arterial duplex, IVUS may be used to judge the efficacy of a peripheral intervention,

allowing minimization of contrast in patients with renal insufficiency. Owing to these

attributes, IVUS is becoming more commonly used during endovascular aneurysm

repair.[30]

Newer catheters utilizing a phased array microtransducer and automated pull-back

systems now allow for improved plaque characterization using 3D reconstruction,

virtual histology and color flow.[31] The automated pull-back system allows for

accurate determination of lesion length as well as 3D reconstruction of the plaquealong the artery. Virtual histology creates a color-coded map of the plaque based on

the intensity and frequency of returning signals, which differ depending on whether the

plaque is primarily fibrous, calcified, fibrofatty or has necrotic lipid core.[31] Heavily

calcified plaques and those with thin fibrous caps and associated ulceration may be

more prone to rupture and distal embolization during intervention. Knowledge of plaque

characteristics may prompt the selective use of distal embolic protection, as well as

direct more intensive medical therapy for those patients found to have unstable

atheromas.[32]

Color-flow IVUS detects differences between two sequential adjacent frames, at 30

frames/s, caused by the movement of echogenic blood particles through the artery.

Although a flow velocity cannot be quantified using this technique, a relative color scale

is used, with orange indicating higher velocity flow than red. This feature can be helpful

when performing interventions without contrast to determine if there is no residual flow-

limiting stenosis, which would cause an elevated velocity.[32]

Alternative Imaging Modalities

Positron Emission Tomography

Positron emission tomography is a recognized nuclear medicine technique foranalyzing nutrient flow and uptake in a variety of tissues, including the brain and heart.

Beyond this, studies have demonstrated its applicability in monitoring skeletal muscle

tissue and quantifying regional muscle blood flow, particularly in the lower extremities

of patients with PAD.[3335] Briefly, PET is a functional imaging modality wherein a

positron-emitting radionuclide is attached to a biologically active molecule such as

glucose or water. The molecule is then introduced into the body, and the system

detects the uptake of the biologically active molecule in imaged tissue via -rays


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released by the annihilation of emitted positrons. Currently, the most frequently used

radionuclides for assessing skeletal muscle tissue and regional blood flow in PAD are

fluorodeoxyglucose (FDG) and oxygen-15-water (H2 15O).

No trials have yet been conducted on PET specifically for diagnosis of PAD; however,

studies have returned positive results in its use for assessing the severity of PAD andtissue response to therapeutic interventions. FDG-PET can measure significant

differences in uptake between viable and nonviable skeletal muscle tissue in patients

with PAD.[33] Furthermore, FDG-PET has shown high rates of reproducibility in

measuring inflammation of atherosclerotic plaque lesions in carotid, iliac and femoral

arterial disease.[34] This suggests possible utility for PET in tracking changes in

disease severity over time and after therapy. Studies using H2 15O PET do not show

differences in blood flow determination between PAD patients and control patients at

rest; however, flow reserve (as calculated by the ratio of adenosine-induced changes in

blood flow to baseline flow) shows marked attenuation in PAD patients compared with

healthy controls.[35] PET showed greater resolution in measuring flow reserve than

standard thermodilution and plethysmography techniques.

Although PET is a well-studied imaging modality, diagnostic applications in PAD have

not been a priority for this technology. Most clinical examinations of PET in PAD

patients have focused on its possible use for assessing therapies aimed at increasing

flow and angiogenesis in arterial disease. Compared with currently available

technologies and clinical evaluation for the diagnosis and assessment of PAD, PET

also has significant economic costs associated with it. In the USA, PET studies that

may take up to 12 h are reimbursed by Medicare at a median amount of US$952.83.

[36] However, this may still be cost effective in patients strongly considered for surgery

or prolonged hospitalization.

Hyperspectral Imaging

Hyperspectral imaging, with regards to PAD, is a novel noninvasive technique that can

create a 2D anatomic oxygenation map of imaged tissue. The technology is a method

of scanning spectroscopy based on local chemical composition. A spectral separator is

used to admit varying wavelengths of light to generate a diffuse reflectance spectra for

an imaged object that is compared with standard transmission solutions to calculate

the relative concentrations of oxyhemoglobin and deoxyhemoglobin in each pixel.[37]

Currently available imagers have a pixel size of 0.1 0.1 mm. The wavelengths

admitted by the spectral separator are in the range of 500660 nm to includeoxyhemoglobin and deoxyhemoglobin absorption peaks. In this wavelength range, light

penetrates into the tissue to a depth of approximately 12 mm. Therefore, the

oxygenation information is predominantly from vessels in the subpapillary plexus.[38]

Despite the superficial nature of these oxygenation measurements, data have linked

decreased tissue perfusion measured by hyperspectral imaging with drug-induced

decreases in arterial blood flow analogous to the vascular dysfunction of PAD.[39]


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Unpublished clinical studies are underway to confirm differences in oxygenation

measured by hyperspectral imaging in patients with and without known PAD.

This imaging modality is still in its infancy for biomedical applications; however, as the

technology develops it could offer a number of advantages in the diagnostic imaging

and monitoring of PAD. Current imagers record only in the visible spectrum of light atan approximately 12-inch focal distance. This makes hyperspectral imaging completely

noninvasive and noncontact, and thus very well tolerated by patients, especially those

with painful ulcers secondary to vascular disease. In addition, the automated nature of

the imager makes this modality less vulnerable to the inaccuracies possibly associated

with more user-dependent technologies such as Doppler waveform analysis. Since

hyperspectral technology returns a 2D oxygenation map, useful local tissue perfusion

information can be acquired in addition to the more general information inferred about

PAD diagnosis as opposed to current point-measurement oximeters. Values of up to

86% sensitivity, 88% specificity and 96% positive-predictive value have been

demonstrated in studies for the use of hyperspectral imaging in predicting the healing

of diabetic foot ulcers after 6 months.[38,40] Other unpublished studies are also beingconducted regarding the value of hyperspectral technology in imaging PAD patients

perioperatively and for lower extremity amputation planning (Figure 4).


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Figure 4. Visual, integrated oxyhemoglobindeoxyhemoglobin, and

deoxyhemoglobin hyperspectral images of the plantar metatarsal angiosome for

a foot (A) without and (B) with peripheral arterial disease . The foot with PAD has

substantially decreased oxyhemoglobin and deoxyhemoglobin values throughout the

angiosome (see scale on the right of each image). Oxydeoxy: Oxyhemoglobin

deoxyhemoglobin; PAD: Peripheral arterial disease.

While hyperspectral imaging presents a potentially advantageous new modality that

could help streamline PAD diagnosis and care, further study is necessary. Published

data are relatively sparse compared with established diagnostic techniques such as the

anklebrachial index and Doppler waveform analysis. Furthermore, no large-scale

studies have been conducted thus far that have included substantial numbers of

patients with PAD, particularly those with PAD severe enough to require surgical


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All forms of diagnostic imaging for PAD have evolved and improved over the last few

years. Frequently, the most effective form of imaging is institutionally dependent. One

hospital may have excellent MRA, but inferior CTA, while at another the reverse may be

true. The vascular laboratory and technicians often vary in availability and technical

ability. Differences in generations of equipment, software and radiologic expertise create

these institutional differences. Vascular interventionalists need to be aware of their owninstitutional imaging capabilities, as well as work with the departments involved in

providing the imaging services to improve imaging for patients with PAD.

Five-year View

Spatial resolution will continue to improve with the addition of detectors to multidetector

CT scanners. Furthermore, the development of noncontrast imaging modalities such as

MRA will result in significant advances in vascular imaging by obviating the need for

potentially nephrotoxic or systemically toxic contrast agents. With an increasing

awareness of the hazards associated with cumulative radiation exposure to both the

patient and the clinician, improvements in radiation exposure are likely to be realized.

Cost limitations may drive future adoption of arterial duplex as the primary pre-, during

and postintervention imaging modality. Knowledge gained about how specific lesion

characteristics on preintervention imaging react to various endovascular treatment

modalities will improve the future effectiveness of endovascular therapy for PAD.

Advances in molecular imaging will allow interventions to be targeted to those patients

with vulnerable plaque, as well as determine which patients are more likely to progress

to critical limb ischemia.

Sidebar

Key Issues

Preintervention imaging by duplex ultrasonography, magnetic resonance angiography or

computed tomographic angiography should be part of the standard protocol for all

patients with peripheral arterial disease being considered for intervention.

Institutions differ on the availability and effectiveness of various imaging modalities;

vascular interventionalists need to be familiar with their own institutional capabilities in

order to most effectively apply diagnostic imaging to patients with peripheral arterial

disease.

Effective use of any imaging modality requires close coordination between the vascular

interventionalist and the radiology department or vascular laboratory providing theimaging modality.

Patient tolerance, characteristics (e.g., calcification, obesity or leg edema) and

comorbidities (especially renal insufficiency) will strongly influence which imaging

modality will be the most effective at imaging their arterial tree.

Research imaging modalities such as hyperspectral imaging, PET scanning and

molecular imaging may eventually enter the clinical arena, but will likely be more useful


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in assessing patient response to medical therapies directed against atherosclerosis

rather than for use in peripheral interventions.

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Acknowledgements

Duplex images were provided by Eugene Zierler, Director of the University of

Washington and Harborview Medical Center Vascular Laboratories. MRA images were

provided by Jeffrey Maki, Associate Professor of Radiology at the University of

Washington.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization

or entity with a financial interest in or financial conflict with the subject matter or

materials discussed in the manuscript. This includes employment, consultancies,

honoraria, stock ownership or options, expert testimony, grants or patents received or

pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Expert Rev Cardiovasc Ther. 2010;8(10):1447-1455. 2010 Expert Reviews Ltd.

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Advances in Diagnostic Imaging for Peripheral Arterial Disease