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Advanced vascular imaging for lower extremity peripheral artery disease

Advanced vascular imaging for lower extremity peripheral artery disease
Literature review current through: Jan 2024.
This topic last updated: May 06, 2022.

INTRODUCTION — Vascular imaging confirms a diagnosis of peripheral artery disease (PAD), assesses the severity and extent of disease, and is also used to plan and guide revascularization (open surgical or endovascular).

The increasing prevalence of chronic limb-threatening ischemia (CLTI) is fueling the concomitant need for vascular imaging for accurately diagnosing and providing treatment [1]. Each imaging study has inherent benefits and risks that need to be understood to optimize patient outcomes.

The benefits, risks, and imaging advances in duplex ultrasound, intravascular ultrasound, computed tomographic (CT) angiography, magnetic resonance (MR) angiography, and digital subtraction angiography are reviewed. In addition, functional imaging, such as positron emission tomography (PET), single-photon emission CT, and perfusion studies are also reviewed as they relate to the evaluation and treatment of PAD, predominantly CLTI.

The classification, clinical features, and management of PAD are reviewed separately. (See "Overview of lower extremity peripheral artery disease" and "Clinical features and diagnosis of lower extremity peripheral artery disease" and "Management of claudication due to peripheral artery disease" and "Management of chronic limb-threatening ischemia".)

BASIC PRINCIPLES OF VASCULAR IMAGING — The incidence and prevalence of PAD have increased, particularly among those suffering from chronic limb-threatening ischemia (CLTI) [2]. PAD is present in approximately 10 percent of the United States population, with an annual incidence of 2.4 percent [3]. CLTI (ischemic rest pain, tissue loss) affects approximately 11 percent of patients with PAD, with an annual incidence between 0.2 and 0.4 percent [3,4] and a prevalence of 1.3 percent [3]. Fueling the increase in PAD is the increasing proportion of individuals over 60 years of age in the United States (over 20 percent of the population in 2020) [5]. The prevalence of PAD is increased twofold among patients with diabetes mellitus when compared with similarly aged Americans without diabetes [6]. This is particularly significant, given that diabetes affects between 9 to 10 percent of American adults [7]. (See "Epidemiology, risk factors, and natural history of lower extremity peripheral artery disease".)

Initial diagnostic studies — The diagnosis of PAD can be established with clinical evaluation that includes noninvasive pressure assessments and vascular ultrasound. Each is noninvasive and not associated with toxicities or other significant side effects. Noninvasive pressure assessments comprise segmental pressures, ankle-brachial indices, toe pressures, and waveforms, which quantify the amount of flow in a given arterial segment. The ultrasound examination uses both B-mode and color-flow duplex mode to identify the location and severity of stenotic lesions and is increasingly being used intraprocedurally to evaluate the efficacy of interventions. Vascular ultrasound and physiologic testing are performed in conjunction with one another in the evaluation of PAD, as they provide complementary information. The noninvasive diagnosis of PAD is reviewed separately. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Physiologic testing' and "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Duplex ultrasound'.)

Contrast agents — Contrast is required to differentiate vessels from surrounding soft tissue and to distinguish segments that are patent from those that are stenotic or occluded. Different agents are used depending upon the type of study that is performed.

Iodine-based — Iodinated contrast media is used to perform computed tomographic (CT) angiography and digital subtraction angiography (DSA). In general, ionic compounds with high osmolarity are more nephrotoxic (figure 1). Contrast nephropathy is the third leading cause of acute kidney injury that requires dialysis among hospitalized patients, in spite of hydration protocols and/or medications used to mitigate the risk [8]. Patient evaluation prior to administration of radiocontrast media and preventive measures are discussed separately. Hypersensitivity reactions (immediate, delayed) can also occur. (See "Patient evaluation prior to oral or iodinated intravenous contrast for computed tomography" and "Prevention of contrast-associated acute kidney injury related to angiography" and "Radiocontrast hypersensitivity: Nonimmediate (delayed) reactions" and "Allergy evaluation of immediate hypersensitivity reactions to radiocontrast media".)

The ionic charge and the osmolality have been decreased with covalent bonding of iodine at three positions on the benzene ring to create tri-iodinated benzene compounds [9]. The remaining three positions on the benzene ring can be modified to customize the properties of the contrast agent or to allow dimerization with another tri-iodinated benzene ring. The modifications of the noniodinated positions result in agents that differ slightly with respect to iodine content and ionic, osmolarity, and viscous properties [9].

Over time, iterative developments have resulted in contrast agents that do not dissociate into anions and cations and have low osmolality (600 to 800 mOsm/kg) without sacrificing iodine content [9]. Moreover, the injection of nonionic compounds with lower osmolarity is associated with reduced sensations of pain and warmth. Viscosity also increases the transit time of the contrast within the renal tubules. Less viscous agents are ideal, as it is easier to administer larger volumes through smaller catheters [9].

Novel agents continue to be developed that are nonionic, with iso-osmolality or low osmolality, low viscosity, and low molecular weight. Moreover, researchers are exploring adding elements with higher atomic weights, which may result in nonionic agents with improved radiographic attenuation. Since improved radiographic contrast can be accomplished with fewer molecules, these high atomic weight elements can minimize osmolality and overall molecular weight [9,10]. These modifications continue to improve the usability and safety profile of contrast agents for digital vascular imaging modalities that require it.

Gadolinium-based — Gadolinium (Gd)-based contrast agents can be used during magnetic resonance (MR) angiography but are sufficiently radiopaque to be used for DSA. Patient evaluation prior to administration of radiocontrast media is discussed separately. Hypersensitivity reactions can also occur. (See "Patient evaluation before gadolinium contrast administration for magnetic resonance imaging" and "Allergy evaluation of immediate hypersensitivity reactions to radiocontrast media", section on 'Gadolinium-based contrast agents'.)

Eight Gd-based contrast agents have been approved for use in the United States. Gd is metabolized in the kidney without adverse effect in patients with healthy kidney function. The recommended dose for a particular agent should not be exceeded, and Gd-based contrast agents are avoided in patients with a glomerular filtration rate of <30 mL/1.73 m2 [11].

The ligand that binds Gd for each of the approved agents has a different chemical structure that dictates the retention within the body in the context of impaired renal function [12]. Longer retention times increase the likelihood that the Gd can be displaced by another ion from the ligand. Once released from the ligand, Gd can combine with other anions to generate low-solubility compounds, which precipitate and accumulate in the soft tissue. Fibrosis ensues with significant increases in cellularity but without significant inflammatory infiltrate [13]. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease".)

Others

Carbon dioxide — Carbon dioxide (CO2) is a naturally occurring, useful alternative contrast agent for patients undergoing DSA who have an iodine hypersensitivity or renal insufficiency, in whom iodine-based or Gd-based contrast agents may be harmful [14]. Improved technique and experience have resulted in an excellent diagnostic accuracy of 92 percent, compared with the gold standard of iodinated contrast DSA [15].

CO2 is excreted in the lungs. There is no known hypersensitivity or nephrotoxicity to CO2. However, due to the possibility of causing gas embolus to the cerebral or coronary circulations, the use of CO2 as a contrast agent above the diaphragm is contraindicated [14]. Moreover, suspicion of a large right-to-left arteriovenous shunt is a relative contraindication to CO2 angiography due to the large volume of CO2 that may accumulate in the right atrium. Lastly, nitrous anesthesia should be avoided with CO2 angiography since the nitrous oxide will saturate the soft tissue, diffuse into the CO2 bubble, and decrease visualization.

CO2 acts as a negative contrast, which, after digital subtraction, creates an image that is the inverse of a contrast injection, with the patent vessels appearing hyperintense [14]. Postprocessing can invert these images, enabling CO2 angiography to appear similar to contrast angiography. Higher frame rates and a resultant increased radiation exposure are also necessary with CO2 angiography.

CO2 is highly soluble in blood, dissolving in 15 to 20 seconds. This allows for its safe excretion via the lungs. It is also buoyant, with low viscosity, and is highly compressible [14]. CO2 is also widely available and inexpensive. The buoyancy of CO2 must also be accommodated for when performing angiography, particularly below the knee [14-16]. (See 'Conduct and technical improvements' below.)

In spite of several reports of death after CO2 angiography, large retrospective series have validated the excellent safety profile of CO2 angiography, with a procedure-related mortality of 0.4 percent [15,16]. Modern CO2 delivery systems have been devised to minimize air contamination with delivery. These systems also incorporate air filters and one-way valves to prevent the reflux of blood into the system. Prevention of air contamination is critical to avoid air emboli and ischemic complications [15]. If air is introduced, oxygen and nitrogen can diffuse into larger trapped bubbles of CO2 due to differential partial pressures [15]. Such a gas bubble can persist in nondependent portions of the circulation because oxygen and nitrogen are less soluble in the blood, resulting in ischemia distal to the bubble [15].

Ferumoxytol — Ferumoxytol, which was initially developed to treat iron deficiency anemia, is an ultrasmall super-paramagnetic iron oxide (USPIO) that can be used as an alternative contrast agent to Gd for MR angiography [17,18]. Ferumoxytol functions due to its high relaxivity during T1, resulting in a high intravascular signal on T1-weighted images. Ferumoxytol cannot diffuse through the blood vessels and leak into the interstitium because of its molecular size. Ferumoxytol is cleared by the macrophages within lymph nodes and spleen. The half-life is 15 hours, which permits image acquisition any time after steady state has been achieved after administration. The iron component is absorbed into the body's iron stores.

Study selection — In general, the least invasive and least toxic vascular imaging modality that will accomplish the intended goal is selected. The timing of obtaining a specific imaging modality depends upon multiple factors. Often, it is the urgency of patient presentation that factors more heavily into the modality and rapidity of imaging acquisition. Institutional factors also influence clinician decision-making. As an example, vascular ultrasound might be preferred for first-line imaging, but the capability at a given institution is often more variable, and a high-quality study may not be available off-hours.

Coupled with a careful history and physical examination, duplex ultrasound and physiologic pressure examinations can often provide sufficient data to confirm the diagnosis and severity of PAD to guide initial decision-making. If noninvasive studies do not provide the required information or are not available, further imaging may be necessary. CT angiography or MR angiography demonstrate the anatomic distribution and severity of PAD with high sensitivity and specificity, but CT or MR angiography and particularly DSA are more often reserved for patients in whom a decision has been made to proceed with intervention. Variants of MR angiography or measurements of tissue perfusion are institution-, practitioner-, and case-specific, without sufficient data to provide recommendations for routine use.

Study selection also depends on patient comorbidities. As an example, imaging studies using iodinated contrast or Gd are generally avoided in patients with chronic kidney disease (CKD). However, with dialysis-dependent CKD, contrast is not absolutely contraindicated. In addition to judicious selection of contrast agent (group 1 agents contraindicated), some authors use a regimen of dialysis immediately after Gd-contrast administration and for the subsequent two days, resulting in 98 percent clearance of the contrast [19]. Similarly, it is recommended that dialysis be performed early after iodinated contrast administration to reduce the systemic concentration of iodinated contrast to limit damage to residual functional nephrons [20]. For patients with lower stages of CKD, the clinician may opt to obtain a study that uses a nephrotoxic agent if the benefits of obtaining the study outweigh the risks. (See "Patient evaluation before gadolinium contrast administration for magnetic resonance imaging" and "Patient evaluation prior to oral or iodinated intravenous contrast for computed tomography".)

Diabetes mellitus causes specific changes in the vasculature that warrant particular considerations when selecting vascular imaging studies. Advanced diabetes mellitus results in medial calcification, which is often most pronounced below the knee, in the peroneal, anterior tibial, and posterior tibial arteries. Calcification interferes with virtually all imaging modalities. Calcification especially obfuscates noninvasive vascular studies, including ultrasound, physiologic studies, and CT.

Toe waveforms and pressures are relied on in patients with CLTI, particularly those with diabetes, since leg pressure measurements are often falsely elevated. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'High ABI' and "Overview of peripheral artery disease in patients with diabetes mellitus".)

Mural calcification also causes artifact for duplex ultrasound and particularly CT angiography, leading to unreliable estimates of the degree of stenosis. (See 'Computed tomographic angiography' below.)

MR angiography and DSA may be less susceptible to calcification artifact; however, these studies imperfectly surmount calcium-induced artifacts.

Postprocessing — Postprocessing refers to the use of software or hardware circuits to augment radiographic images after they have been obtained. Postprocessing improves detail acquisition and anatomic perception by the interventionalist, which enhance procedural planning and performance. Postprocessing differs somewhat for CT/MR angiography compared with DSA, and each are reviewed below. (See 'Three-dimensional rendering' below and 'Image processing' below.)

Radiation safety — The average effective doses for interventional procedures in adults are available [21-25]. The actual dose for a given patient may differ from the reported average effective dose by up to 10-fold (table 1). For lower extremity angiography, the effective dose a patient receives tends to be the highest in the abdomen and pelvis, because the amount of tissue the x-rays must traverse is the thickest in these locations [26]. Mean dose-area product ranges between 252 and 262 Gy-cm2 for interventions involving the aortoiliac segments. The dose-area product decreases for interventions involving more distal arteries. Femoropopliteal interventions require a mean dose-area product between 145 to 153 Gy-cm2. Infrageniculate procedures have the lowest mean dose-area product at 128 Gy-cm2. The amount of radiation imparted to the interventionalist and his/her team is variable, given the variable gantry angles required to image the patient's anatomy appropriately.

Measures to improve the safety of the patient and the interventionalist are reviewed separately. Specific tactics to limit the radiation dosage are reviewed below. (See 'Imaging modalities' below and 'Conduct and technical improvements' below.)

Patient (see "Radiation-related risks of imaging")

Interventionalist (see "Radiation risk to healthcare workers from diagnostic and interventional imaging procedures")

IMAGING MODALITIES

Computed tomographic angiography — Computed tomographic (CT) angiography has multiple advantages compared with other vascular imaging modalities for the evaluation of the lower extremity vasculature. CT angiography is less operator dependent compared with catheter-based digital subtraction angiography (DSA) and ultrasonography with CT protocols that can coordinate the contrast bolus with the image acquisition sequencing, which improves the delineation of areas of stenosis, even in smaller vessels such as the tibial vasculature. CT angiography uses almost fourfold less radiation exposure and is less invasive and less expensive compared with DSA [27].

Protocols for performing CT angiography are not the same as those used for conventional cross-section imaging of the abdomen. CT angiography is performed using thinner slices to enhance resolution and is performed with only intravenous contrast (ie, no gastrointestinal contrast). Gastrointestinal contrast obscures visualization of the arterial circulation, and the effect cannot be mitigated with postprocessing. Gastrointestinal contrast is particularly problematic when performing vascular interventions.

Evolution and advances — CT angiography relies on the emission and detection of x-rays while the patient moves through a gantry that rotates the x-rays in a 360-degree arc. The acquired data are three-dimensional, with each discrete data unit described as a voxel [27]. Intravenous iodinated contrast is used to accentuate the vasculature and differentiate it from the surrounding tissues [27]. (See 'Contrast agents' above.)

Early-generation helical CT scanners rotated a single detector around the gantry arc to acquire image slices but lacked the software to postprocess the images. Obtaining a complete exam was slow, and the images lacked detail to accurately identify the location and severity of stenoses within the lower extremity vasculature. Later generation scanners use multiple detectors (ie, multidetector [MDCT] angiography) to simultaneously detect x-rays as the patient passes though the center of the gantry, which rotates through 360 degrees. MDCT acquires multiple slices simultaneously, resulting in rapid acquisition of increasingly precise three-dimensional voxels (volume element) with a higher spatial resolution compared with earlier-generation scanners, without increases in radiation or iodinated dye exposure [28]. Early-generation MDCT scanners had only four detectors; up to 320 detectors are now available. With modern hardware and software, CT angiography is highly accurate for the aortoiliac segments and femoropopliteal regions, with a sensitivity of 93 percent and specificity of 92.7 percent, respectively. Advances and improvements including three-dimensional software rendering (see 'Three-dimensional rendering' below) have improved CT angiography, such that it has become the primary diagnostic vascular imaging modality used in patients with claudication who typically have disease located in the more proximal vasculature [29].

Unfortunately, for lesions located in the infrapopliteal segment, sensitivity is less at 91.6 percent, with a decreased accuracy of 73.3 percent and a positive predictive value of 78.5 percent [29,30]. The limitations of CT angiography for the infrageniculate vessels are compounded by their small size, decreased contrast delivery in hypoperfused limbs, and calcification/stent artifact. For anatomic evaluation and planning intervention in patients with chronic limb-threatening ischemia (CLTI), practice patterns vary widely with disparate data reported. The use of CT angiography is individualized. The interventionist is in the best position to determine the appropriate diagnostic testing for a given patient to avoid unnecessary (and potentially harmful) complications. While CT angiography is relatively safe, for many patients with CLTI, the best option may be identifying the location and severity of arterial disease using noninvasive vascular testing and then proceeding directly to angiography/intervention using carbon dioxide to minimize the amount of iodinated contrast. However, a novel technique, dynamic volume perfusion CT, may enable quantitative evaluation of the blood flow to the foot to diagnose PAD and also to assess flow following revascularization [31,32].

Limitations of CT — In addition to reduced accuracy for the distal vasculature, computed tomographic (CT) angiography has several other limitations:

The bolus of intravenous contrast required for CT angiography of the aorta and bilateral lower extremities ranges between 100 and 120 mL [33]. This amount of contrast is a concern for some patients, particularly those with chronic kidney disease, although the risk posed may be less compared with arterial contrast injection [34]. (See 'Contrast agents' above.)

Streak and blooming artifacts occur in areas of vessel calcification or metal stent placement. These artifacts occur due to beam hardening and Compton scatter and can result in overestimation of stenoses in these regions [33]. Beam hardening causes the edges of an object to appear hyperintense at the center. Compton scatter attenuates x-rays and photons upon interaction with charged ions, resulting in dark streaks that can obscure visualization of vital features of the vasculature.

The timing and dose of contrast, coupled with upstream stenoses/occlusions, can limit opacification of the below-the-knee vasculature. Saline chaser boluses and delayed imaging of the infrapopliteal segments can help to opacify these vessels, although in the context of severe PAD, there are limits to the resolution of the images that can be acquired.

While the radiation dose is considerably less for CT angiography compared with DSA, iterative examinations, such as the use of CT angiography for surveillance, can result in significant accumulation of ionizing radiation over the patient's lifetime. A decrease in the tube voltage from 120 to 100 kVP (kilovoltage peak) can reduce the radiation dose by 23 percent without significantly deteriorating image quality [35]. However, for patients who are obese, a higher tube voltage is still required to overcome background noise. (See 'Radiation safety' above.)

Three-dimensional rendering — Three-dimensional volume-rendered images improve the operator's ability to rapidly interpret areas of disease (image 1). These images can also be superimposed over live fluoroscopic images to aid in case planning and performance, particularly when traversing difficult stenoses.

Maximum intensity projections remove much of the distracting adjacent soft tissue anatomy and appear similar in appearance to conventional angiography images (image 2). Multiplanar reconstructions (MPRs) are generated by constructing a center-line (either automated or manually (image 3)). This provides cross-sectional and longitudinal views (curved or straightened) of the vessel around the centerline, which are helpful for distinguishing significant stenoses in tortuous vessels. MPR is also useful for accurately measuring the degree of stenosis [36].

Magnetic resonance angiography — Magnetic resonance (MR) angiography is an alternative vascular imaging modality that provides strikingly clear images. MR angiography capitalizes on the differential relaxation times associated with the magnetic and axial vectors of individual tissues within the body. The main advantage is avoidance of ionizing radiation; however, MR angiography is time consuming, and results are variable between institutions.

MR angiography can be performed with or without contrast. The contrast agent used for MR angiography is gadolinium (Gd) (see 'Gadolinium-based' above), which, coupled with mask subtraction, provides sharp detail to the vasculature [36]. The postprocessing features that are available for CT angiography are also available for MR angiography.

Contrast-enhanced MR angiography — Among the magnetic resonance (MR)-based imaging modalities, contrast-enhanced MR angiography is the most commonly used and is the standard against which other MR-based imaging modalities are measured [37]. Contrast-enhanced MR angiography overcomes limitations associated with CT angiography with regard to calcification or stent-related artifact. The main limitation of MR angiography imaging is the rare, but incurable, disabling iatrogenic complication of nephrogenic systemic fibrosis (NSF). (See 'Gadolinium-based' above.)

Sensitivity (93 percent) and specificity (94 percent) are excellent for contrast-enhanced MR angiography and consistent between the aortoiliac, femoral, and tibial segments. A systematic review failed to show any significant differences between CT angiography and contrast-enhanced MR angiography [37]. With specialized protocols, MR angiography can be used effectively to image the infrageniculate and pedal vasculature [29]. Such expertise, however, is not widespread. Thus, in many centers, MR angiography retains similar limitations as with CT angiography.

For patients with normal renal function, Gd-based contrast-enhanced MR angiography is performed in a multistation approach, which helps to limit the contrast bolus and acquisition time. Doses of Gd vary depending upon the institution and agent used. Typically, the dose of Gd is approximately 0.2 mmol/kg of patient's body weight [36]. To limit venous contamination during lower extremity examination, thigh compression cuffs or a semicircular pillow behind the knee can be used to create a stagnant column within the venous system, preventing flow and therefore dilution of contrast into the venous system [36]. More commonly, the tibial vasculature is imaged prior to the more proximal vessels to prevent venous contamination [36].

Ferumoxytol is an ultrasmall super-paramagnetic iron oxide (USPIO) (see 'Ferumoxytol' above) that can be used as an alternative contrast agent to Gd for MR angiography [17,18]. The most common dose administered is 2 to 5 mg/kg (maximum dose 510 mg) [18,38,39]. The contrast is diluted in two to four parts normal saline and administered slowly over 15 minutes with 8 mg of dexamethasone [18]. Data remain limited to small series, but ferumoxytol shows promise. In a small blinded study of five males undergoing Gd-MR angiography and five undergoing MR angiography with ferumoxytol, there was no significant difference in the overall quality of the studies as judged by four vascular surgeons [40]. Clinical decision-making based upon these images was unchanged 89 percent of the time, showing good concordance.

While the results using ferumoxytol are encouraging, further data are needed. Unfortunately, there have been several reports of life-threatening anaphylaxis associated with ferumoxytol administration, resulting in a black box warning from the US Food and Drug Administration (FDA) [41]. Future study is needed to ensure safety and further compare inter- and intraobserver variability of USPIO MR angiography in comparison with Gd-MR angiography. (See "Treatment of iron deficiency anemia in adults", section on 'Allergic and infusion reactions'.)

Non-contrast-enhanced MR angiography — Several protocols are available for MR image acquisition that do not use contrast, thereby avoiding issues related to Gd (or ferumoxytol). (See 'Gadolinium-based' above and 'Ferumoxytol' above.)

The earliest of the non-contrast-enhanced MR angiography techniques is two-dimensional time of flight (2D-TOF) [42]. 2D-TOF exploits the fact that flow enhances the magnetic spin relative to tissues that are not moving; thus, no intravenous contrast is required. Sensitivity (43 to 67 percent) and specificity (74 to 89 percent) for this technique are modest [36]. 2D-TOF also does not perform as well as Gd-based MR angiography. Moreover, there are significant flow-related artifacts associated with stenoses, prolonged acquisition time, difficulty obtaining perpendicular views, and difficulty imaging deeper vessels in the abdomen. Because of these limitations, 2D-TOF is not used very often.

With the electrocardiogram-fast spin echo (ECG-FSE) technique, a high intravascular signal during the T2 phase is acquired during diastole. Next, during systole, fast-spin echo data are acquired, in which the intravascular signal is suppressed on T2 imaging. Subtraction of the three-dimensional slab of tissue in the region of interest between diastole and systole reveals the signal from the arteries, with the remainder of the signals cancelling themselves out in the background [17]. Precise gating to determine systole and diastole in each tissue block is essential and may require several iterations per patient to perform properly [17,43]. With some stenoses, there is flow throughout diastole, such as at the aortic bifurcation, which limits the signal generated on T2 during diastole, resulting in a smaller difference between systole and diastole and an overestimation of stenosis. Other limitations include the prolonged examination time, which can result in multiple motion artifacts due to patient movement from discomfort. Early data suggested that the sensitivity and specificity of this technique were 85 and 76 percent, respectively [43]. The degree of stenosis was overestimated in 22 percent of subjects.

Balanced steady-state free precession (bSSFP) pulse sequence is another method in which blood, fat, and fluid appear bright on T2 imaging. This technique capitalizes on the unique T1 and T2 signatures of arterial blood (approximately 1400 and 250 msec, respectively, at 1.5 Tesla). The arteries upstream of the vessels of interest are tagged with a magnetic pulse that provides these red blood cells with a particular spin label. When the blood reaches the area of interest, the T1 recovery time is then acquired [36]. The arteries are then selectively enhanced by using shift-selective fat saturation to limit the signal emanating from fat. T2 preparations are then applied to decrease the signal from myocardial or skeletal muscle. An advantage of this technique is that it is independent of flow, which is useful when attempting to identify areas with low flow, such as ischemic vascular beds [17].

The quiescent interval slice selective (QISS) techniques have been developed specifically for evaluating ischemic arterial beds [17,36]. QISS is a variant of bSSFP. The key differences are:

A saturation burst of radiofrequency energy is used to fill the field of interest.

The burst is followed by a quiescent period, in which arterial flow replaces the red blood cells within the arteries with only red blood cells that have unsaturated spins. The arterial flow is detected by the difference in the signal of unsaturated spins (no T1 or T2 relaxation) and the surrounding tissue with saturated spins.

A rapid, single-shot acquisition is obtained in the area of interest.

The advantages of QISS include the rapid acquisition and less artifact from background tissues, particularly surrounding fat [17,36]. Early data suggested that QISS MR angiography compares favorably to carbon dioxide (CO2) angiography. A study compared CO2 angiography and QISS MR angiography, both of which were performed in 16 patients [44]. Four different radiologists compared the images in random order. The sensitivity and specificity for QISS MR angiography were 91.5 and 94.2 percent, respectively, with a positive predictive value of 86 percent. There was less interobserver variability with QISS MR angiography compared with CO2 angiography.

Digital subtraction angiography — Catheter-based digital subtraction angiography (DSA) has been the gold standard for the diagnosis of a variety of peripheral vascular pathologies. With the maturation of endovascular technologies over the past several decades, DSA has also evolved to provide improved image clarity and image-processing capability and an improved safety profile. Many of the latest advancements have arisen from fusions of CT or MR images with DSA images to improve intraprocedural localization of vascular structures necessary for the conduct of an intervention.

Conduct and technical improvements — DSA underwent explosive early development in the 1960s and 1970s with significant advances in roadmapping and image storage [45]. While advances in technology, software, and experience have resulted in nearly unrecognizable evolution and miniaturization of the equipment, the central tenets of DSA remain unchanged. A generator produces x-rays, which pass through the patient and are captured by an image intensifier. The data collected via the image intensifier are transferred via an image processor. The images present prior to contrast injection are then digitally removed, or subtracted, from the postcontrast image, resulting in an image of the vasculature congruent to the flow of contrast. These images are then presented on a display screen in the angiography suite or hybrid operating room.

Iodine-based contrast is typically used for conventional DSA (image 4), because the higher atomic weight results in better differential x-ray attenuation relative to surrounding tissues (see 'Iodine-based' above). However, two properties of iodine-based contrast can result in nephrotoxicity: high osmolality and the extent of ionic charge associated with the contrast agent [9]. CO2 is a useful alternative contrast agent [14]. Elevating the limbs on several pillows can maximize the amount of CO2 delivered to the tibial vessels, improving imaging to accommodate the buoyancy of CO2 [14-16]. Prevention of air contamination during CO2 delivery is critical, as the other gaseous components within air mixtures are less soluble in blood and can result in air emboli and ischemia distal to a gaseous bubble [15]. Modern CO2 delivery systems incorporate air filters and one-way valves to prevent the reflux of blood into the system to minimize air contamination. Improved techniques and experience have resulted in an excellent diagnostic accuracy of 92 percent, with iodine-based contrast DSA as the standard [15]. (See 'Carbon dioxide' above.)

Iterative technical advancements have improved image quality and functionality for the operator while decreasing radiation doses. These advancements include [46]:

High-heat capacity x-ray tube – The generation of x-rays creates heat as a byproduct. Older x-ray tubes suffered from overheating, which diminished the number of x-rays that could be performed in a given time frame. Hence, procedural duration was limited. High-heat capacity x-ray tubes permit the operator to perform much more prolonged procedures.

Dose reduction spectral shaping filter – Copper or aluminum filters remove the low-energy portion of the x-ray beam, which is responsible for excessive noise in the signal. Without filters, the voltage of the x-ray tube must be increased to increase the signal to the areas of interest. With the filter in place, the voltage required to generate a clear image and, hence, the radiation dose are reduced.

High-frequency inverter generator with high-performance switching – The generator, x-ray tube, and the filter are all tied together by a variety of circuits and software logic that help to maximize image quality while reducing radiation dose in concert with one another. These function to switch the intensity of the x-ray beam delivered from high to low intensity when a high intensity is unnecessary. The need to switch depends upon the angle of the gantry, distance of the object to the detector, and the thickness of tissue the x-ray must penetrate to image the area of interest. The specifics of the performance logic are proprietary and vary somewhat depending upon the brand of fluoroscopy equipment used.

Flat-panel image receptor – Flat panels digitize the radiographic image rather than projecting the image onto a film. Digitization enables software to process the image, and multiple postprocessing algorithms aid the acquisition of images necessary for the performance of complex interventions. (See 'Image processing' below.)

In spite of the advances made with DSA, several limitations remain. DSA cannot provide a quantitative assessment of the flow reaching the foot without specialized postprocessing software [47]. This hinders the operator's ability to determine whether the blood supply is adequate for alleviating symptoms or whether further intervention is required. DSA is also invasive, with significant complications that include access site hematoma, vascular dissection, and thromboembolism, which may result in limb loss, which can occur in as many as 2 percent of patients who develop complications [48,49]. However, major complications requiring surgical intervention are rare [49]. Systemic complications related to the contrast media may also occur. (See 'Iodine-based' above and 'Carbon dioxide' above.)

Image processing — Many of the advances in DSA stem from improvements in hardware and software capabilities of the imaging units. Software programs can be used to maximize visualization of anatomic structures and improve the efficiency of angiography. While these have been available in the past, improvements have enhanced the capability of interventionalists to process images immediately after they have been acquired in real time. Each of the image processing features has been automated with improved software and user-friendly interfaces that allow the operator to easily manipulate each of these functions as needed from the tableside console. In addition, image processing tools have been vital in reducing the radiation dose administered to the interventionalist and patients. These tools include more precise adjustment of the gantry angle as necessary to optimally image the vascular lesions and improvement in detector size and its ability to discriminate differences in density with less radiation. (See 'Radiation safety' above.)

Fundamental image processing tools used in DSA include:

Last image hold – Last image hold allows the operator to display the last image acquired by fluoroscopy. This permits the operator to examine the image for anatomic details without having to continuously image the structures of interest [50]. Grayscale processing permits the operator to adjust the pixel values of the image around a set value of gray. In a sense, this functions to modulate the contrast and brightness of the image. Temporal frame averaging will average multiple frames together and average the current frame with several of the prior frames. This helps to limit noise in the image but is limited by patient motion [50]. Edge enhancement can be used to sharpen the borders between structures with different pixel values.

Road mapping – Road mapping aids the interventionalist with the placement of catheters and wires into the vessel(s) of interest. After an angiogram is performed, the image in which the vessels of interest are maximally opacified is overlaid upon a static image of the vasculature and subtracted from subsequent live fluoroscopic images. This provides a shadow in the shape of the vessel of interest on the live fluoroscopic images through which wires and catheters are still visible. In this fashion, the structure that the operator wishes to navigate is outlined on live fluoroscopic images [50]. To further facilitate visualization, the intensity of the roadmap overlay can be adjusted to the operator's preference.

Bolus-chase angiography – Single-injection linear angiography is more commonly referred to as bolus-chase angiography. Initially, a precontrast mask of the legs and abdomen is generated. Next, a bolus of contrast is administered in the abdomen, and the image intensifier follows, or "chases" the bolus of contrast as it travels down the vessels of either or both lower extremities. While this technique can be more efficient, there are also limitations. The single injection requires more time, which increases the potential for motion artifact. Also, with bilateral studies, if the PAD is asymmetric, it may be impossible to opacify the side with more severe obstructions before the contrast completely washes out contralateral extremity [50].

Pixel shifting – Pixel shifting is used to accommodate for motion artifact and occurs when the pre- and postcontrast subtraction images are shifted with respect to one another until the anatomic structures lie upon one another. The image is then resubtracted, generating an opacified image of the vessel of interest [50]. Finally, image summation or "stacking" permits the addition of serial images as the contrast passes. The first image in which contrast is visible is "stacked" upon subsequent images in which the contrast passes further. The end result is a single image that shows the summation of all of the contrast that passed through a particular vessel. "Stacking" can be useful in lower extremity occlusive disease when there are significant obstructions preventing uniform opacification of the vessel [50].

Rotational arteriography — Rotational arteriography using cone-beam computed tomography (CBCT) has also improved the ability to image and traverse atherosclerotic lesions. CBCT uses x-rays that are emitted at angles from one another, forming a cone. As the x-rays are emitted, the gantry is rotated around the region of interest, which is placed at isocenter to acquire volumetric data. Software rendering results in three-dimensional images that can be rotated in any direction as required by the operator. Moreover, the precise location of the image can be matched to the gantry angle of the x-ray emitter and image-intensifier. By matching the table position with known anatomic landmarks, the three-dimensional rotational arteriogram can then be superimposed upon live fluoroscopic images, providing a three-dimensional roadmap that can be used to guide interventions more precisely. The three-dimensional image provides more detail regarding plaque morphology, which is often misinterpreted when seen on a traditional two-dimensional DSA image. Sizing errors associated with this technique are less than 2 percent compared with the actual target vessel diameter and length [51]. Given the small median sizes of peripheral vessels, this results in a coefficient of variance of less than 0.5 mm. Further prospective evaluation is required to validate rotational angiography as a method of sizing and guiding peripheral vascular interventions.

Further advances include the superimposition of the rotational angiographic image upon a CT angiographic or MR angiographic image. This can be done in unique cases to guide access, wire, and/or stent placement. The author has found this technique most useful for aortoiliac applications, as the tibial vessels remain too miniature to accurately image with rotational angiographic techniques. With increased prevalence of cone-beam computed tomography (CBCT) utilization, clinical applications of CBCT are expanding. CBCT is proving to be increasingly reliable and precise in quantifying lesion severity [52]. Future prospective multicenter cohorts will be required to further quantify the marginal benefits of CBCT in PAD, but emerging data are encouraging.

Fiberoptic laser guidance and electromagnetic tracking systems — Several image guidance systems have been developed to limit the amount of radiation, thereby improving the safety of fluoroscopic procedures [53,54]. These require coregistration with CBCT or preoperative CT angiography to determine the location of the vascular structures of interest. Fiberoptic laser guidance uses catheters or wires with multiple fiberoptic laser wires. Within the wall of the catheter or within the center of the wire lies a fiberoptic sensor, which detects the changes in the optical length of the laser depending upon the shape and position of the wire or catheter in space [53,55]. When coregistered with the prior CBCT, or CT angiography, this permits navigation of the intravascular structures without further use of fluoroscopy [53,55].

Similarly, electromagnetic tracking systems also require coregistration of anatomic landmarks with a prior CBCT and/or CT angiography [54]. Electromagnetic systems require generation of an electromagnetic field from a generator placed underneath the patient. Within the catheters and wires are sensors that detect the position of the catheters and wires within the electromagnetic field. When superimposed upon the coregistered three-dimensional images, the operator can navigate the vasculature without further use of fluoroscopy [54].

Both of these technologies have been in development for at least 10 years, but data documenting their efficacy are limited to small case series, case reports, and animal models [54,55]. Further validation will be required with larger, multicenter cohorts. Moreover, imaging of the infrapopliteal vessels remains difficult due to the limitations of CBCT and/or CT angiography to reliably resolve the anatomy of this region. Hence, applications of these technologies are limited to the aortoiliac region. Still, these technologies offer the best promise of accurate navigation with the minimal exposure to radiation.

Intravascular ultrasound — Intravascular ultrasound (IVUS) has been increasingly used during vascular procedures to improve the quantification of the severity of vascular stenoses beyond two-dimensional DSA alone. The character of specific atherosclerotic lesions can be defined, which is difficult or not possible with other imaging methods. Nevertheless, we reserve IVUS for the rare cases in which there are conflicting data regarding the etiology or severity of a stenosis. In these cases, IVUS can help intraprocedural diagnoses and/or decision-making. However, in most cases, IVUS is not needed. (See "Intravascular ultrasound, optical coherence tomography, and angioscopy of coronary circulation".)

The original experience using IVUS during coronary artery procedures was initially translated to aid imaging of the superficial femoral artery [56,57]. IVUS can help to characterize lesions in the periphery when DSA fails to provide sufficient data to guide appropriate intraprocedural decision-making. In a prospective review of IVUS in 59 patients undergoing superficial femoral artery percutaneous interventions, angiography alone failed to detect hemodynamically significant lesions (>50 percent), which were detected on subsequent IVUS [57]. IVUS may also help to distinguish between thrombus and arterial dissection and has also been used to characterize the lipid content as well as calcium burden of atherosclerotic plaques in the superficial femoral artery [56]. As promising as these early studies appear to be, intraprocedural IVUS remains in the early stages, without clear indications for its use.

MEASURES OF PERFUSION — Conventional vascular imaging modalities can quantify the hemodynamic significance and anatomic location of atherosclerotic lesions; however, all are limited in their ability to quantify perfusion to a specific area of the foot. This is desirable when there is a tissue loss, and the clinician is unsure whether perfusion will be adequate to heal a wound, particularly among patients with diabetes. Complex collateral networks and variable anatomy can also confound predictions of the perfusion of a given area of tissue distal to a stenosis/occlusion. Moreover, the distal arterioles and capillaries are often involved in the disease process, further limiting the ability to quantify the amount of blood supplying a given wound. Traditional methods to estimate distal perfusion include transcutaneous oxygen measurements, toe pressures, and ankle-brachial indices. Several novel measures of perfusion have been developed, though high-quality data supporting their use are not available. These novel measures include microcirculatory imaging and molecular and cellular imaging.

Some of the later methods have been combined with noninvasive measures to surmount the limitations of both. However, all suffer from a dearth of data and measurement reliability. As an example, transcutaneous oxygen measurement (TcPO2) has been combined with a variety of other modalities (eg, laser Doppler); however, series are very small, and it seems that most investigators are moving away from using TcPO2 in conjunction with other studies due to its well described limitations. Traditional measures of perfusion are reviewed separately. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Ankle-brachial index' and "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Segmental pressures' and "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Transcutaneous oxygen measurements'.)

Microcirculatory imaging

Indocyanine green angiography — Indocyanine green (ICG) angiography is most commonly used as a qualitative, rather than quantitative measure of perfusion. However, this may change as further prospective data are generated to validate quantitative parameters associated with PAD outcomes, such as wound healing and limb salvage.

ICG is a water-soluble, inert agent with a half-life of three minutes. After intravenous injection, a laser at 830 nm is applied to the region of interest, exciting the ICG, resulting in bright enhancement of the tissues in which the ICG is present. Perfusion is inferred by measuring several parameters of intensity that correspond to the amount of arterial perfusion to the region (image 5) [58]. The optimal parameter of ICG intensity remains unclear in the literature. However, multiple studies confirm that measures such as the rate of ingress of ICG, maximal intensity, and egress rate are all associated with the degree of perfusion to the region of interest [58,59]. Due to its short half-life, ICG can be used intraprocedurally to guide whether further intervention is required. ICG angiography can also measure perfusion within a given wound bed, unlike transcutaneous oxygen measurements.

Data regarding adverse reactions to ICG are derived from other medical indications, since the use of ICG in patients with PAD remains relatively novel. hypersensitivity reactions occur in 1 in 40,000. Moderate reactions, comprised of non-life-threatening wheezing or urticaria, occur in 0.2 percent. Anaphylactic reactions are rare, occurring in 0.05 percent [60]. ICG is excreted by the biliary system and is therefore safe in renal insufficiency. ICG does contain iodine. Thus, appropriate precautions should be taken as in the case of iodine hypersensitivity reactions. (See 'Iodine-based' above.)

Hyperspectral imaging — Hyperspectral imaging exploits the unique absorption peaks for oxygenated versus deoxygenated blood under white light to generate maps of the perfusion of the subpapillary dermis, which is located 1 to 2 mm below the skin (image 6) [61]. Hyperspectral imaging is noninvasive and does not require exogenous contrast or any ionizing radiation. This feasibility of the technology was illustrated in a study that reported significantly higher oxyhemoglobin values among healed diabetic foot ulcerations compared with diabetic foot ulcerations that failed to heal [62]. Unfortunately, inflammation or infection creates local hyperemia and therefore falsely elevates recorded oxyhemoglobin values [61]. Further validation is required comparing hyperspectral imaging with other measures of perfusion.

Laser Doppler — In spite of being available for over 20 years, laser Doppler has not been widely adopted due to high inter- and intraobserver variability, which is due to the changes that occur due to ambient temperature [63,64]. Doppler can quantify differences in microcirculatory flow to a depth of 1 to 6 mm. The laser is shone upon the area of interest, and the magnitude and frequency of the changes in wavelength (fluxmetry) describe perfusion in that area relative to other areas. If one area is presumed to have normal perfusion, laser fluxmetry can be used to compare relative deficits in perfusion in adjacent areas or wounds [63]. In one study, the use of laser Doppler flow accurately identified 82 percent of patients who did not have sufficient perfusion to salvage their limb at six months from their revascularization [64].

Molecular and cellular imaging (SPECT and PET) — Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) provide functional assessments of perfusion and have been used to evaluate atherosclerotic plaque characteristics, tissue perfusion, and tissue viability [65]. The extent of angiogenesis, which is essential to the development of collateral networks in ischemic tissue, has also been studied. Cost, local expertise, and equipment availability limit more widespread application. Still, the sensitivity and ability to target the tracers to specific biologic processes provide SPECT and PET the ability to quantify processes with which no other modality can compete. Further research in these technologies will help to clarify the most practical applications for PET and SPECT.

SPECT uses radiotracers and gamma ray detectors. Frequently used radiotracers include thallium-201 (201Tl), technetium-99m (99mTc) sestamibi, 99mTc-tetrofosmin, and 99mTc-pyrophosphate [65]. In both animal models and human studies, SPECT has been used to evaluate lower extremity perfusion [66,67]. SPECT can measure processes that are occurring at minute concentrations, measured in pico- or nanomoles [65]. Hence, the sensitivity of SPECT is superior to the microcirculatory modalities discussed above. (See 'Microcirculatory imaging' above.)

PET has been used similarly to SPECT. For vascular applications, PET uses labeled oxygen-15 (15O), N-13 (13N) ammonia, rubidium-82 (82Rb), and fluorine-18 (18Fl) [65]. These radioligands are bound to a biologically active molecule that corresponds to the biologic process of interest.

Perfusion angiography — Postprocessing software has been used to assess perfusion using digital subtraction angiography [47,68]. For these applications, the diagnostic catheter is placed in the popliteal artery and iodinated contrast is injected at a specific rate (3 cc/sec). The software generates a curve that shows the density of contrast in a given area over time. These data are then superimposed upon the two-dimensional image of the foot in a given projection. How well two-dimensional perfusion angiography predicts outcomes such as wound healing or limb salvage is unknown. Given the widespread availability of angiography, immediately evaluating perfusion of the foot before and after a percutaneous intervention is attractive. Future prospective evaluation will help to determine the marginal utility of two-dimensional angiography.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".)

SUMMARY AND RECOMMENDATIONS

Advance vascular imaging for peripheral artery disease – The initial diagnosis of lower extremity peripheral artery disease (PAD) is clinical, with initial confirmation using noninvasive vascular assessment in a vascular laboratory (pressure measurements, duplex ultrasound). Advanced vascular imaging confirms the severity and extent of disease and is used to plan and guide revascularization (endovascular or open surgical). Advancements in imaging hardware and software have enabled increasingly precise determination of the severity of culprit lesions and improved methods of measuring perfusion. (See 'Introduction' above and 'Basic principles of vascular imaging' above.)

Vascular contrast agents – Contrast is generally required to differentiate blood vessels from surrounding soft tissue and to distinguish vascular segments that are patent from those that are stenotic or occluded. Each agent has its distinct advantages and disadvantages, which are described above. Vascular contrast agents include (see 'Contrast agents' above):

Iodine-based agents – Iodine-based agents (figure 1), which are used for computed tomographic (CT) angiography and catheter-based digital subtraction angiography (DSA)

Gadolinium – Gadolinium (Gd), which is used for magnetic resonance (MR) angiography but can also be used for DSA

Ferumoxytol – Ferumoxytol (an ultrasmall super-paramagnetic iron oxide [USPIO]) as an alternative to Gd for MR angiography

Carbon dioxide – Carbon dioxide, which can be used for DSA in those with contraindications to other contrast agents.

Characteristics and selection of vascular imaging study – Study selection is determined by the nature and urgency of the patient's presentation (eg, stable claudication, deterioration of chronic limb-threatening ischemia [CLTI]), availability of a particular study and high-quality interpretation, and the patient's risk for adverse effects for a given study (eg, hypersensitivity reactions, comorbidities such as diabetes and chronic kidney disease). Each advanced vascular imaging modality has advantages and disadvantages. In general:

CT angiography – CT angiography has high sensitivity and specificity for the location and severity of stenotic/occluded vascular lesions. It is limited by ionizing radiation (though a single study uses less than DSA), nephrotoxicity of iodinated contrast, and artifact, particularly those that originate from calcific plaques and metallic stents. CT angiography is best suited for the evaluation and case-planning of occlusive disease of the aortoiliac and femoropopliteal segments. (See 'Computed tomographic angiography' above.)

MR angiography – MR angiography has similarly high sensitivity and specificity as CT angiography and is more useful for imaging the vasculature below the knee, including the foot. MR angiography avoids radiation and may be less susceptible to calcium or stent artifact but is time consuming, and results are variable between institutions. It is also limited by complications related to the use of Gd. However, several protocols for noncontrast MR angiography methods are available and appear to show promise. (See 'Magnetic resonance angiography' above.)

Digital subtraction angiography – Digital subtraction angiography (DSA) remains the gold standard for peripheral vascular imaging and is used primarily for the guidance of intervention. DSA has evolved to provide high-quality imaging, image-processing capability (last image hold, road mapping, bolus-chase angiography, pixel shifting), and improved functionality for the operator while decreasing radiation doses. Additional advancements in vascular imaging have arisen from fusions of CT or MR images with DSA images (rotational arteriography), which improves intraprocedural localization of vascular lesions to aid precise placement of vascular devices. Future iterations may combine fiberoptic or electromagnetically guided catheters and wires with cone-beam CT to guide interventions with markedly reduced radiation doses. (See 'Digital subtraction angiography' above.)

Intravascular ultrasound – Intravascular ultrasound (IVUS) can be used during vascular intervention to improve quantification of the severity of vascular stenotic lesions and has been used to aid placement of vascular devices. (See 'Intravascular ultrasound' above.)

Perfusion imaging – Vascular imaging studies all have limited ability to quantify perfusion, particularly perfusion to the foot in patients with CLTI. Traditional methods to estimate distal perfusion (eg, transcutaneous oxygen measurement) also have limitations. Alternative measures of perfusion include indocyanine angiography, hyperspectral imaging, single-photon emission computed tomography (SPECT), two-dimensional angiography, and positron emission tomography (PET) scanning. Data supporting the use of each of these modalities remain sparse, though are expected to increase as the need to better understand perfusion to specific wound beds has increased. (See 'Measures of perfusion' above.)

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Topic 101673 Version 6.0

References

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