The development of PAD is a complex process involving many different cell types, as well as a wide range of regulatory and environmental factors. A thorough understanding of PAD pathophysiology is still quite incomplete at this time. However, based on what is known, atherosclerosis is clearly the precursor to the development of PAD. Recently, there has been important progress in delineating the basic mechanisms that underlie atherosclerosis and its clinical manifestations in the peripheral vasculature. These advances in knowledge provide important clues about PAD pathophysiology and offer insights as to how this condition might be better diagnosed and treated. Therefore, the time seems right to consider an in-depth analysis of the current state of diagnostic imaging for PAD so that new knowledge about disease pathophysiology can be translated into improvements in patient care.
Current Diagnostic Imaging Techniques
Angiography is considered to be the gold standard for imaging PAD. It has the ability to accurately visualize the site, nature, and severity of lesions, and thus assist in treatment planning. It can be done in a variety of ways. Conventional x-ray angiography involves the injection of contrast media into the bloodstream. A series of x-rays are then taken which can demonstrate the arterial vessels and any stenosis or occlusions that may be present. Magnetic Resonance Angiography (MRA) provides a non-invasive alternative to conventional x-ray angiography. High-resolution images of the arterial vessels can be obtained without the need for x-ray radiation or the injection of contrast media. Despite its high accuracy, using angiography to specifically diagnose PAD has limitations. It is an invasive procedure that carries risk. For patients with severe PAD and significant co-morbidities, the risks may outweigh the benefits. Furthermore, it is impractical for large-scale screening and has limited utility in following disease progression or response to treatment due to its invasive nature.
Angiography
Despite the high resolution and direct imaging of the vascular lumen, arteriographic imaging has several limitations. It is an invasive procedure which can be complicated by vessel trauma, thrombosis or contrast allergy. The imaging is limited to the arterial lumen and the severity of peripheral atherosclerotic occlusive disease can be underestimated due to inability to visualize the vessel wall and presence of collateral circulation. This hazard of complications and limited visualization has shifted the favor of diagnosis of PAD to non-invasive techniques.
Initial techniques such as hand and foot vessel dissections to sound out the anatomy, arteriography in various forms has been the method of choice for the investigation of PAD. Antegrade technique via common femoral puncture and catheterization of the aorta or targeted vessel using fluoroscopic guidance is the conventional mode of performing an arteriogram. With advances in radiology, contrast volume and radiation dose has been reduced by the use of smaller catheters, selective catheterization and low rated fluoroscopic runs.
Doppler Ultrasound
An area of CTA technology that requires further advancement to allow broad clinical application is reduction in the amount of contrast agent required. This is essential for patients with renal impairment in whom iodinated contrast agents may exacerbate their condition.
In the current climate, CT angiography (CTA) is the emerging technique for detailed assessment of arterial anatomy. Due to its high accuracy in detecting significant stenosis, CTA is already being employed to plan reconstructive vascular surgery. This is likely to become the principal role of CTA. Simulation of angiography from CTA data also offers a non-invasive means of monitoring disease progression and effectiveness of medical therapy.
The development of imaging techniques that provide viewing of cross-sectional arterial anatomy has allowed a more precise diagnosis of the presence and nature of arterial disease. The use of magnetic resonance angiography (MRA) has shown promise but is limited by availability and cost and still requires further assessment of its accuracy.
High frequency ultrasound can also be used in the assessment of vein bypass grafts and is a useful adjunct to the clinical examination of limbs suspected of having arterial disease.
Duplex ultrasound provides anatomic information regarding the site and nature of arterial stenosis in addition to Doppler waveforms. It has become the investigation of choice when considering the use of endovascular techniques and provides reliable follow-up of such patients. Duplex ultrasound has been shown to have a sensitivity of 92% and specificity of 96% for the detection of clinically significant iliac stenosis when compared with contrast angiography.
When ultrasound is applied to the study of blood flow, the most common initial technique used is continuous wave Doppler. Continuous wave Doppler provides information regarding the presence and location of stenosis. Angiography of the relevant arterial segment may be required to guide planning for surgical intervention. However, with careful use of a combination of blood pressure measurements and Doppler waveforms, many patients can be managed without the requirement for more invasive angiography.
Computed Tomography Angiography (CTA)
CTA is valuable because it gives an actual picture of the entire blood vessel and the area surrounding it. This visualization is a unique asset of CTA compared to other imaging modalities. CTA can identify and localize arterial stenosis and occlusions. Visualization of bifurcation lesions is well achieved. This localization ability is important for the surgeon or interventional radiologist who will be performing the revascularization procedure. Knowledge of the proper anatomy and any potentially complicating adjacent structures increases the chance of a successful procedure and reduces the risk of any iatrogenic damage. A further unique and useful attribute of CTA is its ability to visualize the atheromatous plaque. Knowledge of whether a plaque is soft, calcified, ulcerated, or thrombosed can help predict the potential subsequent success of different types of revascularization techniques and also adds information on the severity of a stenosis. National Institute of Clinical Excellence (NICE) guidelines stated that for patients with diabetes mellitus or symptomatic PAD, CTA is the most suitable imaging modality as guidance for further intervention can be determined from the findings. It can also be used to screen the aorta for aneurysmal disease, an important associated disease that requires treatment in patients with PAD.
Computed tomography angiography (CTA) uses an X-ray technique to create detailed images of the blood vessels. Intravenous contrast material is injected, and a scan is then performed.
Innovations in Diagnostic Imaging
For decades, the basic examination method carried out for patients with peripheral arterial disease has been through the use of angiography, mainly because it is considered the definitive test. However, the development of less invasive methods of diagnosis has broadened the possibilities available for patients and clinicians. The innovation in diagnostic imaging of magnetic resonance angiography (MRA) has been a significant step towards non-invasive testing. It is a technique that provides a reliable alternative to conventional angiography. The virtues of MRA are that it is non-invasive and does not require the insertion of a catheter. It provides multiplanar imaging, localization of disease, dynamic contrast enhancement and visualization of runoff vessels. The technical advancements in MRA have shown accuracies of over 90% at identifying significant stenoses and occlusions in both the lower limb and renal arteries and similar to conventional angiography, provides information on stenotic morphology. MRA has become widely available and is a cost efficient procedure. Further studies on the cost effectiveness of MRA over the more invasive angiography will provide substantial evidence on the superior method of testing. This evidence may prompt an eventual change in the guidelines of diagnosis for peripheral artery disease in the future.
Magnetic Resonance Angiography (MRA)
Though time of flight MRA is excellent for vascular screening, it can sometimes provide too much contrast in differentiating blood from surrounding tissues, which is necessary for precise anatomic detail and diagnosis assessment. Phase contrast MRA and gadolinium-enhanced MRA are techniques that provide images similar to conventional angiograms, which can be viewed as a series of images or reconstructed into 3D images. Phase contrast uses flow-related enhancement and a pulse that causes flow void to produce images from which anatomic and pathologic detail can be assessed, while gadolinium-enhanced MRA uses an intravenous injection of gadolinium contrast to provide images with improved contrast between blood and surrounding tissues. With these techniques, there is the ability to improve detection and assessment of stenotic lesions and aneurysms. Due to the ability to morph 3D images, these techniques are also useful for surgical and/or endovascular planning. It is felt that MRA will eventually replace contrast arteriography as the sole diagnostic imaging modality for many vascular conditions. Unfortunately, at the present time, MRA has limitations in imaging small vessels and is not the best test for critical limb ischemia.
Time of flight MRA uses the natural flow-related enhancement of blood to create an image in which blood vessels are bright. A background saturation pulse is applied in this technique to cause signal loss in static tissues. This causes the image to have high contrast and appear as if the blood vessels are seen “flowing” amidst a black background. This black and white image is optimal for the detection of flow-related abnormalities such as stenosis or aneurysm, and with the saturation technique can be repeated to provide dynamic imaging that is useful for presurgical planning.
Magnetic resonance angiography is used mostly for the imaging of large vessels and is a very accurate test. With the newer generation of machines, there have been increasing reports of its use in imaging the entire lower extremity using techniques to provide improved visualization of distal vessels. This modality is able to provide imaging of the arterial system without ionizing radiation and is an excellent test for patients with renal insufficiency in whom contrast arteriography is relatively contraindicated.
Contrast-Enhanced Ultrasound (CEUS)
Sonicated gas-filled microspheres are the most commonly used contrast agents in ultrasound. These are highly compressible, making them excellent reflectors of sound, and they have a high nonlinear oscillation threshold, which enables differentiation from tissue on the basis of higher harmonic and ultraharmonic signals. This form of contrast agent and the development of specific software have allowed 3-dimensional contrast-enhanced ultrasound imaging, which has been shown to be as accurate as computed tomography angiography in assessing renal tumors and more sensitive in the detection of vascularity in certain focal liver lesions.
Contrast-enhanced ultrasound has emerged as a highly useful and minimally invasive means of assessing vascularity, from the aorta to microvasculature, of peripheral organs with recent popularity in the assessment of peripheral arterial disease. Ultrasonic contrast agents are microspheres composed of various materials such as albumin, lipid, or gas, encapsulated in a stabilizing shell. They vary in size from 1-8 ÎĽm and are injected intravenously. The microspheres are purely intravascular tracers, and their size reflects their behavior in the microcirculation. The outer shell confers inert behavior and resistance to pressure and temperature variations. This allows differentiation between microvasculature and larger vessels due to contrast microspheres remaining within the microcirculation until diffusion across capillary walls.
Ultrasound has long been a useful tool in the diagnosis of peripheral arterial disease due to its non-invasive nature and low cost. However, its usefulness has been limited in the past by inadequate visualization of distal vessels and operator dependence. Recent technological advances have allowed substantial improvements in the quality and utility of ultrasound. The development of higher frequency transducers and multi-frequency transducer arrays has allowed higher resolution imaging of superficial structures such as the carotid arteries and has resulted in vastly improved image quality throughout the peripheral vasculature. The development of wideband Doppler has permitted marked improvement in the sensitivity, specificity, and accuracy of hemodynamic information that can be gained from ultrasound. This is a significant advance as it allows determination of disease severity and progression without the need for more invasive procedures.
Positron Emission Tomography (PET)
PET imaging has been around for some time and is particularly well-established in the field of oncology. PET is now being proposed as a tool for the molecular imaging of peripheral arterial disease. The major advantage of PET is its ability to detect changes at the cellular and molecular level before anatomic changes occur. This is very attractive, as it is believed that changes in the arterial wall at the cellular level, in particular inflammatory changes, precede narrowing of the lumen. By identifying these changes, it may be possible to both understand the natural history of PAD and identify targets for future therapeutic interventions.
Positron Emission Tomography (PET) imaging involves the use of positron-emitting radioisotopes which are often bound to biologically active molecules. When the radioisotope decays, it emits a positron which subsequently annihilates with an electron resulting in the production of two high energy photons which are emitted in opposite directions. The scanner detects these photons and a computer-generated image of the concentration of the PET tracer is produced.
Optical Coherence Tomography (OCT)
Atherosclerosis is known to be a focal and multifocal disease in its initial stages and often occurs at arterial bifurcations where flow patterns are disturbed. Establishment of virtual histology by OCT is technology which uses the specific light absorption and dispersion characteristics of different tissue components to differentiate them on an image. This will enable the determination of different plaque types such as fibrous, calcified, lipid, and necrotic, and also the reconstruction of flow patterns and correlation with the location of the lesion, very useful information for determining the risk and benefit of treatment options in individual cases with atherosclerosis in affected arteries.
High-resolution 3-D imaging has been developed, which allows accurate and quantitative examination of plaque volume and characterization. This is beneficial for frequent observation of arterial condition in patients and for research purposes in the development of new treatments for different types of PAD.
Software-based micro-assembly of intravascular OCT images has attained a high level of aggregated image quality by canceling broadcast and intensity artifacts. This has been advantageous for the appearance of diseases affecting the arterial wall as it permits detailed visualization of the condition and the microstructure of atherosclerotic plaques for effective diagnosis and formulation of a treatment strategy.
In recent years, OCT has been adapted for application in other areas of the body such as the gastrointestinal tract, bladder, and coronary artery. OCT systems can be categorized as time-domain or frequency-domain systems, with the latter providing a better image acquisition rate and dynamic range.
OCT is a new diagnostic method used for imaging the microstructure of biological tissues. The use of low-coherence interferometry permits the extension of imaging range compared with confocal microscopy. It has been successfully applied in ophthalmology for imaging the retina, cornea, and anterior segment of the eye and providing an effective alternative to invasive histological methods.
Future Directions and Conclusion
Initial attempts to detect PAD and measure severity of PAD have significantly increased the biologic and imaging understanding of PAD, but have not had a major impact on the treatment options for patients with PAD. Measurement of ABI and segmental pressures have helped to define the nature and anatomic location of PAD in some patients, but in many patients with CLI Class IV or those with severe foot or leg ischemia, comorbidities or anatomic considerations have made the nature and location of PAD difficult to assess and treatment decisions difficult to make. In some of these high-risk patients, potentially limb-saving treatments have carried significant risks and the inability to identify which patients are most likely to benefit from these therapies presents another dilemma. The ability to identify patients at high risk for poor health outcomes or for complications of revascularization would have a significant influence on the decision to pursue revascularization vs. medical treatment, and the choice of a specific revascularization treatment. Prediction of therapy type and expected outcome provides an ideal setting for the use of Decision Analysis Models such as Markov or Micro-simulation Models, which can be used to determine optimal long-term strategies for patients with multifaceted chronic disease. This modeling has been highly successful in heart disease but has yet to be attempted in PAD.
Future directions—The veterans seen at VAMC medical clinics have multiple co-morbidities which have the potential to significantly impact their health, functionality, utilization of healthcare services, and mortality. As such, it would be important to gain a better understanding of patterns and changes in patient-centered outcomes, and utilization of healthcare resources in this setting. To do so, it would be important to combine the abilities to detect PAD and measure severity of PAD with other clinical and imaging data to predict future changes in health status and utilization of resources in veterans with PAD. Outcome and utilization data could be compared between veterans with and without PAD who are identified in this fashion. The identification of PAD specific diagnostic and severity related codes and charges would enhance this capability. The finding of significant changes in health status and/or utilization due to PAD would likely lead to the development and testing of interventions to improve health and quality of life in veterans with PAD.
