Peripheral arterial disease (PAD) is a condition that is caused by a problem with the vessels (arteries) carrying blood to the peripheral areas of the body, mainly the legs. The arteries become clogged with plaque, fatty material, and calcium, which is caused by a buildup of cholesterol on the artery wall. When a person with PAD walks, runs, or takes part in activity using the legs, the muscles in the affected limb can be starved of the necessary blood and oxygen needed for energy creation. This is because the clogged artery is not able to release enough blood past the blockage to supply the limb, so therefore it becomes ischemic. This leads to symptoms and signs (which will be explained later) and if left untreated can result in further complications with the limb, including amputation. However, this is relatively rare in the UK. The legs are the most common location of PAD, due to the increased atherosclerosis seen in individuals of older age. PAD can, however, also occur in the arteries supplying blood to the arms, the abdominal organs, etc. PAD in the arms is less common in comparison to the legs due to the same reason as the fact that the legs are more commonly affected, and often times it is very mild with little symptoms.
Definition and Overview
PAD is a common, debilitating disorder that occurs due to the persistent occlusion of large arteries. It is mainly seen in the aorta and lower extremities, and is also referred to as peripheral vascular disease. The epidemiology of the disease reveals a major public health problem in the Western world; PAD is affecting about 10 million men and women in the United States, and is found to be more prevalent in women than men. Despite exhibiting severe symptoms in some patients, a majority of individuals are oligo-symptomatic. IC, or intermittent claudication occurs in 2.5% of the general population ages 40 and above, and is a classic symptom of PAD, though only one third of these individuals will experience marked functional impairment. IC is a reliable marker for the presence of underlying atherosclerotic disease, and is an independent predictor for CAD and cerebrovascular disease.
Importance of Early Diagnosis
In summary, given the high prevalence of PAD, its atypical presentation and association with high cardiovascular and cerebrovascular morbidity and mortality, and the availability of intervention proven to effectively reduce cardiovascular risk in all patients with atherosclerosis, there is a pressing need for improved early diagnosis of both symptomatic and asymptomatic PAD.
The public-health impact of PAD and the paucity of data regarding the effectiveness of medical therapy for intermittent claudication make the identification of patients with asymptomatic PAD a high priority. Unfortunately, the initial diagnosis of PAD in its pre-symptomatic phase most often occurs in the setting of a cardiovascular event related to atherothrombosis in other arterial beds, rather than recognition of leg ischemia. This may in part be due to the lack of a readily available, widely accepted and reliable tool for early diagnosis of PAD.
This emphasizes the importance of identifying PAD in its early stages, before the onset of claudication or development of peripheral embolism, so the aggressive cardiovascular risk factor modification which has been proven to reduce cardiovascular events in patients with and without known.
Other investigations have demonstrated that the prognosis of symptomatic PAD is worse than that of many symptomatic cardiovascular diseases. Hirsch et al found that the 4-year cardiovascular mortality and morbidity after a myocardial infarction was 30% compared with 50% in patients with symptomatic PAD.
Data from the Walking and Leg Circulation Study, a multicenter study of 460 men and women with symptomatic PAD, demonstrated that the presence of PAD is an independent predictor of mortality in patients with symptomatic.
In the Edinburgh Artery Study, a population-based study of 1592 men and women aged 55 to 74 years, those with claudication had a significantly greater all-cause mortality rate compared with those without claudication (hazard ratio 1.58) and a 2-fold increase in cardiovascular mortality after adjustment for age and sex, despite a similar prevalence of coronary heart disease at baseline.
Once patients with peripheral artery disease develop claudication, intermittent leg pain with walking, only approximately 5% will progress to limb-threatening ischemia and another 5% to 10% will have improvement in claudication. However, among those with claudication, mortality can be as high as 20% to 25% in 5 years, consistent with the high prevalence of cardiovascular disease in these patients.
Importance of Early Diagnosis in PAD
Diagnostic Methods
High blood pressure should be suspected in patients with PAD, but the diagnosis can only be established by blood pressure measurements. A systolic bruit heard with a stethoscope is suggestive of arterial stenosis. Any investigation of other cardiovascular risk factors should be guided by the history and physical examination. Random blood lipid measurements can be considered in patients with claudication and other cardiovascular risk factors or those who are candidates for coronary revascularization.
Skeletal muscle vascular function or functional status in patients with PAD can be evaluated by the peripheral arterial questionnaire (see later chapter on quality of life and functional status). Please refer to the questionnaire for assessment of intermittent claudication in the article on conservative management of peripheral arterial disease, which is recommended in the development of outcome measures for clinical trials. This may be completed over the telephone and is a potentially low-cost method for the assessment of functional status of patients with claudication.
A careful evaluation of the hips and thighs may reveal that some patients with buttock or thigh claudication have an abnormal aorto-iliac pulse. A history of stroke is an important predictor of concomitant coronary artery disease or cerebrovascular disease. Any patient with suspected PAD should be questioned about cardiovascular or cerebrovascular symptoms and risk factors, and there should be a general inquiry about symptoms and risk factors for atherosclerosis in other organ beds. This can be noted under typical angina, which has been used to describe angina of recent change of probable atherosclerotic origin. A history of other atherosclerotic and related disorders can be used to assess the risk of cardiovascular events and the 10-year risk of myocardial infarction, stroke, or death.
In addition to claudication, some patients with PAD present with pain at rest. Ischemic leg pain at rest is indicative of more severe ischemia and is often due to critical limb ischemia. Symptoms of rest pain include sudden onset severe pain that is associated with paraesthesia, paralysis, or coldness in the limb. Sudden onset severe limb pain suggests the presence of acute limb ischemia.
Medical history. Claudication, a reproducible ache or cramping pain in the muscles in the lower extremity, is the classic symptom of intermittent claudication. It is defined as ischemia-induced muscle pain that is promptly relieved by rest and is highly specific for PAD. Typically, the distance the patient can walk to the point of onset of claudication symptoms is used as an objective measurement of severity. The severity of PAD cannot be accurately graded by symptoms or physical examination alone.
Medical History and Physical Examination
Factors that affect functional capacity: Determine how far the patient can walk and at what speed before the onset of claudication pain. Inquire about the ability to climb flights of stairs, walk uphill, or do heavy labor. Symptoms that occur with shorter periods of exercise suggest more severe PAD. Symptoms that occur with mild exercise suggest moderate or severe PAD. Symptoms that occur at rest may indicate critical limb ischemia. This is a medical emergency, and patients should be referred to a vascular specialist immediately.
Peripheral arterial disease (PAD) is detected based on a careful history and physical examination and confirmed with non-invasive and/or invasive testing. A classical symptom of intermittent claudication is suggestive of PAD; however, many patients do not volunteer this symptom unless specifically asked. Thus, it is important to inquire about claudication symptoms in a systematic manner. Other symptoms related to specific anatomic locations of PAD (aortoiliac, renal, mesenteric, upper extremity) may suggest the diagnosis. Ask about the duration and character of symptoms. Determine any functional limitation imposed by symptoms.
Ankle-Brachial Index (ABI) Testing
An ABI of 0.9-1.3 is considered normal. An ABI of less than 0.9 indicates the possibility of the presence of PVD. An ABI of less than 0.6 is indicative of severe disease. An ABI of over 1.3 is indicative of vessel calcification. Ankle pressures can also be used in isolation to give an indication of disease location and severity.
ABI = ankle systolic pressure / highest arm pressure
An ABI is the ratio of the systolic blood pressure at the ankle relative to that in the arm. Measurements are usually made in the supine position to minimize the possibility of leg edema affecting the result. The patient should be rested for at least 10 minutes and not have smoked in the last 2 hours. Pressures should be measured in both arms to rule out subclavian stenosis; the higher pressure is used for the ABI calculation. Systolic pressures are measured in the brachial arteries using a sphygmomanometer and a Doppler probe. The posterior tibial artery is most commonly used for measuring the ankle pressure; however, if disease is suspected in this vessel, the dorsalis pedis should be used instead. The cuff size should be appropriate for the size of the patient’s limb; using a cuff that is too small can artificially elevate pressures, and a cuff that is too large can lower them. Pressures are recorded twice, and the average used for the calculation.
Doppler Ultrasound
Doppler ultrasound uses sound waves to measure blood flow and blood pressure in the arteries. By measuring the rate of blood flow at different points in the lower extremities, an experienced operator can often determine whether there is a significant narrowing of an artery. In addition to providing guidance to the best area to obtain an arterial blood pressure, this simple, non-invasive test also provides an indication of the severity of the disease present. Unfortunately, it can be difficult to obtain good results with Doppler ultrasound in individuals with very severe PAD who also suffer from heart failure. High blood pressure in one or more of the ankle arteries is an indication of significant blockage, and low blood pressure in the ankle is an indication of poor blood flow to the extremity. ABI or ankle-brachial index, is derived from the blood pressure measured at the arms and the ankles. It is calculated by dividing the higher of the two pressures in the ankle by the pressure in the brachial artery at the arm. An ABI index less than 0.9 is an indication of PAD. This test can be somewhat falsely elevated in individuals with diabetes due to calcification of the arteries. This simple test is the mainstay of diagnosis for PAD due to its simplicity and predictive value. Unfortunately, it does not provide a visual representation of the blockages present.
Angiography
Angiography is a diagnostic method that provides an anatomic visualization of the arterial system. It can be performed by several methods, but catheter angiography is considered the most definitive and accurate method. The most conventional method of catheter angiography involves insertion of a catheter into a large artery or vein and injection of contrast media under fluoroscopic imaging. Magnification and serial film exposure may be used to provide detailed images of the arterial system. Digital subtraction angiography is another form of angiography in which images are captured digitally and contrast media is subtracted from the images. This reduces the amount of contrast media used and has a shorter procedure time. Intravascular ultrasound is an angiographic procedure in which an ultrasound probe is inserted with a catheter to provide images of the arterial walls. Magnetic resonance angiography and computed tomography angiography are non-invasive methods of angiography that provide detailed images of the arterial system. These methods continue to improve and are becoming almost as accurate as catheter angiography. Due to varying success rates of the non-invasive methods, catheter angiography remains the standard method of angiography.
Additional Diagnostic Tools
Computed tomography (CT) is a diagnostic medical imaging test. It uses a combination of X-rays and computer technology to produce cross-sectional images of the body. Within these images, blood vessels can be highlighted by injecting a contrast dye into the bloodstream. A recent technological advancement known as “spiral” CT scanning means that large sections of the body can be imaged in one quick scan. Spiral CT scans, combined with new software to reformat the images, have greatly improved how blood vessels can be imaged. CT angiography involves the examination of blood vessels after injection of a radio-opaque contrast agent and is non-invasive. It can be carried out on any electronic scanner, such as those used for the spiral CT scan. Electrocardiogram (ECG) gating is being used to obtain images at specific points in the cardiac cycle to improve visualization of the arteries of the heart. CT angiography of the coronary arteries is affected by motion artifact and calcification, which can shift the radio-opaque contrast agent and is not ready to replace invasive angiography. High-quality images of peripheral arterial disease are reliably obtained, as shown in the pictures below. A specific identification of lesions that will affect the management of the disease can be made. Where a decision has been made for invasive treatment, CTA may now be used to plan the intervention by detecting the extent, precise location, and characteristics of the narrowed or obstructed blood vessels. Although it has been estimated that around 12-15% of patients with PAD cannot safely undergo invasive angiography, there is no reason why they cannot have a CT angiography. This means there is indeed a place for CTA in the diagnosis of PAD, although its exact role has yet to be defined. Currently, the use of CTA for PAD is increasing, and further evidence of its clinical usefulness is expected.
Computed Tomography Angiography (CTA)
Computed Tomography Angiography (CTA) CT is widely available and is the most frequently used imaging modality in PAD. Its ease of performance and superior resolution of the arterial lumen make it the technique of choice for imaging the distal aortoiliac segment and for surgical planning. The demonstration of calcification by CT is also useful in regions difficult to assess by other modalities, where heavily calcified vessels may be considered for surgery. The primary limitation of CT is its relatively poor ability to characterize atheromatous plaque and to distinguish non-flow limiting stenoses from occlusions. These limitations may be addressed to some extent by new or emerging CT-based technologies. Dynamic CT using continuous infusion of intravenous contrast medium has been assessed in small studies for the characterization of soft plaque and for quantification of perfusion or blood volume changes in the calf musculature in the setting of critical limb ischaemia. Spiral (or helical) CT and electron beam CT are ultrafast techniques that allow volumetric imaging and might permit improved characterization of stenoses by enhancing the identification of vascular remodeling. They may also prove useful in defining the extent of disease in the lower limb with improved vessel coverage and thus may be particularly relevant in the setting of pedal bypass surgery. The further potential for CTA to replace digital subtraction angiography in the diagnostic work-up of PAD will depend on the demonstration of acceptable diagnostic accuracy and cost-effectiveness. Current evidence from small series suggests that CTA has a high sensitivity and specificity for the detection of significant iliac and femoropopliteal stenoses and occlusions. This remains an important area of research given the known limitations of formal angiography as a reference standard, the need to perform non-invasive tests in randomized trials of PAD therapy, and the increasing application of endovascular procedures to treat PAD.
Magnetic Resonance Angiography (MRA)
Because of its non-invasive nature, MRA is a particularly attractive alternative to standard angiography in patients with renal failure or contrast allergies. It may also be used to guide open or endovascular interventions and bypass surgery in selected patients. Difficulty visualizing distal vessels in patients with severe peripheral arterial disease does limit MRA. However, newer technology, such as blood-pool contrast agents and faster and higher resolution MRI, will likely overcome these limitations.
Magnetic resonance angiography (MRA) is a study that uses MRI technology with intravenous injection of gadolinium-based contrast agents to produce images of the arterial system. It is non-invasive and has the capability of imaging large volumes of the body. Standard contrast angiography only visualizes a very small portion of the vasculature system and fluoroscopic guidance cannot localize the exact anatomical position of stenosis. This makes MRA a very powerful tool for diagnosing PAD. MRA has shown to be very accurate for diagnosing high-grade renal and aorto-iliac PAD.
Blood Tests and Biomarkers
Blood tests and biomarkers are the simplest mode of analysis and are useful tools to screen for vascular disease. A complete blood count (CBC) with differential and platelet count is useful to detect anemia (a common cause of leg fatigue and exacerbator of claudication) and may suggest the presence of infection. Measurement of fasting glucose can identify diabetes, which is an important risk factor for and co-existent disease with PAD. Control of glycemic status can be monitored more accurately through measurement of glycosylated hemoglobin. High levels of cholesterol (and in particular low-density lipoprotein-cholesterol) are associated with vascular disease. Measurement of triglyceride and high-density lipoprotein-cholesterol levels have been shown to be better predictors of cardiovascular events than LDL-C in patients with intermittent claudication. Hyperhomocysteinemia is another marker risk factor for atherosclerosis and cardiovascular disease; however, treatment of elevated homocysteine has not been shown to reduce cardiovascular events and is not recommended. C-reactive protein is an acute phase reactant produced by the liver in response to injury or inflammatory stimuli. It is a marker for systemic inflammation and has been shown to be an independent risk factor for PAD and increased cardiovascular mortality. Although there is not clear evidence base, measurement of CRP and lipid homocysteine levels are potentially useful in patients, particularly at high risk. Various other inflammatory mediators have been associated with atherosclerosis, and efforts are being made to identify those which may influence disease presence and prognosis. With recent advances in technology, screening methods such as proteomics and metabonomics have shown promise for detection of biomolecules that could serve as indicators for presence of disease or response to therapeutic intervention. Although there are many potential blood tests and newer tests are continually being developed, it is important to recognize that not all are necessary or cost-effective in the management of any given patient.
Challenges and Limitations
PAD is often not the only cause for symptoms in the lower limbs, and atypical presentations of spinal stenosis, peripheral neuropathy, neurogenic and joint disease can cause differential diagnosis confusion. Treatment for limb-threatening PAD in these cases may not resolve the initial symptoms and other disease treatment may result in a further delay in resolution of PAD symptoms.
A diagnostic imaging test can present a false negative finding when disease severity is mild due to decreased sensitivity of the test in mild disease. The specific findings for test limitations are discussed in relevant chapters.
Causes for false negative and false positive findings in diagnostic exams are debated. A false negative finding with ABI occurs because the blood pressure cuff is not properly positioned above the artery being measured. It can also occur due to the presence of medial artery calcification. A false positive finding occurs when an individual has pain at the calf muscle when the cuff is being inflated above the knee, this is called pain at a higher level and is indicative of possible LSS.
For example, a duplex ultrasound has decreased sensitivity and specificity in individuals with renal failure and endovascular imaging often provides poor quality images in individuals with severe calcification. Understanding the limitations of each test can help to avoid further testing and imaging in a patient, leading to a more cost-effective diagnosis.
Challenges and Limitations: This chapter discusses the difficulties that occur when trying to diagnose PAD and other conditions accurately. These challenges often lead to wrong or inconclusive diagnoses. The misinterpretation of diagnostic test results can often lead to inappropriate medical or surgical treatment. Therefore, identifying the limitations associated with a given test is very important.
4.1 Interpretation of Results
Analogous difficulty with interpretation of test results may occur in patients who present with leg pain or difficulty with walking and have multiple coexisting clinical conditions that cause lower extremity functional limitations. Elderly patients frequently have coexisting leg and foot arthritis, peripheral neuropathy, and vascular claudication. In such patients, noninvasive testing may identify multiple arterial lesions, but it may be difficult to determine the relative contribution of each of these lesions to the patient’s symptoms and level of functioning. Finally, interpretation of test results may be confounded by discrepancies in findings between various noninvasive tests on the same patient. Inconsistent findings between different tests may lead to uncertainty about the correct diagnosis.
The interpretation of results from noninvasive testing represents one of the most crucial elements in the evaluation of patients with suspected lower-extremity peripheral arterial disease (PAD). Unfortunately, interpretation of the significance of a given test in individual patients is not always straightforward. In general, test findings are correlated with the patient’s symptoms to determine whether lower extremity symptoms are attributable to PAD. However, because noninvasive testing for PAD is a direct assessment of lower extremity arterial structure and function, in some cases testing may reveal previously undiagnosed PAD in patients with leg symptoms that were attributed to other clinical conditions. The most definitive example is leg claudication occurring in a patient with known lumbar spinal stenosis. In such patients, a finding of PAD may represent an incidental finding, and the true effect of this lesion on the patient’s symptoms may be difficult to determine without therapies such as lumbar decompression or lower extremity revascularization.
False-Negative and False-Positive Findings
The diagnosis of disease is almost never problem-free. Herein lies a paradox: the more sophisticated and refined the diagnostic tools, the more likely the data could be misleading. This is important to consider when interpreting results of diagnostic tests of PAD. We now focus on an issue of critical importance with regard to the clinical usefulness of noninvasive tests: the rates of false positive and false negative results. This issue is relevant both to individual tests and the extent of testing overall to detect PAD. Medical decision-making with regard to the need for therapy is heavily influenced by the severity and certainty of the diagnosis. High-risk, symptomatic PAD with limb threat or disabling claudication is a relatively easy and certain syndrome to diagnose non-invasively and the need for revascularization or other specific therapy is clear. On the other hand, in patients with atypical leg symptoms, patients being screened for PAD in an apparently healthy state or those with multiple other medical problems, the perceived risk and severity of the putative PAD or the potential benefit of treating it may not justify extensive testing if test accuracy is low and there is risk of harm with treatment.
Coexisting Conditions and Differential Diagnosis
Atherosclerosis is not a localized disease, and many patients have coexisting disease in the coronary or carotid vessels. A history of symptoms suggesting myocardial ischemia or transient cerebral ischemia raises the suspicion of coexisting arterial disease at these sites. In such patients, a resting electrocardiogram and simple non-invasive tests such as exercise tolerance and radionuclide ventriculography are useful to exclude or confirm coronary artery disease. Similarly, carotid artery disease is best evaluated by non-invasive tests such as ultrasound, CT or MRI. When limb and other arterial disease are present simultaneously, the extent of atherosclerosis is generally diffuse and patients have a particularly poor long-term outlook. If viable treatment options are available, it is important in such patients to identify the arterial beds where symptoms are most disabling. This is generally achieved by reviewing the claudication history in the context of the distribution of arterial disease. When the precise location of symptoms is unclear, functional tests such as segmental pressure measurement or exercise stress testing can provide guidance as to the most appropriate site for revascularization. In some cases, it will be difficult to distinguish between new symptoms related to acute-on-chronic limb ischemia and recurrent symptoms arising from subacute graft closure. In the absence of a painful, pulseless or gangrenous limb, the use of functional tests and assessment of global cardiovascular risk may be preferable to invasive procedures in clarifying the diagnosis.
