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Peripheral Artery Disease
Peripheral artery disease (PAD) is an important manifestation of systemic atherosclerosis with significant morbidity and mortality.PAD affects the lower extremities and is defined as a stenosis or occlusion in the aorta or the arteries supplying blood to the legs, including the iliac, femoral, popliteal, or infrapopliteal vessels (peroneal, posterior tibial, and anterior tibial arteries). Stenosis is typically caused by atherosclerosis. Nonatherosclerotic causes of vascular disease also can obstruct the peripheral arteries (see later discussion). There are two major clinical consequences of PAD. First, PAD can cause leg symptoms that include intermittent claudication, which impairs walking ability and diminishes the quality of life, and rest pain, which occurs when there is critical limb ischemia (CLI). Second, as an atherosclerotic disorder, PAD is associated with as much as a four- to six-fold increased risk of cardiovascular death, myocardial infarction (MI), and stroke. This chapter reviews the epidemiology, pathophysiology, and management of PAD.
Epidemiology
Prevalence and Incidence
The prevalence of PAD has been determined from several epidemiologic studies. Early studies determined the prevalence of PAD from the presence of symptoms, such as intermittent claudication, or a history of peripheral revascularization. Many patients with PAD are asymptomatic, and the use of noninvasive diagnostic testing, specifically the measurement of the ankle-brachial index (ABI), has provided further clarification of the overall prevalence of the disease. In most of these studies, an ABI of 0.90 or less was used to define PAD. The prevalence of PAD in adults 40 years of age or older is estimated to be 7.2%, accounting for approximately 8.5 million adults in the United States alone. In addition, PAD is estimated to affect as many as 202 million individuals worldwide, with increasing prevalence in both high and low-middle income countries. There is a sharp increase in the prevalence of PAD with increasing age, approximating 16.8% of women and 19.8% of men older than age 65 years in the German Epidemiological Trial on ABI (GetABI study). There is a similar trend in the US, as ∼20% of adults older than 70 years have PAD, with a higher prevalence among those with a history of diabetes or smoking. Recent studies have also shown higher PAD prevalence in populations of lower socioeconomic status, including lower education and lower income levels, as well as a disproportionate burden among some race/ethnicity groups, particularly blacks, as compared with Hispanic or non-Hispanic white populations.
The incidence of PAD, which is largely based on the development of symptomatic disease, is less well established. Data from the Framingham Heart Study show an incidence rate of intermittent claudication of less than 0.4 per 1000 per year in younger men (35 to 45 years) and a rate as high as 6 per 1000 per year in older men (older than 65 years). The incidence of symptomatic PAD is lower in women in most age groups, although the estimates are more comparable in the oldest age group. Estimates of the incidence of PAD based on ABI are less commonly reported. One such study reports an incidence of 1.7 per 1000 person-years for ages 40 to 54 years, 1.5 per 1000 person-years for ages 55 to 64 years, and 17.8 per 1000 person-years for ages 65 years and older. When the diagnosis of PAD is based on ABI alone, the differences in incidence between men and women are less evident. In the Cardiovascular Health Study, for example, there are no gender differences in the incidence of PAD based on ABI after adjusting for cardiovascular risk factors. At the other end of the spectrum, CLI represents approximately 11% of the patients with PAD. The incidence of CLI is estimated to be approximately 2% per year in the US or 400 to 1000 per million individuals per year.
Risk Factors
Atherosclerotic risk factors, including smoking, diabetes, hypertension, hyperlipidemia, renal insufficiency, and inflammation, contribute to the development of PAD (see Chapter 142 ).
In virtually all population-based studies, smoking has been one of the strongest risk factors for PAD. The risk is highest for current smokers compared with nonsmokers, with two to four times increased odds of PAD and the risk of PAD increases in a dose-dependent manner relative to the number of cigarettes smoked and the duration of tobacco use. In the Women's Health Study, smoking more than 15 cigarettes per day increased the risk of incident PAD approximately 17-fold, and the risk was lower in former smokers than in active smokers. In the Edinburgh Artery Study, smoking was two to three times more likely to cause lower extremity PAD compared with coronary artery disease (CAD).
Diabetes is also a potent risk factor for PAD and increases the risk of PAD by two- to four-fold. Data from the Rotterdam study and the San Luis Valley Diabetes study reveal that upwards of 12% to 20% of individuals with PAD have coexisting diabetes. Moreover, the risk of PAD increases depending on the duration and severity of diabetes. In the Strong Heart Study, individuals with PAD had a more than two-fold higher prevalence of diabetes compared with those without PAD, and diabetes tended to be of longer duration and associated with higher glycosylated hemoglobin levels. Patients with PAD who have concomitant diabetes are also more likely to develop intermittent claudication and ischemic ulceration and to require major amputation compared with those without diabetes.
Hypertension is a more modest risk factor for the development of PAD compared with its importance as a risk factor for coronary and cerebrovascular disease. Although evidence suggests that hypertension increases the prevalence of PAD by 1.5- to 2.2-fold, the association of hypertension with an incident or symptomatic PAD is less clear. Among Native Americans in the Strong Heart Study, those with PAD had a higher mean systolic blood pressure, and the prevalence of PAD was significantly higher in those with established hypertension. In the Framingham Heart Study, hypertension increased the risk of developing intermittent claudication. In the Women’s Health study, the risk of incident PAD increased by 43% with every 10 mm Hg increase in systolic blood pressure. In the Atherosclerosis Risk in Communities (subjects with diabetes) study, individuals with systolic blood pressure greater than 130 mm Hg were significantly more likely to develop PAD. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, both low (<120 mm Hg) and high (>160 mm Hg) systolic blood pressures were associated with PAD events (PAD-related hospitalization, PAD-related procedure, outpatient PAD medical therapy, or PAD-related death).
Dyslipidemia, specifically elevated total cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides, and reduced high-density lipoprotein (HDL) cholesterol, is associated with PAD. Epidemiologic studies, such as the Cardiovascular Health Study and the Framingham Heart Study, have shown that a 10-mg/dL increase in total cholesterol increases the risk of PAD by 5% to 10%. In the Strong Heart study, individuals with PAD had significantly higher levels of total cholesterol, triglycerides, and LDL cholesterol than those without. The Whitehall study also demonstrated that an elevated total cholesterol level was associated with symptoms of intermittent claudication.
Chronic renal insufficiency has been recognized to be significantly associated with PAD in several studies. In the NHANES, renal insufficiency (defined as a glomerular filtration rate <60 mL/min) was associated with a 2.5-fold higher odds of PAD even after adjustment for other cardiovascular risk factors. In the Heart and Estrogen/Progesterone Replacement (HERS) study, renal insufficiency was also associated with an increased risk of incident peripheral vascular events, including revascularization and amputation. In The Chronic Renal Insufficiency Cohort study (CRIC), women less than 70 years old were 50% more likely than men to develop PAD. Moreover, renal insufficiency or albuminuria increases the mortality risk in patients with PAD irrespective of other risk factors, including diabetes.
Several nontraditional factors have been associated with PAD. Markers of systemic inflammation, such as C-reactive protein (CRP), are elevated in patients with PAD. In the Physicians’ Health Study, the risk of developing symptomatic PAD was approximately two-fold higher in those in the highest CRP quartile compared with those in the lowest quartile. Although several markers of inflammation, such as soluble intercellular adhesion molecule 1, chemokine ligand 2, galactin-3, and others have been studied in patients with PAD, none are routinely measured in clinical practice. Insulin resistance is associated with both prevalent PAD as shown in data from the NHANES study and with incident PAD as demonstrated in the Cardiovascular Health Study.
Pathobiology
Atherosclerosis is a progressive vascular disease characterized by lipid accumulation and the formation of plaque in the arterial walls (see Chapter 145 ). The pathophysiology of atherosclerosis includes endothelial dysfunction, vascular inflammation, and cellular proliferation. Early in the atherogenic process, recruitment of inflammatory cells and accumulation of lipids promote the development of a lipid-rich atheroma. Inflammation promotes the elaboration of proteases that weaken the vessel wall and allow positive remodeling with the outward expansion of the arterial wall to accommodate the intimal expansion that occurs as a result of plaque formation. Although positive remodeling initially preserves the arterial lumen, continued plaque growth results in progressive narrowing of the lumen, which then limits blood flow and oxygen supply to target organs. This process may be enhanced by biomechanical factors, such as turbulent blood flow, particularly in areas of altered shear stress. This phenomenon is of particular significance at branch points along the arterial tree, which is predisposed to atherosclerotic plaque formation.
Pathologic studies primarily involving coronary arteries have shown that atherosclerotic plaque formation is a dynamic biologic process that exhibits marked heterogeneity; some plaques remain “stable,” while others have a more “unstable” pathophysiology. Stable atherosclerotic plaques may be asymptomatic, or symptoms can occur with exertion if demand exceeds supply. On the other hand, “vulnerable” or unstable plaques are prone to acute rupture, and superimposed thrombi may cause sudden arterial insufficiency, and cause events such as MI, or theoretically acute limb ischemia (see Chapter 142, Chapter 145 ). Whereas atherosclerotic plaque contributes importantly to PAD, recent pathologic studies have demonstrated an important role of thrombosis detected in amputated limbs of patients with CLI. Specifically, in almost 75% of patients with CLI, thrombosis contributed to luminal stenosis. Significant atherosclerosis, often with associated thrombus, was found in most lesions in the femoral-popliteal arteries, whereas thrombus without significant atherosclerosis was found in the majority of infrapopliteal arteries, indicative of embolism from a more proximal site, or thrombosis in situ. It is notable that a recent genome-wide association study showed an association between PAD and Factor V Leiden (FVL; F5 p.R506Q), further highlighting the potential pathophysiologic role of thrombosis in PAD.
Although PAD is mostly caused by atherosclerosis, other causes include thromboembolism, vasculitides (e.g., thromboangiitis obliterans, giant cell arteritis, Takayasu arteritis), trauma, popliteal artery entrapment, cystic adventitial disease, fibromuscular dysplasia, and endofibrosis of the iliac artery ( Table 146.1 ). Nonvascular causes of leg pain should also be considered in the differential diagnosis, including lumbosacral spine disease (causing pseudoclaudication), venous diseases, hip, knee, or ankle osteoarthritis, chronic compartment syndrome, myositis, and others ( Table 146.2 ).
Table 146.1
Nonatherosclerotic Causes of Peripheral Artery Disease
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Table 146.2
Nonarterial Causes of Leg Pain (Differential Diagnosis for Intermittent Claudication Symptoms)
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Clinical Manifestations
Most patients with PAD are asymptomatic at presentation. Typical claudication symptoms are present in only 10% to 35% of patients and CLI in approximately 11%. The classic symptoms of PAD include intermittent claudication and rest pain, the latter occurring in patients with CLI. Intermittent claudication is defined as exertional discomfort in the muscles of the lower extremities that is variably described as pain, aching, burning, fatigue, or heaviness. Symptoms arise with leg exercise, typically walking, and are relieved after a predictable duration of rest (usually <10 minutes). Intermittent claudication occurs with effort and not at rest, and symptoms do not abate until activity ceases; a change in position is unnecessary. Although many patients with PAD report atypical symptoms, most have impaired walking ability exemplified by reduced walking speed or distance. CLI arises when there is inadequate perfusion to meet the resting metabolic demands of the tissues. Patients with CLI have pain at rest, typically affecting the toes, feet, or both; they may have accompanying tissue loss with nonhealing ulcers, tissue necrosis, or gangrene ( Fig. 146.1 ).
Diagnosis
The diagnosis of PAD is often evident from the history and physical examination. An important diagnostic feature is diminished or absent pulses in the legs. The examiner should palpate the femoral, popliteal, dorsalis pedis, and posterior tibial pulses. The absence of selected pulses provides insight into the location of critical stenoses. The groin should be auscultated for femoral artery bruits, which may be indicative of turbulent flow from atherosclerotic plaque. Other findings suggestive of PAD include pallor of the soles of the feet upon leg elevation and the development of rubor when the feet are then placed in the dependent position. Signs of chronic limb ischemia include muscle atrophy; hair loss; thickened nails; and in severe stages, cyanosis, pallor, and coolness of the skin of the feet.
Ankle–Brachial Index
The ABI is a simple, non-invasive test for the diagnosis of PAD. Normally, when measured in the supine position, the systolic blood pressure in the legs is the same as that in the arms. However, pulse wave amplification may yield a higher systolic pressure at the ankle. Therefore, the ratio of the ankle to the brachial systolic pressure, designated as the ABI, should be 1.0 or slightly higher. A diminution of the ankle systolic blood pressure relative to the brachial artery pressure indicates a stenosis or occlusion in the aorta or arteries of the lower extremities.
The ABI is determined by measuring the systolic blood pressure in both arms (brachial arteries) and both ankle arteries (dorsalis pedis and posterior tibial arteries) after the patient has been in the supine position for at least 5 to 10 minutes. To measure these pressures, sphygmomanometric cuffs are sequentially inflated at each location to suprasystolic pressures. The onset of systole with subsequent cuff deflation is determined with a Doppler device that is placed over the artery. The ABI for each leg is calculated by dividing the higher of the two ankle pressures by the higher of the two arm pressures. Considering the intrinsic variability in blood pressure over time, an ABI of 0.90 or less is indicative of PAD. At this threshold, the ABI has excellent sensitivity (90%) and specificity (>95%) compared with angiography. An ABI of 0.91 to 1.0 is considered borderline. Vascular calcification, as often occurs in patients with diabetes or renal insufficiency, may preclude accurate determination of systolic blood pressure at the ankle. For this reason, an ABI that is markedly elevated (e.g., >1.4) is considered inaccurate and indicative of vascular calcification. In this circumstance, other simple noninvasive diagnostic tests, such as assessment of the toe–brachial index, pulse volume recording (PVR), or continuous wave Doppler may be useful to detect PAD. In some cases of PAD, the ABI is normal at rest. This is particularly common in patients who have a proximal disease, such as iliac artery stenosis, and an extensive collateral circulation. In such cases, measurement of the ABI after walking will detect a decrease in the ankle systolic pressure relative to brachial artery systolic pressure, thereby revealing the presence of PAD.
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