Mark A. Creager MD1
1Professor of Medicine, Harvard Medical School, Director, Vascular Center, and Member, Vascular Medicine Section, Cardiovascular Division, Brigham and Women's Hospital
The author has received grant or research support from the Bristol-Myers Squibb'sanofi-Aventis Partnership; he has served as a consultant for ARYx, Bristol-Myers Squibb'sanofi-Aventis, Genzyme, Sigma Tau, Vasogen, and Wyeth; and he has participated in the speakers' bureau for Bristol-Myers Squibb'sanofi-Aventis.
Peripheral arterial diseases comprise those disorders that compromise blood flow to the limbs. Causes of limb artery obstruction include atherosclerosis, thrombus, embolism, vasculitis, arterial entrapment, adventitial cysts, fibromuscular dysplasia, arterial dissection, trauma, and vasospasm.
The most freqently encountered cause of peripheral arterial disease is atherosclerosis. The pathology of atherosclerosis that affects the limbs is similar to that of atherosclerosis of the aorta, coronary arteries, and extracranial cerebral arteries. Of patients who present with symptoms of peripheral atherosclerosis, approximately 80% have femoropopliteal artery stenoses, 30% have lesions in the aorta or iliac arteries, and 40% have tibioperoneal artery stenoses. Most patients have multiple stenoses.
The prevalence of peripheral atherosclerosis, both asymptomatic and symptomatic, increases with age, ranging from 3% in persons younger than 60 years to greater than 20% in persons 75 years of age and older.1,2,3 An epidemiologic study in Germany found that the overall prevalence of peripheral arterial disease in patients older than 65 years was 20% in men and 17% in women.4 A community-based survey in primary physicians' offices in the United States found that of patients who were between the ages of 50 and 69 years who had diabetes mellitus or smoked cigarettes or who were older than 70 years, 29% had peripheral arterial disease.5
The prevalence of claudication ranges from 1% to 5%.1 The peak incidence of claudication occurs between the sixth and seventh decades and develops later in women than in men. Each year, approximately 2% to 4% of all patients with intermittent claudication develop critical limb ischemia.6
Long-term survival is reduced in patients with peripheral atherosclerosis. The risk of death in populations with peripheral atherosclerosis is increased twofold to fourfold. Most patients die as a consequence of myocardial infarction or stroke.7 Patients with claudication have a 5-year survival rate of approximately 15% to 30%, and patients with critical limb ischemia have a 1-year survival rate of approximately 25%.1,2,6,7,8 Overall, there is an inverse relationship between the severity of peripheral arterial disease and survival.
The risk factors associated with the development of peripheral atherosclerosis are similar to those associated with coronary atherosclerosis. These include cigarette smoking, diabetes mellitus, dyslipidemia, hypertension, a family history of premature atherosclerosis, and hyperhomocysteinemia. The risk of developing intermittent claudication is twofold to fivefold higher in smokers than in nonsmokers.9,10Moreover, continued cigarette smoking greatly increases the risk of progression from stable claudication to severe limb ischemia and amputation. Diabetes mellitus is associated with a threefold to fourfold increase in the risk of peripheral arterial disease.9,11 Peripheral atherosclerosis is often more severe and extensive in diabetic patients than in nondiabetic patients with atherosclerosis; in addition, the tibial and peroneal arteries are involved more frequently in diabetic patients than in nondiabetic patients. Prognosis is poor for patients with diabetes who have claudication: 30% to 40% develop critical limb ischemia over a 6-year period. The risk of amputation in diabetic patients is sevenfold to 15-fold higher than in nondiabetic patients with peripheral arterial disease.2,12 Dyslipidemia, particularly hypercholesterolemia, is present in 40% of patients with peripheral atherosclerosis. The relative risk of peripheral arterial disease is 1.2 to 1.4 for each 40 to 50 mg/dl increase in total cholesterol.10 Hypertriglyceridemia and an elevated plasma concentration of lipoprotein(a) each increase the risk of developing peripheral arterial disease. Hypertension increases the risk of claudication by at least twofold in men and by fourfold in women.10 Hyperhomocysteinemia has emerged as an important risk factor for atherosclerosis and increases the risk of peripheral atherosclerosis by twofold to threefold.13 Elevations in markers of inflammation, including levels of C-reactive protein and soluble intercellular adhesion molecule-1, are also independent predictors of the development of symptomatic peripheral arterial disease in otherwise healthy men.14,15
The two principal symptoms of peripheral atherosclerosis are intermittent claudication and rest pain. However, many patients with peripheral arterial disease are asymptomatic, have symptoms that do not fit the typical pattern of intermittent claudication, or have symptoms from comorbid conditions (e.g., arthritis) that blur the presentation.16
Intermittent claudication is described as discomfort, pain, fatigue, or heaviness that is felt in the affected extremity during walking and resolves within a few minutes of resting. Intermittent claudication occurs when the metabolic demand of an exercising muscle exceeds supply. A hemodynamically significant stenosis prevents blood-flow augmentation during exercise. The increased pressure gradient that develops across the stenosis compromises perfusion pressure to the exercising muscle. As ischemia develops, autoregulatory mechanisms cause local vasodilatation and a further reduction in perfusion pressure, and extravascular forces created by the exercising muscle reduce perfusion pressure even further. The location of the symptom depends on the site of stenosis. Thigh, hip, or buttock claudication may develop in cases of proximal arterial occlusive disease involving the aorta or iliac arteries. Involvement of the femoral and popliteal arteries typically causes calf claudication. Tibial and peroneal artery stenoses may cause pedal claudication.
Rest pain occurs when the blood supply does not adequately meet the basic nutritional requirements of the tissues of the affected extremity. Pain typically occurs in the toes or foot. Initially, the pain is worse at night when the patient is lying in bed with the legs in a neutral position. Sitting up and dangling the leg may alleviate the discomfort, because this maneuver increases perfusion pressure via gravitational forces. Conversely, leg elevation worsens the pain. With persistent severe ischemia, skin breakdown occurs, leading to ulceration, necrosis, and gangrene. Even minor trauma to an ischemic foot may produce a skin lesion that fails to heal.
The most reliable physical finding in patients with peripheral arterial disease is decreased or absent pulses. Examination of femoral, popliteal, posterior tibial, and dorsalis pedis pulses may indicate sites of stenosis. Bruits auscultated in the abdomen, pelvis, and inguinal areas also may indicate the presence of arterial stenosis. Foot pallor may be observed at rest, with leg elevation, or after exercise of the calf muscles. Signs of chronic limb ischemia include subcutaneous atrophy; hair loss; coolness; pallor; and cyanosis, dependent rubor, or both [see Figure 1]. Additional signs of critical limb ischemia include petechiae, fissures, ulceration, and gangrene. Ulcers often involve the tips of the toes or the heel of the foot and occur at sites of trauma or pressure caused by poor-fitting footwear. Arterial ulcers have pale bases and irregular borders and are usually quite painful.
Figure 1. Ischemic Right Foot
Photograph shows an ischemic right foot demonstrating dependent rubor.
Several classifications have been proposed to characterize the severity of limb ischemia in patients with peripheral arterial disease. The most widely recognized classification was developed by René Fontaine [see Table 1]. A contemporary classification scheme takes into consideration symptoms, physical findings, perfusion pressure, and exercise capacity; the classification scheme comprises four grades and seven categories [see Table 2].17
Table 1 Fontaine Classification of Chronic Limb Ischemia
Table 2 Clinical Categories of Chronic Limb Ischemia72
Noninvasive Diagnostic Tests
Several noninvasive diagnostic tests can be used to evaluate patients with peripheral arterial disease. Segmental blood pressure measurement of the extremity is a quantitative means to assess the presence and severity of arterial stenoses [see Table 3]. Pneumatic cuffs are positioned along the leg and are inflated to suprasystolic pressures. During cuff deflation, the onset of flow (i.e., systolic blood pressure) is assessed by use of a Doppler probe placed over the dorsalis pedis or the posterior tibial arteries. Normally, the systolic blood pressure in the leg is the same as that in the arm. However, because of reflected waves, systolic blood pressure in the leg may be slightly higher than that in the arm. The normal ankle:brachial systolic blood pressure ratio (i.e., the ankle:brachial index) is therefore 1.0 or slightly greater. Taking into consideration the variability in blood pressure measurements, an ankle:brachial index less than 0.95 is considered abnormal. Patients with leg claudication typically have an ankle:brachial index less than 0.8; in patients with ischemia at rest, the ankle:brachial index is frequently less than 0.4 [see Table 3].
Table 3 Leg Segmental Pressure Measurements in Patient with Right Calf Claudication and Right Foot Pain*
Measurement of the ankle:brachial index can be performed in a medical office. It is a sensitive indicator of peripheral arterial disease; it is more closely associated with leg function in patients with peripheral arterial disease than is intermittent claudication or other leg symptoms.18 Because atherosclerosis is a systemic problem, a decreased ankle:brachial index suggests that the burden of disease is increased throughout the body, including the coronary arteries; for that reason, the lower the ankle:brachial index, the higher the risk of a cardiovascular event.19,20
In patients with peripheral arterial disease, the pressure gradient across a stenosis increases during exercise, as vascular resistance in the exercising muscle decreases. The exercise-induced increase in systemic pressure (i.e., brachial artery pressure) is not accompanied by a comparable increase in ankle pressure. Thus, the ankle:brachial index will be lower immediately after the patient has exercised than when the patient is at rest.
Plethysmographic devices are used to record the change in limb artery volume that occurs with each pulse (pulse volume recordings). The pulse volume waveform comprises a systolic upstroke with a sharp peak, a dicrotic wave, and a downsloping component. Distal to the site of an arterial stenosis, the amplitude of the pulse volume waveform is diminished, and the dicrotic wave disappears. In the presence of severe ischemia, the waveform may be entirely absent [see Figure 2].
Figure 2. Pulse Volume Recordings
Pulse volume recordings provide a qualitative assessment of blood flow to the extremity. In this example from a patient with right calf claudication and right foot pain, the pulse volume recordings are abnormal in the right calf, right ankle, and right metatarsal segments. In the right calf and ankle, the amplitude of the pulse is diminished and the rate of rise is delayed. No pulse volume can be recorded in the right metatarsal segment. The pulse volume recordings in the left leg are normal.
Doppler ultrasonography can identify vessels with stenotic lesions. A Doppler probe is positioned at various sites along the limb's arteries. The Doppler waveform has three components, which correspond to three phases of blood flow: high-velocity antegrade flow during systole, transient flow reversal during early diastole, and low-velocity antegrade flow during late diastole. When stenosis is present, this triphasic waveform is altered distal to the stenosis: the amplitude is decreased, the rate of rise is delayed, and the reverse-flow component disappears. Duplex ultrasound scanning is a direct, noninvasive test that combines B-mode ultrasonography and pulsed Doppler ultrasonography to assess peripheral arterial stenoses. A B-mode scan identifies areas of intimal thickening, plaque formation, and calcification. Color Doppler imaging detects blood-flow abnormalities caused by arterial stenoses. An increase of greater than twofold in the systolic velocity is indicative of a hemodynamically significant stenosis, usually one that exceeds 50% of the artery diameter.
Transcutaneous oximetry, which measures the transcutaneous oxygen tension with oxygen-sensing electrodes placed at various sites on the legs, is used to assess the severity of skin ischemia in patients with peripheral arterial disease. Normally, the transcutaneous oxygen tension of the resting foot is approximately 60 mm Hg; it is often less than 40 mm Hg in patients with ischemia.
Magnetic resonance angiography (MRA) and CT angiography can be used to evaluate the location and severity of peripheral atherosclerosis21; thus, these modalities can help determine whether a patient is a candidate for an endovascular intervention. In addition, they are free of the risks of conventional angiography. MRA is more widely used, although it is somewhat slower than CT angiography. The current generation of CT angiography machines can provide highly detailed images within minutes; however, CT angiography requires iodinated contrast and radiation exposure, which makes it less suitable for patients with renal insufficiency or contrast allergy.
In most patients, clinical evaluation and noninvasive testing are sufficient for confirming the diagnosis of peripheral arterial disease. Conventional catheter-based angiography is typically performed only when a diagnosis is in doubt or as a prelude to endovascular interventions or surgical reconstruction [see Figure 3]. Digital subtraction angiography is a computer-enhancing technique that is used to improve resolution; it is particularly useful in conjunction with the intra-arterial administration of radiographic contrast agent.
Figure 3. Arteriogram in Critical Ischemia of the Right Foot
Arteriogram of a patient with critical ischemia of the right foot. The left panel shows a long, total occlusion of the right superficial femoral artery. The popliteal artery reconstitutes via collaterals. The right panel reveals evidence of anterior tibial, posterior tibial, and peroneal artery occlusions with poor runoff.
Risk Factor Modification and Antiplatelet Therapy
Risk factors for atherosclerosis should be identified and treated; this reduces the likelihood of progression of atherosclerosis and also helps to prevent adverse cardiovascular events in patients with peripheral arterial disease.22,23 Patients who stop smoking cigarettes have a more favorable prognosis than those who continue to smoke. Aggressive lipid-lowering therapy reduces progression of peripheral atherosclerosis, but it has not been established that it prevents progression of symptoms from claudication to critical limb ischemia. Cholesterol-lowering therapy with statin drugs reduces adverse cardiovascular events in patients with atherosclerosis and may improve walking ability.24,25,26,27
Antihypertensive agents should be tailored to bring blood pressure into a normotensive range to reduce the risk of adverse events such as stroke, congestive heart failure, and renal insufficiency.2,28 Occasionally, marked reduction of blood pressure may reduce perfusion pressure to an ischemic extremity and potentially aggravate symptoms. Angiotensin-converting enzyme inhibitors are effective antihypertensive drugs that may also reduce the risk of adverse cardiovascular events in patients with atherosclerosis, including those with peripheral arterial disease.29 Beta blockers do not worsen intermittent claudication but may cause reflex peripheral cutaneous vasoconstriction and exacerbate critical limb ischemia.30 Beta blockers are indicated to reduce the risk of myocardial infarction and death in patients with coronary artery disease—a condition that frequently coexists with peripheral arterial disease.
Aggressive treatment of diabetes mellitus reduces microangiopathic complications such as retinopathy and nephropathy.2,28,31 It is not known whether aggressive treatment of diabetes reduces progression of atherosclerosis or prevents critical limb ischemia or foot ulceration. B-complex vitamins, such as folic acid, cobalamin, and pyridoxine, may lower homocysteine levels, but it is not yet known whether such therapy reduces cardiovascular events or prevents progression of peripheral atherosclerosis.
There is little information regarding the efficacy of platelet inhibition in treating symptoms of peripheral arterial disease. In one study, primary prevention with aspirin was shown to reduce the need for surgical revascularization in patients with peripheral arterial disease.32Small angiography trials have suggested that platelet inhibitors reduce the risk of acute peripheral arterial occlusion.33 These agents may prevent thrombosis after plaque rupture in the peripheral arteries, as they do in coronary arteries. Antiplatelet therapy has been shown to reduce the risk of adverse cardiac events such as nonfatal myocardial infarction and stroke and has been shown to reduce cardiovascular mortality in patients with atherosclerosis.2,23,34 In one study, clopidogrel was more effective than aspirin in reducing the risk of adverse cardiovascular events, particularly in patients with peripheral arterial disease.35
Hygiene and Physical Therapy
Local measures are used to prevent skin ulceration and foot infection, particularly in patients with critical limb ischemia. The feet should be kept clean, and moisturizing cream should be applied to prevent drying and fissuring. The skin of the feet should be inspected frequently, and minor abrasions should be treated promptly. Stockings should be made of natural, absorbent fibers. Elastic hose are contraindicated because they restrict skin blood flow. Shoes should be carefully fitted to reduce the possibility of pressure-induced skin breakdown. In patients with critical limb ischemia, the limbs should be maintained in a dependent position to increase perfusion pressure. This can be achieved by angling the mattress so that the affected limb is below heart level. Cotton wicks placed between the toes absorb moisture and reduce friction. Sheepskin placed beneath the heels of the feet reduces pressure and necrosis. A warm environment is recommended to reduce vasoconstriction. Ulcerations and necrotic areas should be kept dry and covered with dry, nonadhesive material. Infections should be drained. Local antibiotics should be avoided. Pain should be treated with analgesics.
Supervised exercise training programs improve walking capacity in patients with peripheral arterial disease.2,36 Among the most likely factors that account for the improvement are more efficient skeletal muscle metabolic function and changes in ergonomics.37 Most studies have not found that exercise training improves blood flow to the exercising extremity, but investigations into the potential angiogenic effects of exercise are ongoing. Training programs should be individualized for each patient. Because supervised settings provide structure and guidance, patients have achieved the most success with supervised training. Programs typically involve treadmill exercise for approximately 1 hour three times a week for at least 3 months. Patients are encouraged to walk independently outside the supervised program.
Pharmacotherapy of Claudication and Critical Limb Ischemia
Drug therapy has generally not been successful in improving symptoms of claudication or reducing the complications of critical limb ischemia.22 Although arterioles dilate in response to the metabolic demands of exercise, blood-flow augmentation is limited by critical stenoses. Thus, perfusion pressure distal to a stenosis falls further during exercise. Pharmacologic vasodilators may not reduce resistance to blood flow any more than endogenous vasodilators released during exercise. However, vasodilator drugs may increase blood flow to unaffected regions and thereby steal blood away from the ischemic limb.
Two drugs are approved by the Food and Drug Administration for the treatment of intermittent claudication: pentoxifylline and cilostazol. Pentoxifylline is a xanthine derivative with hemorrheologic properties. It has been reported to improve red cell flexibility and decrease blood viscosity. Pentoxifylline improved patients' exercise capacity in several but not all clinical trials.30,38
Cilostazol is a quinolinone derivative that inhibits phosphodiesterase III and thereby prevents the degradation of cyclic adenosine monophosphate. It has vasodilatory and platelet inhibitory properties, but its precise mechanism of action in patients with peripheral arterial disease is not known. Several trials have found that cilostazol leads to an increase in the distance walked before onset of claudication and also in the maximal walking distance in patients with peripheral arterial disease.39,40,41,42
Metal-chelating compounds, such as ethylenediaminetetraacetic acid (EDTA), are not useful in the treatment of patients with peripheral arterial disease.43
Several classes of drugs are currently undergoing investigation for use in the treatment of claudication, critical limb ischemia, or both. Some drug treatments are designed to increase the efficiency of substrate utilization, which enhances cellular energetics. L-Carnitine and its analogue, propionyl-L-carnitine, may decrease the ratio of acetyl coenzyme A (acetyl CoA) to CoA via the action of CoA:carnitine acetyltransferase and thereby stimulate glucose oxidation and energy production. Small placebo-controlled trials have found that treatment with L-carnitine or propionyl-L-carnitine improves exercise capacity in patients with intermittent claudication.44,45
In one study, L-arginine, the precursor of nitric oxide, improved endothelium-dependent vasodilatation and increased claudication distance after 3 weeks of intensive therapy.46 Initial trials of prostaglandin E1 (PGE1) and prostacyclin (PGI2) or their synthetic analogues suggested that these agents could increase the distance walked before onset of claudication, but subsequent definitive trials failed to show improvement in symptoms.47,48 Angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), are undergoing intensive investigation for their potential efficacy in patients with peripheral arterial disease. These angiogenic factors may be delivered parenterally as recombinant proteins or through gene transfer using intra-arterial catheter techniques or intramuscular injection. Both VEGF and bFGF increase collateral blood vessel development and improve blood flow in experimental models of hindlimb ischemia. The efficacy of angiogenic growth factors in patients with intermittent claudication or critical limb ischemia is an active area of investigation. Several placebo-controlled trials in patients with claudication have been reported. In one trial, intra-arterial infusion of recombinant FGF-2 resulted in a significant increase in peak walking time at 90 days.49 In another study, intramuscular administration of VEGF did not improve exercise performance.50
Autologous implantation of bone marrow mononuclear cells is a promising area of study. These cells have the potential to promote angiogenesis, because they can supply endothelial progenitor cells and they secrete angiogenic factors.51
Revascularization procedures are indicated for patients with disabling claudication, ischemic rest pain, or impending limb loss. Revascularization can be achieved by catheter-based endovascular interventions [see Figure 4] or surgical reconstruction.
Figure 4. Claudication of the Left Leg
Arteriograms of a patient with disabling claudication of the left leg. A focal stenosis (arrow) of the superficial femoral artery is apparent (a). After percutaneous transluminal angioplasty, patency is restored (b).
Percutaneous transluminal angioplasty (PTA) of iliac arteries has an initial success rate of 90%.52,53 Patency rates after 4 to 5 years are approximately 60% to 80% and are even higher with implantation of a stent.54,55,56 The success rate of PTA of femoral and popliteal arteries is lower than that of PTA of iliac arteries. Patency rates at 1, 3, and 5 years are approximately 60%, 50%, and 45%, respectively.54The patency rate is better when PTA is performed for relief of claudication rather than for limb salvage and is also better in patients with good runoff (i.e., in patients with open distal vessels). Stents have not been shown to improve the patency rates of femoral and popliteal arteries over PTA alone. PTA of tibial and peroneal arteries is associated with poorer outcome than PTA of more proximal lesions and is usually performed in patients with critical limb ischemia who are considered at high risk for vascular surgery. Limb salvage rates of 1 to 2 years range from 50% to 75%. Thrombolytic therapy is not used routinely for the treatment of peripheral atherosclerosis but may be effective in restoring patency of native arteries and bypass grafts after acute arterial occlusion [see Acute Arterial Occlusion, below].
The operative procedures used in vascular reconstruction depend on the location and severity of the arterial stenoses. Aortobifemoral bypass with a bifurcated Dacron or polytetrafluoroethylene prosthetic graft is the standard treatment for aortoiliac disease. Operative mortality ranges from 1% to 3% at centers with expertise in this technique. Long-term patency and relief of symptoms exceed 80% over 10 years.57Intra-abdominal aortoiliac reconstructive surgery is not feasible in patients whose comorbid conditions pose excessive surgical risk. Axillobifemoral bypass can circumvent the abdominal aorta and achieve revascularization of both legs. Femorofemoral bypass can be performed with the patient under regional anesthesia and is appropriate in cases of unilateral iliac artery obstruction.
Infrainguinal bypass procedures include femoral-popliteal and femoral-tibioperoneal reconstruction. Two techniques are generally used: the in situ saphenous vein bypass graft and the reversed autologous saphenous vein bypass graft. Femoral-popliteal reconstruction is most successful when the distal anastomosis is constructed proximal to the knee. The 5-year patency rate for all saphenous vein infrainguinal bypass grafts, including grafts that have undergone revision, is approximately 75% to 80%.54,58 Patency rates are higher in claudicants than in patients with critical limb ischemia. Synthetic grafts made of polytetrafluoroethylene are used when veins are not available.59 The patency of prosthetic grafts is inferior to those composed of veins, particularly because of early thrombotic occlusion. Synthetic grafts inserted below the knee have a very low patency rate and are typically not used for tibioperoneal reconstruction. Operative mortality for infrainguinal vascular reconstruction is 1% to 2%.58 Antiplatelet agents should be administered to maintain graft patency after bypass grafts.2,23,33
Lumbar sympathectomy is used rarely to treat patients with critical limb ischemia. The pathophysiology of limb ischemia suggests that ischemic vessels are maximally vasodilated; thus, lumbar sympathectomy may not increase blood flow.
Amputation is a surgical alternative for patients with advanced limb ischemia in whom revascularization procedures are not possible or have failed. It is a final alternative for patients with unremitting rest pain or gangrene. Selection of the amputation level requires assessment of perfusion. Transphalangeal amputation causes minimal disability. Transmetatarsal amputation of the forefoot may affect balance, but patients are usually able to ambulate after rehabilitation. Patients who undergo below-the-knee amputation and subsequently use a prosthesis expend 10% to 40% more energy to walk on a horizontal surface than a person who has use of both legs. Patients who undergo amputations above the knee and use a prosthetic device expend 65% more energy to walk than a person who has use of both legs. Overall prognosis after major leg amputation is poor, usually because of coexisting coronary and cerebrovascular disease.
Acute Arterial Occlusion
Acute arterial occlusion is to be distinguished from the gradual development of limb artery obstruction caused by peripheral atherosclerosis. The causes of acute arterial occlusion include embolism, thrombosis, dissection, and trauma. The most common cause is arterial embolism. The majority of systemic emboli arise from cardiac sources, including atrial fibrillation, valvular heart disease, congestive heart failure, left ventricular aneurysm, acute myocardial infarction, and cardiac tumors (e.g., left atrial myxomas). Noncardiac sources of embolism include aneurysms of the aorta and aneurysms of the iliac, femoral, and popliteal arteries. A deep vein thrombus may enter the systemic circulation via an intracardiac shunt, resulting in what is termed paradoxical embolism. Thrombosis in situ may develop in peripheral atherosclerotic arteries at a site of plaque rupture and in bypass grafts. Thrombus may also develop in otherwise normal vessels of patients with procoagulant disorders such as hyperhomocysteinemia (including homocysteinuria), antiphospholipid antibody syndrome, and heparin-induced thrombocytopenia. Arterial thrombus formation is uncommon in patients with resistance to activated protein C and in patients deficient in protein C, protein S, or antithrombin. Aortic dissection and trauma may acutely occlude arteries by disrupting the integrity of the vessel lumen.
Acute arterial occlusion may cause severe limb ischemia, resulting in pain, paresthesia, and motor weakness distal to the site of occlusion. There is loss of peripheral pulses, cool skin, and pallor or cyanosis distal to the obstruction site. Noninvasive tests can provide additional evidence of peripheral arterial occlusion and may reveal the severity of ischemia, but definitive treatment should not be delayed. Arteriography is used to define the site of acute arterial occlusion and may distinguish thrombus in an atherosclerotic vessel from an arterial embolism. Once the diagnosis is made, anticoagulation with heparin should be initiated to prevent propagation of the thrombus.
Acute severe limb ischemia requires urgent revascularization. Catheter-directed intra-arterial thrombolysis with agents such as recombinant human tissue plasminogen activator may restore patency in acutely occluded arteries and bypass grafts. An embolectomy catheter can be used to remove arterial emboli. Surgical reconstruction to bypass the occlusion is considered if embolectomy is unsuccessful or not possible. The decision to utilize thrombolysis or surgery for acute arterial occlusion depends in part on the severity of ischemia and urgency of revascularization.60,61
Atherothrombotic debris from friable plaques in the aorta or other large arteries may dislodge and embolize to small distal limb arteries. Atheroembolism occurs spontaneously, although it occasionally occurs as a complication of arterial catheterization.62 Violaceous discoloration, petechiae, and livedo reticularis appear when emboli occlude small vessels. Occlusion of digital vessels causes painful cyanotic toes (the blue toe syndrome), despite the presence of palpable pedal arteries [see Figure 5]. Embolic occlusion of intramuscular vessels causes pain and tenderness. Abnormal laboratory findings include an elevated eosinophil count and an increased erythrocyte sedimentation rate. Anemia, thrombocytopenia, and hypocomplementemia may also occur. Azotemia may occur if there is concurrent atheroembolism to the kidneys. Sites of shaggy atheroma may be identified by imaging the aorta with transesophageal echocardiography or MRA.63Confirmation of the diagnosis is made by skin or muscle biopsy. Tissue examination will reveal elongated needle-shaped clefts in small arteries that are associated with intimal thickening, perivascular fibrosis, inflammatory cells, and lipid-laden giant cells.
Figure 5. Ischemia of the Toes of the Right Foot
Ischemia of the toes of the right foot caused by atheroemboli. There is fixed violaceous discoloration of several toes and the lateral aspect of the right foot.
The risk of recurrence of atheroembolism is high. Platelet inhibitors have been used in this disorder, although it has not been established that these agents prevent recurrent atheroemboli. The role of warfarin is even less clear. Some investigators have found that warfarin reduces the likelihood of atheroembolism in patients with mobile atheromas, whereas others have suggested that warfarin may contribute to the development of atheroemboli in persons with a predisposition to the disease.64,65,66 Surgical bypass of occluded vessels usually is not possible, because the emboli typically lodge in small distal arteries. If a proximal source, such as an aneurysm, is identified, bypass surgery and removal of the source from the circulation may reduce the risk of recurrence. Risk-factor modification—in particular, lipid-lowering therapy—can serve to stabilize atheromatous plaques and may reduce the risk of cardiovascular events; it is not known whether lipid-lowering therapy can prevent atheroembolism.66
Popliteal Artery Entrapment
Popliteal artery entrapment is caused by a congenital anomaly in which the medial head of the gastrocnemius muscle compresses or displaces the popliteal artery. In young patients who present with symptoms of intermittent claudication or rest pain, popliteal artery entrapment should be considered a possible diagnosis. It occurs more frequently in men than in women and is unilateral in two thirds of cases.67
The diagnosis is made by measuring ankle pressures before and after exercising the calf muscle, because contraction of the gastrocnemius muscle compresses the popliteal artery. Duplex ultrasonography can demonstrate popliteal artery compression and cessation of blood flow during gastrocnemius contraction. Angiography is used to confirm the diagnosis by delineating the altered course of the popliteal artery and may reveal a popliteal artery thrombus and poststenotic dilatation.
Popliteal artery entrapment should be treated surgically, preferably by relieving compression of the popliteal artery. Occasionally, thrombectomy or bypass grafting is required.
Thromboangiitis obliterans is a vasculitis that is also known as Buerger disease.68 In the United States, the prevalence is approximately 1 per 10,000 population. It occurs throughout the world but is most prevalent in Asia, portions of Eastern Europe, and Israel. Thromboangiitis obliterans affects men primarily but may also occur in women. Onset of the disease usually occurs before 45 years of age. The most important predisposing factor is tobacco use.
Thromboangiitis obliterans affects small and middle-sized arteries and veins in the extremities. Inflammatory cells, particularly polymorphonuclear leukocytes, infiltrate the intima, media, and adventitia; thrombi typically occlude the lumen. Leukocytes and multinucleated giant cells may be found within or surrounding the thrombus. The internal elastic lamina and media remain intact.
Involvement of limb arteries causes forearm, calf, or foot claudication. Severe ischemia of the hand and foot causes rest pain, ulcerations, and skin necrosis. Raynaud phenomenon, which is indicative of digital artery obstruction, occurs in approximately 45% of patients. Migratory superficial vein thrombosis develops in approximately 40% of patients.
There are no specific serologic laboratory tests to diagnose thromboangiitis obliterans; however, serologic tests are used to exclude other causes of vasculitis. Serum immunologic markers such as antinuclear antibodies, rheumatoid factor, and antiphospholipid antibodies should not be present, and acute-phase reactants are usually normal. The diagnosis can be supported by arteriography, which reveals interspersed affected and normal segments of blood vessels. Collateral vessels circumventing sites of occlusion are often present. Biopsy of affected vessels should reveal the typical pathologic findings described above but is rarely indicated.
The most effective treatment for patients with thromboangiitis obliterans is smoking cessation. The risk of progression to critical limb ischemia and amputation is greater in patients who continue to smoke. Surgical revascularization is not usually an option because of involvement of small distal vessels. There is no established pharmacologic intervention. The use of vasodilator prostaglandins may be beneficial in some patients. Intramuscular administration of naked plasmid DNA encoding the 165 amino acid isoform of human vascular endothelial growth factor [phVEGF (165)] was reported to heal ulcers and relieve pain in some patients with thromboangiitis obliterans.69The efficacy of platelet inhibitors, anticoagulants, and thrombolytic therapy has not been established.
Raynaud phenomenon is episodic vasospastic ischemia of the digits. It is characterized by digital blanching, cyanosis, and rubor after exposure to cold and rewarming and can also be induced by emotional stress. Although many patients describe a triphasic color response, most experience only one or two color changes. The digital discoloration is confined primarily to the fingers or toes. Occasionally, the tongue, tip of the nose, or earlobes are affected. Blanching represents the ischemic phase of the phenomenon, caused by digital vasospasm. Cyanosis results from deoxygenated blood in capillaries and venules. With rewarming and resolution of the digital vasospasm, a hyperemic phase ensues, causing the digits to appear red.70
Raynaud phenomenon is categorized as primary or secondary [see Table 4]. The primary form of Raynaud phenomenon is also called Raynaud disease. Diagnostic criteria for Raynaud disease include episodic digital ischemia, absence of arterial occlusion, bilateral distribution, absence of symptoms or signs of other diseases that also cause Raynaud phenomenon, and duration of symptoms for 2 years or longer. Most people with Raynaud disease develop symptoms before they reach 40 years of age. It can occur in young children. Raynaud disease affects women three to five times more frequently than men. The prevalence is lower in warm climates than in cold climates.
Table 4 Secondary Causes of Raynaud Phenomenon
The mechanisms postulated to cause Raynaud phenomenon include increased sympathetic nervous system activity, heightened digital vascular reactivity to vasoconstrictive stimuli, circulating vasoactive hormones, and decreased intravascular pressure. The sympathetic nervous system mediates the digital vasoconstrictive response to cold exposure and emotional stress, but sympathetic nervous system activity has been discounted as a primary causal mechanism. Some investigators have suggested that increased sensitivity, increased numbers of postsynaptic alpha2-adrenergic receptors, or both enhance the vasoconstrictive reactivity to sympathetic stimulation.71 In some cases of Raynaud phenomenon, endogenous vasoactive substances (e.g., angiotensin II, serotonin, and thromboxane A2) and exogenous vasoconstrictors (e.g., ergot alkaloids and sympathomimetic drugs) may cause digital vasospasm. Many patients with Raynaud phenomenon have low blood pressure. Decreased digital vascular pressure caused by proximal arterial occlusive disease or by digital vascular obstruction may increase the likelihood of digital vasospasm when vasoconstrictive stimuli occur.
Noninvasive vascular tests that are occasionally used to evaluate patients with Raynaud phenomenon include digital pulse volume recordings and measurement of digital systolic blood pressure and digital blood flow. Nail-fold capillary microscopy is normal in patients with Raynaud disease, whereas deformed capillary loops and avascular areas are present in patients with connective tissue disorders or other conditions that cause digital vascular occlusion.72 Determinations of the erythrocyte sedimentation rate and titers of antinuclear antibody, rheumatoid factor, cryoglobulins, and cold agglutinins are useful in excluding specific secondary causes of Raynaud phenomenon. Angiography is not necessary to diagnose Raynaud phenomenon but may be indicated in patients with persistent digital ischemia secondary to atherosclerosis, thromboembolism, or thromboangiitis obliterans to identify a cause that may be treated effectively with a revascularization procedure.
Patients with Raynaud phenomenon should avoid unnecessary exposure to cold and should wear warm clothing. The hands, feet, trunk, and head should be kept warm to avoid reflex vasoconstriction. Pharmacologic intervention is indicated in patients who do not respond satisfactorily to conservative measures. Calcium channel blockers, such as nifedipine, and sympathetic nervous system inhibitors, such as prazosin and its longer-acting analogues, can be used to treat Raynaud phenomenon. Intravenous infusion of vasodilator prostaglandins, including PGE1, PGI2, and their analogues, has been reported to facilitate healing of digital ulcers in patients with scleroderma.73 In patients with persistent severe digital ischemia, selective digital sympathectomy and microarteriolysis may facilitate ulcer healing and improve symptoms. Cervical and limb sympathectomy may also be considered in persons with severe Raynaud phenomenon, but long-term efficacy is not ensured.
Raynaud phenomenon should be distinguished from acrocyanosis, a condition in which there is persistent bluish discoloration of the hands or feet.74 Like Raynaud phenomenon, cyanotic discoloration intensifies during cold exposure, and rubor may appear with rewarming. Acrocyanosis affects both men and women; the age at onset is usually between 20 and 45 years. The prognosis of patients with idiopathic acrocyanosis is good, and loss of digital tissue is uncommon. Patients should avoid exposure to cold and should dress warmly. Pharmacologic intervention usually is not necessary. Alpha-adrenergic blocking agents and calcium channel blockers may be effective in some patients with acrocyanosis.
Editors: Dale, David C.; Federman, Daniel D.