# 55 - 292 Arterial Diseases of the Extremities ### 292 Arterial Diseases of the Extremities Hensley SE, Upchurch GR Jr: Repair of abdominal aortic aneu­ rysms: JACC focus seminar, part 1. J Am Coll Cardiol 80:831, 2022. Isselbacher EM et al: 2022 ACC/AHA guideline for the diagnosis and management of aortic disease: A report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation 146:e334, 2022. Kadian-Dodov D et al: Inflammatory diseases of the aorta: JACC PART 6 Disorders of the Cardiovascular System focus seminar, part 2. J Am Coll Cardiol 80:832, 2022. Pitcher A et al: Angiotensin receptor blockers and β blockers in Marfan syndrome: An individual patient data meta-analysis of ran­ domised trials. Lancet 400:822, 2022. Vilacosta I et al: Acute aortic syndrome revisited: JACC state-of-theart review. J Am Coll Cardiol 78:2106, 2021. Mark A. Creager, Joseph Loscalzo Arterial Diseases of the Extremities ■ ■PERIPHERAL ARTERY DISEASE Peripheral artery disease (PAD) is defined as a clinical disorder in which there is a stenosis or occlusion in the aorta or the arteries of the limbs. Atherosclerosis is the leading cause of PAD in patients >40 years old. Other causes include thrombosis, embolism, vasculitis, fibromus­ cular dysplasia, entrapment, cystic adventitial disease, and trauma. The highest prevalence of atherosclerotic PAD occurs in the sixth and sev­ enth decades of life. Prevalence of PAD is similar in men and women, is greater in persons identified as black than non-Hispanic white, and is associated with lower socioeconomic status. As in patients with atherosclerosis of the coronary and cerebral vasculature, there is an increased risk of developing PAD in cigarette smokers and in persons with diabetes mellitus, hypercholesterolemia, elevated lipoprotein(a), hypertension, or renal insufficiency. Pathology  Segmental lesions that cause stenosis or occlusion are usually localized to large and medium-size vessels. The pathology of the lesions includes atherosclerotic plaques with calcium deposition, thinning of the media, patchy destruction of muscle and elastic fibers, fragmentation of the internal elastic lamina, and thrombi composed of platelets and fibrin. The primary sites of involvement are the abdomi­ nal aorta and iliac arteries (30% of symptomatic patients), the femoral and popliteal arteries (80–90% of patients), and the more distal ves­ sels, including the tibial and peroneal arteries (40–50% of patients). Atherosclerotic lesions occur preferentially at arterial branch points, which are sites of increased turbulence, altered shear stress, and intimal injury. Involvement of the distal vasculature is most common in elderly individuals and patients with diabetes mellitus. Clinical Evaluation  Fewer than 50% of patients with PAD are symp­ tomatic, although many have a slow or impaired gait. The most typical symptom is intermittent claudication, which is defined as a pain, ache, cramp, numbness, or a sense of fatigue in the muscles; it occurs during exercise and is relieved by rest. The site of claudication is distal to the location of the occlusive lesion. For example, buttock, hip, thigh, and calf discomfort occurs in patients with aortoiliac disease, whereas calf claudica­ tion develops in patients with femoral-popliteal disease. Symptoms are far more common in the lower than in the upper extremities because of the higher incidence of obstructive lesions in the former region. In patients with severe arterial occlusive disease in whom resting blood flow cannot accommodate basal nutritional needs of the tissues, chronic limb-threat­ ening ischemia may develop. Patients complain of rest pain or a feeling of cold or numbness in the foot and toes. Frequently, these symptoms occur at night when the legs are horizontal and improve when the legs are in a dependent position. With severe ischemia, rest pain may be persistent. A comprehensive vascular examination includes palpation of the peripheral pulses, including the femoral, popliteal, dorsalis pedis, and posterior tibial arteries; auscultation of the abdomen and groin for bruits; and inspection of the legs and feet. Important physical findings of PAD include decreased or absent pulses distal to the obstruction, the presence of bruits over the narrowed artery, and muscle atrophy. With more severe disease, hair loss, thickened nails, smooth and shiny skin, reduced skin temperature, and pallor or cyanosis are common physical signs. In patients with chronic limb-threatening ischemia, ulcers or gangrene may occur. Elevation of the legs and repeated flex­ ing of the calf muscles produce pallor of the soles of the feet, whereas rubor, secondary to reactive hyperemia, may develop when the legs are dependent. The time required for rubor to develop or for the veins in the foot to fill when the patient’s legs are transferred from an elevated to a dependent position is related to the severity of the ischemia and the presence of collateral vessels. Patients with severe ischemia may develop peripheral edema because they keep their legs in a dependent position much of the time. Ischemic neuropathy can result in numb­ ness and hyporeflexia. Noninvasive Testing  The history and physical examination are often sufficient to establish the diagnosis of PAD. An objective assess­ ment of the presence and severity of disease is obtained by noninvasive techniques. Arterial pressure can be recorded noninvasively in the legs by placement of sphygmomanometric cuffs at the ankles and the use of a Doppler device to auscultate or record blood flow from the dorsalis pedis and posterior tibial arteries. Normally, systolic blood pressure in the legs and arms is similar. Indeed, ankle pressure may be slightly higher than arm pressure due to pulse-wave amplification. In the presence of hemodynamically significant stenoses, the systolic blood pressure in the leg is decreased. Thus, the ratio of the ankle and brachial artery systolic pressures (termed the ankle-brachial index, or ABI) is 1.00–1.40 in normal individuals. ABI values of 0.91–0.99 are considered “borderline,” and those ≤0.90 are abnormal and diagnostic of PAD. ABIs >1.40 indicate noncompressible arteries secondary to vascular calcification, as may occur in patients with diabetes mellitus or chronic kidney disease. When an ABI cannot be accurately assessed due to vascular calcification, the presence of PAD can be detected by measuring the systolic pressure of the great toe and calculating a toebrachial index (TBI). A TBI of ≤0.70 is considered abnormal. Other noninvasive tests include segmental pressure measurements, segmental pulse volume recordings, duplex ultrasonography (which combines B-mode imaging and Doppler flow velocity waveform analysis), transcutaneous oximetry, and stress testing (usually using a treadmill). Placement of pneumatic cuffs enables assessment of systolic pressure along the legs. The presence of pressure gradients between sequential cuffs provides evidence of the presence and location of hemodynamically significant stenoses. In addition, the amplitude of the pulse volume contour becomes blunted in the presence of signifi­ cant PAD. Duplex ultrasonography is used to image and detect stenotic lesions in native arteries and bypass grafts. Treadmill testing allows the physician to assess functional limi­ tations objectively. Decline of the ABI immediately after exercise provides further support for the diagnosis of PAD in patients with equivocal symptoms and findings on examination. Magnetic resonance angiography (MRA), computed tomographic angiography (CTA), and conventional catheter-based angiography should not be used for routine diagnostic testing, but are performed before potential revascularization (Fig. 292-1). Each test is useful in defining the anatomy to assist planning for endovascular and surgical revascularization procedures. Prognosis  The natural history of patients with PAD is influenced primarily by the extent of coexisting coronary artery and cerebrovascu­ lar disease. Approximately one-third to one-half of patients with symp­ tomatic PAD have evidence of coronary artery disease (CAD) based on clinical presentation and electrocardiogram, and over one-half have B A FIGURE 292-1  Magnetic resonance angiography of a patient with intermittent claudication, showing stenoses of the distal abdominal aorta and right common iliac artery (A) and stenoses of the right and left superficial femoral arteries (B). (Courtesy of Dr. Edwin Gravereaux, with permission.) significant CAD by coronary angiography. Patients with PAD have a 15–25% 5-year mortality rate and a two- to fourfold increased risk of death from cardiovascular disease. Measurement of ABI is useful for detecting PAD and identifying persons at risk for adverse cardiovascu­ lar and limb events. Mortality rates are highest in those with the most severe PAD. The ABI worsens in almost 40% of patients, and symptoms progress in ~20–25% when assessed over a period of 5 years. Approxi­ mately 11% of patients with symptomatic PAD ultimately develop chronic limb-threatening ischemia, and without revascularization, approximately 25% of patients with chronic limb-threatening ischemia undergo amputation within 1 year. The prognosis is worse in patients who continue to smoke cigarettes or have diabetes mellitus. TREATMENT Peripheral Artery Disease Patients with PAD should receive therapies to reduce the risk of associated cardiovascular events, such as myocardial infarction and death, and to improve limb symptoms, prevent progression to chronic limb-threatening ischemia, and preserve limb viability. Risk factor modification and antithrombotic therapy should be initiated to improve cardiovascular outcomes. The importance of discontin­ uing cigarette smoking cannot be overemphasized. The physician must assume a major role in this lifestyle modification. Counseling and adjunctive drug therapy with the nicotine patch, bupropion, or varenicline increase smoking cessation rates and reduce recidivism. It is important to control blood pressure in hypertensive patients. Angiotensin-converting enzyme inhibitors and angiotensin recep­ tor blockers may reduce the risk of cardiovascular events in patients with symptomatic PAD. β-Adrenergic blockers do not worsen claudication and may be used to treat hypertension, especially in patients with coexistent CAD. Treatment of hypercholesterolemia with statins and, if needed, adjunctive lipid-lowering agents such as ezetimibe or a PCSK9 inhibitor, are advocated to reduce the risk of myocardial infarction, stroke, and death. Statins and PCSK9 inhibitors also are associated with a decreased risk of adverse limb events, including amputation, in patients with PAD. The 2018 American Heart Association (AHA)/American College of Cardiol­ ogy (ACC) Guideline on the Management of Blood Cholesterol recommends high-intensity statin treatment in patients with ath­ erosclerotic disorders, including PAD, with the aim of achieving a 50% or greater reduction in low-density lipoprotein cholesterol. CHAPTER 292 Arterial Diseases of the Extremities Intensive glucose lowering reduces the risk of amputations in patients with diabetes mellitus. Among patients with diabetes and established cardiovascular disease, including PAD, the glucagonlike protein (GLP)-1 agonists and the sodium-glucose cotrans­ porter 2 (SGLT2) inhibitors have beneficial cardiovascular effects. GLP-1 agonists also may reduce the risk of amputation. Platelet inhibitors, including aspirin and the adenosine diphosphate (ADP) antagonist clopidogrel, reduce the risk of adverse cardiovascular events in patients with atherosclerosis and are recommended for patients with symptomatic PAD, including those with intermittent claudication or chronic limb-threatening ischemia or prior lower extremity revascularization. Outcomes with ticagrelor are similar to those with clopidogrel. The benefit of dual antiplatelet therapy with both aspirin and clopidogrel compared with aspirin alone in reducing cardiovascular morbidity and mortality rates in patients with PAD is uncertain. When added to other antiplatelet therapy, vorapaxar, a protease-activated receptor-1 antagonist that inhibits thrombin-mediated platelet activation, decreases the risk of adverse cardiovascular events in patients with atherosclerosis, including PAD. It also reduces the risk of acute limb ischemia and peripheral revascularization; however, it is associated with an increased rate of moderate bleeding. The anticoagulant warfarin is as effective as antiplatelet therapy in preventing adverse cardiovascular events but causes more major bleeding; therefore, it is not indicated to improve outcomes in patients with chronic PAD. The combination of a low dose of the oral factor Xa inhibitor rivaroxaban and aspirin improves cardiovascular and limb outcomes in patients with ath­ erosclerosis, including those with established PAD, as well as those who have undergone peripheral revascularization, but is associated with increased risk of bleeding. Therapies for intermittent claudication and chronic limbthreatening ischemia include supportive measures, medications, exer­ cise training, endovascular interventions, and surgery. Supportive measures include meticulous care of the feet, which should be kept clean and protected against excessive drying with moisturizing creams. Well-fitting and protective shoes are advised to reduce trauma. Elastic support hose should be avoided, as it reduces blood flow to the skin. In patients with chronic limb-threatening ischemia, shock blocks under the head of the bed together with a canopy over the feet may improve perfusion pressure and ameliorate some of the rest pain. Patients with claudication should be encouraged to exercise regu­ larly and at progressively more strenuous levels. Supervised exercise training programs for 30- to 45-min sessions, at least three times per week for 12 weeks, prolong walking distance. The beneficial effect of supervised exercise training on walking performance in patients with claudication often is similar to or greater than that realized after a revascularization procedure. Structured home and community-based exercise programs are also effective. Pharmaco­ logic treatment of PAD has not been as successful as the medical treatment of CAD (Chap. 284). In particular, vasodilators as a class have not proved to be beneficial. During exercise, peripheral vasodilation occurs distal to sites of significant arterial stenoses. As a result, perfusion pressure falls, often to levels lower than those generated in the interstitial tissue by the exercising muscle. Drugs such as α-adrenergic blocking agents, calcium channel antagonists, and other vasodilators have not been shown to be effective in patients with PAD. PART 6 Disorders of the Cardiovascular System Cilostazol, a phosphodiesterase-3 inhibitor with vasodilator and antiplatelet properties, increases claudication distance by 40–60% and improves measures of quality of life. The mechanism of action accounting for its beneficial effects is not known. Pentoxifylline, a substituted xanthine derivative, increases blood flow to the micro­ circulation and enhances tissue oxygenation. Although several placebo-controlled studies have found that pentoxifylline modestly increases the duration of exercise, its efficacy has not been con­ firmed in other clinical trials. Statins appeared effective for treat­ ment of intermittent claudication in initial clinical trials, but more studies are needed to confirm the efficacy of this class of drugs. There is no definitive medical therapy for chronic limbthreatening ischemia. Vasodilators, including prostaglandins, are not effective in relieving symptoms or preventing limb loss. Enthu­ siasm for therapy with angiogenic growth factors abated when clinical trials of intramuscular gene transfer of DNA encoding vas­ cular endothelial growth factor, fibroblast growth factor, hepatocyte growth factor, or hypoxia-inducible factor 1α failed to demonstrate improvement in symptoms or outcomes in patients with intermit­ tent claudication or critical limb ischemia. Most clinical trials of bone marrow–derived vascular progenitor cells to promote angio­ genesis and preserve limb viability in patients with critical limb isch­ emia have failed to demonstrate benefit, although a meta-analysis of these trials suggested a modest reduction in the risk of amputation. REVASCULARIZATION Revascularization procedures, including catheter-based, open sur­ gical, and hybrid interventions, are indicated for patients with chronic limb-threatening ischemia to relieve pain and prevent limb loss. These procedures are also indicated for patients with disabling, progressive, or severe symptoms of intermittent claudica­ tion despite medical therapy in order to improve walking distance and functional capacity. When revascularization is performed in conjunction with a supervised exercise program, walking distance improves more than with exercise training alone. MRA, CTA, or conventional angiography should be performed to assess vascular anatomy in patients who are being considered for revascularization. Endovascular interventions include percutaneous transluminal balloon angioplasty (PTA) (including drug-coated balloons), stent placement (including drug-eluting stents), stent grafts, and ather­ ectomy (Chap. 287). Several operative procedures are available for treating patients with PAD. The preferred operative procedure depends on the location and extent of the obstruction(s) and the general medical condition of the patient. Operative procedures for aortoiliac disease include aortobifemoral bypass, axillofemo­ ral bypass, femoro-femoral bypass, and aortoiliac endarterectomy. Operative therapy for femoral-popliteal and tibioperoneal artery disease includes in situ and reverse autogenous saphenous vein bypass grafts, placement of polytetrafluoroethylene (PTFE) or other synthetic grafts, and thromboendarterectomy. The decision to use an endovascular, open surgical, or a hybrid revascularization strategy depends on the vascular anatomy, including the location and extent of the arterial occlusions, the availability of suitable saphenous vein segments, comorbidities, and the skill and experience of the operator. Preoperative cardiac risk assessment may identify individuals who are especially likely to experience an adverse cardiac event during the perioperative period. Patients with angina, prior myo­ cardial infarction, heart failure, diabetes, or renal insufficiency are among those at increased risk. Stress testing with treadmill exercise (if feasible), radionuclide myocardial perfusion imaging, or echocardiography permits further stratification of risk in these patients, particularly those with poor or unknown functional capacity (Chap. 287). Patients with abnormal test results require close supervision and adjunctive management with anti-ischemic medications. Coronary angiography and coronary artery revas­ cularization compared with optimal medical therapy do not improve outcomes in most patients undergoing peripheral vas­ cular surgery, but cardiac catheterization should be considered in patients with unstable angina and angina refractory to medical therapy as well as those suspected of having left main or threevessel CAD. ■ ■FIBROMUSCULAR DYSPLASIA Fibromuscular dysplasia (FMD) is a hyperplastic disorder that typi­ cally affects medium-size and small arteries, but it can also affect larger arteries. The most common histologic characteristics include medial deposition of collagen causing fibromuscular ridges alternating with areas of thinned media. FMD occurs predominantly in females and usually involves the renal and carotid/vertebral arteries but can involve coronary and mesenteric arteries, as well as extremity vessels such as the iliac and subclavian arteries. FMD may cause stenosis, dissection, aneurysm, or thrombosis in affected arteries. When limb vessels are involved, clinical manifestations are similar to those for atherosclerosis, including claudication and rest pain. A contemporary classification based on the angiographic appear­ ance divides FMD into two types: multifocal, identified by a “string of beads” appearance caused by the thickened fibromuscular ridges contiguous with thin, less-involved portions of the arterial wall; and focal, identified as either unifocal (<1 cm) or tubular (≥1 cm) stenoses. Aspirin is recommended to reduce the risk of thrombosis in affected vessels. PTA and surgical reconstruction are beneficial in patients with debilitating symptoms or threatened limbs. ■ ■THROMBOANGIITIS OBLITERANS Thromboangiitis obliterans (Buerger’s disease) is an inflammatory occlusive vascular disorder involving small and medium-size arteries and veins in the distal upper and lower extremities. Cerebral, visceral, and coronary vessels may be affected rarely. This disorder develops most frequently in men <40 years of age. The prevalence is higher in Asians and individuals of Eastern European descent. Although the cause of thromboangiitis obliterans is not known, there is a definite relationship to cigarette smoking in patients with this disorder. In the initial stages of thromboangiitis obliterans, polymorpho­ nuclear leukocytes infiltrate the walls of the small and medium-size arteries and veins. The internal elastic lamina is preserved, and a cellular, inflammatory thrombus develops in the vascular lumen. As the disease progresses, mononuclear cells, fibroblasts, and giant cells replace the neutrophils. Later stages are characterized by perivascular fibrosis, organized thrombus, and recanalization. The clinical features of thromboangiitis obliterans often include a triad of claudication of the affected extremity, Raynaud phenom­ enon, and migratory superficial vein thrombophlebitis. Claudica­ tion usually is confined to the calves and feet or the forearms and hands because this disorder primarily affects distal vessels. In the presence of severe digital ischemia, trophic nail changes, painful ulcerations, and gangrene may develop at the tips of the fingers or toes. The physical examination shows normal brachial and popliteal pulses but reduced or absent radial, ulnar, and/or tibial pulses. MRA, CTA, and conventional arteriography are helpful in making the diag­ nosis. Smooth, tapering segmental lesions in the distal vessels are characteristic, as are collateral vessels at sites of vascular occlusion. Proximal atherosclerotic disease is usually absent. The diagnosis can be confirmed by excisional biopsy and pathologic examination of an involved vessel. There is no specific treatment except abstention from tobacco. The prognosis is worse in individuals who continue to smoke, but results are discouraging even in those who stop smoking. Arterial bypass of the larger vessels may be used in selected instances, as well as local debridement, depending on the symptoms and severity of ischemia. Antibiotics may be useful; anticoagulants and glucocorticoids are not helpful. If these measures fail, amputation may be required. ■ ■OTHER VASCULITIDES Other vasculitides may affect the arteries that supply the upper and lower extremities. Takayasu arteritis and giant cell (temporal) arteri­ tis are discussed in Chap. 375. ■ ■ACUTE LIMB ISCHEMIA Acute limb ischemia occurs when arterial occlusion results in the sud­ den cessation of blood flow to an extremity. The severity of ischemia and the viability of the extremity depend on the location and extent of the occlusion and the presence and subsequent development of collat­ eral blood vessels. Principal causes of acute arterial occlusion include embolism, thrombus in situ, arterial dissection, and trauma. The most common sources of arterial emboli are the heart, aorta, and large arteries. Cardiac disorders that cause thromboembolism include atrial fibrillation; acute myocardial infarction; ventricular aneurysm; cardiomyopathy; infectious and marantic endocarditis; thrombi associated with prosthetic heart valves; and atrial myxoma. Emboli to the distal vessels may also originate from proximal sites of atherosclerosis and aneurysms of the aorta and large vessels. Less frequently, an arterial occlusion results paradoxically from a venous thrombus that has entered the systemic circulation via a patent fora­ men ovale or another septal defect. Arterial emboli tend to lodge at vessel bifurcations because the vessel caliber decreases at those sites; in the lower extremities, emboli lodge most frequently in the femoral artery, followed by the iliac artery, aorta, and popliteal and tibiopero­ neal arteries. Acute arterial thrombosis in situ occurs most frequently in athero­ sclerotic vessels at the site of an atherosclerotic plaque or aneurysm and in arterial bypass grafts. Trauma to an artery may disrupt continuity of blood flow and cause acute limb ischemia via formation of an acute arterial thrombus or by disruption of an artery’s integrity and extrava­ sation of blood. Arterial occlusion may complicate arterial punctures and placement of catheters; it also may result from arterial dissection if the intimal flap obstructs the artery. Less common causes include thoracic outlet compression syndrome, which causes subclavian artery occlusion, and entrapment of the popliteal artery by abnormal place­ ment of the medial head of the gastrocnemius muscle. Polycythemia and hypercoagulable disorders (Chaps. 108 and 121) are also associ­ ated with acute arterial thrombosis. ■ ■CLINICAL FEATURES The symptoms of an acute arterial occlusion depend on the location, duration, and severity of the obstruction. Often severe pain, paresthe­ sia, numbness, and coldness develop in the involved extremity within 1 h. Paralysis may occur with severe and persistent ischemia. Physi­ cal findings include loss of pulses distal to the occlusion, cyanosis or pallor, mottling, decreased skin temperature, muscle stiffening, loss of sensation, weakness, and/or absent deep tendon reflexes. If acute arterial occlusion occurs in the presence of an adequate collateral circulation, as is often the case in acute graft occlusion, the symp­ toms and findings may be less severe. In this situation, the patient complains about an abrupt decrease in the distance walked before claudication occurs or of modest pain and paresthesia. Pallor and coolness are evident, but sensory and motor functions generally are preserved. The clinical evaluation includes Doppler assessment of peripheral blood flow. The diagnosis of acute limb ischemia is usu­ ally apparent from the clinical presentation. In most circumstances, duplex ultrasound, MRA, CTA, or catheter-based arteriography is used to confirm the diagnosis and demonstrate the location and extent of arterial occlusion. TREATMENT Acute Limb Ischemia Once the diagnosis is made, the patient should be anticoagu­ lated with intravenous heparin to prevent propagation of the clot and recurrent embolism. In cases of severe ischemia of recent onset, particularly when limb viability is jeopardized, immediate intervention to ensure reperfusion is indicated. Catheter-directed thrombolysis/thrombectomy, surgical thromboembolectomy, and arterial bypass procedures are used to restore blood flow to the ischemic extremity promptly, particularly when a large proximal vessel is occluded. CHAPTER 292 Arterial Diseases of the Extremities Intraarterial thrombolytic therapy with recombinant tissue plas­ minogen activator, reteplase, or tenecteplase is most effective when acute arterial occlusion is recent and caused by a thrombus in an atherosclerotic vessel, arterial bypass graft, or occluded stent. Thrombolytic therapy is also indicated when the patient’s overall condition contraindicates surgical intervention or when smaller distal vessels are occluded, thus preventing surgical access. Meticu­ lous observation for hemorrhagic complications is required during intraarterial thrombolytic therapy. Ultrasound-emitting catheters may accelerate reperfusion by improving thrombus permeability to thrombolytic agents. Another endovascular approach to thrombus removal is percutaneous mechanical thrombectomy using devices that employ hydrodynamic forces or rotating baskets to fragment and remove the clot. These treatments may be used alone but usu­ ally are used in conjunction with pharmacologic thrombolysis. Surgical revascularization is preferred when restoration of blood flow must occur within 24 h to prevent limb loss. Amputation is performed when the limb is not viable, as characterized by loss of sensation, paralysis, and the absence of Doppler-detected blood flow in both arteries and veins. Long-term anticoagulation is indicated when acute limb ischemia is caused by cardiac thromboembolism. Emboli resulting from infec­ tive endocarditis, the presence of prosthetic heart valves, or atrial myxoma often require surgical intervention to remove the cause. ■ ■ATHEROEMBOLISM Atheroembolism is another cause of limb ischemia. In this condi­ tion, multiple small deposits of fibrin, platelets, and cholesterol debris embolize from proximal atherosclerotic lesions or aneurysmal sites. Large protruding aortic atheromas are a source of emboli that may lead to limb ischemia, as well as stroke and renal insufficiency. Atheroem­ bolism may occur after intraarterial procedures. Since atheroemboli to limbs tend to lodge in the small vessels of the muscle and skin and may not occlude the large vessels, distal pulses usually remain palpable. Patients complain of acute pain and tenderness at the site of emboliza­ tion. Digital vascular occlusion may result in ischemia and the “blue toe” syndrome; digital necrosis and gangrene may develop (Fig. 292-2). Localized areas of tenderness, pallor, and livedo reticularis (see below) occur at sites of emboli. Skin or muscle biopsy may demonstrate cho­ lesterol crystals. Ischemia resulting from atheroemboli is notoriously difficult to treat. Local foot care and occasionally amputation may be needed to treat necrotic areas. Analgesics are indicated for pain relief. Usually neither surgical revascularization procedures nor thrombolytic therapy is helpful because of the multiplicity, composition, and distal location of the emboli. Therapy with antiplatelet drugs and statins improves cardiovascular outcome in patients with atherosclerosis, but it is not established whether either class of drugs prevents recurrent athero­ embolism. Similarly, it is not known whether anticoagulant therapy is effective. Endovascular or surgical intervention to exclude or bypass the atherosclerotic vessel or aneurysm that causes the recurrent ath­ eroemboli may be necessary. ■ ■THORACIC OUTLET COMPRESSION SYNDROME This is a symptom complex resulting from compression of the neu­ rovascular bundle (artery, vein, or nerves) at the thoracic outlet as it PART 6 Disorders of the Cardiovascular System FIGURE 292-2  Atheroembolism causing cyanotic discoloration and impending necrosis of the toes (“blue toe” syndrome). courses through the neck and shoulder. Cervical ribs, abnormalities of the scalenus anticus muscle, proximity of the clavicle to the first rib, or abnormal insertion of the pectoralis minor muscle may compress the subclavian artery, subclavian vein, and brachial plexus as these struc­ tures pass from the thorax to the arm. Depending on the structures affected, thoracic outlet compression syndrome is divided into arte­ rial, venous, and neurogenic forms. Patients with neurogenic thoracic outlet compression may develop shoulder and arm pain, weakness, and paresthesias. Patients with arterial compression may experience claudication, Raynaud phenomenon, and even ischemic tissue loss and gangrene. Venous compression may cause thrombosis of the subclavian and axillary veins; this is often associated with effort and is referred to as Paget-Schroetter syndrome. APPROACH TO THE PATIENT Arterial Thoracic Outlet Compression Syndrome Examination of a patient with arterial thoracic outlet compres­ sion syndrome is often normal unless provocative maneuvers are performed. Occasionally, distal pulses are decreased or absent and digital cyanosis and ischemia may be evident. Several maneuvers that support the diagnosis of arterial thoracic outlet compression syndrome may be used to precipitate symp­ toms, cause a subclavian artery bruit, and diminish arm pulses. These maneuvers include the abduction and external rotation test, in which the affected arm is abducted by 90° and the shoulder is externally rotated; the scalene maneuver (extension of the neck and rotation of the head to the side of the symptoms); the cos­ toclavicular maneuver (posterior rotation of shoulders); and the hyperabduction maneuver (raising the arm 180°). A chest x-ray will indicate the presence of cervical ribs. Duplex ultrasonography, CTA, MRA, and contrast angiography can be performed during provocative maneuvers to demonstrate thoracic outlet compression of the subclavian artery. Neurophysiologic tests such as the electro­ myogram, nerve conduction studies, and somatosensory evoked potentials may be abnormal if the brachial plexus is involved, but the diagnosis of neurogenic thoracic outlet syndrome is not necessarily excluded if these tests are normal owing to their low sensitivity. Most patients can be managed conservatively. They should be advised to avoid the positions that cause symptoms. Many patients benefit from shoulder girdle exercises. Surgical procedures such as removal of the first rib and resection of the scalenus anticus muscle are necessary occasionally for relief of symptoms or treatment of ischemia. ■ ■POPLITEAL ARTERY ENTRAPMENT Popliteal artery entrapment typically affects young athletic men and women when the gastrocnemius or popliteus muscle compresses the popliteal artery and causes intermittent claudication. Thrombo­ sis, embolism, or popliteal artery aneurysm may occur. The pulse examination may be normal unless provocative maneuvers such as ankle dorsiflexion and plantar flexion are performed. The diagnosis is confirmed by duplex ultrasound, CTA, MRA, or conventional angi­ ography. Treatment involves surgical release of the popliteal artery or vascular reconstruction. ■ ■POPLITEAL ARTERY ANEURYSM Popliteal artery aneurysms are the most common peripheral artery aneurysms. Approximately 50% are bilateral. Patients with popliteal artery aneurysms often have aneurysms of other arteries, especially the aorta. The most common clinical presentation is limb ischemia secondary to thrombosis or embolism. Rupture occurs less frequently. Other complications include compression of the adjacent popliteal vein or peroneal nerve. Popliteal artery aneurysm can be detected by palpa­ tion and confirmed by duplex ultrasonography. Repair is indicated for symptomatic aneurysms or when the diameter exceeds 2–3 cm, owing to the risk of thrombosis, embolism, or rupture. ■ ■ARTERIOVENOUS FISTULA Abnormal communications between an artery and a vein, bypassing the capillary bed, may be congenital or acquired. Congenital arterio­ venous fistulas are a result of persistent embryonic vessels that fail to differentiate into arteries and veins; they may be associated with birthmarks, can be located in almost any organ of the body, and frequently occur in the extremities. Acquired arteriovenous fistulas either are created to provide vascular access for hemodialysis or occur as a result of a penetrating injury such as a gunshot or knife wound or as complications of arterial catheterization or surgical dissection. An uncommon cause of arteriovenous fistula is rupture of an arterial aneurysm into a vein. The clinical features depend on the location and size of the fistula. Frequently, a pulsatile mass is palpable, and a thrill and a bruit last­ ing throughout systole and diastole are present over the fistula. With long-standing fistulas, clinical manifestations of chronic venous insufficiency, including peripheral edema; large, tortuous varicose veins; and stasis pigmentation become apparent because of the high venous pressure. Evidence of ischemia may occur in the distal por­ tion of the extremity. Skin temperature is higher over the arteriove­ nous fistula. Large arteriovenous fistulas may result in an increased cardiac output with consequent cardiomegaly and high-output heart failure (Chap. 264). The diagnosis is often evident from the physical examination. Com­ pression of a large arteriovenous fistula may cause reflex slowing of the heart rate (Nicoladoni-Branham sign). Duplex ultrasonography may detect an arteriovenous fistula, especially one that affects the femoral artery and vein at the site of catheter access. CTA and conventional angiography can confirm the diagnosis and are useful in demonstrat­ ing the site and size of the arteriovenous fistula. Management of arteriovenous fistulas may involve surgery, radio­ therapy, or embolization. Congenital arteriovenous fistulas are often difficult to treat because the communications may be numerous and extensive, and new communications frequently develop after ligation of the most obvious ones. Many of these lesions are best treated conserva­ tively using elastic support hose to reduce the consequences of venous hypertension. Occasionally, embolization with autologous material, such as fat or muscle, or with hemostatic agents, such as gelatin sponges or silicon spheres, is used to obliterate the fistula. Acquired arteriove­ nous fistulas are usually amenable to surgical treatment that involves division or excision of the fistula. Occasionally, autogenous or synthetic grafting is necessary to reestablish continuity of the artery and vein. ■ ■RAYNAUD PHENOMENON Raynaud phenomenon is characterized by episodic digital isch­ emia, manifested clinically by the sequential development of digital B C A E F D FIGURE 292-3  Vascular diseases associated with temperature: A. Raynaud phenomenon; B. acrocyanosis; C. livedo reticularis; D. pernio; E. erythromelalgia; and F. frostbite. blanching, cyanosis, and rubor of the fingers or toes after cold expo­ sure and subsequent rewarming. Emotional stress may also precipitate Raynaud phenomenon. The color changes are usually well demarcated and are confined to the fingers or toes. Typically, one or more digits will appear white when the patient is exposed to a cold environment or touches a cold object (Fig. 292-3A). The blanching, or pallor, rep­ resents the ischemic phase of the phenomenon and results from vaso­ spasm of digital arteries. During the ischemic phase, capillaries and venules dilate, and cyanosis results from the deoxygenated blood that is present in these vessels. A sensation of cold or numbness or paresthesia of the digits often accompanies the phases of pallor and cyanosis. With rewarming, the digital vasospasm resolves, and blood flow into the dilated arterioles and capillaries increases dramatically. This “reactive hyperemia” imparts a bright red color to the digits. In addi­ tion to rubor and warmth, patients often experience a throbbing, painful sensation during the hyperemic phase. Although the triphasic color response is typical of Raynaud phenomenon, some patients may develop only pallor and cyanosis; others may experience only cyanosis. Raynaud phenomenon is broadly separated into two categories: idiopathic, termed primary Raynaud phenomenon, and secondary Raynaud phenomenon, which is associated with other disease states or known causes of vasospasm (Table 292-1). Primary Raynaud Phenomenon  This appellation is applied when the secondary causes of Raynaud phenomenon have been excluded. Over 50% of patients with Raynaud phenomenon have the primary form. Women are affected about five times more often than men, and the age of presentation is usually between 20 and 40 years. The fingers are involved more frequently than the toes. Initial episodes may involve only one or two fingertips, but subsequent attacks may involve the entire finger and may include all the fingers. The toes are affected in 40% of patients. Although vasospasm of the toes usually occurs in patients with symptoms in the fingers, it may happen alone. CHAPTER 292 Arterial Diseases of the Extremities Rarely, the earlobes, the tip of the nose, tongue, nipple, or penis are involved. Raynaud phenomenon occurs frequently in patients who also have migraine headaches or variant angina from coronary vasospasm. These associations suggest that there may be a common predisposing cause for the vasospasm. Results of physical examination are often entirely normal; the radial, ulnar, and pedal pulses are normal. The fingers and toes may be cool between attacks and may perspire excessively. Nailfold capillaroscopy reveals normal superficial capillaries, which appear as regularly spaced hairpin loops. Thickening and tightening of the digital subcutaneous tissue (sclerodactyly) develop in 10% of patients. Angiography of the digits for diagnostic purposes is not indicated. TABLE 292-1  Classification of Raynaud Phenomenon Primary or idiopathic Raynaud phenomenon Secondary Raynaud phenomenon      Collagen vascular diseases: scleroderma, systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, polymyositis, mixed connective tissue disease, Sjögren syndrome      Arterial occlusive diseases: atherosclerosis of the extremities, thromboangiitis obliterans, acute arterial occlusion, thoracic outlet syndrome      Pulmonary hypertension      Neurologic disorders: intervertebral disk disease, syringomyelia, spinal cord tumors, stroke, poliomyelitis, carpal tunnel syndrome, complex regional pain syndrome      Blood dyscrasias: cold agglutinins, cryoglobulinemia, cryofibrinogenemia, myeloproliferative disorders, lymphoplasmacytic lymphoma      Trauma: vibration injury, hammer hand syndrome, electric shock, cold injury, typing, piano playing      Drugs and toxins: ergot derivatives, methysergide, b-adrenergic receptor blockers, bleomycin, vinblastine, cisplatin, gemcitabine, vinyl chloride In general, patients with primary Raynaud disease have milder clinical manifestations. Fewer than 1% of these patients lose a part of a digit. After the diagnosis is made, the disease improves spontaneously in ~15% of patients and progresses in ~30%. Secondary Causes of Raynaud Phenomenon  Raynaud phe­ nomenon occurs in 80–90% of patients with systemic sclerosis (sclero­ derma) and is the presenting symptom in 30% (Chap. 372). It may be the only symptom of scleroderma for many years. Abnormalities of the digital vessels may contribute to the development of Raynaud phenomenon in this disorder. Ischemic fingertip ulcers may develop and progress to gangrene and autoamputation. About 20% of patients with systemic lupus erythematosus (SLE) have Raynaud phenomenon (Chap. 368). Occasionally, persistent digital ischemia develops and may result in ulcers or gangrene. In most severe cases, the small ves­ sels are occluded by a proliferative endarteritis. Raynaud phenomenon occurs in ~30% of patients with dermatomyositis or polymyositis (Chap. 377). It frequently develops in patients with rheumatoid arthri­ tis and may be related to the intimal proliferation that occurs in the digital arteries. PART 6 Disorders of the Cardiovascular System Atherosclerosis of the extremities is a common cause of Raynaud phenomenon in men aged >50 years. Thromboangiitis obliterans is an uncommon cause of Raynaud phenomenon but should be consid­ ered in young men, particularly those who are cigarette smokers. The development of cold-induced pallor in these disorders may be confined to one or two digits of the involved extremity. Occasionally, Raynaud phenomenon may follow acute occlusion of large and medium-sized arteries by a thrombus or embolus. Embolization of atheroembolic debris may cause digital ischemia. The latter situation often involves one or two digits and should not be confused with Raynaud phenom­ enon. In patients with thoracic outlet compression syndrome, Raynaud phenomenon may result from diminished intravascular pressure, stimulation of sympathetic fibers in the brachial plexus, or a combina­ tion of both. Raynaud phenomenon occurs in patients with primary pulmonary hypertension (Chap. 294); this is more than coincidental and may reflect a neurohumoral abnormality that affects both the pul­ monary and digital circulations. A variety of blood dyscrasias may be associated with Raynaud phe­ nomenon. Cold-induced precipitation of plasma proteins, hyperviscos­ ity, and aggregation of red cells and platelets may occur in patients with cold agglutinins, cryoglobulinemia, or cryofibrinogenemia. Hypervis­ cosity syndromes that accompany myeloproliferative disorders and lym­ phoplasmacytic lymphoma (Waldenström macroglobulinemia) should also be considered in the initial evaluation of patients with Raynaud phenomenon. Raynaud phenomenon occurs often in patients whose vocations require the use of vibrating hand tools, such as chain saws or jackham­ mers. The frequency of Raynaud phenomenon also seems to be increased in pianists and keyboard operators. Electric shock injury to the hands or frostbite may lead to the later development of Raynaud phenomenon. Several drugs have been causally implicated in Raynaud phenom­ enon. They include ergot preparations, methysergide, β-adrenergic receptor antagonists, and the chemotherapeutic agents bleomycin, vinblastine, cisplatin, and gemcitabine. TREATMENT Raynaud Phenomenon Most patients with Raynaud phenomenon experience only mild and infrequent episodes. These patients need reassurance and should be instructed to dress warmly and avoid unnecessary cold exposure. In addition to gloves and mittens, patients should protect the trunk, head, and feet with warm clothing to prevent cold-induced reflex vasoconstriction. Tobacco use is contraindicated. Drug treatment should be reserved for severe cases. Dihy­ dropyridine calcium channel antagonists such as nifedipine and amlodipine decrease the frequency and severity of Raynaud phe­ nomenon. Diltiazem may be considered but is less effective. The postsynaptic α1-adrenergic antagonist prazosin has been used with favorable responses; doxazosin and terazosin may also be effective. Phosphodiesterase type 5 inhibitors such as sildenafil, tadalafil, and vardenafil may improve symptoms in patients with secondary Raynaud phenomenon, as occurs with systemic sclerosis. There is also evidence that topical nitroglycerin preparations are effective. Digital sympathectomy is helpful in some patients who are unre­ sponsive to medical therapy. Injection of botulinum toxin into the perivascular tissue of the wrist or palm improved ischemic mani­ festations of severe Raynaud phenomenon in case series, although controlled clinical trials have yielded inconsistent results. ■ ■ACROCYANOSIS In this condition, there is arterial vasoconstriction and secondary dila­ tion of the capillaries and venules with resulting persistent cyanosis of the hands and, less frequently, the feet. Cyanosis may be intensified by exposure to a cold environment. Acrocyanosis may be categorized as primary or secondary to an underlying condition. In primary acrocya­ nosis, women are affected much more frequently than men, and the age of onset is usually <30 years. Generally, patients are asymptomatic but seek medical attention because of the discoloration. The prognosis is favorable, and pain, ulcers, and gangrene do not occur. Examina­ tion reveals normal pulses, peripheral cyanosis, and moist palms (Fig. 292-3B). Trophic skin changes and ulcerations do not occur. The disorder can be distinguished from Raynaud phenomenon because it is persistent and not episodic, the discoloration extends proximally from the digits, and blanching does not occur. Ischemia secondary to arterial occlusive disease can usually be excluded by the presence of normal pulses. Central cyanosis and decreased arterial oxygen saturation are not present. Patients should be reassured and advised to dress warmly and avoid cold exposure. Pharmacologic intervention is not indicated. Secondary acrocyanosis may result from hypoxemia, vasopressor medications, connective tissue diseases, atheroembolism, antiphospho­ lipid antibodies, cold agglutinins, or cryoglobulins and is associated with anorexia nervosa and postural orthostatic tachycardia syndrome. Treatment should be directed at the underlying disorder. ■ ■LIVEDO RETICULARIS In this condition, localized areas of the extremities develop a mottled or rete (netlike) appearance of reddish to blue discoloration (Fig. 293-3C). There are primary and secondary forms of livedo reticularis. The pri­ mary, or idiopathic, form of this disorder may be benign or associated with ulcerations. The benign form occurs more frequently in women than in men, and the most common age of onset is the third decade. The mottling typically is symmetric and uniform and may be more prominent after cold exposure and improve with warming. Patients with the benign form are usually asymptomatic and seek attention for cosmetic reasons. These patients should be reassured and advised to avoid cold environments. No drug treatment is indicated. Primary livedo reticularis with ulceration is also called atrophie blanche en plaque. The ulcers are painful and may take months to heal. Secondary livedo reticularis can occur with atheroembolism (see above), SLE and other vasculitides, antiphospholipid antibodies, hyperviscosity, cryo­ globulinemia, and Sneddon’s syndrome (ischemic stroke and livedo reticularis). Livedo racemosa is the term used to characterize second­ ary livedo reticularis, when the mottling is irregular and disrupted, and does not improve with warming. Rarely, skin ulcerations develop. ■ ■PERNIO (CHILBLAINS) Pernio is a vasculitic disorder associated with exposure to cold; acute forms have been described. Raised erythematous lesions develop most commonly on the toes or fingers in cold weather (Fig. 292-3D). They are associated with pruritus and a burning sensation, and they may blister and ulcerate. Pathologic examination demonstrates angiitis characterized by intimal proliferation and perivascular infiltration of mononuclear and polymorphonuclear leukocytes. Giant cells may be present in the subcutaneous tissue. Patients should avoid exposure to cold, and ulcers should be kept clean and protected with sterile dressings. Sympatholytic drugs and dihydropyridine calcium channel antagonists may be effective in some patients.