Nonatherosclerotic Vascular Disease

Vasospastic Disorders

Raynaud syndrome (RS), variant angina, and migraine headache are the most frequent vasospastic disorders seen in clinical practice, with RS being the most common vasospastic condition referred to vascular surgeons.

Episodic digital ischemia (or RS) was first described by Maurice Raynaud in 1862. The digital ischemia in patients with this condition traditionally manifests as tricolor changes—white, blue, and red—although one or more of these color changes may be absent. The affected digits return to normal 10 to 15 minutes after removal of the precipitating stimulus (usually environmental cold or emotional stress), and the fingers remain normal between attacks.

The prevalence of RS in the general population varies with climate and, probably, ethnic origin. In cool, damp climates such as the Pacific Northwest, Scandinavia, and Great Britain, the prevalence approaches 20% to 25%. It is not known whether the lower prevalence in warm, dry climates is due to a decreased occurrence of the syndrome or merely lack of patient complaints. RS occurs most frequently in young women. The median age of onset of RS is 14 years, with only 27% of cases beginning after age 40. Approximately one-quarter of patients have a family history of RS in a first-degree relative.

The mechanism of vasoconstriction in RS remains a subject of debate. Raynaud speculated that sympathetic nervous system hyperactivity was responsible, a proposition disproved by Lewis in the 1920s when he demonstrated that blockade of digital nerve conduction did not prevent vasospasm. Lewis then proposed the theory of a local vascular fault, the nature of which remains undefined.

In recent years, the focus in RS pathophysiology has been on alterations in peripheral adrenoceptor activity. Increased finger blood flow was noted in patients following α-adrenergic blockade with drugs such as reserpine. Oral and intraarterial reserpine were the cornerstones of medical management of RS for several years, but are no longer available Fig. 8.1 .

Research in human vessel models demonstrated increased α ₂ receptor sensitivity to cold exposure. α ₂ Adrenoceptors appear to have a major role in the production of the symptoms of RS. Possible mechanisms of α ₂ -adrenergic–induced RS include an elevation in the number of α ₂ receptor sites, receptor hypersensitivity, and alterations in the number of receptors exposed at any one time.

The response of subcutaneous resistance vessels to acetylcholine has been shown to be diminished in patients with RS compared with controls, indicating a possible endothelium-dependent mechanism. The possible roles of the vasoactive peptide endothelin, a potent vasoconstrictor, and calcitonin gene-related peptide (CGRP), a vasodilator, have also been investigated. Serum endothelin levels increased significantly with cold exposure in patients with RS compared with controls. Depletion of endogenous CGRP may also contribute, because increased skin blood flow in response to CGRP infusion has been demonstrated in patients with RS compared with that in controls.

Based on observations at the Mayo Clinic 70 years ago by Allen and Brown, patients with Raynaud symptoms have traditionally been classified as having either Raynaud disease or Raynaud phenomenon, depending on the absence or presence of an associated systemic disease process. However, Raynaud disease may precede the development of an associated disease by years. In addition, this system does not address the underlying palmar and digital artery disease that may be present. Patients with cold- or stress-induced digital ischemia are referred to as having RS, thus avoiding the semantic conflict of disease versus phenomenon .

It is useful to subdivide patients with RS into two distinct pathophysiologic groups: obstructive and vasospastic, based on the presence or absence of arterial occlusive disease. Patients with vasospastic RS have patent digital arteries and normal digital artery pressures at room temperature. These patients have an abnormally forceful vasoconstrictive response to cold exposure or emotional stress, leading to digital arterial closure and episodic digital ischemic symptoms. Patients with obstructive RS have significant obstruction of either the palmar and digital arteries or the proximal arm arteries, with a concomitant reduction in resting digital arterial pressure. In these patients, a normal vasoconstrictive response to cold appears to be sufficient to cause digital arterial closure with resultant episodic digital ischemia.

In patients with obstructive RS, the mechanism of the obstructive process is variable. Patients with connective tissue disease typically have an autoimmune vasculitis, which is probably the mechanism underlying the widespread digital and palmar artery occlusions. Patients who work with vibrating tools have a similar process and frequently develop a fibrotic form of palmar and digital artery obstruction, presumably associated with injury from repeated shear stress. Hypercoagulable states may appear with digital artery occlusions, as can emboli from various sources, including valvular heart disease and subclavian, axillary, and ulnar aneurysms. Atherosclerosis involving the upper extremities is rarely seen in the younger age group but is occasionally observed in older patients.

A number of diseases have been recognized in association with RS, among which the connective tissue diseases are the most frequent; scleroderma is the most common. Associated diseases recognized in patients with RS are shown in Table 8.1 . Estimates of the percentage of patients with RS and an associated disease range from 30% to 80%. It is important to note that the data from most series come from tertiary-care referral centers; therefore, they might not reflect the actual incidence in the general population and may overestimate the actual prevalence of associated diseases. The diagnosis of RS is made by history and physical examination. Noninvasive vascular laboratory testing is used to differentiate obstructive from vasospastic RS. Symptoms are typically described as coldness, numbness, or mild discomfort. Significant pain during attacks is conspicuously absent. Classically, both hands are involved, with frequent sparing of the thumbs. The lower extremities are infrequently involved. Most episodes are induced by cold; however, the cold threshold varies from patient to patient. Emotional stimuli can induce attacks in some patients. Episodes typically commence with blanching of one or several fingers extending as far as the metacarpophalangeal joint, rarely involving the palm or extending proximally to the wrist. This phase corresponds to vasoconstriction with the absence of blood in digital arteries. After rewarming, the first blood to reach the skin is desaturated, leading to finger cyanosis. Finally, reactive hyperemia leads to digital rubor. Episodes usually last as long as the cold stimulus is present and resolve within 10 to 15 minutes of rewarming. The hands and fingers are normal between attacks.

A history suggestive of an associated connective tissue disease should be sought, including arthralgias, dysphagia, sclerodactyly, xerophthalmia, or xerostomia, as well as any prior history of large vessel occlusive disease, malignancy, hypothyroidism, frostbite, trauma, use of vibrating tools, and drug use. More than half of patients with carpal tunnel syndrome can have coexistent RS. The examiner should carefully evaluate the pulses and assess the digits for evidence of active or healed ulceration, sclerodactyly, telangiectasia, and calcinosis. The optimal serologic evaluation has not been defined. It is common to obtain a complete blood cell count, erythrocyte sedimentation rate, antinuclear antibody titer, and rheumatoid factor. Patients who exhibit sudden-onset digital ischemia should be evaluated for hypercoagulable states. Tests for specific connective tissue diseases are obtained based on clinical suspicion. Importantly, the physical examination in patients with RS is frequently normal, and the diagnosis relies on history and noninvasive tests.

Routine vascular laboratory testing consists of digital photoplethysmography and digital blood pressures. The digital photoplethysmographic recording provides qualitative information on the character of the arterial waveform. Normal digital blood pressure is within 30 mm Hg of brachial pressure. Patients with obstructive RS have blunted waveforms, whereas patients with vasospastic RS have either normal waveforms or a “peaked pulse.” The peaked pulse pattern, first described by Sumner and Strandness, appears to reflect increased vasospastic arterial resistance.

The utility of cold provocation testing remains controversial. Tests involving immersion of patients' hands in ice water are not clinically useful because of low specificity and reproducibility. Of greater clinical utility is a digital hypothermic cold challenge test described by Nielson and Lassen. This test is performed with a liquid-perfused cuff placed on the proximal phalanx of the target finger. The cuff is inflated to suprasystolic pressure for 5 minutes while it is perfused with cold water. The pressure at which blood flow is detected on deflation of the cuff is recorded. A control finger on the same hand is tested at room temperature. The test is repeated at several temperatures, and the result is expressed as the percentage drop in finger systolic pressure with cooling. This test has an overall sensitivity and accuracy of approximately 90%, but is limited due to lack of widespread availability.

Duplex scanning does not appear to have a major role in the diagnosis of RS, although it can be used to search for proximal arterial obstructive or aneurysmal disease. Laser Doppler imaging quantifies digital microvascular blood flow and may have future diagnostic applications in RS. Angiography was used extensively in the past, particularly in the evaluation of patients with obstructive RS. Patients with an underlying systemic disease process and bilateral palmar and digital arterial obstructive disease documented by vascular laboratory testing do not require angiography to confirm digital artery occlusive disease. Patients with unilateral disease, particularly those who have only one or two digits of one arm involved, should be considered for angiography to determine both the presence of bilateral disease and the presence of any proximal arterial disease.

Avoidance of triggering stimuli, such as cold or emotional stress, is the hallmark of conservative treatment. We advise all patients with RS to avoid tobacco use, although a multicenter epidemiologic study suggested that RS is not strongly influenced by tobacco consumption. Medications that have been associated with the causation of RS symptoms, such as ergot alkaloids and β-blockers, should be avoided if appropriate alternative therapies exist. More than 90% of patients with RS respond adequately to these simple conservative measures and require no additional treatment. The small number of patients who develop digital ulcers in association with obstructive RS can also be managed conservatively. A healing rate of 85% has been achieved with simple treatment consisting of soap and water scrubs, antibiotics as selected by culture, and conservative debridement.

Calcium channel blockers are the most widely used pharmacologic agent for the treatment of RS. As a rule, patients with vasospastic RS respond more favorably to medical therapy than do those with occlusive RS. The dihydropyridine calcium channel blockers are most effective, and nifedipine has been the most studied, with a significant decrease in attack frequency and severity in numerous trials. Potential side effects include headache, ankle swelling, pruritus, and, rarely, severe fatigue. Other calcium channel blockers include nicardipine, amlodipine, and felodipine. Second-line medications with proven efficacy include α-blockers (prazosin), angiotensin II receptor blockers (losartan), serotonin reuptake inhibitors (fluoxetine), phosphodiesterase 5 inhibitors (sildenafil, tadalafil), and topical nitrates. Intravenous prostaglandins, such as Iloprost, an analog of prostacyclin, have been shown to be effective in treating RS associated with systemic sclerosis but have not been shown to be effective in oral form. Endothelin receptor antagonists (bosentan) have also shown benefit in preventing and treating digital ulcers, but have a high rate of liver toxicity and are approved by US Food and Drug Administration only for treatment of pulmonary hypertension. Temperature biofeedback, in which patients are taught hand warming through behavioral techniques, was initially believed to reduce symptom frequency in patients with vasospastic RS. However, a randomized trial showed no improvement in symptoms after 1 year compared with a control technique. Transcutaneous electrical nerve stimulation, which has been described as causing vasodilatation, resulted in only mild increases in skin temperature; it caused no improvements in digital plethysmography or transcutaneous partial pressure of oxygen in test hands and had a negligible effect on symptoms. Anecdotal reports of the use of spinal cord stimulators report reduced pain and improved ulcer healing in refractory RS. Acupuncture has also been suggested as a possible treatment alternative, with a significant reduction in frequency and severity of attacks.

Several small case series have demonstrated decreased frequency of attacks and improved ulcer healing with chemical sympathectomy using an interdigital injection of botulinum toxin. Surgical cervicothoracic sympathectomy has not been shown to have a lasting benefit in most series, with recurrence rates as high as 82% at 16 months of follow-up. In a large series of patients undergoing thoracoscopic sympathectomy, increased digital artery perfusion was maintained out to 5 years of follow-up, although symptom recurrence occurred in 28% of patients. Lumbar sympathectomy remains a viable option in patients with severely symptomatic lower extremity vasospasm and is amenable to minimally invasive laparoscopic techniques. Periarterial neurectomy is performed by removing the adventitia of the radial, ulnar, palmar, or common digital arteries. Results have been mixed, with some series reporting improved quality of life and ulcer healing, although complication rates are as high as 37% ; therefore, widespread use is generally discouraged. Another recently described surgical technique involves autogenous fat grafting, in which fat harvested from the abdomen is injected at multiple sites in the hand. In small case series, improvements in pain and hand perfusion have been reported. The mechanism is unknown but may involve generation of vascular growth factors from adipose-derived stem cells.

The long-term outcome of patients with RS is not known with certainty, although epidemiologic studies have shown that up to one-third of patients with RS can experience symptom resolution over time. We reviewed our experience with more than 1000 RS patients followed for up to 23 years and found RS to be a relatively benign condition in the majority of patients. We divided the patients into four groups at presentation to determine whether this classification scheme provided prognostic information: vasospastic RS with negative serologies, vasospastic RS with positive serologies, obstructive RS with negative serologies, and obstructive RS with positive serologies. Patients with no evidence of an associated disease or arterial obstruction did extremely well, with minimal risk of severe finger ischemia or development of an associated disease; those with obstruction and positive serologies were most likely to develop worsening finger ischemia and ulceration. A summary is presented in Table 8.2 . Patients without a diagnosable connective tissue disorder, but with one or more clinical signs or laboratory tests suggesting such a disease, are much more likely to receive a diagnosis of connective tissue disorder at a later date. Current estimates of disease progression range from 2% to 6% in patients with initially negative serologic tests, and 30% to 75% in patients with positive serologic tests at presentation.

Systemic Vasculitis

Vasculitis has a deceptively simple definition—inflammation, often with necrosis and occlusive changes of the blood vessels—but its clinical manifestations are diverse and complex. The term arteritis has been used to describe many of these syndromes, but vasculitis is a more precise term, because many of the entities involve veins as well as arteries. Vasculitis can be generalized or localized. Knowledge of this condition is incomplete, and the currently used classification systems are filled with exceptions and overlapping syndromes. The most frequently used classification system is based on the size of the vessels (small, medium, large) involved in the vasculitic process ( Box 8.1 ). Medium and small vessel vasculitis is further subdivided by the presence or absence of antineutrophil cytoplasmic antibodies (ANCAs), a group of autoantibodies formed against enzymes found in primary granules of neutrophils. The most common ANCA-positive vasculitides include Wegener granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome, which are rarely encountered by vascular surgeons.

The cause and pathogenesis of most vasculitides are complex and are currently either unknown or incompletely understood. The basic pathologic mechanism of vasculitis implicates immune-mediated injury, which can include recognition of a vascular structure as antigen, deposition of immune complexes in a vessel wall with complement activation and injury, direct deposition of antigen in a vessel wall, or a delayed hypersensitivity reaction.

The majority of vasculitides are associated with a cellular immunoreaction involving the production of soluble mediators including cytokines, arachidonic acid metabolites, and fibrinolytic and coagulation by-products. The production of cytokines results in neutrophilic, eosinophilic, monocytic, and lymphocytic interactions at the inflammatory site. Endothelial cells express cell membrane receptors specific for many of these inflammatory cells. Binding of inflammatory cells to the endothelial cell triggers intracellular production of additional endothelial cytokines that affect the local inflammatory environment. Complement binding is thought to aid the attachment of leukocytes to endothelial cells. Platelet interactions with both intact and injured endothelium can contribute to the inflammatory process through activation of coagulation pathways and release of cytokines capable of stimulating and modifying immune responses. The vascular surgeon attends to the sequelae of vasculitic injury in these diseases. Thrombosis, aneurysm formation, hemorrhage, or arterial occlusion may all follow or accompany transmural damage created by inflammatory reactions on the vascular wall. An abbreviated list of the vasculitides that have potential significance to vascular surgeons is presented in Box 8.1 and is considered in this section.

Large Vessel Vasculitis

Giant Cell Arteritis Group

The two conditions included in the giant cell arteritis (GCA) group are systemic giant cell, or temporal, arteritis and Takayasu disease. Although they have fairly distinctive clinical patterns ( Table 8.3 ), the two entities likely represent different manifestations of the same disease process and are histologically similar with pathognomonic giant cells. Glucocorticoids constitute the hallmark of therapy for each, although a variety of nonsteroidal immunosuppressants have also been employed with mixed results. Surgical and endovascular therapy are less frequently used but have a role in selective refractory patients.

Table 8.3

Clinical Patterns in Giant Cell Arteritis

	Temporal Arteritis	Takayasu Disease
Age, sex	Elderly, white women	Young females
Pathology	Inflammatory cellular infiltrates giant cells	Same
Area of involvement	Usually branches of carotid; may involve any artery	Aortic arch and branches; pulmonary artery
Complications	Blindness	Hypertension, stroke
Response to steroids	Excellent	Unpredictable, unproved

Systemic giant cell arteritis (temporal arteritis).

Systemic GCA occurs mainly in patients older than 50 years, is two- to sixfold more frequent in women, and is more prominent in whites. The annual incidence in white women older than 50 years is 15 to 25 cases per 100,000.

GCA can involve any large artery of the body, although it has a propensity to affect branches of the carotid artery. The clinical history usually begins with a febrile myalgic process involving primarily the back, shoulder, and pelvic regions. Headache, malaise, anorexia, weight loss, and jaw claudication are common. Polymyalgia rheumatica, a clinical syndrome of aching and stiffness of the hip and shoulder girdle muscles lasting 4 weeks or longer and associated with an elevated erythrocyte sedimentation rate, is present in 50% to 75% of patients with temporal arteritis.

The most characteristic complaint is severe pain along the course of the temporal artery, accompanied by tenderness and nodularity of the artery and overlying skin erythema. The involvement is frequently bilateral. Visual disturbances occur in more than 50% of patients. The mechanism of the visual alterations may be ischemic optic neuritis, retrobulbar neuritis, or occlusion of the central retinal artery. Unilateral blindness occurs in as many as 17% of patients with GCA, followed by contralateral, usually permanent, blindness in one-third of these patients within 1 week. Amaurosis fugax is an important warning sign that precedes visual loss in 44% of patients.

GCA can cause aneurysms or stenoses of the aorta or its main branches. Classic arteriographic findings of GCA include smooth, tapering stenoses of subclavian, axillary, and brachial arteries ( Fig. 8.2 ). Both true thoracic aortic aneurysms and dissecting aneurysms can occur. Patients with GCA have a 17-fold increased risk of thoracic aortic aneurysms and a 2.4-fold increased risk of abdominal aortic aneurysms compared with age-matched controls. Aortic involvement is best visualized with computed tomography (CT) or magnetic resonance angiography (MRA), in which aortic wall thickening is demonstrated. Although rare, lower extremity involvement has also been described. Laboratory findings supporting a diagnosis of GCA include an elevated erythrocyte sedimentation rate. The diagnostic criteria of the American College of Rheumatology include an erythrocyte sedimentation rate of at least 50 mm/h. However, up to 25% of patients with GCA have a normal sedimentation rate at the time of diagnosis, and this finding should not preclude treatment if clinical suspicion is high. C-reactive protein may be a more sensitive indicator of disease activity than the sedimentation rate.

Temporal artery biopsy remains the gold standard of diagnosis in patients suspected of having GCA. Because of skip lesions, a specimen at least 2 cm long should be obtained. When possible, temporal artery biopsy should be performed before corticosteroid treatment; however, histologic evidence of arteritis may be found after up to 2 weeks of treatment. Bilateral sequential temporal artery biopsies are frequently performed if the results of unilateral biopsy are inconclusive, but in 97% of cases, the two specimens show the same findings. Characteristic findings on color-flow duplex scans have been described, typically a hypoechoic halo around the artery corresponding with associated periarterial inflammation, with a sensitivity of 75% and specificity of 83% compared with temporal artery biopsies.

The importance of a precise and early diagnosis lies in the early initiation of steroid therapy. Prompt steroid therapy frequently results in restoration of pulses and prevention of lasting visual disturbances. Typical treatment consists of initial high-dose intravenous steroids followed by a gradual oral taper. Most patients require at least 1 year of treatment, although some require lifelong therapy. Although corticosteroids remain the cornerstone of medical therapy, cytotoxic agents (e.g., methotrexate), immunosuppressants (e.g., azathioprine, cyclosporin), tumor necrosis factor (TNF) inhibitors (infliximab, etanercept), and pyrimidine synthesis inhibitors (leflunomide) are used occasionally. However, trials of steroid-sparing drugs have had mixed results. Surgical and endovascular therapy for GCA is rare due to overall good results with medical therapy. With the exception of those with aortic dissections, the life expectancy of patients with GCA is the same as that of the general population.

Takayasu disease.

Takayasu disease frequently affects the aorta and its major branches and, in contrast to GCA, the pulmonary artery. The majority of patients are Asian, about 85% are female, and the median age at onset is between 25 and 41 years. The disease has two recognized stages. The first stage is characterized by fever, myalgia, and anorexia in approximately two-thirds of patients. In the second stage, these symptoms may be followed by multiple arterial occlusive symptoms, with manifestations dependent on disease location.

The cardiovascular areas of involvement have been characterized as types I, II, III, and IV and are shown in Fig. 8.3 . Type I is limited to involvement of the arch and arch vessels and occurs in 8.4% of patients. Type II involves the descending thoracic and abdominal aorta and accounts for 11.2% of cases. Type III involves the arch vessels and the abdominal aorta and its branches and accounts for 65.4% of cases. Type IV consists primarily of pulmonary artery involvement, with or without other vessels, and accounts for 15% of patients. Most of the lesions are stenotic, although localized aneurysms have been reported. Arteriography has traditionally been the imaging modality of choice. However, color-flow duplex scanning, CT, magnetic resonance imaging (MRI), and positron emission tomography (PET) scanning have emerged as important alternatives, providing information about both luminal and mural involvement in affected vessels.

Cardiovascular findings include diminished peripheral arterial pulsations and hypertension. The hypertension may be due to aortic coarctation or renal artery stenosis. Neurologic symptoms can result from hypertension or central nervous system ischemia associated with large artery occlusion or stenosis. Coronary artery involvement in Takayasu disease is rare. The cardiac pathologic feature most frequently found is nonspecific and appears to result from heart failure associated with systemic and pulmonary hypertension.

Available information suggests that a conservative surgical approach is best for these patients. The same spectrum of pharmacologic agents used to treat GCA is used in patients with Takayasu arteritis, with corticosteroids again being the primary agent used. Results of medical therapy, in general, are less consistent in patients with Takayasu arteritis. A poor long-term outcome is predicted by the presence of major complications (retinopathy, hypertension, aortic insufficiency, aneurysm formation) and a progressive disease course.

Surgical intervention is generally reserved to treat symptomatic stenotic or, less commonly, aneurysmal lesions resulting from chronic Takayasu arteritis. Surgical intervention is best performed with the disease in a quiescent state. Restenosis rates in the presence of active disease are approximately 45%, compared with 12% restenosis rates with quiescent disease. Acute phase reactants, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are often used to determine disease activity; however, these markers are not consistent. PET-CT may play an important role in defining metabolic activity associated with acute and quiescent states. Successful surgical management requires bypass graft implantation into disease-free arterial segments and continuation of corticosteroid therapy. Excellent long-term survival rates of up to 75% at 20 years have been reported in large operative series. Owing to its inflammatory nature, endarterectomy has resulted in early failure and is generally not recommended.

Percutaneous transluminal angioplasty and stenting has had mixed success, with high early success rates of up to 90% ; however, high rates of in-stent restenosis have been reported. In general, surgical intervention remains a more durable option.

Radiation-Induced Arterial Damage

Radiation given for the treatment of regional malignancy causes well-recognized changes in arteries within the irradiated field. The primary changes consist of intimal thickening and proliferation, medial hyalinization, proteoglycan deposition, and cellular infiltration of the adventitia. Normal endothelium has a slow rate of turnover, and following irradiation, endothelial cells do not proliferate. Pleomorphic endothelial cells can develop as a result of irradiation, with exposure of the basement membrane leading to thrombosis of small vessels. Postirradiation changes in large arteries often resemble atherosclerosis ( Fig. 8.4 ).

Arteries in an irradiated area may develop stenosis years after exposure, thought to be due to chronic oxidative stress with upregulation of matrix metalloproteinases, proinflammatory cytokines, smooth muscle cell proliferation and apoptosis, with downregulation of nitric oxide. There is an high incidence of carotid artery stenosis in patients years after neck irradiation, along with an increased likelihood of stroke. The lesions vary from diffuse scarring to areas of typical atheromatous narrowing, with a preponderance of the latter. Patients who have had regional irradiation, especially of the cervical region, should have careful vascular follow-up, including noninvasive vascular laboratory examinations. Stenoses of the subclavian and axillary arteries have been demonstrated in patients undergoing radiation therapy for breast cancer and Hodgkin lymphoma, and aortoiliac involvement has been noted in patients undergoing abdominal or pelvic radiation therapy.

Vascular surgery on irradiated arteries can be performed using standard techniques. Prosthetic and autogenous bypass grafts, as well as endarterectomy, have all been performed satisfactorily. Prudence suggests avoidance of a prosthetic graft in a field in which infection may be expected, such as a radical neck dissection after irradiation, and autologous vein reconstruction is preferred. Late graft infections occurring 2 to 5 years after surgery have been described. The treatment of carotid artery stenosis in irradiated areas with percutaneous angioplasty and stenting has been reported, with excellent results, although rates of restenosis and reintervention are significantly higher than in nonirradiated arteries and historical surgical controls. Although data are limited, endovascular treatment of other arterial beds appears to be safe and effective in selected cases.

Medium Vessel Vasculitis

Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is a disseminated disease characterized by focal necrotizing lesions involving primarily medium-sized muscular arteries. This is a rare disorder with a prevalence of 2 to 16 per 1 million, a male-female preponderance of 2-4:1, and a peak incidence in patients in their 40s. The clinical manifestations of PAN are varied. It can involve only one organ or multiple organs simultaneously or sequentially over time. The most frequent manifestations of PAN include a characteristic crescent-forming glomerulonephritis, polyarteritis, polymyositis, and abdominal pain. A cutaneous form also exists, presenting with subcutaneous nodules, livedo reticularis, and cutaneous ulcers.

The essential pathologic feature of PAN is focal transmural arterial inflammatory necrosis. The process begins with medial destruction, followed by a sequential acute inflammatory response, fibroblastic proliferation, and endothelial damage. The vascular injury is resolved by intimal proliferation, thrombosis, or aneurysm formation, all of which may culminate in luminal occlusion, with consequent organ ischemia and infarction.

The ESR, CRP, and factor XIII–related protein, all nonspecific serologic markers of inflammation, are elevated in PAN. Positive hepatitis B serologies are common in adults with PAN. This is also the most common vasculitis associated with hepatitis C and the human immunodeficiency virus (HIV).

The hallmark of PAN is the formation of multiple saccular aneurysms associated with inflammatory destruction of the media, with the most frequently involved organs being the kidney, heart, liver, and gastrointestinal tract. Rupture of intraabdominal PAN aneurysms has been well described and may represent a surgical emergency. Coil embolization of ruptured visceral aneurysms in PAN has also been described and represents an alternative to surgical intervention. These aneurysms have been documented to regress on occasion after vigorous steroid and cyclophosphamide therapy, which should be recommended for all asymptomatic visceral aneurysms. An arteriogram of a patient with PAN showing the typical visceral and renal artery aneurysms is shown in Fig. 8.5 . Visceral PAN lesions can also lead to visceral artery narrowing incident to the inflammatory process, which can progress to occlusion. The visceral ischemia can manifest as cholecystitis, appendicitis, enteric perforation, gastrointestinal hemorrhage, or ischemic stricture formation with bowel obstruction.

The routine use of steroid therapy has improved 5-year survival from 15% to the current 50% to 80%. Cyclophosphamide can be added to the steroid regimen in acute, severe cases. Antiviral agents can be used in hepatitis B virus (HBV)-induced PAN. Prognosis is influenced by the absence or presence of creatinemia, proteinuria, cardiomyopathy, and gastrointestinal or central nervous system involvement at the time of presentation. Five-year mortality with zero, one, or two or more of these signs was 12%, 26%, and 46%, respectively. During the acute phase of PAN, renal and gastrointestinal lesions account for the majority of deaths, whereas cardiovascular and cerebral events account for mortality in chronic cases.

Kawasaki Disease

In the 1960s, Kawasaki observed 50 cases of a febrile exanthematous illness in Japan and coined the term mucocutaneous lymph node syndrome . Over the next decade, the spread of the disease was noted worldwide, and it became known as Kawasaki disease. The disease occurs in all ethnic groups, although children of Japanese ancestry appear to be most susceptible. The annual incidence in Japan is 140 cases per 100,000 children younger than 5 years, compared with the incidence in the United States of approximately 17 cases per 100,000 children. The vasculitis associated with Kawasaki disease has a propensity to affect the coronary arteries, making it the most common cause of acquired heart disease in children in the developed world.

The clinical criteria for diagnosis include: (1) high fever present for 5 days or more, (2) conjunctival congestion, (3) changes in the mucous membranes of the oral cavity, (4) peripheral edema or desquamation, (5) polymorphous exanthem, and (6) acute nonsuppurative swelling of the cervical lymph nodes. The presence of a prolonged high fever and any four of the five remaining criteria, in the absence of concurrent evidence of bacterial or viral infection, establishes the diagnosis.

Kawasaki disease has a unimodal peak incidence at 1 year of age; it has not been described in neonates and is rarely observed for the first time in those older than 5 years. The acute symptoms can persist for 7 to 14 days before improvement occurs as the fever subsides. Notable laboratory features include elevation of the ESR and CRP, thrombocythemia, and elevated levels of von Willebrand factor.

The etiology of Kawasaki disease is likely multifactorial. An infectious cause has long been assumed, given the self-limited nature of the disease, its seasonal incidence, and geographic outbreaks. However, no single infectious agent has been demonstrated. An immunologic defect has also been postulated, because there appears to be an altered immunoregulatory state in these patients, with decreased numbers of T cells and an increased proportion of activated helper T4 cells. Genetic susceptibility also appears to have a role in pathogenesis. The most serious disease manifestation is coronary arteritis. The spectrum of documented coronary artery pathologic changes consists of active arteritis, thrombosis, calcification, and stenosis, although the distinguishing feature of Kawasaki disease is the formation of diffuse fusiform and saccular coronary artery aneurysms.

Routine echocardiography in patients with Kawasaki disease has demonstrated coronary artery dilation or aneurysms in 25% to 50%, with the aneurysms typically appearing in the second week of illness and reaching a maximum size from the third to eighth week after the onset of fever. Echocardiography may show dilation of the right, left, or anterior descending coronary arteries, whereas the circumflex coronary artery is rarely involved.

Systemic arteritis also occurs in Kawasaki disease, with iliac arteritis as prevalent as coronary arteritis. Aneurysm formation is far less frequent in the systemic arteries than in the coronary arteries, with one report identifying systemic arterial aneurysms (axillary and iliac) in 3.3% of 662 patients with Kawasaki disease and coronary artery aneurysms. The healing process in the systemic arterial lesions can lead to focal arterial stenosis or aneurysm formation, just as in the coronary arteries. The coexistence of peripheral arterial involvement (subclavian and axillary arteries) and coronary artery aneurysms is shown in Fig. 8.6 .

Thrombosis of coronary artery aneurysms is the overwhelming cause of death in the early stages of Kawasaki disease, causing acute myocardial infarction or arrhythmia. Coronary aneurysm rupture has also been described. With the initiation of aspirin and immune globulin therapy in the acute phase, the mortality from Kawasaki disease has decreased to 1.1%, and among patients with no cardiac sequelae does not differ from the general population. Intravenous gamma globulin is typically given as a single-infusion high dose of 2 g/kg. Aspirin is given orally at a dose of 80 mg/kg per day until the child is afebrile, then continued in low-dose form (3 to 5 mg/kg per day) for an additional 6 to 8 weeks. Approximately 10% to 15% of patients are refractory to standard therapy, and corticosteroids or other immunosuppressant agents (e.g., infliximab, cyclosporin) are considered in these patients. Appropriate medical therapy during the acute phase can lead to aneurysm regression, with arteries less than 4 mm in diameter universally regressing, and those greater than 8 mm unlikely to regress.

Coronary artery bypass grafting was first used in Kawasaki disease in 1976. The first procedure used the saphenous vein as a conduit; however, concerns over its potential to grow with the child have been raised. This concern led to the use of the internal mammary artery (unilateral or bilateral) and the right gastroepiploic artery for coronary revascularization in patients with Kawasaki disease. Five- and 15-year patency rates of internal mammary grafts are 91% in children older than 12 years of age, but only 73% and 65%, respectively, in patients younger than 12. Percutaneous angioplasty of anastomotic lesions, however, has improved 10-year patency rates in this group to 94%. Primary catheter-based interventions, such as stent implantation and coronary rotational ablation, have also had excellent results in selected cases of focal coronary artery stenosis. Cardiac transplantation for severe ischemic heart disease as a sequela of Kawasaki disease is considered in patients who are not candidates for revascularization because of distal coronary stenosis or aneurysms and those with severe irreversible myocardial dysfunction. Overall survival of surgically treated patients is up to 95% at 25 years, although approximately one-third require reintervention during this time interval.

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