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Pathologic features of aortitis
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Pathologic Features of Aortitis Renu Virmani, MD, and Allen P. Burke, MD From the Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, D.C.
Acquired diseases of the aorta may result from degenerative changes of aging, atherosclerosis, and hypertension, or from specific inflammatory diseases. Aortitis is defined as inllammation of the wall of the aorta with or without disruption of elastic fibers, aortic wall necrosis, and/or fibrosis. Most authorities consider atherosclerosis as a noninflammatory condition. However, chronic inflammation of the adventitia, media, and intima are common in atherosclerosis and may play a significant role in its progression. Also, atherosclerosis is often superimposed on aortitis, adding to the difficulty of determining the underlying etiology of aortitis. IntIammatory conditions of the aorta are classified into infectious and noninfectious causes (Table 1). There is overlap in the gross and microscopic findings of the different aortitis syndromes, especially in later stages of disease; clinical and radiologic information is often crucial in diagnosis. The classic tree-bark appearance of the aortic intimal surface results from obliteration of the vasa vasorum resulting in medial necrosis; tree barking can occur in syphilitic and noninfectious aortitis. Medial scarring and inflammation is common to all types of aortitis and may result in aortic dilatation, aneurysm formation, accelerated atherosclerosis, and superimposed fibrointimal proliferation with luminal narrowing. In classical cases of Takayasu’s disease (the prototype aortitis syndrome), in cases of known syphilis, and in patients with previously diagnosed collagen vascular diseases or giant cell arteritis, the differential diagnosis of aortitis is not problematic. However, in some patients the clinical history is not straightforward, and although differential features may suggest a certain diagnosis, aortitis may remain unclassifiable. In these cases, the Manuscript received April 7, 1994; accepted April 13, 1994. From the March 13,1994 Symposium sponsored hy the Society for Cardiovascular Pathology, Inc. (under the Auspices of the United States and Canadian Academy of Pathology), San Francisco, California. The opinions or assertions contained herein are the private views of the authors and are not to he construed as official or reflecting the views of the Department of the Army, the Department of the Air Force, or the Department of Defense. Address for reprints: Renu Virmani, MD, Dept. of Cardiovascular Pathology, Department of Defense, Armed Forces Institute of Pathology, Washington, DC 20306-6000.
Published 1994 by Elsevier Science Inc.
term “nonspecific” or Wopathic” aortitis is sometimes used. The following discussion will highlight salient diagnostic features of known causes of aortitis, and the reader should be aware that in some instances a specific diagnosis is impossible.
‘Ihkayasu’s Arteritis Takayasu’s arteritis (aortic arch syndrome, pulseless disease, reversed coarctation, occlusive thromboaortopathy, and young female arteritis) was first described by the Japanese ophthalmologist ‘lhkayasuin 1908 in a 2 l-year-old woman with ocular changes (1). It was not until 1951, however, that Shimizu and Sano (2) detailed the clinical features of this disorder which, in 1954, was termed Takayasu’s arteritis. CIinieal manifestations. The disease tiits women more frequently than men, in a ratio of 8:l. The majority of the reported cases have been in Asian and African patients, but the disease has a worldwide distribution (3-5). The age at diagnosis ranges from 3.5 to 66 years, with a mean of 20 to 50 years (3,5-7). In the early phase of the disease, patients have nonspecific systemic illness characterized by malaise, weakness, fever, night sweats, arthralgias, arthritis, myalgia, weight loss, pleuritic pain, and anorexia. This phase may vary widely in severity and often precedes the occlusive phase by weeks to months, or an asymptomatic period may intervene for up to 6 to 8 years; in some patients there is no history of a systemic phase. Most symptoms of the late phase are related to disease of the aorta and arch vessels and include diminished or absent pulses in 96 % of patients, bruits in 94 %, hypertension in 74 %, and heart failure in 28% (3). The late or occlusive form of the disease was classically described in young Asian women with signs and symptoms of occlusion of the aortic arch vessels. Retinopathy is seen in only 25% of patients and is associated with carotid artery involvement. Involvement of the aortic root and aortic valve occurs in 10% to 20% of cases and may lead to aortic insufficiency as an associated or isolated finding (8-10). Coronary arteries are involved in 15% lOS4-8807/94/$7.00
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Table 1. Classification
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of Aortitis
Noninfectious aortitis Takayasu’s arteritis Giant cell arteritis Aortitis of collagen vascular disease Rheumatoid arthritis Aukylosing spondylitis Reiter’s syndrome Behpet’s disease Systemic lupus erythematosus Iut%immatory aneurysms of the abdominal aorta Sarcoidosis Infectious aortitis Syphilitic aortitis Tuberculosis Pyogeuic (bacterial [mycotic aneurysm] or fungal)
of patients. Angina or myocardial infarction may be secondary to ostial stenosis or involvement of the proximal coronary artery segment (l&12). Congestive heart failure may result from hypertension or aortic insufficiency, but inflammation of the myocardium is rare. In addition to stenotic lesions, aneurysmal dilatations are reported in 10% to 30% of patients. Complications of aneurysms include palpable pulsatile masses, embolism from mural thrombi, and, rarely, sudden death from rupture of a rapidly expanding aneurysm. Ueda et al. have subdivided Takayasu’s disease into three types based on the distribution of the lesions (13). Qpe I denotes involvement of the aortic arch and the brachiocephalic vessels; in type II, there is involvement of the descending thoracic aorta and abdominal aorta without involvement of the arch; type III is a combination of types I and II and is the most frequent type in autopsy series (14). Lupi-Herrera et al. suggested an additional variant (Type IV), with features of Type I, II, or III and, in addition, involvement of the pulmonary arteries (3) (Fig. 1).
Type1
Type II
Type Ill
Type IV
Figure 1. Clinical classification of Thkayasu’s disease proposed by Ueda et al. (13) and modified by Lupi-Herrera et al. (3). Type I: Disease is limited to the aortic arch and its branches. Type II: Lesions affect the descending thoracic and the abdominal aorta without involvement of the arch. Type III: Extensive lesions include the arch and the thoracic and abdominal aorta. Type IV The features of types I, II, and III are incorporated, and there is pulmonary artery involvement as well. The thickened lines represent the areas of in-
volvement .
Figure 2. A 51-year-old white woman presented with severe congestive heart failure. Physical examination revealed aortic incompetence and pericarditis. Coronary angiography showed bilateral ostial stenosis. At autopsy them was marked thickening of the ascending aorta, aortic arch, and a portion of the descending thoracic aorta. A diagnosis of Takayasu’s arteritis was made. (A) The left ventricular outflow tract with aortic valve (AV) , coronary ostia and ascending aorta exposed. Note the thickened and fibrotic aortic valve but no commissural fusion; there is mild widening (arrows) of the commissures, ostial narrowing especially of the right (arrowhead), and the aortic wall is markedly thickened. (B) Ascending aorta with both coronary ostia (arrows), ascending aorta (AA), arch and descending thoracic aorta showing marked thickening. Note sparing of the distal thoracic aorta (TA). The arch vessels show moderate narrowing. Reproduced with permission from Virmani et al. (11).
Laboratory abnormalities in Takayasu’s disease include elevated sedimentation rate, low-grade leukocytosis, and mild normochromic normocytic anemia in the systemic phase; these abnormalities regress in the chronic phase of illness. Elevated serum IgG and IgM and immune complexes are frequently present. An association between Takayasu’sarteritis and HLA
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Figure 3. Takayasu’s aortitis. (A) Histologic section of the ascending aorta showing diffise sclerosis of the adventitia (A) and intima (I).
(B) There is disruption of the media (M) and moderate intimal thickening. (C) The adventitial vasa vasorum show intimal proliferation and marked luminal narrowing with perivascular lymphoplasmacytic infiltrate. (D) The media shows neovascularization and areas of necrosis (arrowheads) with mild inflammation. Q Rare giant cells can be present. (A, Hematoxylin-eosin stain, X5; B, Movat pentachrome stain, ~25: C, hematoxylin-eosin stain, x160; D, hematoxylin-eosin stain, x160; E, hematoxylin-eosin stain, x250.)
B5, Bw 52, and Dw 12 antigens has been proposed. Patients with these tissue types are more likely to have active inflammation and a rapidly progressive course (15). Pathology. Pathologic features of Takayasu’s arteritis reflect the stage of the disease. Grossly, involved vessels appear edematous in early involvement (Fig. 2). Histologically, there is florid infiltration by lymphocytes, plasma cells, occasional giant cells, and histiocytes. The process is most marked in the outer two thirds of the media, with extension into the adventitia and surrounding fat and cuffing of the vasa vasorum (Fig. 3); the intima is spared. The vasa vasorum may show intimal proliferation with obliteratin but no fibrinoid
necrosis. In early stages there are patches of coagulation necrosis with surrounding histiocytes and occasional giant cells. The giant cells are both of Langhans’ and foreign body type and usually are few, congregating in the vicinity of disintegrated elastic fibers. Large numbers of giant cells are more suggestive of giant cell aortitis than Takayasu’s disease. The late phase is characterized by marked intimal and adventitial thickening of the vessels, with a marked proliferation of connective tissue and neovascularization, giving rise to fibrosis and adventitial scarring. During the cicatricial stage, the gross appearance of the aorta resembles tree bark, which is a common finding in aortitis of many etiologies (Fig. 2).
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Figure 4. Histologic sections of the aorta (A) and arch vessel (B) demonstrate focal loss of medial elastic tissue and marked intimal fibrosis in the absence of inflammatory infiltrate (healed Thkayasu’s arteritis). Reproduced with permission from Virmani et al. (11).
The stenotic lesions are produced by a circumferentially thickened intima with a glossy, grey, or myxoid appearance of the cut surface. On microscopic examination, the intima is hypocellular with scattered smooth muscle cells and fibroblasts in an abundant proteoglycan matrix (Fig. 4). The medial elastic laminae are disorganized or focally absent and replaced by collagen and new blood vessels. In T’akayasu’s disease there is a predilection for involvement of vessels at their point of origin from the aorta. Multisegmental involvement with areas of normal between affected segments are characteristic, although there may be diffise involvement of the aorta and isolated disease of individual arteries. In a series of patients from the United States, the most frequently affect arteries were the subclavian (90%), carotid (45 %), vertebral (25 %), and renal (20%) (4). In another study the subclavian arteries, mesenteric arteries, and abdominal aorta were commonly involved, each in nearly 80 % of cases (5316).
‘hatment. Both medical and surgical therapy may be useful in the treatment of Takayasu’s arteritis. Medical therapy given early may prevent surgical intervention. Corticosteroid therapy with or without cyclophosphamide has been reported to be useful during the acute phase of the disease. Surgical bypass may be necessary for the chronic phase. Recently, percutaneous transluminal angioplasty has been reported to be successful in relieving obstructive lesions of Takayasu’s arteritis (16). The course of the disease is unpredictable, but slow progression over a period of months to years is usual. In some series, a 97 % uneventful survival over 5 to 7 years in patients
without major complications has been reported, as compared with a 57% survival in patients with complications (17).
Giant Cell Arteritis Giant cell arteritis (granulomatous arteritis, cranial or temporal arteritis, and arteritis of the aged) is a systemic panarteritis that affects predominantly elderly patients. It consists of focal granulomatous inflammation of large- and medium-sired arteries, especially the temporal artery. The aorta and its major branches are affected in 15 % of cases (18). Giant cell arteritis was first described by Hutchinson in 1890 and by Horton et al. in 1932 (cited in reference 19). It was at first considered to be relatively rare, but today it is recognized more frequently: 15 to 30 cases per year per 100,000 persons over the age of 50 years (20). The disease occurs predominantly in women, is more common in blacks than whites, and is uncommon in Hispanics. The etiology of giant cell arteritis is unknown. A viral etiology has been suspected because of apparent temporal relationship to prior immunization or a viral illness, and an autoimmune etiology has also been suggested. Clinical manifestations. Giant cell arteritis produces a wide range of symptoms; frequent manifestations are fatigue, fever, headaches, jaw claudication, loss of vision, scalp tenderness, polymyalgia rheumatica, and aortic arch syndrome (19). Most patients have symptoms at some time related to the artery of involvement. Visual symptoms range from blurring to diplopia and visual loss and are seen in 25% to 50% of
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of the aorta in a 74year-old womanwith giant cell aortitis. Note the wrinkling and mild focal atherosclerosis. Reproducedwith permissionfrom Virmaniand McAllister(32).
FIgwe 5 Gross appearmce
patients. Pblymyalgia rheumatica is present in 40% of patients and is characterized by pain and stiffness in the shoulder and pelvic girdles without atrophy or weakness, elevated erythrocyte sedimentation rate, and response to treatment with steroids. Giant cell arteritis is rarely an immediate or direct cause of death; survival of patients with giant cell arteritis is comparable to that of general population. Most reported fatal cases have been patients without appropriate treatment with steroids and with involvement of the aorta and its major branches. Symptoms that suggest aortic involvement are claudication of upper or lower extremities, paresthesias, Raynaud’s phenomenon, abdominal angina, coronary ischemia, transient ischemic attacks, and aortic arch and great vessel “steal” syndrome. Rarely there may be aortic aneurysms, aortic regurgitation, aortic dissection, and myocardial infarction (21-23). Dissecting aneurysms of the aorta, as well as epicardial and intramyocardial coronary artery involvement with myocardial infarction, have been reported. Unlike Takayasu’sarteritis, renal artery involvement is never seen (18). Laboratory manifestations of giant cell arteritis include a very high sedimentation rate, elevated acute phase reactants, hypergammaglobulinemia, and increased serum C3 abd Cq complement levels (16), the levels of which often reflect disease activity. Other nonspecific laboratory findings include a normocytic, normochronic anemia. The diagnosis is confirmed by biopsy of the artery of involvement, usually the temporal artery. Angiography is indicated for the diagnosis of giant cell arte-
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ritis involving the aorta and its branches, which are not amenable to biopsy. Klein et al. (18) described the following angiographic features of giant cell aortitis and arteritis: long, smooth-tapering stenosis with segments of normal or even some dilatation, an absence of ulcerated atherosclerotic plaques, and involvement of the subclavian, axillary, and brachial arteries. Pathology. There is panarteritis with all three layers of the vessel wall involved. The gross lesions of the aorta -“tree bark” appearance (Fig. 5)-are similar to that seen in other inflammatory diseases of the aorta. The inflammatory infiltrate is mononuclear, consisting of lymphocytes, plasma cells, and histiocytes (Fig. 6). There is disruption of the internal elastic lamina with fragmentation and a giant cell reaction of the Langerhans’ type. The inflammation usually involves the inner half of the aorta. The intensity of the inflammatory reaction varies within and between arteries, as well as with time. The finding of a large number of giant cells is helpful but is not considered a prerequisite for the diagnosis, because in some cases only a few such cells are formed either in the temporal artery or in the other arteries at autopsy. In healed lesions, intimal fibrosis predominates and minimal cellular reaction remains; however, elastic tissue stains demonstrates extensive disruption of the elastic fibers. It is usually the combination of the clinical features and the microscopic findings that help separate the giant cell arteritis from other arteritic diseases (24). Treatment. Corticosteroid therapy is the treatment of choice. Occasionally, involvement of the aorta and large arteries may occur when corticosteroid therapy for temporal arteritis is being tapered. Methotrexate may be helpful in patients with steroid-resistant symptoms.
Rheumatoid
Arthritis
Involvement of the heart in rheumatoid arthritis has long been recognized and is manifested by rheumatoid myocarditis with or without valvular involvement (25,26). Rheumatoid aortitis, previously considered to be rare and of no clinical significance, was reported as incidental rheumatoid nodules in the adventitia or media found at autopsy (27). Recently, Gravallese et al. reported 10 cases of aortitis among 188 consecutive autopsies of patients with rheumatoid arthritis (28). There were 5 men and 5 women with a mean duration of rheumatoid arthritis of 10 years. Grossly, the aortic wall was thickened with focal necrosis and dilatation; there were two thoracic and one abdominal aortic aneurysms. The infhunmatory infiltrate consisted predominantly of lymphocytes and plasma cells with variable amounts of histiocytes. The inflammation was present throughout the aortic wall in 3 patients and was limited to the media and adventitia in 7 patients. Perivascular cuffing by lymphocytes and plasma cells of the vasa vasorum was present, but no endarteritis with obliteration of the vessel lumen was noted in any of the cases. The inflammation was accompanied by necrosis of the smooth muscle cells and
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Figure 6. Giant cell aortitis. (A, B) Histologic sections of the aorta at low magnification show marked granulomatous inflammation in the middle third of the aortic wall within the intima (A), and within the media (B). Higher magnifications (C, D) show granulomatous reaction at the junction of the necrotic media and the inflammatory infiltrate. (Hematoxylin-eosin stain; A x15, B ~25, C x250, D x400.)
loss of medial elastic fibers. Rheumatoid granulomas, consisting of a central area of necrosis with surrounding palisading histiocytes intermixed with lymphocytes and plasma cells and occasional giant cells (Fig. 7), were seen in 5 of the 10 cases. Aortitis was a cause of death in 3 cases, 2 from congestive heart failure and 1 from rupture of an aortic aneurysm. The aortitis of rheumatoid arthritis resembles that of ankylosing spondylitis (see below). Morphologically, the two diseases have many similarities, although rheumatoid granulomas are absent in ankylosing spondylitis, and involvement of the aorta in ankylosing spondylitis is restricted to the ascending portion. Clinical information is essential in the differential diagnosis; ankylosing spondylitis is more prevalent in men, there are characteristic rheumatologic findings, and the severity of aortitis is related to the duration of the disease. In contrast, the severity of aortitis in patients with
rheumatoid arthritis appears more closely associated with the severity of disease than with duration (28).
Ankylosing Spondylitis Ankylosing spondylitis is an idiopathic inflammatory disorder of young men, characterized by progressive bilateral sacroiliitis. The inflammation typically involves the vertebrae, peripheral joints, and eye. Aortic disease in patients with ankylosing spondylitis has been described since the 1950s (29,30). The incidence of aortic involvement in ankylosing spondylitis varies from 1% to 10% and is related to the duration of the disease, although aortic involvement may rarely precede arthritis (30). Pathologically, the proximal ascending aorta is preferentially affected in ankylosing spondylitis, and there is inflam-
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Figure 7. A 57-year-old woman had a history of rheumatoid arthritis, myocardial infarction, and congestive heart failure. At autopsy there were rheumatoid nodules in the aortic, mitral, and tricuspid valves; left ventricle; and aorta. Photomicrographs demonstrating aortic (A and B) and coronary artery (C and D) involvement with a rheumatoid granuloma in aorta (B) and in coronary artery wall (D). (Hematoxylineosin stain; A ~25, B x160, C ~48, D x150.) Reproduced with permission from Virmani and McAllister (32).
mation and scarring of the sinus of Valsalva and several centimeters of the proximal tubular aorta. In the active phase, there is endarteritis obliterans and perivascular infiltration by lymphocytes and plasma cells. In the chronic phase there is fibrosis, which involves the adventitia, media, and intima; calcification may be present. The coronary ostia may be narrowed, and the aortic valve is invariably thickened. Fibrosis extends into the membranous and muscular septum and onto the anterior leaflet of the mitral valve, resulting in a characteristic “bump” seen at autopsy (31,32). The clinical manifestations of aortic involvement in patients with ankylosing spondylitis reflect the pathologic extent of inflammation and fibrosis. Aortic valve disease results in aortic regurgitation, and extension of the fibrotic process in the membranous and muscular septa may result in heart block, conduction defects, and even sudden death.
The etiology of ankylosing spondylitis is uncertain, although the unusually high frequency of HLA-B27 antigen (up to 95% of affected patients and in 50% of their first-degree relatives) provides overwhelming evidence of genetic linkage (33).
Reiter’s Syndrome Reiter’s syndrome is characterized by the triad of nongonococcal urethritis, conjunctivitis, and polyarthritis. Young men are most often affected, and the arthritis is typically located in the sacroiliac joint. Cardiovascular involvement in Reiter’s syndrome is uncommon and is remarkably similar to ankylosing spondylitis. Of patients with Reiter’s syndrome, 2 % to 5 % suffer from aortitis with dilatation of the aortic root and aortic regurgitation. Other cardiovascular manifesta-
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Figure !3. Inllammatory aneurysm. Histologic section of an abdominal aneurysm in a 49-year-old man. Note extensive atherosclerosis of the intimal with almost complete loss of media and extensive adventitial fibrosis (A) entrapping fat and nerves (B). Higher magnification
shows fibrosis and chronic inflammation (C) consisting of lymphocytes and plasma cells (D). Reproduced with permission from Virmani and Mcallister (32).
tions include pericarditis, myocarditis, and various conduction delays (34). The latter are probably secondary to aortic root inflammation extending into the area of the atrioventricular node. Like a&losing spondylitis, aortic involvement is limited to the ascending aorta. Microscopically, there is disruption of elastic tissue and infiltration by chronic inflammatory cells (32).
Behget’s Disease Behcet’s disease is a recurring illness characterized by aphthous stomatitis, genital ulceration, and uveitis (35). It occurs worldwide, but most patients are from the Mediterranean region, Middle East, and Japan (35). The etiology of Behcet’s disease is unknown, although viral, bacterial, and chemical factors have been suggested.
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round cell inflammatory infiltrate occurs in the media and adventitia with predominance of inflammatory cells around proliferating vasa vasorum. Rarely, giant cells may be seen (36). In the late stages there is fibrous thickening of the intima and adventitia with mild perivascular inflammatory infiltrate and proliferation of vasa vasorum. Aneurysms may involve the aorta, pulmonary artery, and other large arteries and are of the saccular or dissecting type. Arterial aneurysms are more frequent than arterial occlusions, although the two may occur together in the same patient. Large venous lesions represent thrombophlebitis with organizing luminal thrombi .
Inflammatory Aneurysms of the Abdominal Aorta
Figure 9. Gross appearance of the aortic valve and ascending aorta in a 58-year-old man with syphilis. Note marked wrinkling of the aorta and aneurysmal dilatation (A) and thickening of the aortic valve (B, arrows).
Behcet’s disease has been classified into neuro- entero-, and vasculo-Behcet’s disease; the skin, joints, and, less frequently, the heart may also be affected. Cardiac involvement consists of pericarditis, myocarditis, and valvular insufficiency. Common to all types is a systemic small-vessel arteritis, which is the cause of pathologic lesions. Vascular Behcet’s disease occurs in 17.9% of cases (36) and consists of arterial aneurysms, arterial occlusions, aortitis, and venous thrombi. In a series of patients with vascular involvement, the patients’ ages ranged from 31 to 56 years and there was a slight male predominance. In a different series, large vessel involvement occurred in 1.5% to 2.2% of all Behcet’s patients (37). Aortitis in Behcet’s disease can be divided into active and scar stages. In active aortitis, intense
Inflammatory aneurysms of the aorta as a distinct entity were first described by Walker et al. in 1972 (38). It is sometimes considered a variant of abdominal atherosclerotic aneurysm, and the most common site of atherosclerotic and inflammatory aortic aneurysms is infrarenal(39). The incidence of inflammatory abdominal aneurysm is 11%of all operated abdominal aortic aneurysms. The male/female ratio is 9:1, similar to atherosclerotic abdominal aneurysm (32). Inflammatory abdominal aneurysms usually present with abdominal pain, a mass, or both, and in some patients there is an elevated erythrocyte sedimentation rate. Computed tomographic and ultrasonographic scans demonstrate an area of soft tissue density surrounding the atherosclerotic portion of the aneurysmal wall; this density corresponds pathologically to the marked fibrosis and perianeurysmal inflammation (40). At surgery, this inflamed fibrotic process distinguishes inflammatory aneurysms from pure atherosclerotic aneurysms and is recognized as a thick wall extending into the retroperitoneum. There is occasionally displacement and obstruction of the ureters, duodenum, jejuno-ileum, mesentery, sigmoid colon, renal artery and vein, and inferior vena cava. Spontaneous rupture is unusual. Pathologically, the inner surface of the wall of the aneurysm consists of atherosclerotic plaque. There is no clear demarcation between plaque, attenuated media, and periadventitial fibrous tissue (32). Microscopically, the aneurysmal aortic wall consists of complex atherosclerotic plaque; the underlying media is attenuated, fragmented, or replaced by fibrous tissue. The adventitia is replaced by a dense comiective tissue almost in direct continuity with the atherosclerotic plaque (Fig. 8). The fibrous tissue extends beyond the adventitia and entraps fat, nerves, ganglia, and lymph nodes. Within the fibrous tissue there is either focal or diffuse heavy lymphocytic and plasma cell inflammatory infiltrate. Some cases show phlebitis and occlusion of small periaortic veins. The etiology of inllammatory abdominal aneurysm is unknown. No infectious organism has been identified consistently. The condition resembles idiopathic retroperitoneal
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Figur B 10. Histologic sections of the ascending aorta showing perivascular lymphocytes and plasma cells in the adventitia and thicke ning of the vasa vasorum (A and B) . Photomicrograph of the media demonstrating lymphoplasmacytic infiltrate (C) and predominantly pla sma cell intitrate (D). (Hematoxylin-eosin stain; A ~25, B ~115, C and D x300.) Reproduced with permission from Virmani and McAllister (:32).
fibrosis, which begins in the periaortic connective tissue but does not generally result in aortic aneurysm (40). Inflamrnatory aneurysm of the abdominal aorta may coexist with coronary arteritis, which suggests a localized manifestation of systemic vasculitis or an autoimmune disease (41).
Syphilitic Aortitis _Cardiovascular syphilis once accounted for 5 % to 10% of all cardiovascular deaths; however, today only an occasional case of syphilis is seen at the autopsy table. Cardiac complications occur in approximately 10% of untreated cases of
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syphilis. The latent period varies from 5 to 40 years, with the usual being 10 to 25 years (16). Syphilitic heart disease can be divided into four categories: (i) syphilitic aortitis, (ii) syphilitic aortic aneurysm, (iii) syphilitic aortic valvulitis with aortic regurgitation, and (iv) syphilitic coronary ostial stenosis. Of 126 patients reported by Heggtveit, 42 (33%) had only syphilitic aortitis and 84 (66 %) had one or more of the major complications of aneurysm, aortic regurgitation, and coronary ostial stenosis (42). The clinical diagnosis of syphilitis was made in only 20 % of the cases (42). Pathology. Characteristically, syphilitic aortitis involves the proximal aorta and does not extend below the renal arteries, probably because of rich vascular and lymphatic circulation, which is limited to the thoracic aorta (42). On gross examination the aortic intima has a “tree bark” appearance with focal areas of intimal thickening, which appears white and shiny (Fig. 9). In late stages, the characteristic lesions are obscured by atherosclerosis. The aortic wall is thickened, and in later stages calcification and dilatation occurs. Microscopic examination shows perivascular infiltrate consisting of lymphocytes and plasma cells around vasa vasorum of the adventitia with extension into the media (32) (Fig. 10). The inllammation causes destruction of the media, which with time is replaced by scar tissue, resulting in wrinkling and scarring (43). The inIkunmation may extend into the aortic root, resulting in aortic regurgitation from dilatation of the aortic annulus. Because of aortic root involvement and superimposed intimal thickening, there may be coronary ostial narrowing. Within the aortic media, microgummas may occur, which consist of a central area of necrosis showing a faint outline of dead cells and surrounding palisading macrophages, lymphocytes, and plasma cells. Treponemas are scant in these gummas and are difficult to demonstrate. Aortic aneurysms are a common complication of syphilitic aortitis and occur because of weakness and destruction of the aortic wall. Aneurysms are located in the ascending aorta and arch of the aorta. Aneurysms usually occur above the diaphragm and are extremely rare below the renal arteries. Syphilitic aneurysms may be saccular or fusiform, and the frequency of various sites is as follows: sinus of Valsalva, 10 % ; ascending aorta, 46 % ; transverse arch, 24 % ; descending arch, 5 % ; descending thoracic aorta, 5 % ; upper abdominal aorta, 7 %; and multiple sites, 4% (32). Large aneurysm may cause superior vena cava syndrome from compression, rupture, or bony erosion. Dissections of the syphilitic aorta are extremely rare. Diagnosis. Usually there is a history of syphilis, and other manifestations of tertiary syphilis are seen in 10% to 30% of the patients with cardiovascular syphilis. Serologic tests, like VDRL, Treponem pullidum immobilization (TPI), or fluorescent treponemal antibody absorption (FTA-ABS), are positive (16). Because the histologic appearance of syphilitic aortitis may mimic that of noninfectious aortitis, we do not advise rendering a diagnosis of syphilitic aortitis based only on histology in the absence of serologic evidence of syphilis.
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Pyogenic Aortitis The original description by Osler of “mycotic aneurysm” has been gradually replaced by “infected aneurysm” to avoid confusion with true fungal infections (44). There are four routes of invasion of the aorta by bacteria: (i) implantation on intimal surface, (ii) emboliz.ation of bacteria into vasa vasorum, (iii) direct extension of infection from contiguous extravascular site, and (iv) traumatic inoculation of contaminated material into vessel wall (45). Before the advent of antibiotics, streptococcal species-including pneumococcus, staphylococci, and gonococcal organisms-were the most common pathogens responsible for pyogenic aortitis. More recently, salmonella species have been most frequently isolated from infected aortic aneurysms (44).
References 1. Takayasu M. Case with unusual changes of the central vessels in the retina. Acta Sot Gphthalmol Jpn 1908;112:554-561. 2. Shimizu K, Sano K. Pulseless disease. J Neuropathol
195 1; 1:37-47.
E, Sanchez-Torres G, Marcushamer J, Mispireta J, 3. Lupi-Herrera Horowitz S, Vela JE. Takayasu’s atteritis: clinical study of 107 cases. Am Heart J 1977;93:94-103. 4. Shelhamer JA, Volkman DJ, Parillo JE, et al. Takayasu’s arteritis and its therapy. Ann Intern Med 1985;103:121-126. 5. Hall S, Barr W, Lie JT, Stanson AW, Kazimier FJ. Takayasu’s arteritis: a study of 32 North American patients. Medicine 1985;64:89-99. 6. Gronemeyer PS, deMello DE. Takayasu’s disease with aneurysm of right common iliac artery and iliocaval fistula in a young infant: case report and review of the literature. Pediatrics 1982;69:626-631. 7. Morooka S, Saito Y, Nonaka Y, et al. Clinical feature of aortitis syndrome in Japanese women older than 40 years. Am J Cardiol 1984; 53:859-861. 8. Ishikawa K. Survival and morbidity after diagnosis of occlusive thromboaortopathy (Takayasu’s disease). Am J Cardiol 1981;47:1026-1032. 9. Ueda H, Sugiura M, Ito I, Saito Y, Morooka S. Aortic insufficiency associated with aortitis syndrome. Jpn Heart J 1967;8:107-120. 10. Ishikawa K. Patterns of symptoms and prognosis in occlusive thromboaortopathy (Takayasu’s disease). J Am Co11 Cardiol 1986:8: lC411046. 11. Virmani R, Lande A, McAllister HA, Jr. Pathologic aspects of Takayasu’s art&is. In: Lande A, Berkman YM, McAllister HA, eds. Aortitis: Clinical, Pathologic and Radiographic Aspects. New York: Raven Press, 1986:55-79. 12. Rose AG, Sinclar-Smith CC. Takayasu’s arteritis: a study of 16 autopsy cases. Arch Path01 Lab Med 1980;107:231-237. 13. Ueda A, Morooka A, Ito I, Yamacuchi H, Takeda T, Saito Y. Clinical observations on 52 cases of aortitis syndrome. Jpn Heart J 1969;lO: 227-288. 14. Nasu T. Takayasu’s truncoarteritis in Japan: a statistical observation of 76 autopsy cases. Path01 Microbial 1975;21:208-212. 15. Numano F, Ohta N, Sasazuki T. HLA and clinical manifestations Takayasu’s disease. Jpn Circ J 1982;46: 184-189.
in
16. Eagle KA, DeSanctis RW. Disease of the aorta. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine, 4th ed. Philadelphia: W. B. Saunders, 1992:1528-1557. 17. Subramanyan R, Roy J, Balakrishnan KG. Natural history of aortoarteritis (Takayasu’s disease). Circulation 1989;80:429-437. 18. Klein RG, Hunder GG, Stanson AW, Shepps SG. Large artery involvement in giant cell (temporal) arteritis. Ann Intern Med 1975;83:806-812. 19. Hunder GG, Block DA, Michel BA, et al. The American
College of
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Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 1990;33:1122-1128. 20. Machado EBV, Michet CJ, Ballard DJ, et al. Trends in incidence and clinicalpresentation of temporal art&is in Ohnsted county, Minnesota, 1950-1985. Arthritis Rheum 1988;31:745-749. 2 1. Salisbury RS, Hazleman B. Successful treatment of dissecting aortic aneurysm due to giant cell arteritis. Ann Rheum Dis 1981;40:507-508. 22. Save-Soderbergh J, Malmvall B-E, Andersson R, Bengtsson B-A. Giant cell arteritis as a cause of death: report of nine cases. JAMA 1986;255:493-496. 23. Lie JF, Failoni DD, Davis DC, Jr. Temporal arteritis with giant cell aortitis, coronary arteritis, and myocardial infarction. Arch Path01Lab Med 1986;110:857-860. 24. Fauci AS, Hayes BF, Katz P. The spectrum of vasculitis, clinical, pathologic, immunologic, and therapeutic considerations. AM Intern Med 1978;89:660-676.
25. Cruickshank B. Heart lesions in rheumatoid disease. J Path01Bacterial 1958;76:223-240. 26. Roberts WC, Kehoe JA, Carpenter DF, Golden A. Cardiac valvular lesions in rheumatoid arthritis. Arch Intern Med 1%8;122: 141-146. 27. Reimer KA, Rodgers R, Gyasu R. Rheumatoid arthritis with rheumatoid heart disease and granulomatous aortitis. JAMA 1976;235:25102512. 28. Gravallese EM, Carson JM, Coblyn JS, Pinkus GS, Weinblatt ME. Rheumatoid aortitis: A rarely recognized but clinically significant entity. Medicine 1989;68:95-106. 29. Ansell BM, Bywaters EGL, Doniach I. The aortic lesion of ankylosing spondylitis. Br Heart J 1958;20:507-515.
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32. Virmani R, McAllister HA, Jr. Pathology of the aorta and major arteries. In: Lande A, Borkman YM, McAllister HA, Jr. eds. Aortitis: Clinical, Pathologic, and Radiographic Aspects. New York: Raven Press, 1986:7-53. 33. Brewerton DA, James DC. Histocompatibility antigen (HLA-B27) and disease. Semin Arthritis Rheum 1975;4:191-207. 34. Paulus HE, Pearson CM, Pitts W, Jr. Aortic insufficiency in five patients with Reiter’s syndrome: a detailed clinical and pathologic study. Am J Med 1972$3:4&t-472. 35. Chajek T, Fainara J. Behcet’s disease: report of 41 cases and a review of the literature. Medicine (Baltimore) 1975;54: 179-196. 36. Matsumoto T, Uekusa T, Fukuda Y. Vasculo-Behcet’s disease: a pathologic study of eight cases. Human Path01 1991;22:45-51. 37. Hamza M .Large artery involvement in Behcet’s disease. J Rheumatol 1987;14:554-559. 38. Walker DI, Bloor K, Williams G, Gillie I. Inflammatory aneurysms of the abdominal aorta. Br J Surg 1972;59:609-614. 39. Rose AG, Dent DM. Intlammatory variant of abdominal atherosclerotic aneurysm. Arch Path01 Lab Med 1981;105:409-413. 40. Feiner HD, Raghavendra BN, Phelps R, Rooney L. Inflammatory abdominal aortic aneurysm: report of six cases. Hum Path01 1984; 15:454-459. 41. Cohle SD, Lie JT. Intlammatory aneurysm of the aorta, aortitis, and coronary arteries. Arch Path01 Lab Med 1988;112:1121-1125. 42. Heggtveit HA. Syphilic aottitis: autopsy experience at the Ottawa Generai Hospital since 1950. Can Med Assoc J 1965;92:880-891. 43. Heggtveit HA. Syphilitic aortitis: a clinicopathologic autopsy study of 100 cases, 1950-1960. Circulation 1964;29:346-355.
30. Graham DC, Smythe HA. The card&is and aortitis of ankylosing sportdylitis. Bull Rheum Dis 1958;9:171-174.
44. Worrell JT, Buja LM, Reynolds RC. Pneumococcai aortitis with rupture of the aorta. Am J Clin Path01 1988;89:565-568.
3 1. Bulkley BH, Roberts WC. A&dosing spondilitis and aortic regurgitation: description of the characteristic cardiovascular lesion from study of eight necropsy patients. Circulation 1973;48:1014-1027.
45. Moore WS, Malone JM. Mycotic aneurysm. In: Bergin JJ, Yai JSV, eds. Aneurysm: Diagnosis and treatment. New York: Grune and Stratton, 1982:581-595.
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Pathologic Features of Aortitis Renu Virmani, MD, and Allen P. Burke, MD From the Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, D.C.
Acquired diseases of the aorta may result from degenerative changes of aging, atherosclerosis, and hypertension, or from specific inflammatory diseases. Aortitis is defined as inllammation of the wall of the aorta with or without disruption of elastic fibers, aortic wall necrosis, and/or fibrosis. Most authorities consider atherosclerosis as a noninflammatory condition. However, chronic inflammation of the adventitia, media, and intima are common in atherosclerosis and may play a significant role in its progression. Also, atherosclerosis is often superimposed on aortitis, adding to the difficulty of determining the underlying etiology of aortitis. IntIammatory conditions of the aorta are classified into infectious and noninfectious causes (Table 1). There is overlap in the gross and microscopic findings of the different aortitis syndromes, especially in later stages of disease; clinical and radiologic information is often crucial in diagnosis. The classic tree-bark appearance of the aortic intimal surface results from obliteration of the vasa vasorum resulting in medial necrosis; tree barking can occur in syphilitic and noninfectious aortitis. Medial scarring and inflammation is common to all types of aortitis and may result in aortic dilatation, aneurysm formation, accelerated atherosclerosis, and superimposed fibrointimal proliferation with luminal narrowing. In classical cases of Takayasu’s disease (the prototype aortitis syndrome), in cases of known syphilis, and in patients with previously diagnosed collagen vascular diseases or giant cell arteritis, the differential diagnosis of aortitis is not problematic. However, in some patients the clinical history is not straightforward, and although differential features may suggest a certain diagnosis, aortitis may remain unclassifiable. In these cases, the Manuscript received April 7, 1994; accepted April 13, 1994. From the March 13,1994 Symposium sponsored hy the Society for Cardiovascular Pathology, Inc. (under the Auspices of the United States and Canadian Academy of Pathology), San Francisco, California. The opinions or assertions contained herein are the private views of the authors and are not to he construed as official or reflecting the views of the Department of the Army, the Department of the Air Force, or the Department of Defense. Address for reprints: Renu Virmani, MD, Dept. of Cardiovascular Pathology, Department of Defense, Armed Forces Institute of Pathology, Washington, DC 20306-6000.
Published 1994 by Elsevier Science Inc.
term “nonspecific” or Wopathic” aortitis is sometimes used. The following discussion will highlight salient diagnostic features of known causes of aortitis, and the reader should be aware that in some instances a specific diagnosis is impossible.
‘Ihkayasu’s Arteritis Takayasu’s arteritis (aortic arch syndrome, pulseless disease, reversed coarctation, occlusive thromboaortopathy, and young female arteritis) was first described by the Japanese ophthalmologist ‘lhkayasuin 1908 in a 2 l-year-old woman with ocular changes (1). It was not until 1951, however, that Shimizu and Sano (2) detailed the clinical features of this disorder which, in 1954, was termed Takayasu’s arteritis. CIinieal manifestations. The disease tiits women more frequently than men, in a ratio of 8:l. The majority of the reported cases have been in Asian and African patients, but the disease has a worldwide distribution (3-5). The age at diagnosis ranges from 3.5 to 66 years, with a mean of 20 to 50 years (3,5-7). In the early phase of the disease, patients have nonspecific systemic illness characterized by malaise, weakness, fever, night sweats, arthralgias, arthritis, myalgia, weight loss, pleuritic pain, and anorexia. This phase may vary widely in severity and often precedes the occlusive phase by weeks to months, or an asymptomatic period may intervene for up to 6 to 8 years; in some patients there is no history of a systemic phase. Most symptoms of the late phase are related to disease of the aorta and arch vessels and include diminished or absent pulses in 96 % of patients, bruits in 94 %, hypertension in 74 %, and heart failure in 28% (3). The late or occlusive form of the disease was classically described in young Asian women with signs and symptoms of occlusion of the aortic arch vessels. Retinopathy is seen in only 25% of patients and is associated with carotid artery involvement. Involvement of the aortic root and aortic valve occurs in 10% to 20% of cases and may lead to aortic insufficiency as an associated or isolated finding (8-10). Coronary arteries are involved in 15% lOS4-8807/94/$7.00
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Table 1. Classification
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of Aortitis
Noninfectious aortitis Takayasu’s arteritis Giant cell arteritis Aortitis of collagen vascular disease Rheumatoid arthritis Aukylosing spondylitis Reiter’s syndrome Behpet’s disease Systemic lupus erythematosus Iut%immatory aneurysms of the abdominal aorta Sarcoidosis Infectious aortitis Syphilitic aortitis Tuberculosis Pyogeuic (bacterial [mycotic aneurysm] or fungal)
of patients. Angina or myocardial infarction may be secondary to ostial stenosis or involvement of the proximal coronary artery segment (l&12). Congestive heart failure may result from hypertension or aortic insufficiency, but inflammation of the myocardium is rare. In addition to stenotic lesions, aneurysmal dilatations are reported in 10% to 30% of patients. Complications of aneurysms include palpable pulsatile masses, embolism from mural thrombi, and, rarely, sudden death from rupture of a rapidly expanding aneurysm. Ueda et al. have subdivided Takayasu’s disease into three types based on the distribution of the lesions (13). Qpe I denotes involvement of the aortic arch and the brachiocephalic vessels; in type II, there is involvement of the descending thoracic aorta and abdominal aorta without involvement of the arch; type III is a combination of types I and II and is the most frequent type in autopsy series (14). Lupi-Herrera et al. suggested an additional variant (Type IV), with features of Type I, II, or III and, in addition, involvement of the pulmonary arteries (3) (Fig. 1).
Type1
Type II
Type Ill
Type IV
Figure 1. Clinical classification of Thkayasu’s disease proposed by Ueda et al. (13) and modified by Lupi-Herrera et al. (3). Type I: Disease is limited to the aortic arch and its branches. Type II: Lesions affect the descending thoracic and the abdominal aorta without involvement of the arch. Type III: Extensive lesions include the arch and the thoracic and abdominal aorta. Type IV The features of types I, II, and III are incorporated, and there is pulmonary artery involvement as well. The thickened lines represent the areas of in-
volvement .
Figure 2. A 51-year-old white woman presented with severe congestive heart failure. Physical examination revealed aortic incompetence and pericarditis. Coronary angiography showed bilateral ostial stenosis. At autopsy them was marked thickening of the ascending aorta, aortic arch, and a portion of the descending thoracic aorta. A diagnosis of Takayasu’s arteritis was made. (A) The left ventricular outflow tract with aortic valve (AV) , coronary ostia and ascending aorta exposed. Note the thickened and fibrotic aortic valve but no commissural fusion; there is mild widening (arrows) of the commissures, ostial narrowing especially of the right (arrowhead), and the aortic wall is markedly thickened. (B) Ascending aorta with both coronary ostia (arrows), ascending aorta (AA), arch and descending thoracic aorta showing marked thickening. Note sparing of the distal thoracic aorta (TA). The arch vessels show moderate narrowing. Reproduced with permission from Virmani et al. (11).
Laboratory abnormalities in Takayasu’s disease include elevated sedimentation rate, low-grade leukocytosis, and mild normochromic normocytic anemia in the systemic phase; these abnormalities regress in the chronic phase of illness. Elevated serum IgG and IgM and immune complexes are frequently present. An association between Takayasu’sarteritis and HLA
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Figure 3. Takayasu’s aortitis. (A) Histologic section of the ascending aorta showing diffise sclerosis of the adventitia (A) and intima (I).
(B) There is disruption of the media (M) and moderate intimal thickening. (C) The adventitial vasa vasorum show intimal proliferation and marked luminal narrowing with perivascular lymphoplasmacytic infiltrate. (D) The media shows neovascularization and areas of necrosis (arrowheads) with mild inflammation. Q Rare giant cells can be present. (A, Hematoxylin-eosin stain, X5; B, Movat pentachrome stain, ~25: C, hematoxylin-eosin stain, x160; D, hematoxylin-eosin stain, x160; E, hematoxylin-eosin stain, x250.)
B5, Bw 52, and Dw 12 antigens has been proposed. Patients with these tissue types are more likely to have active inflammation and a rapidly progressive course (15). Pathology. Pathologic features of Takayasu’s arteritis reflect the stage of the disease. Grossly, involved vessels appear edematous in early involvement (Fig. 2). Histologically, there is florid infiltration by lymphocytes, plasma cells, occasional giant cells, and histiocytes. The process is most marked in the outer two thirds of the media, with extension into the adventitia and surrounding fat and cuffing of the vasa vasorum (Fig. 3); the intima is spared. The vasa vasorum may show intimal proliferation with obliteratin but no fibrinoid
necrosis. In early stages there are patches of coagulation necrosis with surrounding histiocytes and occasional giant cells. The giant cells are both of Langhans’ and foreign body type and usually are few, congregating in the vicinity of disintegrated elastic fibers. Large numbers of giant cells are more suggestive of giant cell aortitis than Takayasu’s disease. The late phase is characterized by marked intimal and adventitial thickening of the vessels, with a marked proliferation of connective tissue and neovascularization, giving rise to fibrosis and adventitial scarring. During the cicatricial stage, the gross appearance of the aorta resembles tree bark, which is a common finding in aortitis of many etiologies (Fig. 2).
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Figure 4. Histologic sections of the aorta (A) and arch vessel (B) demonstrate focal loss of medial elastic tissue and marked intimal fibrosis in the absence of inflammatory infiltrate (healed Thkayasu’s arteritis). Reproduced with permission from Virmani et al. (11).
The stenotic lesions are produced by a circumferentially thickened intima with a glossy, grey, or myxoid appearance of the cut surface. On microscopic examination, the intima is hypocellular with scattered smooth muscle cells and fibroblasts in an abundant proteoglycan matrix (Fig. 4). The medial elastic laminae are disorganized or focally absent and replaced by collagen and new blood vessels. In T’akayasu’s disease there is a predilection for involvement of vessels at their point of origin from the aorta. Multisegmental involvement with areas of normal between affected segments are characteristic, although there may be diffise involvement of the aorta and isolated disease of individual arteries. In a series of patients from the United States, the most frequently affect arteries were the subclavian (90%), carotid (45 %), vertebral (25 %), and renal (20%) (4). In another study the subclavian arteries, mesenteric arteries, and abdominal aorta were commonly involved, each in nearly 80 % of cases (5316).
‘hatment. Both medical and surgical therapy may be useful in the treatment of Takayasu’s arteritis. Medical therapy given early may prevent surgical intervention. Corticosteroid therapy with or without cyclophosphamide has been reported to be useful during the acute phase of the disease. Surgical bypass may be necessary for the chronic phase. Recently, percutaneous transluminal angioplasty has been reported to be successful in relieving obstructive lesions of Takayasu’s arteritis (16). The course of the disease is unpredictable, but slow progression over a period of months to years is usual. In some series, a 97 % uneventful survival over 5 to 7 years in patients
without major complications has been reported, as compared with a 57% survival in patients with complications (17).
Giant Cell Arteritis Giant cell arteritis (granulomatous arteritis, cranial or temporal arteritis, and arteritis of the aged) is a systemic panarteritis that affects predominantly elderly patients. It consists of focal granulomatous inflammation of large- and medium-sired arteries, especially the temporal artery. The aorta and its major branches are affected in 15 % of cases (18). Giant cell arteritis was first described by Hutchinson in 1890 and by Horton et al. in 1932 (cited in reference 19). It was at first considered to be relatively rare, but today it is recognized more frequently: 15 to 30 cases per year per 100,000 persons over the age of 50 years (20). The disease occurs predominantly in women, is more common in blacks than whites, and is uncommon in Hispanics. The etiology of giant cell arteritis is unknown. A viral etiology has been suspected because of apparent temporal relationship to prior immunization or a viral illness, and an autoimmune etiology has also been suggested. Clinical manifestations. Giant cell arteritis produces a wide range of symptoms; frequent manifestations are fatigue, fever, headaches, jaw claudication, loss of vision, scalp tenderness, polymyalgia rheumatica, and aortic arch syndrome (19). Most patients have symptoms at some time related to the artery of involvement. Visual symptoms range from blurring to diplopia and visual loss and are seen in 25% to 50% of
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of the aorta in a 74year-old womanwith giant cell aortitis. Note the wrinkling and mild focal atherosclerosis. Reproducedwith permissionfrom Virmaniand McAllister(32).
FIgwe 5 Gross appearmce
patients. Pblymyalgia rheumatica is present in 40% of patients and is characterized by pain and stiffness in the shoulder and pelvic girdles without atrophy or weakness, elevated erythrocyte sedimentation rate, and response to treatment with steroids. Giant cell arteritis is rarely an immediate or direct cause of death; survival of patients with giant cell arteritis is comparable to that of general population. Most reported fatal cases have been patients without appropriate treatment with steroids and with involvement of the aorta and its major branches. Symptoms that suggest aortic involvement are claudication of upper or lower extremities, paresthesias, Raynaud’s phenomenon, abdominal angina, coronary ischemia, transient ischemic attacks, and aortic arch and great vessel “steal” syndrome. Rarely there may be aortic aneurysms, aortic regurgitation, aortic dissection, and myocardial infarction (21-23). Dissecting aneurysms of the aorta, as well as epicardial and intramyocardial coronary artery involvement with myocardial infarction, have been reported. Unlike Takayasu’sarteritis, renal artery involvement is never seen (18). Laboratory manifestations of giant cell arteritis include a very high sedimentation rate, elevated acute phase reactants, hypergammaglobulinemia, and increased serum C3 abd Cq complement levels (16), the levels of which often reflect disease activity. Other nonspecific laboratory findings include a normocytic, normochronic anemia. The diagnosis is confirmed by biopsy of the artery of involvement, usually the temporal artery. Angiography is indicated for the diagnosis of giant cell arte-
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ritis involving the aorta and its branches, which are not amenable to biopsy. Klein et al. (18) described the following angiographic features of giant cell aortitis and arteritis: long, smooth-tapering stenosis with segments of normal or even some dilatation, an absence of ulcerated atherosclerotic plaques, and involvement of the subclavian, axillary, and brachial arteries. Pathology. There is panarteritis with all three layers of the vessel wall involved. The gross lesions of the aorta -“tree bark” appearance (Fig. 5)-are similar to that seen in other inflammatory diseases of the aorta. The inflammatory infiltrate is mononuclear, consisting of lymphocytes, plasma cells, and histiocytes (Fig. 6). There is disruption of the internal elastic lamina with fragmentation and a giant cell reaction of the Langerhans’ type. The inflammation usually involves the inner half of the aorta. The intensity of the inflammatory reaction varies within and between arteries, as well as with time. The finding of a large number of giant cells is helpful but is not considered a prerequisite for the diagnosis, because in some cases only a few such cells are formed either in the temporal artery or in the other arteries at autopsy. In healed lesions, intimal fibrosis predominates and minimal cellular reaction remains; however, elastic tissue stains demonstrates extensive disruption of the elastic fibers. It is usually the combination of the clinical features and the microscopic findings that help separate the giant cell arteritis from other arteritic diseases (24). Treatment. Corticosteroid therapy is the treatment of choice. Occasionally, involvement of the aorta and large arteries may occur when corticosteroid therapy for temporal arteritis is being tapered. Methotrexate may be helpful in patients with steroid-resistant symptoms.
Rheumatoid
Arthritis
Involvement of the heart in rheumatoid arthritis has long been recognized and is manifested by rheumatoid myocarditis with or without valvular involvement (25,26). Rheumatoid aortitis, previously considered to be rare and of no clinical significance, was reported as incidental rheumatoid nodules in the adventitia or media found at autopsy (27). Recently, Gravallese et al. reported 10 cases of aortitis among 188 consecutive autopsies of patients with rheumatoid arthritis (28). There were 5 men and 5 women with a mean duration of rheumatoid arthritis of 10 years. Grossly, the aortic wall was thickened with focal necrosis and dilatation; there were two thoracic and one abdominal aortic aneurysms. The infhunmatory infiltrate consisted predominantly of lymphocytes and plasma cells with variable amounts of histiocytes. The inflammation was present throughout the aortic wall in 3 patients and was limited to the media and adventitia in 7 patients. Perivascular cuffing by lymphocytes and plasma cells of the vasa vasorum was present, but no endarteritis with obliteration of the vessel lumen was noted in any of the cases. The inflammation was accompanied by necrosis of the smooth muscle cells and
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Figure 6. Giant cell aortitis. (A, B) Histologic sections of the aorta at low magnification show marked granulomatous inflammation in the middle third of the aortic wall within the intima (A), and within the media (B). Higher magnifications (C, D) show granulomatous reaction at the junction of the necrotic media and the inflammatory infiltrate. (Hematoxylin-eosin stain; A x15, B ~25, C x250, D x400.)
loss of medial elastic fibers. Rheumatoid granulomas, consisting of a central area of necrosis with surrounding palisading histiocytes intermixed with lymphocytes and plasma cells and occasional giant cells (Fig. 7), were seen in 5 of the 10 cases. Aortitis was a cause of death in 3 cases, 2 from congestive heart failure and 1 from rupture of an aortic aneurysm. The aortitis of rheumatoid arthritis resembles that of ankylosing spondylitis (see below). Morphologically, the two diseases have many similarities, although rheumatoid granulomas are absent in ankylosing spondylitis, and involvement of the aorta in ankylosing spondylitis is restricted to the ascending portion. Clinical information is essential in the differential diagnosis; ankylosing spondylitis is more prevalent in men, there are characteristic rheumatologic findings, and the severity of aortitis is related to the duration of the disease. In contrast, the severity of aortitis in patients with
rheumatoid arthritis appears more closely associated with the severity of disease than with duration (28).
Ankylosing Spondylitis Ankylosing spondylitis is an idiopathic inflammatory disorder of young men, characterized by progressive bilateral sacroiliitis. The inflammation typically involves the vertebrae, peripheral joints, and eye. Aortic disease in patients with ankylosing spondylitis has been described since the 1950s (29,30). The incidence of aortic involvement in ankylosing spondylitis varies from 1% to 10% and is related to the duration of the disease, although aortic involvement may rarely precede arthritis (30). Pathologically, the proximal ascending aorta is preferentially affected in ankylosing spondylitis, and there is inflam-
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Figure 7. A 57-year-old woman had a history of rheumatoid arthritis, myocardial infarction, and congestive heart failure. At autopsy there were rheumatoid nodules in the aortic, mitral, and tricuspid valves; left ventricle; and aorta. Photomicrographs demonstrating aortic (A and B) and coronary artery (C and D) involvement with a rheumatoid granuloma in aorta (B) and in coronary artery wall (D). (Hematoxylineosin stain; A ~25, B x160, C ~48, D x150.) Reproduced with permission from Virmani and McAllister (32).
mation and scarring of the sinus of Valsalva and several centimeters of the proximal tubular aorta. In the active phase, there is endarteritis obliterans and perivascular infiltration by lymphocytes and plasma cells. In the chronic phase there is fibrosis, which involves the adventitia, media, and intima; calcification may be present. The coronary ostia may be narrowed, and the aortic valve is invariably thickened. Fibrosis extends into the membranous and muscular septum and onto the anterior leaflet of the mitral valve, resulting in a characteristic “bump” seen at autopsy (31,32). The clinical manifestations of aortic involvement in patients with ankylosing spondylitis reflect the pathologic extent of inflammation and fibrosis. Aortic valve disease results in aortic regurgitation, and extension of the fibrotic process in the membranous and muscular septa may result in heart block, conduction defects, and even sudden death.
The etiology of ankylosing spondylitis is uncertain, although the unusually high frequency of HLA-B27 antigen (up to 95% of affected patients and in 50% of their first-degree relatives) provides overwhelming evidence of genetic linkage (33).
Reiter’s Syndrome Reiter’s syndrome is characterized by the triad of nongonococcal urethritis, conjunctivitis, and polyarthritis. Young men are most often affected, and the arthritis is typically located in the sacroiliac joint. Cardiovascular involvement in Reiter’s syndrome is uncommon and is remarkably similar to ankylosing spondylitis. Of patients with Reiter’s syndrome, 2 % to 5 % suffer from aortitis with dilatation of the aortic root and aortic regurgitation. Other cardiovascular manifesta-
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Figure !3. Inllammatory aneurysm. Histologic section of an abdominal aneurysm in a 49-year-old man. Note extensive atherosclerosis of the intimal with almost complete loss of media and extensive adventitial fibrosis (A) entrapping fat and nerves (B). Higher magnification
shows fibrosis and chronic inflammation (C) consisting of lymphocytes and plasma cells (D). Reproduced with permission from Virmani and Mcallister (32).
tions include pericarditis, myocarditis, and various conduction delays (34). The latter are probably secondary to aortic root inflammation extending into the area of the atrioventricular node. Like a&losing spondylitis, aortic involvement is limited to the ascending aorta. Microscopically, there is disruption of elastic tissue and infiltration by chronic inflammatory cells (32).
Behget’s Disease Behcet’s disease is a recurring illness characterized by aphthous stomatitis, genital ulceration, and uveitis (35). It occurs worldwide, but most patients are from the Mediterranean region, Middle East, and Japan (35). The etiology of Behcet’s disease is unknown, although viral, bacterial, and chemical factors have been suggested.
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round cell inflammatory infiltrate occurs in the media and adventitia with predominance of inflammatory cells around proliferating vasa vasorum. Rarely, giant cells may be seen (36). In the late stages there is fibrous thickening of the intima and adventitia with mild perivascular inflammatory infiltrate and proliferation of vasa vasorum. Aneurysms may involve the aorta, pulmonary artery, and other large arteries and are of the saccular or dissecting type. Arterial aneurysms are more frequent than arterial occlusions, although the two may occur together in the same patient. Large venous lesions represent thrombophlebitis with organizing luminal thrombi .
Inflammatory Aneurysms of the Abdominal Aorta
Figure 9. Gross appearance of the aortic valve and ascending aorta in a 58-year-old man with syphilis. Note marked wrinkling of the aorta and aneurysmal dilatation (A) and thickening of the aortic valve (B, arrows).
Behcet’s disease has been classified into neuro- entero-, and vasculo-Behcet’s disease; the skin, joints, and, less frequently, the heart may also be affected. Cardiac involvement consists of pericarditis, myocarditis, and valvular insufficiency. Common to all types is a systemic small-vessel arteritis, which is the cause of pathologic lesions. Vascular Behcet’s disease occurs in 17.9% of cases (36) and consists of arterial aneurysms, arterial occlusions, aortitis, and venous thrombi. In a series of patients with vascular involvement, the patients’ ages ranged from 31 to 56 years and there was a slight male predominance. In a different series, large vessel involvement occurred in 1.5% to 2.2% of all Behcet’s patients (37). Aortitis in Behcet’s disease can be divided into active and scar stages. In active aortitis, intense
Inflammatory aneurysms of the aorta as a distinct entity were first described by Walker et al. in 1972 (38). It is sometimes considered a variant of abdominal atherosclerotic aneurysm, and the most common site of atherosclerotic and inflammatory aortic aneurysms is infrarenal(39). The incidence of inflammatory abdominal aneurysm is 11%of all operated abdominal aortic aneurysms. The male/female ratio is 9:1, similar to atherosclerotic abdominal aneurysm (32). Inflammatory abdominal aneurysms usually present with abdominal pain, a mass, or both, and in some patients there is an elevated erythrocyte sedimentation rate. Computed tomographic and ultrasonographic scans demonstrate an area of soft tissue density surrounding the atherosclerotic portion of the aneurysmal wall; this density corresponds pathologically to the marked fibrosis and perianeurysmal inflammation (40). At surgery, this inflamed fibrotic process distinguishes inflammatory aneurysms from pure atherosclerotic aneurysms and is recognized as a thick wall extending into the retroperitoneum. There is occasionally displacement and obstruction of the ureters, duodenum, jejuno-ileum, mesentery, sigmoid colon, renal artery and vein, and inferior vena cava. Spontaneous rupture is unusual. Pathologically, the inner surface of the wall of the aneurysm consists of atherosclerotic plaque. There is no clear demarcation between plaque, attenuated media, and periadventitial fibrous tissue (32). Microscopically, the aneurysmal aortic wall consists of complex atherosclerotic plaque; the underlying media is attenuated, fragmented, or replaced by fibrous tissue. The adventitia is replaced by a dense comiective tissue almost in direct continuity with the atherosclerotic plaque (Fig. 8). The fibrous tissue extends beyond the adventitia and entraps fat, nerves, ganglia, and lymph nodes. Within the fibrous tissue there is either focal or diffuse heavy lymphocytic and plasma cell inflammatory infiltrate. Some cases show phlebitis and occlusion of small periaortic veins. The etiology of inllammatory abdominal aneurysm is unknown. No infectious organism has been identified consistently. The condition resembles idiopathic retroperitoneal
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Figur B 10. Histologic sections of the ascending aorta showing perivascular lymphocytes and plasma cells in the adventitia and thicke ning of the vasa vasorum (A and B) . Photomicrograph of the media demonstrating lymphoplasmacytic infiltrate (C) and predominantly pla sma cell intitrate (D). (Hematoxylin-eosin stain; A ~25, B ~115, C and D x300.) Reproduced with permission from Virmani and McAllister (:32).
fibrosis, which begins in the periaortic connective tissue but does not generally result in aortic aneurysm (40). Inflamrnatory aneurysm of the abdominal aorta may coexist with coronary arteritis, which suggests a localized manifestation of systemic vasculitis or an autoimmune disease (41).
Syphilitic Aortitis _Cardiovascular syphilis once accounted for 5 % to 10% of all cardiovascular deaths; however, today only an occasional case of syphilis is seen at the autopsy table. Cardiac complications occur in approximately 10% of untreated cases of
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syphilis. The latent period varies from 5 to 40 years, with the usual being 10 to 25 years (16). Syphilitic heart disease can be divided into four categories: (i) syphilitic aortitis, (ii) syphilitic aortic aneurysm, (iii) syphilitic aortic valvulitis with aortic regurgitation, and (iv) syphilitic coronary ostial stenosis. Of 126 patients reported by Heggtveit, 42 (33%) had only syphilitic aortitis and 84 (66 %) had one or more of the major complications of aneurysm, aortic regurgitation, and coronary ostial stenosis (42). The clinical diagnosis of syphilitis was made in only 20 % of the cases (42). Pathology. Characteristically, syphilitic aortitis involves the proximal aorta and does not extend below the renal arteries, probably because of rich vascular and lymphatic circulation, which is limited to the thoracic aorta (42). On gross examination the aortic intima has a “tree bark” appearance with focal areas of intimal thickening, which appears white and shiny (Fig. 9). In late stages, the characteristic lesions are obscured by atherosclerosis. The aortic wall is thickened, and in later stages calcification and dilatation occurs. Microscopic examination shows perivascular infiltrate consisting of lymphocytes and plasma cells around vasa vasorum of the adventitia with extension into the media (32) (Fig. 10). The inllammation causes destruction of the media, which with time is replaced by scar tissue, resulting in wrinkling and scarring (43). The inIkunmation may extend into the aortic root, resulting in aortic regurgitation from dilatation of the aortic annulus. Because of aortic root involvement and superimposed intimal thickening, there may be coronary ostial narrowing. Within the aortic media, microgummas may occur, which consist of a central area of necrosis showing a faint outline of dead cells and surrounding palisading macrophages, lymphocytes, and plasma cells. Treponemas are scant in these gummas and are difficult to demonstrate. Aortic aneurysms are a common complication of syphilitic aortitis and occur because of weakness and destruction of the aortic wall. Aneurysms are located in the ascending aorta and arch of the aorta. Aneurysms usually occur above the diaphragm and are extremely rare below the renal arteries. Syphilitic aneurysms may be saccular or fusiform, and the frequency of various sites is as follows: sinus of Valsalva, 10 % ; ascending aorta, 46 % ; transverse arch, 24 % ; descending arch, 5 % ; descending thoracic aorta, 5 % ; upper abdominal aorta, 7 %; and multiple sites, 4% (32). Large aneurysm may cause superior vena cava syndrome from compression, rupture, or bony erosion. Dissections of the syphilitic aorta are extremely rare. Diagnosis. Usually there is a history of syphilis, and other manifestations of tertiary syphilis are seen in 10% to 30% of the patients with cardiovascular syphilis. Serologic tests, like VDRL, Treponem pullidum immobilization (TPI), or fluorescent treponemal antibody absorption (FTA-ABS), are positive (16). Because the histologic appearance of syphilitic aortitis may mimic that of noninfectious aortitis, we do not advise rendering a diagnosis of syphilitic aortitis based only on histology in the absence of serologic evidence of syphilis.
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Pyogenic Aortitis The original description by Osler of “mycotic aneurysm” has been gradually replaced by “infected aneurysm” to avoid confusion with true fungal infections (44). There are four routes of invasion of the aorta by bacteria: (i) implantation on intimal surface, (ii) emboliz.ation of bacteria into vasa vasorum, (iii) direct extension of infection from contiguous extravascular site, and (iv) traumatic inoculation of contaminated material into vessel wall (45). Before the advent of antibiotics, streptococcal species-including pneumococcus, staphylococci, and gonococcal organisms-were the most common pathogens responsible for pyogenic aortitis. More recently, salmonella species have been most frequently isolated from infected aortic aneurysms (44).
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