Cardiovascular Pathology

Giant Cell Aortitis

Jagdish W. Butany
University of Toronto and Toronto General Hospital
Toronto, Ontario, Canada


Clinical Summary:
A 62-year-old man was referred for surgery, after echocardiography detected a dilated aortic root (5.5 cm) and aortic insufficiency (AI). He underwent surgery, at which time the ascending aorta was resected and replaced with a DacronŽ graft. The section is from the resected aorta.


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History and Clinical Findings:
This 62-year-old man was referred for surgery after echocardiography detected a dilated aortic root (5.5 cm) and aortic insufficiency (AI). He denied any symptoms of chest pain, dyspnea on exertion or symptoms of congestive heart failure. He also denied any constitutional symptoms of polymyalgia, headache, scalp tenderness, jaw claudication or history of acute loss of vision. His past medical history was significant for uncontrolled hypertension secondary to non-compliance with anti-hypertensive medications. Home blood pressure monitoring, at times, was reported to be as high as 200 mmHg (systolic). He had coronary artery disease (CAD), and had undergone PCI, with 2 stents in the previous two years (circumflex and left anterior descending), dyslipidemia. He was an ex-smoker (quit previous year), and no family history of heart disease.

His medications included acetylsalicylic acid (ASA), bisoprolol, ramipril, valsartan and atorvastatin and he denied any allergies blood pressure was 110/70 mm Hg (on medication), heart rate 70 beats per minute, and cardio-respiratory examination was unremarkable. There was no cardiac murmur (no Austin Flint murmur) relatable to his AI. His blood work was normal; erythrocyte sedimentation rate (ESR) had not been done. ECXG: showed a previous inferior myocardial infarct. He was in normal sinus rhythm.

Surgery:
He underwent replacement of his ascending aorta and transverse arch with a 30 mm tubular Dacron graft, aortic valve repair, and coronary artery bypass graft surgery with no complications.

Pathology:
The excised tissues had a thickened aortic wall measuring between 2-5 mm. All tubular segments were aneurysmal with the intimal wall gray in color. The surfaces were irregular, with a "cobblestone" appearance along with linear intimal folds or grooves. This appearance would suggest an underlying aortopathy. Small patchy areas of atherosclerosis like lesions were seen. Multiple sections were taken for histology. Attempts were made to orient the tissue so that transverse sections were obtained.

microscopic Examination:
abnormalities were found in all tissue layers. The intima consistently exhibited marked fibrocellular intimal hyperplasia. All cases had significant medial changes, comprised of areas of medial destruction, loss of elastic plates and smooth muscle replacement by fibrosis. Other areas showed smooth muscle cells were present but with loss of the intervening elastic plates. Inflammatory cell infiltrates including macrophages and multinucleate giant cells were concentrated around residual elastic plates (Figure 4). Occasional giant cells were seen, around the residual elastic plates and occasional non-necrotizing granulomata were also evident. (Stains for micro organisms were negative). Within the adventitia and around the vasa vasorum, patchy polymorphic aggregates of inflammatory cells (predominantly lymphocytes and plasma cells) were found. The adventitia showed extensive fibrosis and a scattered mild infiltrate of mononuclear cells.

In the context of their clinical presentations, the tissues did not have features of Takayasu arteritis and in fact the findings are those of a giant cell aortitis.

Diagnosis:
A final diagnosis of Giant Cell Arteritis affecting the aorta was made.

Review of Literature:
Giant cell (GCA) arteritis is perhaps the most common systemic vasculitis in the Western hemisphere. It usually affects older adults (age > 50 and usually over 65 years ), with a peak at 70 years. [1] GC arteritis is a granulomatous inflammatory disease which affects large and medium-sized arteries, commonly the temporal artery, but may affect the aorta and even more rarely, the visceral arteries. [2, 3] With regard to the aorta, the ascending aorta appears to be most commonly affected.

Unlike temporal arteritis few, if any, patients with GCA present with any specific clinical symptoms, and the diagnosis is not made pre-operatively. Complications, such as catastrophic dissections, have been reported to be as high as 46% in some studies, with a 2-week mortality of 80% in patients with GC arteritis. [4] Additionally, stroke and myocardial infarction (upon consequent occlusion of their respective vessels) can occur.

Therefore, while it is imperative that the diagnosis of GC arteritis be made as soon as possible- considering the fact that aneurysms can develop and may lead to catastrophic acute aortic dissections and rupture, the diagnosis itself is not made till the surgically excised tissues are available.

The only clinical features that, I think, are suggestive of an aortopathy, are ascending aortic dilatation, in patients who do not have associated aortic valvular disease and in addition do not have any significant atherosclerosis of this part of the aorta... Given the possibility of these serious developments in patients with GC aortitis, it is important to identify any risk factors that may lead to early recognition and diagnosis of this aortopathy.

In reviewing my cases I found four cases of GCA diagnosed at pathological examination, in the last 2 years (approximately 200 ascending aortae are excised annually at UHN). All 4 had been operated upon for ascending aortic dilatation/aneurysm. The following material is based on these cases and a review of the literature.

A clinical diagnosis of GC aortitis is difficult. However the existence of ascending aortic aneurysms concurrent with GC aortitis has been well established. This is complicated by the fact that ascending aortic aneurysms (AAA) are most often associated with hypertension. GC aortitis(GCA) has been reported to occur in 0.4% of 20,000 autopsy cases. [3] Knowledge of significant risk factors which may lead to the suspicion of an underlying inflammatory aortopathy may allow the clinician to consider GCA as part of the differential diagnosis. Herein we have presented four cases that were found to have GCA at histological examination of excised aortic tissue. All 4 (100%) patients were hypertensive, with 3 (75%) cases presenting with non-specific symptoms of chest pain and dyspnea on exertion. None of the cases raised any suspicions of an inflammatory aortitis, pre-operatively. A review of the literature was completed to identify common clinical presentations of GC aortitis patients. The results of these findings are summarized in tables 1 and 2.

Two separate studies have evaluated patients with GC aortitis requiring surgical repair. Kerr et al. studied 19 patients (n=1 029) who were found to have GC aortitis at histological examination of excised tissue. In this cohort 11 (58%) and 6 (19%) had dyspnea and angina symptoms, respectively, at hospital presentation. Hypertension was found in 6 (32%) and a new murmur was noted on precordial examination in 14 (74%) patients. Investigations, such as echocardiography and cardiac catheterization detected AI in 9 (47%) patients. [5] The second study, by Zehr et al., identified the most common co.-morbid conditions in patients operated for aortic complications of GC aortitis. Unlike the study by Kerr et al. whose patients were not treated with steroids pre or post-operatively, some patients in thisstudy were previously treated with steroids for a known history of polymyalgia rheumatica (PMR) and GC temporal arteritis (active phase of disease determined by either symptomatic vasculitis or elevated markers of inflammation). The most common co.-morbid conditions identified in this cohort included hypertension (n=27, 73%), cigarette smoking (n=25, 68%), peripheral vascular disease (n=14, 38%) and CAD (n=11, 30%). [2] Hypertension was found to be common in both cohorts. Since hypertension itself can cause dilatation of the ascending aorta, it is difficult to discern if it is an independent risk factor or a confounding factor. Similarly, cigarette smoking may weaken the aortic wall and predispose to aneurysm formation. The components of cigarette smoke have been found to cause endothelial damage in both in vitro and in vivo models. [6] Because the exact mechanism for aneurysm development is not known, it remains difficult to decide if the development of these aneurysmal aortae is due to the underlying inflammatory process, hypertension, cigarette smoking or a combination of all these factors.

Three studies attempted to identify risk factors in patients who subsequently developed complications of GC aortitis compared to patients with GC arteritis who did not develop such complications. At their institution, Gonzalez-Gay et al. identified 20 biopsy proven GC arteritis cases (n=210) that developed aortic aneurysms or dissections. Among these patients, the authors found that hypertension was much more common in those with aneurysmal disease (p=0.002, hazard ratio=4.73). Signs and symptoms of PMR, with a concomitant elevation of inflammatory markers (erythrocyte sedimentation rate (ESR), hemoglobin and platelets) were also found to be significant (hazard ratio=3.71). [1] Unlike the two studies mentioned previously, these results suggest that patients with hypertension and an underlying severe inflammatory response at the time of diagnosis of aortitis are more likely to develop aneurysmal disease. The second study, by Nuenninghoff et al., found that 30 patients (18%) in their cohort (n=168) developed similar complications. Furthermore, hyperlipidemia and CAD were more common in the aneurysmal group (p=0.049 and 0.020 respectively) than the control group, though the reasons for these associations are unknown and may well be coincidental. Similar to previous discussions of risk factors in the literature, these authors discussed the difficulty in identifying whether hyperlipidemia is an independent risk factor, since it results in vessel wall weakening and may exacerbate dilatation in the background of an inflammatory process. The authors also suggested that the association with CAD may be related to an increased incidence of coronary arteritis in GC arteritis. [7] Similar to the Kerr et al. study, this study also found that a murmur suggestive of AI is significant for an underlying aortopathy (p<0.005, hazard ratio=9.30). The authors also noted that within the high rate of aneurysm/dissection development, some patients developed aortic dissections in the absence of aneurysm or even dilatation or ectasia. As a result, they suggested that in assessing GC aortitis, evaluations should go beyond possible aneurysm development and include investigations of inflammatory wall changes. The study conducted by Evans et al. found no significant risk factors in their investigation. [8]

Of our cases, none had experienced any symptoms indicative of GC aortitis. The first case was a 62-year-old male who had a significant history of hypertension, aortic incompetence, dyspnea, cigarette smoking, dyslipidemia, and CAD. The second, a 56-year-old female patient had a significant presentation of dyspnea, hypertension, aortic incompetence and angina. The third case was a 33-year-old man presenting with dyspnea, aortic incompetence and hypertension in addition to a congenital syndrome with an aortic coarctation and BAV. Notably, in a study of surgical pathology of the ascending aorta (n=513) where 93% of the cases were performed to correct aneurysms or dissections, 8.4% had an aortitis (4.9% GC aortitis) and 7% of these aortitis cases presented with BAV suggesting a low correlation between GC aortitis and ascending aortic aneurysms in the context of BAV. [9] Our fourth case was of a 74-year-old male with a history significant for hypertension, aortic incompetence, cigarette smoking and chest discomfort. All of our cases presented with aneurysmal ascending aortic disease that met the criteria for surgical intervention. In comparing these presentations with the co.-morbid conditions previously identified and associated with aneurysm development, it appears that our patients were at risk for GC aortitis and aneurysmal complication. In patients with classic features of GC arteritis, the diagnosis is easier to make clinically. Isolated GC aortitis patients have a different presentation compared to those with GC temporal arteritis in that they are generally asymptomatic with respect to the vasculitis. [2] Since many patients with aneurysmal disease are asymptomatic and the majority have no history of GC arteritis, definitive diagnosis is only made after the excision of the aneurysmal aorta and detailed pathological examination. As such, these patients often do not receive adequate treatment for GC aortitis. This is especially important given that histological analysis of specimens from a steroid-treated GC arteritis patient was found to have completely recovered from the underlying aortitis, suggesting that GC aortitis is indeed steroid-responsive. [10] Some studies have tracked patients receiving corticosteroid treatment after aneurysm explant and aortitis identification without apparent systemic disease. Rojo-Leyva et al., without a standardized steroid treatment protocol, saw that none of their 11 patients treated with glucocorticoids (mean follow-up 35.5 months) developed new aneurysms, while 6 of 25 that were not treated (mean follow-up 41.2 months) developed subsequent aneurysms. [11] In a study by Miller et al., of 21 patients with isolated ascending aortitis, 19 did not receive corticosteroids and only one of these patients developed a new aneurysm (mean follow-up 81 months. Currently there are no guidelines for treating patients with medical therapy after incidental discovery of GC aortitis post-explantation.

It has been suggested that extracranial GC arteritis is a variant of classical GC arteritis or temporal arteritis. [12] Zehr et al found that only 8% of their GC aortitis patients had a history of temporal arteritis. [2] In a study of idiopathic arteritis, all patients with aortitis remarkable for the presence of giant cells did not have clinical features of GC arteritis at the time of surgery and only 4 of 16 of these patients had a past history of GC arteritis. [11] Furthermore, symptoms are usually related to the aortic aneurysm or aortic valve regurgitation rather than the vasculitis itself. [2] Despite the strong evidence for variants of GC arteritis, it has also been reported that a patient with no indication of temporal involvement and a positive histological identification of GC aortitis was later found to have arteritis of the temporal artery upon biopsy. [13] But, this should be taken in the context of a study that found a fairly high rate of negative temporal artery biopsies in large vessel GC arteritis patients (24 of 57 performed). [12, 14] In fact, there is increasing recognition of localized aortitis with no apparent systemic disease, suggesting that aortitis may in fact be a distinct and completely unrelated entity. Miller et al. distinguish an isolated variant of arteritis specific to the ascending aorta with none of their patients exhibiting any evidence of systemic disease. [15] Burke et al. note similar trends and conclude that aortitis discovered as a result of aortic aneurysm or aortic valve incompetence is usually clinically isolated. [16] Taken together, it is possible that isolated GC aortitis is distinct from GC aortitis coexisting with an underlying temporal arteritis.

Several groups have shown the usefulness of 18-FDG PET (18-fluorodeoxyglucose positron-emission-tomography) in identifying large vessel GC arteritis. [14, 17] Although the use of such a technique is not specific for GC vasculitis, it can be a useful tool in conjunction with appropriate clinical information. [14] For patients who have not yet been diagnosed, a careful history (e.g. history of hypertension, CAD, and signs and symptoms of PMR) and physical exam findings (e.g. new onset of AI murmur), along with results from investigations (e.g. elevated ESR and echocardiographic evidence of new onset AI, positive 18-FDG PET) should suggest the possibility of isolated GC aortitis, consider treatment with immunosuppressant therapy pre and post-surgery, as well as to serially monitor these patients on a long-term basis for other complications.

Table 1: Clinical data: patients with aorta complications of GC arteritis compared to uncomplicated GC arteritis

Author n* (total) n** (AA/AD) n (%) of AA n(%) of AD Co-morbidities identified Clinical factors identified
Thoracic Abdominal Thoracic Abdominal
Gonzalez-Gay et al. 210 20 (9.5%) 16 (7.6%) 6 (2.9%) 2 (1.0 %) 1 (0.5%) HTN (p=0.002; HR=4.73) Symptoms of PMR and elevated ESR (HR=3.71)
Nuenninghoff et al. 168 30 (18%) 18 (11%) 16 (10%) 9 (5%) 1 (1%) Hyperlipidemia (p=0.02)
CAD (p=0.049)		Murmur of AI (p <0.005; HR=9.30)
Evans et al. 96 11 (11%) 11 (11%) 5 (5%) 6 (6%) - No significant findings No significant findings

*: all patients diagnosed with giant cell aortitis

**: all patients with complications from giant cell aortitis

AD: aortic dissection; AA: aortic aneurysm; HTN: hypertension; HR: hazard ratio; PMR: polymyalgia rheumatica; ESR: erythrocyte sedimentation rate; CAD: coronary artery disease; AI: aortic insufficiency

Note: a single patient may have AA and AD in both thoracic and abdominal regions

Table 2: Identifying clinical presentations of patients receiving surgery to correct complications of GC aortitis

Co-morbidities Clinical Symptoms Clinical Signs Investigations*
Author n Age (yrs.) n (%) of AA n (%) of AD temporal arteritis HTN Smoking PVD CAD DM SOB Angina New murmur AI
Thoracic Abdominal Thoracic Abdominal
Zehr et al. 37 69.6 37 - - - 10 (27%) 27 (73%) 25 (67%) 14 (38%) 11 (30%) 3 (8%) 9 (24%) - - 19 (51%)
(44-84)
Kerr et al. 19 73.2 17 (89%) 8 (42%) 2 (11%) 0 (0%) 1 (5%) 6 (32%) - - - - 11 (58%) 6 (32%) 14 (74%) 9 (47%)
(41-85)
Lee et al. (current study) 4 56.3 4 - - - - 4 (100%) 2 (50%) - 1 (25%) - 3 (75%) 1 (25%) - 4 (100%)
(33-74)

*: aortic insufficiency as determined by echocardiography or cardiac catheterization

AA: aortic aneurysm; AD: aortic dissection; HTN: hypertension; PVD: peripheral vascular disease; CAD: coronary artery disease; DM: diabetes mellitus; SOB: shortness of breath; AI: aortic insufficiency

Note: a single patient may have AA and AD in both thoracic and abdominal

References
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  2. Zehr,K.J., Mathur,A., Orszulak,T.A., Mullany,C.J. & Schaff,H.V. Surgical treatment of ascending aortic aneurysms in patients with giant cell aortitis. Ann. Thorac. Surg. 79, 1512-1517 (2005).

  3. Klein,R.G., Hunder,G.G., Stanson,A.W. & Sheps,S.G. Large artery involvement in giant cell (temporal) arteritis. Ann. Intern. Med. 83, 806-812 (1975).

  4. Liu,G., Shupak,R. & Chiu,B.K. Aortic dissection in giant-cell arteritis. Semin. Arthritis Rheum. 25, 160-171 (1995).

  5. Kerr,L.D., Chang,Y.J., Spiera,H. & Fallon,J.T. Occult active giant cell aortitis necessitating surgical repair. J. Thorac. Cardiovasc. Surg. 120, 813-815 (2000).

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  11. Rojo-Leyva,F., Ratliff,N.B., Cosgrove,D.M., III & Hoffman,G.S. Study of 52 patients with idiopathic aortitis from a cohort of 1,204 surgical cases. Arthritis Rheum. 43, 901-907 (2000).

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  14. Janssen,S.P., Comans,E.H., Voskuyl,A.E., Wisselink,W. & Smulders,Y.M. Giant cell arteritis: heterogeneity in clinical presentation and imaging results. J. Vasc. Surg. 48, 1025-1031 (2008).

  15. Miller,D.V. et al. Surgical pathology of noninfectious ascending aortitis: a study of 45 cases with emphasis on an isolated variant. Am. J. Surg. Pathol. 30, 1150-1158 (2006).

  16. Burke,A.P., Tavora,F., Narula,N., Tomaszewski,J.E. & Virmani,R. Aortitis and ascending aortic aneurysm: description of 52 cases and proposal of a histologic classification. Hum. Pathol. 39, 514-526 (2008).

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