Echocardiographic Findings and Cardiac Surgical Implications of Aortitis and Valvulitis in Behçet's Disease

Editorial Comment

Echocardiographic Findings and Cardiac Surgical Implications of Aortitis and Valvulitis in Behc¸et’s Disease Athena Poppas, MD, FASE and Michael Coady, MD, Providence, Rhode Island Inflammatory, noninfectious aortitis is an unusual cause of aortic regurgitation and ascending aortic aneurysm formation, occurring in <10% of patients who present for surgery.1 Takayasu’s arteritis, giant-cell arteritis, and Behc¸et’s disease (BD) are all systemic, autoimmune disorders that may occasionally affect the ascending aorta and aortic valve. Although BD is rare, its preoperative recognition is paramount, because the appropriate use of immunosuppressive agents and the modification of surgical techniques may greatly improve overall survival. DIAGNOSIS BD is a chronic, relapsing autoimmune disorder characterized by recurrent oral and genital ulcers and variable multiple-organ involvement. The pathophysiology involves active inflammation of large and small arteries.2 The presentation is variable, and BD is often an elusive diagnosis. The mean age of onset is between 20 and 30 years, and the disease is rarely seen in children or in patients aged >50 years.3,4 There are no specific pathognomonic tests. The diagnosis is made from a constellation of clinical findings. The International Study Group for Behc¸et’s Disease (ISG) proposed criteria in 1990 for diagnosis to be used for research purposes, but not necessarily to identify the disease process in an individual patient. The ISG criteria require recurrent oral aphthous ulcerations and two of the following: recurrent genital ulcerations, ocular lesions, dermatologic lesions, or positive results on a pathergy skin test.5 Other systemic manifestations of BD include vascular, neurologic, rheumatologic, renal, and gastrointestinal dysfunction. However, involvement of these other organ systems is not required to secure the diagnosis.2 Central nervous system and major vascular involvement are the primary sources of early mortality in BD.3 Importantly, in many retrospective surgical series involving aortic valve replacement (AVR) for the treatment of severe aortic insufficiency, the majority of patients were not diagnosed preoperatively because they had not meet the standard criteria for BD.1,6-8 Therefore, cardiologists and surgeons must have a high index of suspicion for BD when they encounter patients with acute, severe aortic insufficiency and characteristic findings on echocardiography. The incidence, genetics, and phenotypic expression of BD vary by region. Incidence may be as high as 1 in 1,000 in the Middle East and 100-fold lower in the United States.2,4 There is an association of particular human leukocyte antigens (HLAs) with the disease, which also varies by geography. For instance, HLA-B5 (B51) has a much higher prevalence in patients with BD from Italy and the Middle East than other HLA types in other regions.2,9 The severity of and predilection From the Section of Cardiology, Department of Medicine (A.P.), and the Section of Cardiovascular Surgery, Department of Surgery (M.C.), Warren Alpert School of Medicine, Brown University, Providence, Rhode Island. Reprint requests: Athena Poppas, MD, Brown University, Warren Alpert School of Medicine, Department of Medicine, Section of Cardiology, 593 Eddy Street, Main Building, Room 209, Providence, RI 02903. (E-mail: [email protected]). 0894-7317/$36.00 doi:10.1016/j.echo.2009.09.017

for organ involvement seems to have geographic and gender variability. The disease is less severe in women, who usually manifest only mucocutaneous lesions, whereas men have a higher propensity for systemic disease. In a 20-year follow up of 387 patients in Turkey, overall mortality was much higher in men (15%) than in women (2%). Vascular involvement, 80% of which was veno-occlusive disease, was more common in men (49%) than in women (5.6%). Arterial involvement (pulmonary or peripheral arteries) is less common yet more lethal, and also more prevalent in men (8%) than women (<1%).3 In the majority of surgical cases for the treatment of severe aortic insufficiency involving BD, there is also a male predominance (93%,3 79%,6 and 57%8).

CARDIOVASCULAR INVOLVEMENT IN BEHC¸ET’S DISEASE Reports of clinically significant aortic and valvular involvement necessitating intervention are very small, ranging from 1 to 20 reported patients from single centers collected over years to decades. Approximately one third of patients with BD develop clinically significant vascular involvement, typically veno-occlusive disease; aortic aneurysm formation is very rare. In a series of 2,319 patients from Turkey, 332 (14%) had vascular involvement; of these, there were only 4 with larger arterial findings: 3 had involvement of the pulmonary artery and only 1 had systemic arterial lesions.10 In another study of 137 patients, 38 (28%) had vascular involvement, and only 5 were arterial (3 pulmonary, 1 radial, and 1 carotid and popliteal artery aneurysms or occlusions).11 Pulmonary artery aneurysms often present with hemoptysis and have >50% mortality.3,4 In a 1990 Medline search of 728 reported cases of vascular involvement in patients with BD, 160 (22%) were arterial lesions, of which 36 were pulmonary artery aneurysms or occlusions and 17 were aortic aneurysms.11 Venous disease seems to occur earlier in the course of BD, and most arterial involvement manifests years later. Arterial complications may present as life-threatening emergencies requiring immediate surgical treatment. In one series of 20 patients requiring 34 vascular surgeries over 13 years, ruptured abdominal aortic aneurysms and critical limb ischemia were the most common clinical presentations.12 Although clinically significant aortic aneurysms are rare, the aorta does appear to be abnormal in many patients. In a group of 35 patients randomly selected for transesophageal echocardiography (TEE) from a BD clinic in Turkey, 48% had >4-cm dilation of the aorta.13 In a similar study of 30 patients in Italy, 30% had dilation of the ascending aorta on transthoracic echocardiography (TTE).9 In a case-controlled echocardiographic study of 82 patients who met ISG criteria, not only were the thoracic and abdominal aortas noted to be larger than in controls, but the elastic properties (strain, distensibility, and stiffness) were reduced by 2-fold to 3-fold.14 In this study from Greece, the degree of aortic elastic dysfunction was related to the duration of disease. Cardiac disease follows a similar pattern. Clinically significant involvement is exceedingly rare, but echocardiographic abnormalities are quite common. The cardiac spectrum most commonly includes 1275

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Table 1 Echocardiographic findings in BD Jeong et al8

Han et al6

Song et al1

Finding

First OR (n = 19)

Redo OR (n = 27)

First OR (n = 5)

Redo OR (n = 12)

First OR (n = 7)

Redo OR (n = 9)

Cusp aneurysmal change Echo-free space Masslike lesion Pseudoaneurysm IVS dissection

19 8 3 1 2

— 15 0 7 5

4 2 2 NA 0

1 3 4 NA 1

7 4 2 NA NA

— NA NA NA NA

First OR, First operation for AVR; IVS, interventricular septum; NA, not available; redo OR, second operation for prosthetic aortic valve dehiscence.

valvular redundancy with regurgitation and sporadic cases of endocardial fibrosis and intracardiac thrombosis. There are case reports of intracardiac thrombus formation, often recurrent and sometimes associated with pulmonary artery aneurysms.15-17 Cardiac and vascular thrombosis appears to be due to endothelial damage from active inflammation as well as a hypercoagulable state.2,18 Endomyocardial fibrosis was noted in 4 of 350 patients with BD (1%). Echocardiography revealed bright echodensity along the ventricular endocardium.19 Despite similar echocardiographic methods, there is wide variability in reports of valvular pathology. In one case-controlled study of 54 consecutive patients with newly diagnosed BD by ISG criteria, no significant valvular pathology was noted on TTE.20 In two similarly sized case-controlled studies, mitral valve prolapse was noted in 25% and 50% of patients.9,13 The only difference between the positive and negative studies was that those with a higher incidence of mitral valve prolapse included patients later in the course of the disease. On TEE, 40% of these patients had mitral regurgitation, and 31% had interatrial septal aneurysms.13 On TTE and on TEE, 30% and 48% of these patients, respectively, had dilation of the ascending aorta.9,13 In these echocardiographic studies in stable outpatients, aortic root dilation but no aortic valve pathology was noted. Conversely, in surgical series of patients with severe aortic insufficiency, aortic dilation and aneurysm formation were uncommon.1,6 Reports of cardiac function vary considerably depending on the definitions and methods used as well as the populations studied. Left ventricular systolic function, as measured by ejection fraction, appears to be preserved in almost all studies.13,14,20,21 One study, using Doppler tissue imaging, noted lower systolic peak myocardial velocities suggesting subclinical contractile dysfunction.22 There are conflicting reports of diastolic dysfunction among patients with BD. When pulse-wave Doppler of the mitral inflow was used, E/A ratios < 1 were noted more often in patients with BD than in age-matched controls (22% vs 6%20 and 31% vs 5%23). Two other studies found no difference in E/A ratios, but one noted abnormalities in isovolumic relaxation time and deceleration time.14,24 Similar conflicting findings were noted in studies using Doppler tissue imaging of the lateral mitral annulus.20,22,24 Again, some studies noted correlations with the duration of disease14,23 as well as with aortic stiffness, which significantly affects afterload.14,24

ECHOCARDIOGRAPHIC CHARACTERISTICS OF SEVERE AORTIC INSUFFICIENCY DUE TO BEHC¸ET’S DISEASE Given the protean clinical manifestations of BD, the rarity of its occurrence worldwide, and the infrequency with which it can cause severe aortic insufficiency, echocardiographic findings that can distinguish this disease are crucial. In the current issue of JASE, Han el al6 highlight

some distinctive echocardiographic features of severe aortic insufficiency due to aortic valve and root involvement by BD (Table 1). Transesophageal echocardiographic findings of marked thinning and redundancy of aortic leaflets, with or without mobile masses and/or echo-free space within the annulus, may be pathognomonic of BD. In an early case series reported in JASE, 7 patients with BD underwent AVR for severe aortic insufficiency and had these same characteristic findings on TEE.1 The largest surgical series, also from Korea, included 19 patients collected over 22 years. Echocardiography revealed redundant motion of elongated aortic cusps with aneurysmal changes in all 19 patients. Also, 8 had annular echo-free spaces, and 3 had mobile mass lesions.7 This unusual aortic cusp thinning and redundancy are not seen in other diseases. Aortic insufficiency from BD is often acute, and the echocardiographic findings can mimic infectious endocarditis. On TEE, mobile masses noted on valve leaflets are indistinguishable from valvular vegetations, and the echo-free spaces within the annulus and/or ventricular septum are consistent with extension of an infectious process and a root abscess; these two echocardiographic findings in BD could meet major Duke criteria for endocarditis. The diagnosis may be further confounded if a patient presents with active systemic disease with an elevated erythrocyte sedimentation rate (ESR) and fever. In a case report from JASE of BD mimicking infective endocarditis,25 the transesophageal echocardiographic images before and after AVR are identical to those shown by Han et al.6 Similarly, in the above case series of 7 patients requiring AVR, 6 presented with signs and symptoms of acute rather than chronic, severe aortic insufficiency, and 5 had no prior diagnoses, further complicating the differentiation between infective endocarditis and BD.1

PATHOLOGY The large-vessel vasculitis in BD is acute and recurrent rather than chronic and persistent. It is usually associated with systemic symptoms, such as fever and elevated markers of acute inflammation, including ESR or C-reactive protein (CRP).2,4,18 Vasculitis appears to begin within the vasa vasorum, leading to rapid destruction of the vessel wall. Rapid progression to aneurysm, pseudoaneurysm, and rupture can occur.2,4,18 The etiology is not clear, but the pathologic findings are typical. On histologic exam of the aortic valves of 9 patients who went to surgery, diffuse myxoid degeneration was noted.26 In another operative series of 7 patients, the valvular histology revealed central necrosis with granulation tissue, and the aortic wall revealed medial necrosis and inflammatory infiltration of the adventitia.1 This series contrasted the pathologic and echocardiographic findings of acute, active inflammation and friable tissue in BD with the chronic scarring and thickening seen in Takayasu’s arteritis.

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SURGICAL IMPLICATIONS Aortitis due to BD remains one of the most challenging problems for cardiac and vascular surgeons. Surgical management of Behc¸et’s aortitis with associated severe aortic insufficiency is difficult because the aortic tissue involved is routinely inflamed and extraordinarily fragile. For this reason, postoperative complications are frequent and life threatening, requiring redo operations in many patients. Complications include hemorrhage, pseudoaneurysm formation, valve detachment, and paravalvular leakage. BD carries the highest risk for valve detachment after AVR of all the various causes of aortitis. This has been reported to be as high as 50% to 76% in some series.1,7,26 It is thought that in an isolated AVR for treatment of Behc¸et’s aortitis, the stress of the valve function directly affects the rigid sewing ring and causes detachment more frequently.7 Efforts to simply strengthen the suture line with pledgets during AVR are futile. The reoperation-free rates after 5 and 10 years, because of the absence of valve detachment or suture insufficiency, are 64% and 43% for those with BD.7 Thus, although other types of aortitis, including Takayasu’s arteritis, can be treated by conventional AVR, this is not the case for BD. Unlike the experience with conventional AVR, the use of aortic root replacement (ARR) in the treatment of BD has been associated with a significantly lower incidence of valve detachment.7,8 In ARR, detachment is thought to occur less frequently because the flexible tubular prosthesis cushions stresses.7 Thus, the modified Bentall procedure and homograft ARR represent the best available surgical options for BD.8 Ando et al7 in their modified Bentall procedure constructed a composite graft consisting of a vascular graft 1 to 2 cm away from the proximal portion of the vascular tube graft. This was implanted into the aortic valve annulus by means of buttressed everting mattress sutures with a circumferential, beltlike piece of felt outside of the aortic wall. Composite graft reconstruction (ARR) is helpful because it allows circumferential fixation outside the aortic wall and double fixation at the aortic annulus. Also, unlike AVR, the prosthetic valve in a composite valve graft does not apply direct pressure on the annulus.7 Recognizing BD as vasculitis is important, because surgery in the acute phase of the disease, when markers of inflammation such as ESR or CRP are elevated, is accompanied by high morbidity and disruption of suture lines, leading to bleeding in the early phase or pseudoaneurysm formation in the last phase.27 ESR and CRP levels may also be beneficial in determining adequate timing of surgery and for predicting the effectiveness of immunosuppressive therapy.1,8 Opinion is divided on the postoperative use of steroids to prevent valve detachment. Opponents cite the increased risk for infection and impairment in healing. Steroids do, however, decrease inflammation in a disease that is recurrent. Some groups have reported excellent results with the use of preoperative and/or postoperative steroids and immunosuppressive therapy.1,6-8,28 However, there is no consensus about the choice of medication or its duration or delivery.

CONCLUSIONS Diseases involving the aorta and the aortic valve should be carefully evaluated using echocardiography. Echocardiographers must be able to recognize characteristic structural abnormalities that may distinguish individual disease processes. In BD, the ability to make this distinction preoperatively has a significant impact on management strategies and patient outcomes. BD is a chronic, relapsing vasculitis

that is uncommon and must be distinguished from other autoimmune disorders. Patients with BD tend to be male and are commonly from countries along the ancient Silk Road. They present with acute, severe aortic insufficiency. Distinguishing pathologic findings on TEE include thinning and redundancy of the aortic cusps. This novel finding is not seen in other diseases affecting the aortic valve and ascending aorta. The mobile valvular masses and perivalvular echo-free spaces, combined with elevated inflammatory markers, must be distinguished from infective endocarditis. The surgical approach requires ARR irrespective of aortic size. Perioperative immunosuppressive therapy has been shown by some groups to be beneficial in treatment. REFERENCES 1. Song JK, Jeong YH, Kang DH, Song JM, Song H, Choo SJ, et al. Echocardiographic and clinical characteristics of aortic regurgitation because of systemic vasculitis. J Am Soc Echocardiogr 2003;16:850-7. 2. Sakane T, Takeno M, Suzuki N, Inaba G. Behc¸et’s disease. N Engl J Med 1999;341:1284-91. 3. Seyahi E, Fresko I, Seyahi N, Ozyazgan Y, Mat C, Hamuryudan V, et al. The long-term mortality and morbidity of Behcet syndrome: a 2-decade outcome survey of 387patients followed at a dedicated center. Medicine 2003;82:60-76. 4. Seyahi E, Melikoglu M, Yazici H. Clinical features and diagnosis of Behc¸et’s syndrome. Int J Adv Rheumatol 2007;5:8-13. 5. International Study Group for Behc¸et’s Disease. Criteria for diagnosis of Behc¸et’s disease. Lancet 1990;335:1078-80. 6. Han JK, Kim HK, Cho GY, Kim MA, Sohn DW, Park YB. Behc¸et’s disease as a frequently unrecognized cause of aortic regurgitation: suggestive and misleading echocardiographic findings. J Am Soc Echocardiogr 2009;22: 1269-74. 7. Ando M, Kosakai Y, Okita Y, Nakano K, Kitamura S. Surgical treatment of Behc¸et’s disease involving aortic regurgitation. Ann Thorac Surg 1999;68: 2136-40. 8. Jeong DS, Kim KH, Kim JS, Ahn H. Long-term experience of surgical treatment for aortic regurgitation attributable to Behc¸et’s disease. Ann Thorac Surg 2009;87:1775-82. 9. Morelli S, Perrone C, Ferrante L, Sgreccia A, Priori R, Voci P, et al. Cardiac involvement in Behc¸et’s disease. Cardiology 1997;88:513-7. 10. Sarica-Kucukoglu R, Akdag-Kose A, Kayabal IM, Yazganoglu KD, Disci R, Erzengin D, et al. Vascular involvement in Behc¸et’s disease: a retrospective analysis of 2319 cases. Int J Dermatol 2006;45:919-21. 11. Koc Y, Gullu I, Akpek G, Akpolat T, Kansu E, Kiraz S, et al. Vascular involvement in Behc¸et’s disease. J Rheumatol 1992;19:402-10. 12. Iscan ZH, Vural KM, Bayazit M. Compelling nature of arterial manifestations in Behcet disease. J Vasc Surg 2005;41:53-8. 13. Gu¨rgu¨n C, Ercan E, Ceyhan C, Yavuzgil O, Zoghi M, Aksu K, Cinar CS, et al. Cardiovascular involvement in Behc¸et’s disease. Jpn Heart J 2002; 43:389-98. 14. Ikonomidis I, Lekakis J, Stamatelopoulos K, Markomihelakis N, Kaklamanis PG, Mavrikakis M. Aortic elastic properties and left ventricular diastolic function in patients with Adamantiades-Behc¸et’s disease. J Am Coll Cardiol 2004;43:1075-81. 15. Chiari E, Fracassi F, D’Aloia A, Vizzardi E, Zanini G, Rocca P, Metra M, et al. Right ventricular thrombus and pulmonary thromboembolism/ thrombosis in Behc¸et’s disease: a case report. J Am Soc Echocardiogr 2008;21:1079. 16. Ozer N, Ciftc¸i O, Demirci M, Atalar E, Ovu¨nc¸ K, Akso¨yek S, Ozmen F, et al. Right ventricular outflow tract thrombus in a case of Behc¸et’s disease. J Am Soc Echocardiogr 2005;18:380-2. 17. Houman M, Ksontini I, Ben Ghorbel I, Lamloum M, Braham A, Mnif E, et al. Association of right heart thrombosis, endomyocardial fibrosis, and pulmonary artery aneurysm in Behc¸et’s disease. Eur J Intern Med 2002;13:455. 18. Calamia KT, Schirmer M, Melikoglu M. Major vessel involvement in Behcet disease. Curr Opin Rheumatol 2005;17:1-8.

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19. Huong DL, Wechsler B, Papo T, de Zuttere D, Bletry O, Hernigou A, et al. Endomyocardial fibrosis in Behc¸et’s disease. Ann Rheum Dis 1997;56:205-8. 20. Bozkurt A, Akpinar O, Uzun S, Akman A, Arslan D, Birand A. Echocardiographic findings in patients with Behc¸et’s disease. Am J Cardiol 2006;97: 710-5. 21. Ozkan M, Emel O, Ozdemir M, Yurdakul S, Koc¸ak H, Ozdog˘an H, et al. M-mode, 2-D and Doppler echocardiographic study in 65 patients with Behc¸et’s syndrome. Eur Heart J 1992;13:638-41. 22. Yavuz B, Sahiner L, Akdogan A, Abali G, Aytemir K, Tokgozoglu L, et al. Left and right ventricular function is impaired in Behc¸et’s disease. Echocardiography 2006;23:723-8. 23. Gemici K, Baran I, Gullulu S, Kazazoglu AR, Cordan J, Ozer Z. Evaluation of diastolic dysfunction and repolarization dispersion in Behc¸et’s disease. Int J Cardiol 2000;73:143-8.

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24. Tunc SE, Dogan A, Gedikli O, Arslan C, Sahin M. Assessment of aortic stiffness and ventricular diastolic functions in patients with Behc¸et’s disease. Rheumatol Int 2005;25:447-51. 25. Shiran A, Zisman D, Karkabi B, Safadi T, Aravot D, Bitterman H, et al. Behc¸et’s aortitis mimicking aortic valve endocarditis with subaortic complications. J Am Soc Echocardiogr 2006;19:578. e1-4. 26. Lee CW, Lee J, Lee WK, Lee CH, Suh CH, Song CH, et al. Aortic valve involvement in Behc¸et’s disease. A clinical study of 9 patients. Korean J Intern Med 2002;17:51-6. 27. Marzban M, Mandegar MH, Karimi A, Abbasi K, Movahedi N, Navabi MA, et al. Cardiac and great vessel involvement in ‘‘Behc¸et’s disease.’’. J Card Surg 2008;23:765-8. 28. Erer D, Iriz E. Vascular surgery in Behc¸et’s disease. Ann Thorac Surg 2008; 85:1504-6.