Annuloaortic Ectasia and Arteritis: Clinical Features, Treatments of Choice, and Causative Relations

The roles that aortitis plays in the development of annuloaortic ectasia (AAE) remain uncertain, while clinical features of AAE in arteritis are largely unknown. This study was designed to highlight the clinical features of AAE, the treatments of choice, and the causative relations between aortitis and AAE. The morphology of the aortic valve leaflets was normal in half of the patients, while the valves were thin and overstretched in the other half. Most patients had an aortic aneurysm. Half of the patients had severe aortic valve insufficiency, and one-quarter of them had dilation of the sinuses of Valsalva. Takayasu arteritis was prone to develop coronary artery lesions, whereas giant cell arteritis were not. Aortic branch lesions in Takayasu arteritis were stenotic or occlusive in 92.9% of the patients, while in giant cell arteritis, they were all dilated lesions. Most patients (94.7%) required surgical treatment with steroid therapy. However, long-term follow-up results showed a higher anastomotic dehiscence rate, particularly in patients with Takayasu arteritis. Further morphometric and pathological research on AAE in arteritis should be undertaken, and more feasible measures should be warranted for preventing postoperative anastomotic dehiscence.


INTRODUCTION
In 1961, Ellis et al. [1] proposed the concept of annuloaortic ectasia (AAE) representing an entity of dilation of the proximal ascending aorta, sinuses of Valsalva, and aortic annulus with poor coaptation of the valvular leaflets and aortic regurgitation. In the cohort of AAE, patients may have aortic dissection, aneurysm, or rupture [2,3] . Moreover, the echocardiographic features of AAE were marked dilation of the aortic root with a unique posterior
The morphology of aortic valve leaflets was mentioned in six (13.3%) patients: three were normal [27] and three were abnormal (very thin [19] in one, thinned out with lax cusps [29] in one, and overstretch aortic valve leaflets in one patient [37] ).
The timing of occurrence of AAE was reported in only two (4.4%) patients, at two and five years after the diagnosis of GCA was made [27] . The dimensions of aortic annulus were described in 22 (38.6%) patients, measuring 31.5±12.2 (range, 23-60; median, 26) mm (n=15) [7,[14][15][16][17][18][19]34,37] . and the associated pathological changes of the aortic tissue could be disruption of the medial elastic layers and marked medial fibrosis [7,8] . García-Macedo et al. [6] reported a group of 27 patients with AAE and found that 23 (85.2%) were due to cystic medial necrosis, three (11.1%) were due to chronic aortic dissection, and one (3.7%) was due to syphilitic aortic aneurysm. Moreover, aortitis, including the giant cell aortitis (GCA), has been regarded a causative etiology of AAE and the resultant aortic regurgitation [10] . Annular progressive dilation as a consequence of AAE may also affect the long-term stability of a repair [11] . However, the roles that aortitis plays in the development of AAE remain uncertain, and the clinical features of AAE in patients with arteritis are unknown. This study aims to highlight the clinical features of AAE in patients with arteritis, the treatments of choice, and the causative relations between aortitis and AAE.

METHODS
The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement guidelines were followed in this meta-analysis [12] . Publications were systematically searched in the PubMed, Highwire Press, and Cochrane Library databases from January 1990 to August 2018. The MeSH terms and keywords used to identify articles included "giant cell aortitis", "Takayasu arteritis (TA)", "Behçet disease", and "annuloaortic ectasia. " Bibliographic references were tracked down to complete the literature retrieval. Thirty-three articles were found related to the topic and keywords in the literature search; and 28 articles, which met the inclusion and exclusion criteria during preliminary assessment, were included in the review. The exclusion criteria were: unrelative design to AAE (n=4) and no actual patient information available (n=1).
The data were carefully extracted for details of the study population, demographics, diagnostic techniques, clinical features, associated disorders, treatment, follow-up length, and patient's prognosis. Quantitative data were presented as mean±standard deviation with range and median values. The intergroup differences were compared through the independent t-test, and the comparisons of frequencies were made by Fisher's exact test. P<0.05 was considered statistically significant. Amano et al. [14] 54.1±5.3 (range, 32-75; median, 50)
One patient's treatment was not mentioned [18] , one patient was treated conservatively with nonsteroidal medications and died suddenly due to rupture of aneurysm of the Table 3. Nineteen symptoms presented by 12 patients.

DISCUSSION
It has been reported that rolling of free cusps of the aortic valve was a unique finding of AAE [34] . The aortic valve can also be thin, and the aortic valve ring can expand to 60 mm in diameter [19] . At the histologic examination, the aortic leaflets showed signs of inflammation with mononuclear cellular infiltrate, even though true granulomatous-like inflammatory reaction with multinucleated giant cells was not seen.
Dilation of a coronary artery may be secondary to AAE or share a similar etiology to AAE. As a result of cystic medial necrosis of the aorta, AAE is the most common cardiovascular manifestation of Marfan syndrome [40] . Becker and van Mantgem [41] studied the morphology of coronary arteries of Marfan patients and found out that the pathological changes of the coronary artery were cystic medial necroses, similar to those seen in the aorta of arteritis patients. However, in patients without Marfan stigmata, coronary artery ectasia may also be present [42] .
The Bentall procedure is often indicated for aortic regurgitation associated with AAE [43] . The David operation with native aortic valve preservation is useful for preventing some Table 5. Cardiac surgical procedures performed in 54 patients with annuloaortic ectasia.
In TA patients, extensive intimal fibrosis, loss or fragmentation of the elastic lamina, and patchy infiltration of inflammatory cells were found in the aortic tissue [7,17,19] , and the aortic valve leaflet showed mucoid degeneration with inflammatory cell infiltration [37] . In the GCA patients, cystic medial degeneration and dystrophic calcification [21] , and plasma cells and lymphocytes with central hyalinized connective tissues [29] of the aortic wall were noted. the pertinent pathological changes of AAE. TA was prone to develop coronary artery lesions, while GCA was not. The aortic branch lesions in TA were mostly stenotic or occlusive, while in GCA, they were all dilated lesions. Kermani et al. [45] also reported the same findings of predominant stenotic/occlusive lesions in TA, whereas more common aneurysmal disease was noted in GCA. Nevertheless, the pertinent mechanisms leading to the disparity of the vascular changes between the two lesions were not interpreted.
The shortage of information about AAE in arteritis patients in the literature constitutes the major drawback of this study. Currently, some important aspects of AAE in arteritis have not been satisfactorily answered. These questions include the timing of AAE development after arteritis onset, the geometric morphometrics of the aortic valve annulus, the hemodynamic impact of the geometric morphometrics, the pathology of the aortic valve leaflets, the durability of aortic valve repair in relation to these morphometric and pathological features, more feasible measures for the prevention of postoperative anastomotic dehiscence, and comparisons with AAE of other etiologies. These questions are anticipated to be answered in the future.

CONCLUSION
Arteritis can cause AAE, which is characterized by dilated aortic valve annulus, sinuses of Valsalva, and ascending aorta. Some patients show coronary artery and aortic arch branch lesions. The inflammatory cellular infiltrate and enhanced immune biomarkers can be the intriguing contributions of aortitis to the pertinent pathological changes of AAE. The mechanisms of the predominant stenotic/occlusive lesions in TA and more common aneurysmal disease in GCA remain uncertain. Most patients (94.7%) require surgical treatment with steroid therapy. However, long-term follow-up results show a higher anastomotic dehiscence rate, particularly in patients with TA. Further morphometric and pathological research on AAE in arteritis should be undertaken.
complications associated with artificial heart valves [44] . Thus, a "valve-sparing" operation could be used for such patients. However, these patients were young, and the dystrophic changes of the cusps were mild; furthermore, a David operation should be the treatment of choice whenever possible.
Composite graft anastomosed to the aortic annulus with buttress sutures reinforced with Dacron felt may potentially decrease the risk of prosthetic detachment [33] , i.e., dehiscence of the composite graft from the aortic annulus [35] . Long-term results for aortic valvuloplasty or redo-operation after aortic valvuloplasty in TA patients even in the active phase can be good [17] . At the site of the external reinforcement of the aneurysm, further expansion of the ascending aorta may be inavoidable, and an aortic aneurysm may develop at the interface of the aorta and Dacron fabric for wrapping. These complications can be difficult to manage when external reinforcement and aortic valvuloplasty are undertaken during active inflammatory AAE [17] .
Postoperatively, anastomotic dehiscence may occur at the distal anastomosis of Dacron graft and at the non-coronary cusp site of the proximal composite graft. Paravalvular leaks, another surgical complication, have been considered to have begun five years after the initial operation with inflammatory deterioration [31] . Clinical observations revealed that previous saphenous vein and aortoaxillary bypass grafts were markedly enlarged, the prosthetic valve was detached from the annular ring, and the motion was restricted by small thrombus and the remnant of the right coronary cusp [26] . In the patient cohort of Evans et al. [10] , the aortic valve cusps were macroscopically normal and valve incompetence was presumably caused by the lack of leaflets coaptation secondary to aneurysmal dilation of the aortic root. Late death (50%) occurred at a late stage up to a mean of 23.8 months due to severe complications, such as valve detachment or postoperative pseudoaneurysm. Comparisons of preoperative immunological values between the survival and late death groups were made, and the immune biomarkers, such as IgG, IgA, C3, and C4, were significantly higher in the late death group. It was explained that the insertion of the rigid prosthesis in the fragile position might stimulate immunological reactions due to latent inflammation [28] .
Shiono et al. [31] reported that, in initial Bentall procedures, both coronary ostia were directly anastomosed to composite valved graft and wrapped with native aortic wall; the coronary button was lacerated in five years. To avoid laceration of coronary anastomosis, Carrel's button technique is advocated in redooperations [30] . Additionally, the composite graft anastomosed to the aortic annulus with buttress sutures reinforced with a Dacron felt was also recommended. Both coronary orifices were able to be reconstructed with small-sized Dacron grafts, interposed from the coronary orifices to the composite graft [33] .
This study provides typical clinical features of AAE in arteritis. The morphology of the aortic valve leaflets was normal in half of the patients, and the valves were thin and overstretched in the other half. Most patients had an aortic aneurysm. Half of the patients had severe aortic regurgitation, and one-quarter of them had dilation of the sinuses of Valsalva. It could be deduced that the inflammatory cellular infiltrate and enhanced immune biomarkers became the intriguing contributions of aortitis to

SMY
HL Conception or design of the work; acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; final approval of the version to be published Interpretation of data for the work; final approval of the version to be published