Ascending Aortic Wall Degeneration in Patients with Bicuspid Versus Tricuspid Aortic Valve

Ascending Aortic Wall Degeneration in Patients with Bicuspid Versus Tricuspid Aortic Valve | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Ascending Aortic Wall Degeneration in Patients with Bicuspid Versus Tricuspid Aortic Valve Ari Mennander, Ivana Kholova, Saku Pelttari, Timo Paavonen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1152422/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background The magnitude of ascending aortic degeneration in patients with bicuspid aortic valves (BAV) is controversial. Methods The aim of this study was to investigate ascending aortic wall degeneration in patients with BAV as compared with tricuspid aortic valves (TAV). The ascending aortic wall of 67 consecutive patients was processed for histology and immunohistochemistry. The extent of surgery and wall degeneration were investigated. Unadjusted survival was evaluated by Kaplan-Meier analysis. Median follow-up for patients with BAV and TAV was 3.8 years (interquartile range [IQR] 3.5-4.1) and 3.7 years (IQR 3.4-3.9), respectively. Results There were 33 patients with BAV and 34 with TAV. Mid-ascending aorta diameter was 54 mm (IQR 50-60). Replacement of the aortic valve, together with an ascending aortic prosthesis, was more frequent in BAV vs TAV patients (24% vs 3%, P = 0.013). However, medial fibrosis, elastic fiber thinning, incremental medial degeneration and smooth muscle cell nuclei loss were less prominent in BAV vs TAV patients (0.1 ± 0.4 vs 0.8 ± 1.4, P = 0.016; 0.6 ± 1.4 vs 1.6 ± 2.0, P = 0.027; 1.7 ± 0.7 vs 2.2 ± 0.8, P = 0.045 and 2.3 ± 1.5 vs 3.2 ± 1.3, P = 0.026, respectively). Conclusions Since degeneration of the ascending aortic wall was seldom prominent, histopathology alone does not support the need for earlier surgery of the dilated ascending aorta in BAV patients as compared with TAV patients. Aortic wall degeneration ascending aorta bicuspid aortic valve Figures Figure 1 Figure 2 Introduction Bicuspid aortic valve (BAV) is present in 1-2% of the whole population. It has been suggested that patients with BAV are genetically susceptible to early aortic events and poor outcome [1], a conception mainly deduced from circulatory blood flow pattern changes of the ascending aorta [2]. While current recommendations suggest early surgery for dilated ascending aorta in patients with BAV and concurrent risk factors as compared with tricuspid aortic valve (TAV) patients [3], the association of aortic wall degeneration with BAV and outcome after surgery remains controversial [4-7]. The Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology was recently launched to clarify the nomenclature and diagnostic criteria of degeneration [8]. The Consensus statement describes detailed means to investigate degenerative aortic wall changes pertinent to the development of an ongoing aortic disease. As the ultimate aim of surgery for the ascending aorta is to prevent aortic events, the aim of this study was to investigate the presence and significance of ascending aortic wall degeneration in BAV patients as compared with tricuspid aortic valve (TAV) patients undergoing surgery for the ascending aorta in a single-center patient cohort. Methods Study protocol and surgery After institutional review board approval (Ethical Committee of the Tampere University Hospital, Tampere, Finland, R15013), the need for informed consent was waived and the study conforms to the ethical guidelines of the Declaration of Helsinki. The ascending aortic wall resection of 67 consecutive patients undergoing surgery for dilatation of ascending aorta was obtained and processed for histology. Ascending aortic aneurysm was preoperatively confirmed and evaluated with computer tomography (CT). According to our Institutional policy, aortic aneurysm included an aortic diameter more than 5.0-5.5 cm wide or aortic growth more than 1 cm in a year. This definition was adjusted to the presence of Marfan syndrome, gender, patient size and symptoms according to The Yale Center criteria [9]. Surgery was performed between December 2006 and August 2012. The decision on the extension of resection and surgical technique was at the discretion of the operating surgeon. When aortic aneurysm, including the sinotubular junction (STJ), was estimated as the reason for aortic regurgitation, STJ was tailored for a suitable graft in a supracoronary fashion. Whenever dilatation included the aorta root, a radical resection of the dilated ascending aorta, together with the root and the aortic valve, was performed. The graft size was estimated by the principal surgeon. Since the surgical procedure was performed upon surgical decision, the sample was procured from the middle of the resected area of the ascending aorta at the vicinity of STJ including the intact aortic wall. Histology and immunohistochemistry Two to five blocks of resected intact ascending aorta were embedded in paraffin, cut to 4 mm thick segments and stained with Hematoxylin and Eosin, Verhoeff-van Gieson, Elastase-van Gieson and Periodic Acid-Schiff. A representative, 1-cm long piece of ascending aortic wall corresponding to all different staining was evaluated systematically for all resected samples procured during surgery (Figure 1). Aortic wall histology and immunohistochemistry was performed using Ventana Lifesciences Benchmark XT© Staining module for leukocytes, T- and B-lymphocytes, plasma cells, macrophages, smooth muscle cells, cell proliferation, elastase and van Gieson staining. Ventana Lifesciences Antibody Dilution Buffer© was utilized for dilution media. The heights of different layers (adventitia, media and intima) were calculated for each sample [10]. Quantification of medial degeneration Medial degeneration of the ascending aorta was assessed by quantifying 11 different variables describing medial and adventitial damage [8, 11]. These included medial fibrosis, elastic fiber disorganization, elastic fiber loss/fragmentation, elastic fiber thinning, laminar medial collapse, classification of medial degeneration, mucoid extracellular matrix accumulation, smooth muscle cell disorganization, smooth muscle cell nuclei loss and medial thickness of vasa vasorum, and adventitial fibrosis. According to the consensus, the variables describing medial degeneration were categorized as none, mild, moderate and severe on a scale of 0-3 [8]. Follow-up protocol Documentation of mortality and morbidity was available for all the patients. For the included study patients, follow-up consisted of physical examination and echocardiography at three months after surgery, and on-demand thereafter including computed tomography. Statistical analysis Continuous variables were expressed as medians including interquartile (IQR), incremental variables of media layer degeneration as means with standard deviations, and were compared using the Mann-Whitney test. Categorical variables were presented as numbers and percentages, and were compared using χ 2 or Fisher’s exact tests. In order to seek clinical relevance associated with immunohistochemistry, the patients were divided into two groups in accordance with the presence of either BAV or TAV. Unadjusted survival was evaluated by Kaplan-Meier analysis with log-rank tests. All analyses were conducted using the IBM SPSS Statistics version 26.0 (IBM Corporation, Armonk, NY, USA) with P < 0.05 as the criterion for significance. Results Patient characteristics Patient characteristics are shown on Table 1. There were 33 patients with BAV and 34 with TAV. The median age for the patients was 66 years (IQR 56-71). Hypertension was frequent in patients with TAV as compared with BAV patients ( P = 0.001). The median aortic diameter was 53 mm (IQR 50-57) in BAV patients and 55 mm (IQR 52-60) in TAV patients ( P = 0.042). Median follow-up for patients with BAV and TAV was 3.8 years (IQR 3.5-4.1) and 3.7 years (IQR 3.4-3.9), respectively. Operative technique The operative technique is shown on Table 2. A mechanical valve was implanted with or without a conduit prosthesis in 11 out of 33 (33%) BAV patients as opposed to only 4 out of 34 (12%) TAV patients owing to patient age. Altogether, replacement of the aortic valve, together with an ascending aortic prosthesis, but without replacement of the aortic root, was more frequent in BAV vs TAV patients (24% vs 3%, P = 0.013). The aortic valve, the root and the ascending aorta were replaced using a conduit prosthesis in 55% BAV vs 71% TAV patients ( P = 0.212). The ascending aorta only was replaced in 16 patients. Perioperative findings, histology and immunohistochemistry As shown on Table 3, medial fibrosis remained less significant in BAV as compared with TAV patients (0.1 ± 0.4 vs 0.8 ± 1.4, P = 0.016, respectively). Elastic fiber thinning was less present in BAV vs TAV patients (0.6 ± 1.4 vs 1.6 ± 2.0, P = 0.027). Incremental medial degeneration was 1.7 ± 0.7 in BAV as compared with 2.2 ± 0.8 in TAV patients. There was a tendency for decreased mucoid extracellular matrix accumulation in BAV as compared with TAV patients (4.3 ± 0.9 vs 4.9 ± 1.2, P = 0.051). Smooth muscle cell nuclei loss was less prominent in BAV as compared with TAV patients (2.3 ± 1.5 vs 3.2 ± 1.3, P = 0.026). Survival According to Kaplan-Meier analysis (Figure 2), survival did not significantly differ between patients with BAV and TAV (log rank P = 0.240) Discussion This study shows that less prominent ascending aortic wall degeneration with increased mid-ascending aorta diameter at younger age characterized patients with BAV as compared with TAV. The Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology provided a valuable diagnostic platform to evaluate the degree of aortic wall degeneration. Patients undergoing surgery for the ascending aorta have a multifactorial presentation of clinical symptoms [6, 12]. Despite different patient characteristics, current treatment includes surgical resection of the dilated aortic portion together with surgery for the aortic valve whenever needed. The presence of degenerative histological features would further justify resection of the frail aorta. The detailed evaluation of degenerative aortic wall variables aids objective comparison of different aortic diseases associated with aortic valve morphology and may prevent unnecessary resection in those patients without frail aortic wall. The almost 50% incidence of BAV in patients undergoing surgery for the ascending aorta is high in this real-life cohort. Many BAV patients received a mechanical aortic valve prosthesis since BAV patients underwent aortic surgery at a relatively early age. The asymmetry of the BAV cusps is often reflected on the configuration of the ascending aorta; the aortic diameter may considerably differ depending on different projections during CT imaging [2]. A slightly increased asymmetric aortic diameter in BAV patients may not indicate prominent and consistent aortic wall degeneration. Indeed, aortic wall degeneration- as observed by medial fibrosis, elastic fiber thinning, incremental medial degeneration and smooth muscle cell loss of the tissue- was significantly less prominent in BAV as compared with TAV patients. This importantly confirms previous studies suggesting for the degenerative features of the ascending aorta found predominantly in TAV patients [5, 7]. Dilatation of the mid-ascending aorta is not solely associated with the presence of bicuspid aortic valve or increased aortic wall degeneration. Conclusions Ascending aortic dilatation is not associated with increased aortic wall degeneration in BAV patients as compared with TAV patients. The Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology provides an important diagnostic methodology to evaluate the degree of degeneration of the ascending aorta and may correct misconceptions related with aortic valve configuration. This study confirms that the same surgical strategy of resection of the dilated ascending aorta may apply to both patients with either BAV or TAV. Limitations This study represents a real-life single-center contemporary cohort. The limitations of this study include the small number of patients with a relatively short follow-up, and aortic wall histology is obviously only available in patients that underwent surgery. List Of Abbreviations BAV bicuspid aortic valve IQR interquartile range TAV tricuspid aortic valve Declarations Ethics approval and consent to participate After institutional review board approval (Ethical Committee of the Tampere University Hospital, Tampere, Finland, R15013), the need for informed consent was waived and the study conforms to the ethical guidelines of the Declaration of Helsinki. Consent for publication Not applicable. Availability of data and materials The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This work was supported by research funding from The Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospital, Tuberculosis Foundation, The Finnish Heart Association, and The Finnish Cultural Foundation. Authors’ contributions AM analyzed, interpreted the results and was a major contributor in writing the manuscript. IK and SP analyzed and interpreted the results after histological examination of the data. TP interpreted the results after histological examination of the data. All authors read and approved the final manuscript. Acknowledgements Not applicable References Michelena HI, Khanna AD, Mahoney D, Margaryan E, Topilsky Y, Suri RM, Eidem E, Edwards WD, Sundt 3rd TM, Enriquez-Sarano M. Incidence of aortic complications in patients with bicuspid aortic valves. JAMA. 2011;306:1104–1112. Youssefi P, Gomez A, He T, Anderson L, Bunce N, Sharma R, Figueroa CA, Jahangiri M. Patient-specific computational fluid dynamics—assessment of aortic hemodynamics in a spectrum of aortic valve pathologies. J Thorac Cardiovasc Surg. 2017;153:8–20. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). 2014 ESC Guidelines on the Diagnosis and Treatment of Aortic Diseases: Document Covering Acute and Chronic Aortic Diseases of the Thoracic and Abdominal Aorta of the Adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2014;1:2873-2926. Milewski RK, Habertheuer A, Bavaria JE, Siki M, Szeto WY, Krause E, Korutla V, Desai ND, Vallabhajosyula P. Fate of remnant sinuses of Valsalva in patients with bicuspid and trileaflet valves undergoing aortic valve, ascending aorta, and aortic arch replacement. J Thorac Cardiovasc Surg. 2017;154:421–432. Leone O, Corsini A, Pacini D, Corti B, Lorenzini M, Laus V, Foa A, Reggiani MLB, Di Marco L, Rapezzi C. The complex interplay among atherosclerosis, inflammation, and degeneration in ascending thoracic aortic aneurysms. J Thorac Cardiovasc Surg. 2019;1:1–10. Kanekoa T, Shekara P, Ivkovica V, Longfordb NT, Huangc C-C, Sigurdsson MI, Neely RC, Yammine M, Ejiofor JI, Vieira VM, Shahram JT, Habchi KM, Malzberg GW, Martin PS, Bloom J, Isselbacher EM, Muehlschlegel JD, Bicuspid Aortic Valve Consortium (BAVCon), Sundt 3rd TM. Should the dilated ascending aorta be repaired at the time of bicuspid aortic valve replacement? Eur J Cardio-Thorac Surg. 2018;53:560–568. Heng E, Stone JR, Kim JB, Lee H, MacGillivray TE, Sundt TM. Comparative histology of aortic dilatation associated with bileaflet versus trileaflet aortic valves. Ann Thorac Surg. 2015;100:2095–2101. Halushka MK, Angelini A, Bartoloni G, Basso C, Batoroeva L, Bruneval P, Buja LM, Butany J, d’Amati G, Fallon JT, Gallagher PJ, Gittenberger-de Groot AC, Gouveia RH, Kholova I, Kelly KL, Leone O, Litovsky SH, Maleszewski JJ, Miller DV, Mitchell RN, Preston SD, Pucci A, Radio SJ, Rodriguez ER, Sheppard MN, Stone JR, Suvarna SK, Tan CD, Thiene G, Veinot JP, van der Wal AC. Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: II. Noninflammatory degenerative diseases - nomenclature and diagnostic criteria. Cardiovasc Pathol. 2016;25:247–257. Elefteriades, J.A. Thoracic aortic aneurysm: reading the enemy’s playbook. World J Surg. 2008;32:366–374. Levula M, Paavonen T, Valo T, Pelto-Huikko M, Laaksonen R, Kahonen M, Huovila A, Lehtimaki T, Tarkka M, Mennander AA. A disintegrin and metalloprotease -8 and -15 and susceptibility for ascending aortic dissection. Scand J Clin Lab Invest. 2011;71:515–522. Stone JR, Bruneval P, Angelini A, Bartoloni G, Basso C, Batoroeva L, Buja LM, Butany J, d’Amati G, Fallon JT, Gittenberger-de Groot AC, Gouveia RH, Halushka MK, Kelly KL, Kholova I, Leone O, Litovsky SH, Maleszewski JJ, Miller DV, Mitchell RN, Preston SD, Pucci A, Radio SJ, Rodriguez ER, Sheppard MN, Suvarna SK, Tan CD, Thiene G, van der Wal AC, Veinot JP. Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: I. Inflammatory diseases. Cardiovasc Pathol. 2015;24:267–278. Kirsch EW, Radu NC, Gervais M, Allaire E, Loisance DY. Heterogeneity in the remodeling of aneurysms of the ascending aorta with tricuspid aortic valves. J Thorac Cardiovasc Surg. 2006;132:1010–1016. Tables Table 1. Patient characteristics All patients BAV TAV P -value Number of patients 67 33 34 Age (years, interquartile) 66 (56-71) 64 (55-72) 68 (61-71) 0.133 Male, n 50 (75%) 26 24 0.576 Hypertension, n 44 (68%) 15 29 0.001 Diabetes, n 9 (14%) 3 6 0.475 Hypercholesterolemia, n 17 (26%) 11 6 0.166 Vasculitis, n 6 (8%) 1 5 0.198 Arthritis 6 (9%) 2 4 0.673 Asthma, n 4 (6%) 0 4 0.114 Myocardial coronary artery disease, n 14 (21%) 7 7 1 History of stroke 4 (6%) 2 2 1 Earlier abdominal aorta aneurysm surgery 2 (3%) 0 2 0.492 Mid-ascending aorta diameter (mm, interquartile) 54 (50-60) 53 (50-57) 55 (52-60) 0.042 Moderate to severe aortic valve regurgitation, n 36 (56%) 14 22 0.139 BAV= bicuspid aortic valve; TAV= tricuspid aortic valve Table 2. Operative details according to surgical evaluation of extension of diseased aorta All patients BAV TAV P -value 67 33 34 Graft replacement of root and ascending aorta Mechanical conduit 10 (15%) 6 (9%) 4 (6%) 0.512 Biological conduit 32 (48%) 12 (18%) 20 (30%) 0.088 Graft replacement of ascending aorta Mechanical valve + prosthesis 5 (8%) 5 (8%) 0 0.025 Biological valve + prosthesis 4 (6%) 3 (5%) 1 (1%) 0.356 Prosthesis 16 (24%) 7 (11%) 9 (13%) 0.776 BAV= bicuspid aortic valve; TAV= tricuspid aortic valve Table 3. Histology and quantitative immunohistochemistry All patients BAV TAV P - value Adventitial fibrosis 0.2±0.4 0.1±0.3 0.2±0.4 0.221 Medial fibrosis 0.5±1.1 0.1±0.4 0.8±1.4 0.016 Elastic fiber disorganization 1.0±1.0 0.8±0.9 1.1±1.1 0.191 Elastic fiber loss/fragmentation 3.6±1.4 3.3±1.2 3.8±1.6 0.206 Elastic fiber thinning 1.1±1.8 0.6±1.4 1.6±2.0 0.027 Laminar medial collapse 0.6±1.3 0.3±0.9 0.8±1.5 0.184 Classification of medial degeneration 1.9±0.8 1.7±0.7 2.2±0.8 0.045 Mucoid extracellular matrix accumulation 4.6±1.2 4.3±0.9 4.9±1.2 0.051 Smooth muscle cell disorganization 0.6±0.8 0.4±0.7 0.8±0.9 0.121 Smooth muscle cell nuclei loss 2.8±1.4 2.3±1.5 3.2±1.3 0.026 Medial thickness of vasa vasorum 0.2±0.4 0.3±0.5 0.2±0.4 0.407 Mean±standard deviation; BAV= bicuspid aortic valve; TAV= tricuspid aortic valve Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 07 Apr, 2022 Reviews received at journal 17 Mar, 2022 Reviewers invited by journal 17 Mar, 2022 Editor assigned by journal 13 Dec, 2021 First submitted to journal 08 Dec, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1152422","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":91645410,"identity":"24f2f81d-046a-42ce-857c-af7160d27b8a","order_by":0,"name":"Ari Mennander","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-5082-4161","institution":"University of Tampere: Tampereen Yliopisto","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Ari","middleName":"","lastName":"Mennander","suffix":""},{"id":91645411,"identity":"47ac937f-f001-45e5-8e65-1f2b0b4f31eb","order_by":1,"name":"Ivana Kholova","email":"","orcid":"","institution":"Tampere University Hospital: Tampereen yliopistollinen sairaala","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ivana","middleName":"","lastName":"Kholova","suffix":""},{"id":91645412,"identity":"5c65a98d-8782-4a63-a3ee-f41f4f5a3e87","order_by":2,"name":"Saku Pelttari","email":"","orcid":"","institution":"Tampere University: Tampereen Yliopisto","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Saku","middleName":"","lastName":"Pelttari","suffix":""},{"id":91645413,"identity":"c55c8164-065d-4235-9f99-b02f6a3d87b5","order_by":3,"name":"Timo Paavonen","email":"","orcid":"","institution":"Tampere University Hospital: Tampereen yliopistollinen sairaala","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Timo","middleName":"","lastName":"Paavonen","suffix":""}],"badges":[],"createdAt":"2021-12-08 13:37:38","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1152422/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1152422/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":19479860,"identity":"c025ec01-a273-4e85-9500-4ba8bb93eab3","added_by":"auto","created_at":"2022-03-22 13:54:38","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":146043,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative histology of ascending aortic wall histology showing disruptions of elastic laminae indicative for degenerative medial layer (black arrows).\u0026nbsp;\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1152422/v1/a91058d30b76f8e050a89692.jpg"},{"id":19479503,"identity":"02557c99-a579-41df-b432-6432f7ae3b76","added_by":"auto","created_at":"2022-03-22 13:51:38","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":38305,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative survival (%) of patients after surgery for ascending aorta with bicuspid (\u003cem\u003ered line\u003c/em\u003e) and tricuspid aortic valve (\u003cem\u003eblue line\u003c/em\u003e). Time-varying outcome according to Kaplan-Meier estimation. \u003cem\u003eBAV\u003c/em\u003e, bicuspid aortic valve; \u003cem\u003eTAV\u003c/em\u003e, tricuspid aortic valve. Log rank \u003cem\u003eP\u003c/em\u003e = 0.240.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1152422/v1/7d5e2cee42f41c1d20be11e4.jpg"},{"id":19479861,"identity":"5a3f6548-080a-451c-988c-00f44afd0eca","added_by":"auto","created_at":"2022-03-22 13:54:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":513975,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1152422/v1/49b52005-cb56-4500-b92e-80cd01eecdd9.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eAscending Aortic Wall Degeneration in Patients with Bicuspid Versus Tricuspid Aortic Valve\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBicuspid aortic valve (BAV) is present in 1-2% of the whole population. It has been suggested that patients with BAV are genetically susceptible to early aortic events and poor outcome [1], a conception mainly deduced from circulatory blood flow pattern changes of the ascending aorta [2]. While current recommendations suggest early surgery for dilated ascending aorta in patients with BAV and concurrent risk factors as compared with tricuspid aortic valve (TAV) patients [3], the association of aortic wall degeneration with BAV and outcome after surgery remains controversial [4-7].\u003c/p\u003e\n\u003cp\u003eThe Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology was recently launched to clarify the nomenclature and diagnostic criteria of degeneration [8]. The Consensus statement describes detailed means to investigate degenerative aortic wall changes pertinent to the development of an ongoing aortic disease. As the ultimate aim of surgery for the ascending aorta is to prevent aortic events, the aim of this study was to investigate the presence and significance of ascending aortic wall degeneration in BAV patients as compared with tricuspid aortic valve (TAV) patients undergoing surgery for the ascending aorta in a single-center patient cohort. \u0026nbsp;\u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy protocol and surgery\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter institutional review board approval (Ethical Committee of the Tampere University Hospital, Tampere, Finland, R15013), the need for informed consent was waived and the study conforms to the ethical guidelines of the Declaration of Helsinki. The ascending aortic wall resection of 67 consecutive patients undergoing surgery for dilatation of ascending aorta was obtained and processed for histology. Ascending aortic aneurysm was preoperatively confirmed and evaluated with computer tomography (CT). According to our Institutional policy, aortic aneurysm included an aortic diameter more than 5.0-5.5 cm wide or aortic growth more than 1 cm in a year. This definition was adjusted to the presence of Marfan syndrome, gender, patient size and symptoms according to The Yale Center criteria [9]. Surgery was performed between December 2006 and August 2012.\u003c/p\u003e\n\u003cp\u003eThe decision on the extension of resection and surgical technique was at the discretion of the operating surgeon. When aortic aneurysm, including the sinotubular junction (STJ), was estimated as the reason for aortic regurgitation, STJ was tailored for a suitable graft in a supracoronary fashion. Whenever dilatation included the aorta root, a radical resection of the dilated ascending aorta, together with the root and the aortic valve, was performed. The graft size was estimated by the principal surgeon. Since the surgical procedure was performed upon surgical decision, the sample was procured from the middle of the resected area of the ascending aorta at the vicinity of STJ including the intact aortic wall. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHistology and immunohistochemistry\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo to five blocks of resected intact ascending aorta were embedded in paraffin, cut to 4 mm thick segments and stained with Hematoxylin and Eosin, Verhoeff-van Gieson, Elastase-van Gieson and Periodic Acid-Schiff. A representative, 1-cm long piece of ascending aortic wall corresponding to all different staining was evaluated systematically for all resected samples procured during surgery (Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAortic wall histology and immunohistochemistry was performed using Ventana Lifesciences Benchmark XT\u0026copy; Staining module for leukocytes, T- and B-lymphocytes, plasma cells, macrophages, smooth muscle cells, cell proliferation, elastase and van Gieson staining. Ventana Lifesciences Antibody Dilution Buffer\u0026copy; was utilized for dilution media. The heights of different layers (adventitia, media and intima) were calculated for each sample [10].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuantification of medial degeneration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMedial degeneration of the ascending aorta was assessed by quantifying 11 different variables describing medial and adventitial damage [8, 11]. These included medial fibrosis, elastic fiber disorganization, elastic fiber loss/fragmentation, elastic fiber thinning, laminar medial collapse, classification of medial degeneration, mucoid extracellular matrix accumulation, smooth muscle cell disorganization, smooth muscle cell nuclei loss and medial thickness of vasa vasorum, and adventitial fibrosis. According to the consensus, the variables describing medial degeneration were categorized as none, mild, moderate and severe on a scale of 0-3 [8]. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDocumentation of mortality and morbidity was available for all the patients. For the included study patients, follow-up consisted of physical examination and echocardiography at three months after surgery, and on-demand thereafter including computed tomography.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables were expressed as medians including interquartile (IQR), incremental variables of media layer degeneration as means with standard deviations, and were compared using the\u0026nbsp;Mann-Whitney test. Categorical variables were presented as numbers and percentages, and were compared using \u0026chi;\u003csup\u003e2\u003c/sup\u003e or Fisher\u0026rsquo;s exact tests.\u0026nbsp;In order to seek clinical relevance associated with immunohistochemistry, the patients were divided into two groups in accordance with the presence of either BAV or TAV. Unadjusted survival was evaluated by Kaplan-Meier analysis with log-rank tests. All analyses were conducted using the IBM SPSS Statistics version 26.0 (IBM Corporation, Armonk, NY, USA) with\u0026nbsp;\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 as the criterion for significance.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient characteristics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient characteristics are shown on Table 1. There were 33 patients with BAV and 34 with TAV. The median age for the patients was 66\u0026nbsp;years (IQR 56-71). Hypertension was frequent in patients with TAV as compared with BAV patients (\u003cem\u003eP\u003c/em\u003e = 0.001). The median aortic diameter was 53 mm (IQR 50-57) in BAV patients and 55 mm (IQR 52-60) in TAV patients (\u003cem\u003eP\u003c/em\u003e = 0.042). Median follow-up for patients with BAV and TAV was 3.8 years (IQR 3.5-4.1) and 3.7 years (IQR 3.4-3.9), respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOperative technique\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe operative technique is shown on Table 2. A mechanical valve was implanted with or without a conduit prosthesis in 11 out of 33 (33%) BAV patients as opposed to only 4 out of 34 (12%) TAV patients owing to patient age. Altogether, replacement of the aortic valve, together with an ascending aortic prosthesis, but without replacement of the aortic root, was more frequent in BAV vs TAV patients (24% vs 3%, \u003cem\u003eP\u003c/em\u003e = 0.013). The aortic valve, the root and the ascending aorta were replaced using a conduit prosthesis in 55% BAV vs 71% TAV patients (\u003cem\u003eP\u003c/em\u003e = 0.212). The ascending aorta only was replaced in 16 patients.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePerioperative findings, histology and immunohistochemistry\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs shown on Table 3, medial fibrosis remained less significant in BAV as compared with TAV patients (0.1 \u0026plusmn; 0.4 vs 0.8 \u0026plusmn; 1.4, \u003cem\u003eP\u003c/em\u003e = 0.016, respectively). Elastic fiber thinning was less present in BAV vs TAV patients (0.6 \u0026plusmn; 1.4 vs 1.6 \u0026plusmn; 2.0, \u003cem\u003eP\u003c/em\u003e = 0.027). Incremental medial degeneration was 1.7 \u0026plusmn; 0.7 in BAV as compared with 2.2 \u0026plusmn; 0.8 in TAV patients. There was a tendency for decreased mucoid extracellular matrix accumulation in BAV as compared with TAV patients (4.3 \u0026plusmn; 0.9 vs 4.9 \u0026plusmn; 1.2, \u003cem\u003eP\u003c/em\u003e = 0.051). Smooth muscle cell nuclei loss was less prominent in BAV as compared with TAV patients (2.3 \u0026plusmn; 1.5 vs 3.2 \u0026plusmn; 1.3, \u003cem\u003eP\u003c/em\u003e = 0.026).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurvival\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to Kaplan-Meier analysis (Figure 2), survival did not significantly differ between patients with BAV and TAV (log rank \u003cem\u003eP\u003c/em\u003e = 0.240)\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study shows that less prominent ascending aortic wall degeneration with increased mid-ascending aorta diameter at younger age characterized patients with BAV as compared with TAV. The Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology provided a valuable diagnostic platform to evaluate the degree of aortic wall degeneration.\u003c/p\u003e\n\u003cp\u003ePatients undergoing surgery for the ascending aorta have a multifactorial presentation of clinical symptoms [6, 12]. Despite different patient characteristics, current treatment includes surgical resection of the dilated aortic portion together with surgery for the aortic valve whenever needed. The presence of degenerative histological features would further justify resection of the frail aorta. The detailed evaluation of degenerative aortic wall variables aids objective comparison of different aortic diseases associated with aortic valve morphology and may prevent unnecessary resection in those patients without frail aortic wall. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe almost 50% incidence of BAV in patients undergoing surgery for the ascending aorta is high in this real-life cohort. Many BAV patients received a mechanical aortic valve prosthesis since BAV patients underwent aortic surgery at a relatively early age. The asymmetry of the BAV cusps is often reflected on the configuration of the ascending aorta; the aortic diameter may considerably differ depending on different projections during CT imaging [2]. A slightly increased asymmetric aortic diameter in BAV patients may not indicate prominent and consistent aortic wall degeneration.\u003c/p\u003e\n\u003cp\u003eIndeed, aortic wall degeneration- as observed by medial fibrosis, elastic fiber thinning, incremental medial degeneration and smooth muscle cell loss of the tissue- was significantly less prominent in BAV as compared with TAV patients. This importantly confirms previous studies suggesting for the degenerative features of the ascending aorta found predominantly in TAV patients [5, 7]. Dilatation of the mid-ascending aorta is not solely associated with the presence of bicuspid aortic valve or increased aortic wall degeneration.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAscending aortic dilatation is not associated with increased aortic wall degeneration in BAV patients as compared with TAV patients. The Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology provides an important diagnostic methodology to evaluate the degree of degeneration of the ascending aorta and may correct misconceptions related with aortic valve configuration. This study confirms that the same surgical strategy of resection of the dilated ascending aorta may apply to both patients with either BAV or TAV.\u0026nbsp;\u003c/p\u003e"},{"header":"Limitations","content":"\u003cp\u003eThis study represents a real-life single-center contemporary cohort. The limitations of this study include the small number of patients with a relatively short follow-up, and aortic wall histology is obviously only available in patients that underwent surgery.\u003c/p\u003e"},{"header":"List Of Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBAV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebicuspid aortic valve\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTAV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etricuspid aortic valve\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter institutional review board approval (Ethical Committee of the Tampere University Hospital, Tampere, Finland, R15013), the need for informed consent was waived and the study conforms to the ethical guidelines of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by research funding from The Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospital, Tuberculosis Foundation, The Finnish Heart Association, and The Finnish Cultural Foundation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAM analyzed, interpreted the results and was a major contributor in writing the manuscript. IK and SP analyzed and interpreted the results after histological examination of the data. TP interpreted the results after histological examination of the data. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMichelena HI, Khanna AD, Mahoney D, Margaryan E, Topilsky Y, Suri RM, Eidem E, Edwards WD, Sundt 3rd TM, Enriquez-Sarano M. Incidence of aortic complications in patients with bicuspid aortic valves. JAMA. 2011;306:1104\u0026ndash;1112.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoussefi P, Gomez A, He T, Anderson L, Bunce N, Sharma R, Figueroa CA, Jahangiri M. Patient-specific computational fluid dynamics\u0026mdash;assessment of aortic hemodynamics in a spectrum of aortic valve pathologies. J Thorac Cardiovasc Surg. 2017;153:8\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThe Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). 2014 ESC Guidelines on the Diagnosis and Treatment of Aortic Diseases: Document Covering Acute and Chronic Aortic Diseases of the Thoracic and Abdominal Aorta of the Adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2014;1:2873-2926.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMilewski RK, Habertheuer A, Bavaria JE, Siki M, Szeto WY, Krause E, Korutla V, Desai ND, Vallabhajosyula P. Fate of remnant sinuses of Valsalva in patients with bicuspid and trileaflet valves undergoing aortic valve, ascending aorta, and aortic arch replacement. J Thorac Cardiovasc Surg. 2017;154:421\u0026ndash;432.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeone O, Corsini A, Pacini D, Corti B, Lorenzini M, Laus V, Foa A, Reggiani MLB, Di Marco L, Rapezzi C. The complex interplay among atherosclerosis, inflammation, and degeneration in ascending thoracic aortic aneurysms. J Thorac Cardiovasc Surg. 2019;1:1\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKanekoa T, Shekara P, Ivkovica V, Longfordb NT, Huangc C-C, Sigurdsson MI, Neely RC, Yammine M, Ejiofor JI, Vieira VM, Shahram JT, Habchi KM, Malzberg GW, Martin PS, Bloom J, Isselbacher EM, Muehlschlegel JD, Bicuspid Aortic Valve Consortium (BAVCon), Sundt 3rd TM. Should the dilated ascending aorta be repaired at the time of bicuspid aortic valve replacement? Eur J Cardio-Thorac Surg. 2018;53:560\u0026ndash;568.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeng E, Stone JR, Kim JB, Lee H, MacGillivray TE, Sundt TM. Comparative histology of aortic dilatation associated with bileaflet versus trileaflet aortic valves. Ann Thorac Surg. 2015;100:2095\u0026ndash;2101.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHalushka MK, Angelini A, Bartoloni G, Basso C, Batoroeva L, Bruneval P, Buja LM, Butany J, d\u0026rsquo;Amati G, Fallon JT, Gallagher PJ, Gittenberger-de Groot AC, Gouveia RH, Kholova I, Kelly KL, Leone O, Litovsky SH, Maleszewski JJ, Miller DV, Mitchell RN, Preston SD, Pucci A, Radio SJ, Rodriguez ER, Sheppard MN, Stone JR, Suvarna SK, Tan CD, Thiene G, Veinot JP, van der Wal AC. Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: II. Noninflammatory degenerative diseases - nomenclature and diagnostic criteria. Cardiovasc Pathol. 2016;25:247\u0026ndash;257.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElefteriades, J.A. Thoracic aortic aneurysm: reading the enemy\u0026rsquo;s playbook. World J Surg. 2008;32:366\u0026ndash;374.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevula M, Paavonen T, Valo T, Pelto-Huikko M, Laaksonen R, Kahonen M, Huovila A, Lehtimaki T, Tarkka M, Mennander AA. A disintegrin and metalloprotease -8 and -15 and susceptibility for ascending aortic dissection. Scand J Clin Lab Invest. 2011;71:515\u0026ndash;522.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStone JR, Bruneval P, Angelini A, Bartoloni G, Basso C, Batoroeva L, Buja LM, Butany J, d\u0026rsquo;Amati G, Fallon JT, Gittenberger-de Groot AC, Gouveia RH, Halushka MK, Kelly KL, Kholova I, Leone O, Litovsky SH, Maleszewski JJ, Miller DV, Mitchell RN, Preston SD, Pucci A, Radio SJ, Rodriguez ER, Sheppard MN, Suvarna SK, Tan CD, Thiene G, van der Wal AC, Veinot JP. Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: I. Inflammatory diseases. Cardiovasc Pathol. 2015;24:267\u0026ndash;278.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKirsch EW, Radu NC, Gervais M, Allaire E, Loisance DY. Heterogeneity in the remodeling of aneurysms of the ascending aorta with tricuspid aortic valves. J Thorac Cardiovasc Surg. 2006;132:1010\u0026ndash;1016.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Patient characteristics\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003eAll patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003eBAV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003eTAV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003eNumber of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003eAge (years, interquartile)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e66 (56-71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e64 (55-72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e68 (61-71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e0.133\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003eMale, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e50 (75%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e0.576\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003eHypertension, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e44 (68%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003eDiabetes, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e9 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e0.475\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003eHypercholesterolemia, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e17 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e0.166\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003eVasculitis, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e6 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e0.198\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003eArthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e6 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e0.673\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003eAsthma, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e4 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.114\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003eMyocardial coronary artery disease, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e14 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003eHistory of stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e4 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003eEarlier abdominal aorta aneurysm surgery\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e2 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e0.492\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003eMid-ascending aorta diameter (mm, interquartile)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e54 (50-60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e53 (50-57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e55 (52-60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e0.042\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.857142857142854%\"\u003e\n \u003cp\u003eModerate to severe aortic valve regurgitation,\u0026nbsp;n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.770764119601328%\"\u003e\n \u003cp\u003e36 (56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.624584717607974%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.614617940199336%\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.132890365448505%\"\u003e\n \u003cp\u003e0.139\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eBAV= bicuspid aortic valve; TAV= tricuspid aortic valve\u003c/p\u003e\n\u003cp\u003eTable 2. Operative details according to surgical evaluation of extension of diseased aorta\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.436860068259385%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.310580204778157%\"\u003e\n \u003cp\u003eAll patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.969283276450511%\"\u003e\n \u003cp\u003eBAV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.262798634812286%\"\u003e\n \u003cp\u003eTAV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.020477815699659%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.436860068259385%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.310580204778157%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.969283276450511%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.262798634812286%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.020477815699659%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.436860068259385%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.310580204778157%\"\u003e\n \u003cp\u003e67\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.969283276450511%\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.262798634812286%\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.020477815699659%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.436860068259385%\"\u003e\n \u003cp\u003eGraft replacement of root and ascending aorta\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.310580204778157%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.969283276450511%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.262798634812286%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.020477815699659%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.436860068259385%\"\u003e\n \u003cp\u003eMechanical conduit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.310580204778157%\"\u003e\n \u003cp\u003e10 (15%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.969283276450511%\"\u003e\n \u003cp\u003e6 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.262798634812286%\"\u003e\n \u003cp\u003e4 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.020477815699659%\"\u003e\n \u003cp\u003e0.512\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.436860068259385%\"\u003e\n \u003cp\u003eBiological\u0026nbsp;conduit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.310580204778157%\"\u003e\n \u003cp\u003e32 (48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.969283276450511%\"\u003e\n \u003cp\u003e12 (18%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.262798634812286%\"\u003e\n \u003cp\u003e20 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.020477815699659%\"\u003e\n \u003cp\u003e0.088\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.436860068259385%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.310580204778157%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.969283276450511%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.262798634812286%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.020477815699659%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.436860068259385%\"\u003e\n \u003cp\u003eGraft replacement of ascending aorta\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.310580204778157%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.969283276450511%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.262798634812286%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.020477815699659%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.436860068259385%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMechanical valve + prosthesis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.310580204778157%\"\u003e\n \u003cp\u003e\u003cstrong\u003e5 (8%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.969283276450511%\"\u003e\n \u003cp\u003e\u003cstrong\u003e5 (8%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.262798634812286%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.020477815699659%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.025\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.436860068259385%\"\u003e\n \u003cp\u003eBiological valve + prosthesis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.310580204778157%\"\u003e\n \u003cp\u003e4 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.969283276450511%\"\u003e\n \u003cp\u003e3 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.262798634812286%\"\u003e\n \u003cp\u003e1 (1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.020477815699659%\"\u003e\n \u003cp\u003e0.356\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.436860068259385%\"\u003e\n \u003cp\u003eProsthesis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.310580204778157%\"\u003e\n \u003cp\u003e16 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.969283276450511%\"\u003e\n \u003cp\u003e7 (11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"11.262798634812286%\"\u003e\n \u003cp\u003e9 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"8.020477815699659%\"\u003e\n \u003cp\u003e0.776\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eBAV= bicuspid aortic valve; TAV= tricuspid aortic valve\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Histology and quantitative immunohistochemistry\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"43.159609120521175%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.938110749185668%\"\u003e\n \u003cp\u003eAll patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.309446254071661%\"\u003e\n \u003cp\u003eBAV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.843648208469055%\"\u003e\n \u003cp\u003eTAV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.749185667752442%\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e- value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"43.159609120521175%\"\u003e\n \u003cp\u003eAdventitial fibrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.938110749185668%\"\u003e\n \u003cp\u003e0.2\u0026plusmn;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.309446254071661%\"\u003e\n \u003cp\u003e0.1\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.843648208469055%\"\u003e\n \u003cp\u003e0.2\u0026plusmn;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.749185667752442%\"\u003e\n \u003cp\u003e0.221\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"43.159609120521175%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedial fibrosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.938110749185668%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.5\u0026plusmn;1.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.309446254071661%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.1\u0026plusmn;0.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.843648208469055%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.8\u0026plusmn;1.4\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.749185667752442%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.016\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"43.159609120521175%\"\u003e\n \u003cp\u003eElastic fiber disorganization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.938110749185668%\"\u003e\n \u003cp\u003e1.0\u0026plusmn;1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.309446254071661%\"\u003e\n \u003cp\u003e0.8\u0026plusmn;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.843648208469055%\"\u003e\n \u003cp\u003e1.1\u0026plusmn;1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.749185667752442%\"\u003e\n \u003cp\u003e0.191\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"43.159609120521175%\"\u003e\n \u003cp\u003eElastic fiber loss/fragmentation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.938110749185668%\"\u003e\n \u003cp\u003e3.6\u0026plusmn;1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.309446254071661%\"\u003e\n \u003cp\u003e3.3\u0026plusmn;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.843648208469055%\"\u003e\n \u003cp\u003e3.8\u0026plusmn;1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.749185667752442%\"\u003e\n \u003cp\u003e0.206\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"43.159609120521175%\"\u003e\n \u003cp\u003e\u003cstrong\u003eElastic fiber thinning\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.938110749185668%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.1\u0026plusmn;1.8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.309446254071661%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.6\u0026plusmn;1.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.843648208469055%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.6\u0026plusmn;2.0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.749185667752442%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.027\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"43.159609120521175%\"\u003e\n \u003cp\u003eLaminar medial collapse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.938110749185668%\"\u003e\n \u003cp\u003e\u0026nbsp;0.6\u0026plusmn;1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.309446254071661%\"\u003e\n \u003cp\u003e0.3\u0026plusmn;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.843648208469055%\"\u003e\n \u003cp\u003e0.8\u0026plusmn;1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.749185667752442%\"\u003e\n \u003cp\u003e0.184\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"43.159609120521175%\"\u003e\n \u003cp\u003e\u003cstrong\u003eClassification of medial degeneration\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.938110749185668%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.9\u0026plusmn;0.8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.309446254071661%\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.7\u0026plusmn;0.7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.843648208469055%\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.2\u0026plusmn;0.8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.749185667752442%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.045\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"43.159609120521175%\"\u003e\n \u003cp\u003eMucoid extracellular matrix accumulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.938110749185668%\"\u003e\n \u003cp\u003e4.6\u0026plusmn;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.309446254071661%\"\u003e\n \u003cp\u003e4.3\u0026plusmn;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.843648208469055%\"\u003e\n \u003cp\u003e4.9\u0026plusmn;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.749185667752442%\"\u003e\n \u003cp\u003e0.051\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"43.159609120521175%\"\u003e\n \u003cp\u003eSmooth muscle cell disorganization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.938110749185668%\"\u003e\n \u003cp\u003e0.6\u0026plusmn;0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.309446254071661%\"\u003e\n \u003cp\u003e0.4\u0026plusmn;0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.843648208469055%\"\u003e\n \u003cp\u003e0.8\u0026plusmn;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.749185667752442%\"\u003e\n \u003cp\u003e0.121\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"43.159609120521175%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmooth muscle cell nuclei loss\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.938110749185668%\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.8\u0026plusmn;1.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.309446254071661%\"\u003e\n \u003cp\u003e\u003cstrong\u003e2.3\u0026plusmn;1.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.843648208469055%\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.2\u0026plusmn;1.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.749185667752442%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.026\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"43.159609120521175%\"\u003e\n \u003cp\u003eMedial thickness of vasa vasorum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"16.938110749185668%\"\u003e\n \u003cp\u003e0.2\u0026plusmn;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"15.309446254071661%\"\u003e\n \u003cp\u003e0.3\u0026plusmn;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.843648208469055%\"\u003e\n \u003cp\u003e0.2\u0026plusmn;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"10.749185667752442%\"\u003e\n \u003cp\u003e0.407\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eMean\u0026plusmn;standard deviation; BAV= bicuspid aortic valve; TAV= tricuspid aortic valve\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Aortic wall degeneration, ascending aorta, bicuspid aortic valve","lastPublishedDoi":"10.21203/rs.3.rs-1152422/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1152422/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe magnitude of ascending aortic degeneration in patients with bicuspid aortic valves (BAV) is controversial.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe aim of this study was to investigate ascending aortic wall degeneration in patients with BAV as compared with tricuspid aortic valves (TAV). The ascending aortic wall of 67 consecutive patients was processed for histology and immunohistochemistry. The extent of surgery and wall degeneration were investigated. Unadjusted survival was evaluated by Kaplan-Meier analysis. Median follow-up for patients with BAV and TAV was 3.8 years (interquartile range [IQR] 3.5-4.1) and 3.7 years (IQR 3.4-3.9), respectively.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThere were 33 patients with BAV and 34 with TAV. Mid-ascending aorta diameter was 54 mm (IQR 50-60). Replacement of the aortic valve, together with an ascending aortic prosthesis, was more frequent in BAV vs TAV patients (24% vs 3%, \u003cem\u003eP\u003c/em\u003e = 0.013). However, medial fibrosis, elastic fiber thinning, incremental medial degeneration and smooth muscle cell nuclei loss were less prominent in BAV vs TAV patients (0.1 \u0026plusmn; 0.4 vs 0.8 \u0026plusmn; 1.4, \u003cem\u003eP\u003c/em\u003e = 0.016; 0.6 \u0026plusmn; 1.4 vs 1.6 \u0026plusmn; 2.0, \u003cem\u003eP\u003c/em\u003e = 0.027; 1.7 \u0026plusmn; 0.7 vs 2.2 \u0026plusmn; 0.8, \u003cem\u003eP\u003c/em\u003e = 0.045 and 2.3 \u0026plusmn; 1.5 vs 3.2 \u0026plusmn; 1.3, \u003cem\u003eP\u003c/em\u003e = 0.026, respectively).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eSince degeneration of the ascending aortic wall was seldom prominent, histopathology alone does not support the need for earlier surgery of the dilated ascending aorta in BAV patients as compared with TAV patients.\u003c/p\u003e","manuscriptTitle":"Ascending Aortic Wall Degeneration in Patients with Bicuspid Versus Tricuspid Aortic Valve","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-03-22 13:51:36","doi":"10.21203/rs.3.rs-1152422/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2022-04-08T02:46:47+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-03-17T18:47:42+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-03-17T18:35:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-12-13T22:00:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cardiothoracic Surgery","date":"2021-12-08T08:37:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9971c55d-415d-4505-9809-b52bd84fc214","owner":[],"postedDate":"March 22nd, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2022-04-26T21:44:53+00:00","versionOfRecord":[],"versionCreatedAt":"2022-03-22 13:51:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1152422","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1152422","identity":"rs-1152422","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}