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Histopathological Grading of Ascending Aortic Aneurysm: Comparison ...

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    Histopathological Grading of Ascending Aortic Aneurysm: Comparison ... Histopathological Grading of Ascending Aortic Aneurysm: Comparison ... Document Transcript

    • Histopathological Grading of Ascending Aortic Aneurysm: Comparison of Patients with Bicuspid versus Tricuspid Aortic Valve J. F. Matthias Bechtel1, Frank Noack2, Friedhelm Sayk2, Armin W. Erasmi1, Claus Bartels1, Hans-Hinrich Sievers1 1 Department of Cardiac Surgery, University Hospital Lübeck, 2Institute of Pathology, Medical University of Lübeck, Lübeck, Germany Background and aims of the study: Bicuspid aortic smooth muscle cell orientation, elastic fiber frag- valve (BAV) is a common inherited condition that is mentation, and inflammation. often accompanied by ascending aortic aneurysm. A Results: BAVs were present in 26 patients (40%). high level of histological wall abnormalities was Patients with BAV had significantly less aortic wall reported to be present in non-dilated aortas of alterations than patients with tricuspid aortic valves patients with BAV. In patients with tricuspid aortic (p <0.001) in all variables examined. The severity of valve, there appears to exist a direct relationship aortic wall abnormalities was significantly depend- between the diameter of the ascending aorta and ent on aortic diameter in patients with BAV as well as degree of histopathological aortic wall abnormali- tricuspid aortic valve (p = 0.036 and 0.019), but ties. Whether this situation exists in patients with dependent on age (p = 0.009) only in patients with tri- BAV has not yet been investigated. cuspid aortic valve. Methods: Surgical and medical records of all patients Conclusion: The study results provide evidence that undergoing surgery of the ascending aorta were ascending aortic aneurysm in patients with BAV dif- reviewed. A total of 65 patients was identified in fers clinically and histologically from that in patients whom an aortic wall specimen was obtained intraop- with tricuspid aortic valve. Further studies are need- eratively. These specimens were systematically re- ed to elucidate the impact of inherited and acquired evaluated, and graded according to the severity of aortic wall abnormalities on the development of seven histopathological conditions: fibrosis, athero- aneurysms. sclerosis, medionecrosis, cystic medial necrosis, The Journal of Heart Valve Disease 2003;12:54-61 Bicuspid aortic valve is the most common congenital posed in patients with bicuspid aortic valve that man- cardiac defect, with a prevalence among the general ifests both at the valve level and within the aortic wall population of 1-2% (1). Although the prognosis of most (9). patients with bicuspid aortic valve is likely to be good, A recent histological study in patients with non- a significant number of these patients will eventually dilated ascending aorta suggested that those with suffer from aortic valve stenosis, regurgitation or bicuspid aortic valve had more severe aortic wall endocarditis, or will experience aortic dilatation, dis- abnormalities than those with tricuspid aortic valve section or rupture (2). (10). In the latter patients, there appears to be a posi- An association of bicuspid aortic valve with ascend- tive relationship between the degree of aortic dilata- ing aortic aneurysm and dissection has long been rec- tion and the severity of aortic wall abnormalities ognized (3,4). Patients with a bicuspid aortic valve (11,12). Unfortunately, histological data on patients usually have increased diameters of the aortic root, with bicuspid aortic valve and aortic aneurysm are rel- regardless of the functional status of the valve (5-8); atively sparse. Hence, a review was conducted of the therefore, the presence of a genetic defect has been pro- present authors’ experience in ascending aortic sur- gery in order to determine the severity of associated aortic wall abnormalities in patients with bicuspid as Presented in part at the First Biennial Meeting of the Society for Heart Valve Disease, 15th-18th June 2001, Queen Elizabeth II well as tricuspid aortic valve. Conference Centre, London, United Kingdom Address for correspondence: Clinical material and methods Prof. Dr. H. H. Sievers, Klinik fuer Herzchirurgie, Universitaetsklinikum Lübeck, Ratzeburger Allee 160, D-23538 Patient population Lübeck, Germany Between 1995 and 1999, a total of 167 operations on © Copyright by ICR Publishers 2003
    • J Heart Valve Dis Aortic aneurysm histopathology 55 Vol. 12. No. 1 J. F. Matthias Bechtel et al. January 2003 Table I: Clinical characteristics of all patients. Characteristic Aortic valve p-value __________________________________________ Bicuspid Tricuspid Male/female (n) 18/8 25/14 0.79 Age (years)* 53 ± 15 57 ± 14 0.23 Hypertension (n) 10 (42) 24 (63) 0.12 Diabetes mellitus (n) 0 1 (3) 1.0 Marfan syndrome (n) 0 4 (10) 0.14 Aneurysm diameter (mm)* 61 ± 11 58 ± 6 0.41 Dissection (n) 2 (8) 27 (69) <0.001 Need for aortic valve surgery (n) 22 (85) 28 (72) 0.37 Type of aortic surgery (n) 0.40 Replacement 39 (100) 25 (96) Wrapping 0 1 (4) Values in parentheses are percentages. * Values are mean ± SD. the ascending aorta was performed at the authors’ Histopathological evaluation department. Among patients, one aortic leaflet was The resected material was fixed in 4.5% pH-buffered present in one patient (0.6%), while two leaflets were formalin for approximately 24 h. Representative por- present in 42 patients (25.1%) and three leaflets in 96 tions of the resected material were selected macroscop- (57.5%). An unknown number was present in 28 ically for further processing. If necessary, patients (including 10 who had undergone prior aortic decalcification of atherosclerotic lesions was undertak- valve replacement). Patients with bicuspid aortic valve en by use of Ossa fixona solution (Diagonal, Muenster, were significantly younger than those with tricuspid Germany). The tissue was processed for light aortic valve (53 ± 14 versus 62 ± 13 years, respectively; microscopy, embedded in paraffin blocks, and sections p <0.001). Among patients with either a bicuspid or tri- (4 µm thickness) were taken from each specimen. cuspid aortic valve, an aortic wall specimen was Sections were stained with hematoxylin and eosin, elas- excised from the anterior aspect of the convexity of the tica-van Gieson, Alcian blue and Masson’s trichrome ascending aorta at the time of surgery in 65 cases, and stains. For the purpose of this study, all specimens were these specimens form the basis of this report. re-evaluated by two experienced histopathologists who Figure 2: Alcian blue staining of two aortic wall specimens. A) Grade 1 cystic medial necrosis with mucoid material within lamellar units (original magnification, Figure 1: Elastica-van Gieson staining of the aortic wall ×200). B) Grade 3 cystic medial necrosis with mucoid (original magnification, ×100), showing grade 3 elastic material surpassing more than one lamellar unit in the fragmentation with presence of foci of elastic fragmentation presence of fragmented elastic fibers (original in more than ten neighboring elastic lamellae. magnification, ×100).
    • 56 Aortic aneurysm histopathology J Heart Valve Dis Vol. 12. No. 1 J. F. Matthias Bechtel et al. January 2003 Table II: Results of histopathological evaluation. Variable Grade Aortic valve p-value ___________________________________________ Bicuspid (n) Tricuspid (n) Fibrosis None 19 (73) 11 (28) I 3 (12) 15 (39) 0.002 II 3 (12) 11 (28) III 1 (4) 2 (5) Atherosclerosis* None 12 (46) 11 (29) I 10 (39) 9 (24) 0.018 II 2 (8) 5 (13) III 2 (8) 13 (34) Medionecrosis None 18 (69) 9 (23) I 5 (19) 10 (26) <0.001 II 1 (4) 11 (28) III 2 (8) 9 (23) Cystic medial necrosis None 16 (62) 10 (26) I 5 (19) 13 (33) 0.008 II 3 (12) 10 (26) III 2 (8) 6 (15) SMC orientation+ Normal 24 (92) 22 (63) I 1 (4) 7 (20) 0.010 II 1 (4) 6 (17) III 0 0 Elastic fragmentation* None 12 (46) 5 (13) I 6 (23) 6 (16) <0.001 II 6 (23) 6 (16) III 2 (8) 21 (55) Inflammation None 19 (73) 11 (28) I 5 (19) 15 (39) <0.001 II 1 (4) 6 (15) III 1 (4) 7 (18) Aortic wall score‡ 3.8 ± 3.8 9.2 ± 4.6 <0.001 Values in parentheses are percentages. * Variable not evaluated sufficiently in one patient with tricuspid aortic valve. + Variable not evaluated sufficiently in four patients with tricuspid aortic valve. ‡ Values are mean ± SD. SMC: Smooth muscle cell. were blinded to the clinical data. The following histo- Figures 1 and 2. The criteria for histological grading logical alterations were analyzed semiquantitatively: were used as proposed by Schlatman and Becker (13), (1) fibrosis (defined as an increase in interstitial colla- Klima et al. (14) and de Sa et al. (10) and are detailed in gen); (2) atherosclerosis (defined as the presence of inti- Appendix I. The sum of the results of all variables was mal fibrous plaques and/or complex or complicated calculated for each individual patient, and this was atheromas); (3) medionecrosis (defined as a focal loss of referred to as the aortic wall score. smooth muscle cell nuclei in the media); (4) cystic medial necrosis (defined as mucoid material accumula- Statistical analysis tion); (5) changes in smooth muscle cell orientation; (6) Data were presented as absolute numbers and rela- elastic fragmentation (defined as focal fragmentation of tive percentages or mean (± SD), except where other- elastic lamellae in the media); and (7) periaortic inflam- wise stated. Relative frequencies were compared using mation (defined as the presence of inflammatory cells). Fisher’s exact test; continuous data were compared Each variable was graded from 0 (no change) to 3 (most using the Mann-Whitney U-test. Linear regression severe change) when examined at a magnification of analysis was performed with the aortic wall score as ×100 or ×200, using an Olympus microscope (Olympus dependent variable, and age and aortic diameter as BX 50, Japan). The grades were determined on the basis independent variables. All analyses were performed of the worst area observed. Examples are shown in using SPSS for Windows (SPSS Inc., Chicago, IL, USA).
    • J Heart Valve Dis Aortic aneurysm histopathology 57 Vol. 12. No. 1 J. F. Matthias Bechtel et al. January 2003 aortic valve have less severe aortic wall abnormalities according to histological standard criteria than those patients with a tricuspid aortic valve, despite the pres- ence of similar degrees of aortic dilatation. In addition, these results confirm that bicuspid aortic valve is fre- quent among patients undergoing surgery for diseases of the ascending aorta, and that a wide variety of aor- tic wall abnormalities of the ascending aorta can be observed in patients with tricuspid as well as bicuspid aortic valve. In patients with tricuspid aortic valve, there appears to be a direct positive correlation between the degree of ascending aortic dilatation and the degree of histo- logical aortic wall abnormalities (11,12), but whether the same situation exists among patients with bicuspid Figure 3: Scatterplot of ascending aortic diameter versus aortic valve has not yet been investigated. In the pres- aortic wall score. Patients with bicuspid aortic valve ent study, less severe histopathological changes were (triangles) had significantly (p <0.001) lower aortic wall found in patients with bicuspid aortic valve despite a scores than those with tricuspid aortic valve (circles). similar degree of aortic dilatation; thus, these results may be interpreted in such a way that the ‘true’ lesion Results in the aorta of patients with bicuspid aortic valve is not The demographic and surgical data of patients are identified using standard light microscopy criteria and listed in Table I. A total of 26 patients (40%) had bicus- that the mechanism of dilatation may differ from that pid aortic valve. in patients with tricuspid aortic valve. In accordance Five patients had no dectectable histopathological with the first hypothesis, Parai et al. (15) have shown changes; four of these had bicuspid aortic valve (p = there to be subtle (but significant) differences regard- 0.15). The mean aortic wall score was 7.1 ± 5.1. In ing the amount of elastic tissue between the aorta of patients with tricuspid aortic valve, regression analysis patients with bicuspid and tricuspid aortic valve revealed a significant association between age at oper- which could only be identified using morphometry. ation, ascending aortic diameter, and aortic wall score Recently, Bauer et al. (16) confirmed that patients with (aortic wall score = 0.42 × age + 0.33 × diameter; p = bicuspid aortic valve have less elastic tissue in their 0.009 and 0.036, respectively). In contrast, patients with ascending aorta, while Nistri et al. (17) found evidence a bicuspid aortic valve showed a significant associa- that the aorta of patients with bicuspid aortic valve tion between aortic diameter (but not age) and aortic appears to be stiffer when compared with that in wall score (aortic wall score = 0.49 × diameter; p = patients with tricuspid aortic valve. Bonderman et al. 0.019). The association between aortic wall score and (18) found evidence of a generally increased rate of aortic diameter is shown in Figure 3. apoptosis in patients with bicuspid aortic valve, Among patients with hypertension or diabetes mel- whereas in patients with tricuspid aortic valve the rate litus, all of the examined histopathological variables of apoptosis was elevated only in dilated aortas. were of similar severity. Patients with aortic dissection In studying patients with non-dilated aortas, de Sa et had a more severe extent of cystic medionecrosis (p = al. (10) reported that patients with bicuspid aortic 0.017) as compared with patients with aneurysm, but valve had more severe aortic wall abnormalities than all other variables examined were of similar severity. patients with tricuspid aortic valve. These authors also The results of the histopathological evaluation for found that patients with bicuspid aortic valve fre- patients with bicuspid versus tricuspid aortic valve are quently have severe wall abnormalities in the main listed in Table II. Patients with bicuspid aortic valve pulmonary artery, which develops from the same had a significantly lower mean aortic wall score embryological structures as the ascending aorta (19). (3.8 ± 3.8 versus 9.2 ± 4.6; p <0.001) due to significant- This apparent contrast to the results of the present ly less severe histopathological changes in all variables study cannot be explained easily. Indeed, some evi- examined. dence was found of a direct positive correlation between the degree of aortic wall abnormalities and aortic diameter in patients with bicuspid as well as tri- Discussion cuspid aortic valve, but this occurred on a generally The results of this retrospective study suggest that - lower level in patients with bicuspid aortic valve. As at the time of aortic surgery - patients with a bicuspid patients with non-dilated aortas were excluded from
    • 58 Aortic aneurysm histopathology J Heart Valve Dis Vol. 12. No. 1 J. F. Matthias Bechtel et al. January 2003 the present study, the possibility of a two-phase model In conclusion, the present study provides some evi- cannot be excluded: a constant first phase (a constant dence that ascending aortic aneurysm in patients with degree of aortic wall abnormalities in the range of nor- bicuspid aortic valve differs histologically from that in mal aortic diameters) followed by a steady increase of patients with tricuspid aortic valve. Further studies aortic wall abnormalities after a certain degree of should be conducted in order to elucidate the impact dilatation has been exceeded. Further studies should of inherited and acquired (for example, by age or flow be conducted in order to determine the relationship disturbances) aortic wall abnormalities on the devel- between aortic diameter and associated aortic wall opment of aneurysms. abnormalities. Most patients with bicuspid aortic valve will never References experience aortic dilatation, dissection or rupture, 1. Roberts WC. The congenitally bicuspid aortic though some will require ascending aorta replacement valve. A study of 85 autopsy cases. Am J Cardiol early in life (2). Besides genetic differences among 1970;26:72-82 patients with bicuspid aortic valve, other factors such 2. Ward C. Clinical significance of the bicuspid aortic as postvalvular flow may also contribute to this highly valve. Heart 2000;83:81-85 variable prognosis. 3. Gore I. Dissecting aneurysms of the aorta in per- More recent studies have indicated that the aortic sons under 40 years of age. Arch Pathol 1953;55:1- root is an asymmetric, highly complex structure 13 (20,21). Flow in the ascending aorta is usually eccen- 4. Edwards WE, Leaf DS, Edwards JE. Dissecting aor- tric, and studies on prosthetic aortic valves have tic aneurysm associated with congenital bicuspid shown that orientation of the leaflets has a major aortic valve. Circulation 1978;57:1022-1025 impact on blood velocity and the presence of turbu- 5. Hahn RT, Roman MJ, Mogtader AH, Devereux RB. lence in the ascending aorta (22,23). The precise orien- Association of aortic dilation with regurgitant, tation and morphology of the bicuspid aortic valve stenotic and functionally normal bicuspid aortic varies widely (24-26), and thus the morphology of a valves. J Am Coll Cardiol 1992;19:283-288 bicuspid valve may cause abnormal blood flow in the 6. Nistri S, Sorbo MD, Marin M, et al. Aortic root ascending aorta, even in the absence of a significant dilatation in young men with normally functioning degree of valvular disease. Whether these proposed bicuspid aortic valves. Heart 2000;82:19-22 flow disturbances are a cofactor in the development of 7. Keane MG, Wiegers SE, Plappert T, et al. Bicuspid ascending aortic dilatation/dissection has not yet been aortic valves are associated with aortic dilatation investigated, but experimental studies have provided out of proportion to coexistent valvular lesions. some evidence that flow disturbances or hemodynam- Circulation 2000;102(Suppl.III):III-35-III-39 ic stress can cause dilatation of vessels (27,28). The 8. Pachulski RT, Weinberg AL, Chan KL. Aortic impact of flow disturbances on histological aortic wall aneurysm in patients with functionally normal or alterations is, at present, unknown. minimally stenotic bicuspid aortic valve. Am J Cardiol 1991;67:781-782 Study limitations 9. McKusick VA. Association of congenital bicuspid The main limitation of the present study was its ret- aortic valve and Erdheim’s cystic medial necrosis rospective design. Some selection bias was clear: a (letter). Lancet 1972;1:1026-1027 histopathological examination was more likely to be 10. de Sa M, Moshkovitz Y, Butany J, David TE. ordered in younger patients, elective settings, or when Histologic abnormalities of the ascending aorta and no etiology of a dissection (such as bicuspid aortic pulmonary trunk in patients with bicuspid aortic valve or prior valve replacement) was apparent. This valve disease: Clinical relevance to the Ross proce- bias might explain the low incidence of aortic dissec- dure. J Thorac Cardiovasc Surg 1999;118:588-596 tion in patients with bicuspid aortic valve: 18 of the 28 11. Agozzino L, de Vivo F, Falco A, de Luca Tupputi patients with an unknown number of aortic valve Schinosa L, Cotrufo M. Non-inflammatory aortic leaflets had acute type A aortic dissection. However, the root disease and floppy aortic valve as cause of iso- results remain virtually unchanged if all patients with lated regurgitation: A clinico-morphologic study. aortic dissection are excluded from the analysis. Int J Cardiol 1994;45:129-134 Furthermore, aortic wall abnormalities are not sym- 12. Bellitti R, Caruso A, Festa M, et al. Prolapse of the metrically distributed among the ascending aortic cir- ‘floppy’ aortic valve as a cause of aortic regurgita- cumference (29), although the total aortic circumference tion. A clinico-morphologic study. Int J Cardiol was not examined. Nonetheless, any sampling error is 1985;9:399-410 likely to occur at random and it is likely that the main 13. Schlatman TJM, Becker AE. Histologic changes in finding was unaffected by this limitation. the normal aging aorta: Implications for dissecting
    • J Heart Valve Dis Aortic aneurysm histopathology 59 Vol. 12. No. 1 J. F. Matthias Bechtel et al. January 2003 aortic aneurysm. Am J Cardiol 1977;39:13-20 dynamics. Acta Anat 1996;157:261-274 14. Klima T, Spjut HJ, Coelho A, et al. The morphology 29. Agozzino L, Ferraraccio F, Esposito S, et al. Medial of ascending aortic aneurysms. Hum Pathol degeneration does not involve uniformly the whole 2001;14:810-817 ascending aorta: Morphological, biochemical and 15. Parai JL, Masters RG, Walley VM, Stinson WA, clinical correlations. Eur J Cardiothorac Surg Veinot JP. Aortic medial changes associated with 2002;21:675-682 bicuspid aortic valve: Myth or reality? Can J Cardiol 1999;15:1233-1238 Meeting discussion 16. Bauer M, Pasic M, Meyer R, et al. Morphometric analysis of aortic media in patients with bicuspid DR. CRISTINA BASSO (Padova, Italy): It seems that and tricuspid aortic valve. Ann Thorac Surg the histological samples were not re-evaluated by the 2002;74:58-62 pathologist. Which staining do you normally use to 17. Nistri S, Sorbo MD, Basso C, Thiene G. Bicuspid investigate aortic wall pathology? aortic valve: Abnormal aortic elastic properties. J DR. J. F. MATTHIAS BECHTEL (Lübeck, Germany): Heart Valve Dis 2002;11:369-374 The specimens were stained with hematoxylin and 18. Bonderman D, Gharehbaghi-Schnell E, Wollenek G, eosin, and elastica-van Gieson; they were paraffin- et al. Mechanisms underlying aortic dilatation in buffered and sectioned at 10 µm thickness. congenital aortic valve malformation. Circulation DR. BASSO: When you specified the aortic wall 1999;99:2138-2143 abnormalities you mentioned only mucoid degenera- 19. Maron BJ, Hutchins GM. The development of the tion and cystic necrosis - not the elastic fibers. What semilunar valves in the human heart. Am J Pathol was the elastic fiber architecture of the aortic wall? 1974;74:331-344 DR. BECHTEL: These studies were not carried out in 20. Choo SJ, McRae G, Olomon JP, et al. Aortic root all patients, so we only focused on the standard proto- geometry: Pattern of differences between leaflets col. and sinuses of Valsalva. J Heart Valve Dis DR. BASSO: But this is an issue that we must look for 1999;8:407-415 in aortic wall pathology in aortic aneurysm. 21. Dagum P, Green GR, Nistal FJ, et al. Deformational DR. BECHTEL: I agree with that, but in our opinion dynamics of the aortic root. Modes and physiologic the absence of any evident histologic abnormality in determinants. Circulation 1999;100(Suppl.II):II-54- these patients doesn’t exclude the presence of aortic II-62 wall abnormalities - but it does suggest that other fac- 22. Paulsen PK, Nygaard H, Hasenkam JM, et al. tors are operative. In my opinion, these factors are syn- Analysis of velocity in the ascending aorta in ergistic to aortic wall abnormalities. humans. A comparative study among normal aortic DR. JAGDISH BUTANY (Toronto, Canada): Thank valves, St. Jude Medical and Starr-Edwards silastic you for raising such a provocative subject. Do you ball valves. Int J Artif Organs 1988;11:293-302 know how much of the aorta was excised at surgery? 23. Laas J, Kleine P, Hasenkam MJ, Nygaard H. DR. BECHTEL: The aortic wall specimen was usually Orientation of tilting disc and bileaflet aortic valve taken from the anterolateral aspect of the convexity of substitutes for optimal hemodynamics. Ann Thorac the aneurysm. Among the patients with bicuspid aor- Surg 1999;68:1096-1099 tic valve there were no statistical imbalances with 24. Moore GW, Hutchins GM, Brito JC, Kang H. regards to valve surgery or the type of ascending aor- Congenital malformations of the semilunar valves. tic aneurysm surgery performed. Hum Pathol 1980;11:367-372 DR. BUTANY: There have been many reports showing 25. Duran AC, Frescura C, Sans-Coma V, et al. Bicuspid that as we grow older there is a sequential set of aortic valves in hearts with other congenital heart changes in the aortic wall - none of us will escape that. disease. J Heart Valve Dis 1995;4:581-590 So those changes will be present regardless of any 26. Sabet HY, Edwards WE, Tazelaar HD, Daly RC. other changes. I trust you are aware of that. Another Congenitally bicuspid aortic valves: A surgical point is, did you obtain a ring of aortic tissue to exam- pathology study of 542 cases (1991 through 1996) ine for histopathology? The exaggerated changes that and a literature review of 2715 additional cases. you can see will be localized - they won’t be present Mayo Clin Proc 1999;74:14-26 circumferentially, or on the medial side of the inner 27. Holman E. The obscure physiology of poststenotic margin. You have to examine the entire circumference dilatation: Its relation to the development of to detect these changes. A second point is that in the aneurysms. J Thorac Surg 1954;28:109-133 aortic valve, the changes that you showed - the 28. Stehbens WE. Structural and architectural changes shelf-like change - is more than likely a change as a during arterial development and the role of hemo- consequence of aortic incompetence rather than a pri-
    • 60 Aortic aneurysm histopathology J Heart Valve Dis Vol. 12. No. 1 J. F. Matthias Bechtel et al. January 2003 mary change in the aortic valve cusp. So changes in the TIMP expression is very different, and MMP-1 (matrix aortic wall are less likely, if not unlikely, to be related metalloproteinase-1) and MMP-3 are also extremely to that shelf-like change in the aortic valve cusp. The different. So there is more and more convincing evi- changes in the aortic wall probably occurred earlier dence that there is some kind of gene function behind than the development of that shelf in the aortic cusps. that, and that the hemodynamic parameters may offer DR. BECHTEL: We can’t exclude that, but as I men- a secondary explanation. What is you opinion about tioned we did not have circumferential specimens. that? They were usually from the anterolateral aspect of the DR. BECHTEL: To answer your last point, many excel- convexity. lent reports have been published recently providing DR. BUTANY: In a study that we published in evidence that there is a genetically determined aortic Toronto, we showed that even if you didn’t see signif- wall abnormality in patients with bicuspid aortic icant morphological changes, you find many fibrillin valve. A recent paper from De Sa and colleagues in changes - but you have to perform much more exten- Toronto showed pulmonary wall abnormalities also sive studies. occur very frequently, but I don’t want to challenge all DR. BECHTEL: I am aware of those studies, but this is these findings. Nevertheless, we thought it possible a retrospective study that is sort of provocative. We that other factors might be operative in some patients. were not able to re-evaluate the specimens, or to carry For example, hemodynamics may have a major impact out more extensive studies until now. on the question of whether or not these aortic wall DR. KARYN KUNZELMAN (Madison, Wisconsin, abnormalities will develop into an aneurysm, or sim- USA): In the follow up to that, you have acknowl- ply be present. To return to your first point, there are edged that your study is somewhat limited by the lack studies on disk orientation in bileaflet prosthetic heart of histological data due to its retrospective nature. Are valves that show that the exact orientation of the valve you going to continue this in a prospective manner to has a major impact on turbulence behind the valve. It answer some of these questions that are being raised? is possible that this could be why some, but not all, DR. BECHTEL: Yes - these results only included data patients with bicuspid aortic valve develop ascending up to the end of 1999 when the case patient was oper- aortic dissections after aortic valve replacement. ated on. DR. PENNY THOMAS (London, UK): Have you any DR. KUNZELMAN: Have you considered that idea from your specimens whether your bicuspid mechanical stress alterations rather than just hemody- valves arose through the fusion of two leaflets early on namic changes might alter the properties of the root or in development, or whether there were always only the ascending aorta? two leaflets? DR. BECHTEL: I won’t speculate too much on that. I DR. BECHTEL: Most of them were noted in the surgi- used the term ‘hemodynamics’ because I wasn’t quite cal records to be congenitally bicuspid, which means sure what term should be used. I am not sure exactly that there are not always only two sinuses, but most of what caused these aneurysms. We speculate that tur- them were not fused as a result of a pathological bulence is developing behind the valve, and this caus- process in adulthood. es the aneurysms to develop, but it is unclear whether DR. THOMAS: So the valves were like it when the this should be called mechanical stress or whether it is patients were born? hemodynamic inasmuch as you can influence it by DR. BECHTEL: That was the opinion of the operating decreasing dP/dt. surgeons. In this retrospective study I tried to include DR. DANIEL LOISANCE (Creteil, France): Thank only those valves that appeared to be congenitally you for raising a very difficult issue - I am very bicuspid. impressed by your provocative conclusions. However, DR. THOMAS: I am just trying to see if there is any they don’t fit in with what we observe clinically, or link between any abnormality in the wall which might what we see when we examine the specimen very care- be neural crest-related or developmental with the fully. Clinically, how can you explain the appearance of number of leaflets, because neural crest cells do aortic dilatation following aortic valve replacement in approach the leaflets. these patients who had initially a bicuspid valve? It DR. BECHTEL: I tried to include only those that were could be the hemodynamic parameters that explain congenitally bicuspid. this secondary dilatation. A second observation is that DR. GAETANO THIENE (Padova, Italy): Did you when we examine these aortic tissues they appear have cases of aortic dissection with bicuspid valve? If extremely abnormal - not only microscopically but also so, was the aortic wall normal or abnormal? in their subcellular structures. For instance, gly- DR. BECHTEL: We have cases with bicuspid aortic cosaminoglycan production is extremely different, valves and dissection, but I can’t tell you at present TIMP (tissue metalloproteinase) is extremely different, what their pathology was like.
    • J Heart Valve Dis Aortic aneurysm histopathology 61 Vol. 12. No. 1 J. F. Matthias Bechtel et al. January 2003 DR. THIENE: The problem is that it is impossible to DR. BECHTEL: There were no dissections among the dissect the aortic wall in the setting of a bicuspid valve last eight patients I presented - they only had without aortic wall abnormalities, because there is no aneurysms. hypertension there. Appendix I: Criteria for histological grading* Fibrosis Grade 1: an increase in collagen content in an area comprising less than one-third of the total width of the media. Grade 2: an increase in collagen in an area comprising between one- and two-thirds of the total width of the media. Grade 3: an increase in collagen in an area comprising more than two-thirds of the total width of the media. Atherosclerosis Grade 1: intimal fibrous plaques, the thickness of which was less than one-fourth of the thickness of the media. Grade 2: intimal fibrous plaques thicker than one-fourth of the media, or intimal plaques with minimal calcification and/or atheroma. Grade 3: complex or complicated lesions of severe atheroma with thrombosis, calcifications and ulcerations. Medionecrosis Grade 1: focal loss of nuclei in an area comprising less than one-third of the total width. Grade 2: focal loss of nuclei in an area comprising between one- and two-thirds of the medial thickness. Grade 3: focal loss of nuclei in an area comprising more than two-thirds of the total medial thickness. Cystic medial necrosis Grade 1: minute foci of mucoid material (‘cysts’) were present within a single lamellar unit. Grade 2: the amount of mucoid material had increased, so that accumulation of ‘cysts’ covered the total width of one lamellar unit. Grade 3: the extent of mucoid material surpassed more than one lamellar unit, either because of focal accumulation of small ‘cysts’ within intact elastin lamellae or because of large ‘cysts’ in an area with fragmented elastin fibers. Smooth muscle cell orientation Grade 1: small foci with change in the orientation of the smooth muscle cells, which could be spread in different areas. Grade 2: area with change in the orientation of the smooth muscle cell orientation or several areas that together represent between one-third and one-half of the thickness of the media. Grade 3: large area of changes in the smooth muscle cell orientation, consisting more than one-half of the media thickness. Elastic fragmentation Grade 1: fewer than five foci with elastin fragmentation in one microscopic field (magnification ×200), each focus comprising two to four neighboring elastin lamellae. The orientation of smooth muscle cells was preserved. Interruption of one elastin fiber alone was not interpreted as fragmentation. Grade 2: five or more foci with elastin fragmentation in one microscopic field, each focus comprising two to four neighboring elastin lamellae. The foci could be confluent or scattered throughout the media. The orientation of smooth muscle cells was preserved. Grade 3: presence of foci with elastin fragmentation in five or more neighboring elastin lamellae, irrespective of the number of foci per microscopic field. The smooth muscle cells showed alterations in orientation. Inflammation Grade 1: sparse scattered chronic inflammatory cells or an occasional small focus of inflammatory cells. Grade 2: multiple small foci of inflammatory cells. Grade 3: multiple large foci of inflammatory cells or a diffuse, heavy inflammatory cellular infiltrate. * Based on data according to Schlatmann and Becker (13), Klima et al. (14) and de Sa et al. (10).