Ascending aortic aneurysms in unicommissural aortic valve disease

Cardiovascular Pathology 18 (2009) 11 – 18

Original Article

Ascending aortic aneurysms in unicommissural aortic valve disease Jagdish Butany a,b,⁎, Pradeep Vaideeswar a,c , Vidya Dixit a,d , Vidyadhar Lad e , Annette Vegas f , Tirone E. David e a

Department of Pathology, Toronto General Hospital/University Health Network, Toronto, Ontario, Canada b Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada c Cardiovascular and Thoracic Division, Department of Pathology, Seth G.S. Medical College, Mumbai, India d Faculty of Health Studies, University of Waterloo, Waterloo, Ontario, Canada e Department of Cardiovascular Surgery, Toronto General Hospital/University Health Network, Toronto, Ontario, Canada f Department of Anesthesiology, Toronto General Hospital/University Health Network, Toronto, Ontario, Canada Received 18 August 2007; received in revised form 3 December 2007; accepted 17 December 2007

Abstract Background: Aneurysms of the ascending aorta occur as result of intrinsic changes in the aortic wall and have been well documented in patients with bicuspid aortic valve (BAV). In few reported clinical studies, documenting aneurysmal dilatation in unicommissural aortic valves (UAV); there have been no comments on the aortic wall pathology. This study presents the pathological findings of the ascending aorta in patients with UAV. Materials and Methods: The clinical data from 39 patients with concomitant excision of the UAV and aneurysmal aortic tissue were reviewed. In all cases, the gross features of the valve and aortic segments were noted and submitted for histology. The sections of the aorta were semi-quantitatively graded for the extent of medionecrosis, cystic medial change, fibrosis, and elastic tissue changes (fragmentation/ loss) in the media. The medial alterations were correlated with patient age, gender, and valvular dysfunction, and compared to aneurysmal disease in BAV and three-cuspid aortic valves (TAV) excised over a 3-year period. Results: Among 39 patients studied, a majority were males (92.3%), with a mean age at surgery of 39.92 years. Only three patients (7.69%) were above the age of 50 years. Eighteen patients (46.1%) had aortic stenosis with regurgitation. Ascending aorta diameters ranged from 4 to 5.5 cm. The overall pattern of medial changes was nearly the same in all cases of UAV, irrespective of age and nature of valvular dysfunction. Most cases showed mild histological changes, with medionecrosis and fibrosis being the more common and consistent features. However, varying grades of change affected different portions of the media and/or the aortic wall in the same patient. The changes in UAV aortae were comparable to the changes seen in the TAV and BAV, but these differed with the age of onset. Conclusions: This study demonstrates the presence of medial changes in the ascending aortic tissue in all patients of UAV with aneurysms. These changes, while mild to moderate in degree, likely have a similar pathogenetic mechanism as those seen in BAV disease. The significant difference in age, at the time of surgery, suggests a more rapid progression of the aortic changes. © 2009 Elsevier Inc. All rights reserved. Keywords: Aortic valve; Unicuspid; Aneurysm; Ascending aorta

1. Introduction Aneurysms of the aorta are a cause of significant morbidity and mortality, especially in the elderly. A com-

The Guest Editor for this paper is John Veinot. ⁎ Corresponding author. Department of Pathology, 11E-421, Toronto General Hospital, University Health Network Toronto, Ontario, Canada M5G 2C4. Tel.: +1 416 340 3003; fax: +1 416 340 4213. E-mail address: [email protected] (J. Butany). 1054-8807/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.carpath.2007.12.004

bination of factors such as male gender, cigarette smoking, hypertension, and diabetes mellitus in the aging population leads to acceleration of atherosclerosis. The abdominal aorta is the most frequent site of atherosclerotic aneurysms, which are most often atherosclerotic in nature [1]. In contrast, aneurysms of the thoracic aorta are uncommon, with an estimated incidence of 5.9 cases per 100,000 person-years [2] and have a different etiology, natural history, and modes of treatment. Approximately 60% of thoracic aortic aneurysms involve the aortic root and/or ascending aorta, producing a ‘pear’ or

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lumped together with the BAV as congenital defects of the aortic valve. There have been only a few reported studies in the literature having documented the presence of aneurysmal dilatation of the ascending aorta with UAV [6,7]. In none of the studies was there any comment on the aortic wall pathology [7]. We present a detailed analysis of the histological findings from the ascending aorta surgically resected from 39 patients with UAV.

2. Materials and methods

Fig. 1. (A) Transesophageal echocardiography, mid-esophageal aortic valve SAX view (42°) of a unicuspid valve during systole. The valve shows an eccentric rounded orifice with a single posterior commissure (arrow). (B) Gross appearance of the excised UAV in a patient with aortic stenosis and regurgitation. Note diffuse thickening of the entire cusp.

‘tear-drop’ shape or ‘fusiform’ dilatation, and replacement of the ascending aorta accounts for the majority of thoracic aortic procedures [3]. Prominent amongst the etiological factors in this group are well-defined congenital disorders such as the Marfan syndrome, the Ehlers–Danlos syndrome, and bicuspid aortic valve (BAV) disease, where intrinsic changes in the aortic wall result in dilatation, independent of the type and degree of valvular dysfunction [4]. In these patients, a surgical option has been proposed whenever a diameter of 4.5 cm or more is measured at the hinge-points of the aortic valve cusps, the mid-point of the sinuses of Valsalva, the sinotubular junction, and the mid-ascending aorta [5]. In comparison to the BAV, the unicommissural aortic valve (UAV) is seldom seen in adults as it often gets

A review of the pathology records at our institution, an adult tertiary care center, showed 78 cases of UAV (diagnosed at morphological examination by one of the authors, JB) over a 6-year period (2001–2006). Apart from the aortic valvular tissue, aneurysmal aortic tissue had been excised in 48 patients. In 45 cases, the aortic wall excisions were received with the valves in the surgical pathology laboratory and were available for further analysis. Six patients with associated congenital anomalies or the Marfan syndrome were excluded from this study. The clinical data with reference to the age and gender, duration of symptoms, cross-sectional area of the aortic orifice and type of valvular dysfunction, diameter of the aortic root and ascending aorta, type of aneurysm, and mode of surgery were noted in the remaining 39 patients. All the excised tissues had been fixed in 10% buffered formalin and examined/photographed by one of the authors (JB). In the valves, the gross features noted included the size and shape of the orifice and overall status of the commissure, raphe, and cusps. Standardized sections of the valves (longitudinal sections of the cusps and transverse sections of the raphe, or the entire valve if intact and small, were cut horizontally into two parts and both parts submitted) were taken in all cases. Some aneurysmal tissue had been received as rings while in others the tissues were received as one or more separate pieces. In cases of aortic rings, the lengths at the medial and lateral margins; diameters at the proximal, middle, and distal portions of the tubular segment; and wall thickness were recorded. Appearance of the intimal and adventitial surfaces and presence of localized outpouchings were noted. A representative ring of aortic tissue was taken, divided into four parts and submitted as sections from the medial, lateral, anterior, and posterior parts of the aortic ring. Additional pieces of aortic tissues were also assessed with respect to wall thickness and texture of the intima and adventitia. These were then submitted for histology. All sections were stained with the hematoxylin–eosin and elastic trichrome, or Movat pentachrome stains, evaluated initially by one pathologist (JB) and reassessed by two reviewers (PV and JB). The sections of the aorta were semi-quantitatively graded for the extent of medionecrosis, cystic medial change, fibrosis, and elastic tissue changes (fragmentation/loss) [8]. Changes in the intima and adventitia were also assessed. These changes were correlated with patient age, gender, and

J. Butany et al. / Cardiovascular Pathology 18 (2009) 11–18

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Table 1 Patient demographics and overall medial changes (N=39) Age

Valvular dysfunction

AS+AR (n=18)

AS (n=13)

AR (n=8)

≤40 years

Number Age: mean and range (years) M/F Mean orifice area (cm2) Mean aortic diameter (cm) Medionecrosis

10 35 (31–40) 9:1 0.92 4.91 0 3 (30%) 6 (60%) 1 (10%) 0 3 (30%) 6 (60%) 1 (10%) 1 (10%) 9 (90%) 0 0 7 (70%) 3 (30%) 0 0 8 50.63 (44–64) 7:1 0.75 4.4 0 4 (50%) 3 (37.5%) 1 (12.5%) 3 (37.5%) 2 (25%) 2 (25%) 1 (12.5%) 0 4 (50%) 4 (50%) 0 4 (50%) 4 (50%) 0 0

7 31.42 (18–40) 7:0 0.77 4.38 0 2 (28.6%) 4 (57.1%) 1 (14.3%) 1 (14.3%) 3 (42.9%) 3 (42.9%) 0 2 (28.6%) 5 (71.4%) 0 0 5 (71.4%) 1 (14.3%) 1 (14.3%) 0 6 48.3 (43–57) 6:0 0.76 4.63 1 (16.7%) 0 4 (66.6%) 1 (16.7%) 1 (16.7%) 0 3 (50%) 2 (33.3%) 2 (33.3%) 2 (33.3%) 2 (33.3%) 0 0 3 (50%) 2 (33.3%) 1 (16.7%)

5 31.4 (19–38) 4:1 1.6 4.35 0 1 (20%) 4 (80%) 0 1 (20%) 2 (40%) 2 (40%) 0 1 (20%) 4 (80%) 0 0 3 (60%) 1 (20%) 1 (20%) 0 3 45 (41–50) 3:0 1.8 4.65 1 (33.3%) 1 (33.3%) 0 1 (33.3%) 2 (66.7%) 0 1 (33.3%) 0 1 (33.3%) 1 (33.3%) 1 (33.3%) 0 2 (66.7%) 1 (33.3%) 0 0

Cystic medial change

Medial fibrosis

Elastic fragmentation

N40 years

Number Age, mean and range (years) M/F Mean orifice area (cm2) Mean aortic diameter (cm) Medionecrosis

Cystic medial change

Medial fibrosis

Elastic fragmentation

None Mild Moderate Severe None Mild Moderate Severe None Mild Moderate Severe None Mild Moderate Severe

None Mild Moderate Severe None Mild Moderate Severe None Mild Moderate Severe None Mild Moderate Severe

valvular dysfunction, and compared to aneurysmal disease in BAV and three-cuspid aortic valves (TAV) excised over a 3-year period.

3. Results This retrospective study examined aortic tissues from 39 patients with UAV (Fig. 1) with varying degrees of valvular dysfunction, over a 6-year period (Table 1). The age at surgery ranged from 18 to 64 years, with a mean of 38.62 years. Only three patients (7.69%) were above the age of 50 years. These patients, 36 males and three females, had been symptomatic for prolonged periods of time, with exertional dyspnea and palpitation.

Aortic stenosis with regurgitation was the commonest type of valvular dysfunction seen in 18 patients (46.1%). Six patients had undergone either surgical or balloon valvuloplasty. The effective aortic valvular orifice area ranged from 0.7 to 1.8 cm2. Coronary artery disease was present in three. Aneurysmal dilatation of the ascending aorta, noted in these patients, had diameters ranging from 4 to 5.5 cm, as seen on two-dimensional echocardiography (Fig. 1). Surgical procedures performed included the Ross procedure with ascending aortic replacement (AAR) in five and AAR/aortic arch replacement (ARR) in one, aortic valve replacement (AVR) with AAR in 18, AVR with AAR/ARR in eight, and aortic root replacement with AVR, AAR, and/or ARR in seven. Tissue from the ascending aorta was received in small pieces (one to five pieces) in eight cases, while the tissue

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Fig. 2. (A) Dilated ascending aorta with bulge (arrows). Tubular segment of ascending aorta. (B) Aneurysmal bulge seen at the anterolateral aspect (arrow). (C) Cross section at that level showing the localized dilatation (arrow). (D) Opened segment showing single ulcerated atheromatous plaque.

from the remaining 31 cases was received as tubular or ringlike aortic segments (Fig. 2), for morphological examinations. Atheromatous plaques were seen in seven with areas of calcification and ulceration (Fig. 2) in some. Regional aneurysmal bulges, almost invariably involving the lateral two thirds of the circumference (19 cases), were visible in 23 cases. The histological changes in the aortic wall in UAV were comparable to the changes seen in the TAV and BAV (Table 2). However, the mean age at presentation for the TAV was 70 years, 56.33 years for the BAV, and 39.92 years for the UAV. The overall pattern of medial changes (Figs. 3 and 4) was nearly the same in all cases of UAV, irrespective of age and type of valvular dysfunction. Most cases showed mild to moderate changes (Tables 1 and 2). Medionecrosis and fibrosis were the more common and consistent features. In patients, where tubular segments of the aorta were available, variations in the medial abnormalities were noted in different segments of the circumference of the aorta (Table 3). Similarly, in all cases, many sections of the aortic wall showed varying grades of change affecting different portions of the media (Fig. 5).

4. Discussion In this study, we have reported the occurrence of aneurysms of the ascending aorta with UAV and the histopathological findings therein. The aneurysmal dilatations had been recorded in 48 (61.53%) of the 78 patients undergoing excision of the UAV, over a span of 6 years. Since resected ascending aortic tissue was not submitted in three, and six additional patients had been excluded, analysis was performed on 39 cases. This study is, to the best of our knowledge, the first to report on the histology of the surgically excised aorta in UAV and hence there were no UAV-specific data to compare with. In the study by Novarro et al. [6], the prevalence of ascending aortic dilatation was 48% and the mean patient age 39±10%. Agnihotri et al. [7] have documented significant aortic dilatation in six (50%) of their 12 patients and all of these were less than 50 years of age; none had documented histological findings. Of our 39 patients, only three were above 50 years of age (7.69%) and the majority (17 patients, 43.6%) were in their fourth decade. Our study confirms the observations of Agnihotri et al. [7] of the relationship of aortic dilatation and age at presentation

J. Butany et al. / Cardiovascular Pathology 18 (2009) 11–18

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Table 2 Grades of aortic wall changes in TAV, BAV, and UAV Aortic valve status

TAV (n=15)

Valvular dysfunction

AS/AR (n=8) AS (n=7)

Age, range and mean (years) 67.6 (51–77) M/F ratio 1:1 Histological characteristics Medial fibrosis Absent 2 (25%) Mild 3 (37.5%) Moderate 1 (12.5%) Severe 2 (25%) Medionecrosis Absent 0 Mild 3 (37.5%) Moderate 3 (37.5%) Severe 2 (25%) Cystic medial change Absent 3 (37.5%) Mild 3 (37.5%) Moderate 2 (25%) Severe 0 Elastic fragmentation Absent 8 (100%) Mild 0 Moderate 0 Severe 0 Intimal fibrosis and/or atherosclerosis Absent 5 (62.5%) Mild 2 (25%) Moderate 1 (12.5%) Severe 0

BAV (n=22)

UAV (n=39)

AS/AR (n=10) AS (n=9)

72.7 (63–83) 60.7 (27–79) 6:1 9:1

AR (n=3)

AS/AR (n=18) AS (n=13)

54.4 (25–75) 39.3 (20–54) 41.9 (31–64) 9:0 2:1 8:1

0 5 (71.4%) 2 (28.6%) 0

5 (50%) 1 (10%) 3 (30%) 1 (10%)

1 (11.1%) 7 (77.8%) 1 (11.1%) 0

1 (33.3%) 1 (33.3%) 1 (33.3%) 0

1 (5.6%) 13 (72.2%) 4 (22.2%) 0

1 (14.3%) 3 (42.8%) 2 (28.6%) 1 (14.3%)

1 (10%) 2 (20%) 4 (40%) 3 (30%)

0 3 (33.3%) 4 (44.5%) 2 (22.2%)

1 (33.3%) 1 (33.3%) 1 (33.3%) 0

1 (14.3%) 3 (42.8%) 3 (42.8%) 0

2 (20%) 3 (30%) 4 (40%) 1 (10%)

1 (11.1%) 5 (55.5%) 2 (22.2%) 1 (11.1%)

5 (71.4%) 1 (14.3%) 1 (14.3%) 0

10 (100%) 0 0 0

5 (71.4%) 0 0 2 (28.6%)

9 (90%) 0 1 (10%) 0

with an ‘aggressive behavior’ in younger patients. We did not find any age difference among the patients of UAV with and without aneurysmal dilatations. The ascending aortic diameters ranged from 4 to 5.5 cm as measured echocardiographically. However, the diameters in the resected tubular segments (31 cases) ranged from 3.6 to 6.5 cm. This discrepancy can be explained on the basis of contraction of the medial smooth muscle as soon as the tension of blood flow was removed, post-fixation shrinkage of tissue, and perhaps to some extent on the variability of measurements on echocardiography [9]. In general, the etiopathogenesis of abdominal aortic aneurysms is different from thoracic aortic aneurysms. The former generally occur in older individuals, with a strong association with smoking, hypertension, hyperlipidemia, atherosclerosis, and family history [1]. Atherosclerotic plaques were seen in seven of our cases. These were present unifocally and only one of these patients had pure aortic regurgitation. This raises the possibility that the two cases with calcified plaques could be related to the jet of aortic stenosis. Seven patients were smokers, one had hyperlipidemia, but none were hypertensives. A lymphohistiocytic infiltrate was observed mainly on the adventitial aspect in eight cases. No inflammatory cells were seen in the media.

10 (100%) 0 0 0

6 (66.7%) 2 (22.2%) 0 1 (11.1%)

AR (n=8)

39.2 (18–57) 36.5 (19–50) 13:0 8:0

4 (30.8%) 7 (53.8%) 2 (15.4%) 0

1 (12.5%) 2 (25%) 5 (62.5%) 0

0 7 (38.9%) 9 (50%) 2 (11.1%)

1 2 8 2

(7.7%) (15.4%) (61.5%) (15.4%)

1 (12.5%) 2 (25%) 4 (50%) 1 (12.5%)

0 1 (33.3%) 0 2 (66.7%)

3 (16.7%) 5 (27.8%) 8 (44.4%) 2 (11.1%)

2 3 6 2

(15.4%) (23%) (46.2%) (15.4%)

2 (25%) 1 (12.5%) 3 (37.5%) 2 (25%)

2 (66.7%) 0 0 1 (33.3%)

11 (61.1%) 7 (38.9%) 0 0

5 4 3 1

(38.5%) (30.8%) (23%) (7.7%)

5 (62.5%) 2 (25%) 1 (12.5%) 0

2 (66.7%) 1 (33.3%) 0 0

8 (44.4%) 4 (22.2%) 6 (33.4%) 0

4 3 2 4

(30.8%) (23%) (15.4%) (30.8%)

5 (62.5%) 1 (12.5%) 1 (12.5%) 0

Such inflammatory cells, especially macrophages, are reported to be responsible for degradation of the extracellular matrix through matrix metalloproteinases, with resulting abdominal aortic aneurysms [10].

Fig. 3. Focal loss of smooth muscle fibers and collapse of the elastic laminae (medionecroses, arrows) and associated fibrosis. (Movat pentachrome, original magnification ×5.0.)

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J. Butany et al. / Cardiovascular Pathology 18 (2009) 11–18 Table 3 Wall changes in tubular segments of aorta (n=31)

Fig. 4. (A) Multifocal fragmentation of the elastic fibers. (B) Microscopic foci of cystic medial change are scattered throughout. This section shows a bandlike area of collapse of elastic plates due to loss of smooth muscle fibers. (Movat pentachrome, original magnification ×5.0.)

Aneurysms of the ascending aorta are usually associated with medial degeneration, a process that occurs to some extent in the aged and in hypertensives. In bicuspid aortic disease, this process is exaggerated and occurs without valvular dysfunction [11] and is out of proportion to any coexistent stenosis and/or regurgitation [12]. Collapse of the medial elastic plates, elastic fibre fragmentation, loss of smooth muscle cells, and accumulation of ground substance occur in these cases [8] and are likely mediated by reduction of fibrillin-1 content [13], increased expression of matrix metalloproteinases [14], and smooth muscle apoptosis [15]. The intrinsic medial abnormality is related to embryogenesis, which also explains the association of BAV with congenital anomalies such as coarctation [16,17]. Since UAV is a developmental anomaly, it would share its pathologic characteristics with the more common BAV and one would assume that similar medial changes would occur with the aortae from UAV. Besides, UAV is considered to be the more severe form of congenital

AS/AR (n=15)

AS (n=9)

AR (n=7)

Medial fibrosis Anterior—None Mild Moderate Severe Posterior—None Mild Moderate Severe Medial—None Mild Moderate Severe Lateral—None Mild Moderate Severe

0 13 (86.6%) 2 (13.4%) 0 1 (6.6%) 12 (80%) 2 (13.4%) 0 0 13 (86.6%) 2 (13.4%) 0 0 13 (86.6%) 2 (13.4%) 0

1 (11.1%) 7 (77.8%) 1 (11.1%) 0 0 6 (66.7%) 3 (33.3%) 0 0 8 (88.9%) 1 (11.1%) 0 1 (11.1%) 6 (66.7%) 2 (22.2%) 0

1 (14.3%) 6 (85.7%) 0 0 2 (28.6%) 3 (42.8%) 2 (28.6%) 0 2 (28.6%) 5 (71.4%) 0 0 3 (42.8%) 3 (42.8%) 1 (14.3%) 0

Medionecrosis Anterior—None Mild Moderate Severe Posterior—None Mild Moderate Severe Medial—None Mild Moderate Severe Lateral—None Mild Moderate Severe

1 (6.6%) 8 (53.3%) 5 (33.5%) 1 (6.6%) 0 8 (53.3%) 5 (33.5%) 2 (13.4%) 0 9 (60%) 6 (40%) 0 1 (6.6%) 6 (40%) 7 (46.8%) 1 (6.6%)

0 3 (33.3%) 4 (44.5%) 2 (22.2%) 0 4 (44.5%) 3 (33.3%) 2 (22.2%) 1 (11.1%) 5 (55.6%) 2 (22.2%) 1 (11.1%) 1 (11.1%) 1 (11.1%) 5 (55.6%) 2 (22.2%)

1 (14.3%) 4 (57.1%) 1 (14.3%) 1 (14.3%) 1 (14.3%) 2 (28.6%) 4 (57.1%) 0 1 (14.3%) 5 (71.4%) 1 (14.3%) 0 1 (14.3%) 3 (42.8%) 2 (28.6%) 1 (14.3%)

Cystic medial change Anterior—None Mild Moderate Severe Posterior—None Mild Moderate Severe Medial—None Mild Moderate Severe Lateral—None Mild Moderate Severe

3 (20%) 10 (66.6%) 2 (13.4%) 0 3 (20%) 8 (53.3%) 4 (26.7%) 0 4 (26.7%) 7 (46.6%) 4 (26.7%) 0 4 (26.7%) 8 (53.3%) 3 (20%) 0

2 (22.2%) 4 (44.5%) 3 (33.3%) 0 2 (22.2%) 4 (44.5%) 3 (33.3%) 0 2 (22.2%) 6 (66.7%) 1 (11.1%) 0 2 (22.2%) 5 (55.6%) 1 (11.1%) 1 (11.1%)

3 (42.8%) 3 (42.8%) 1 (14.3%) 0 3 (42.8%) 2 (28.6%) 2 (28.6%) 0 3 (42.8%) 3 (42.8%) 1 (14.3%) 0 3 (42.8%) 3 (42.8%) 1 (14.3%) 0

Elastic fragmentation Anterior—None Mild Moderate Severe Posterior—None Mild Moderate Severe

14 (93.4%) 1 (6.6%) 0 0 13 (86.6%) 2 (13.4%) 0 0

6 (66.7%) 2 (22.2%) 1 (11.1%) 0 7 (77.8%) 2 (22.2%) 0 0

4 (57.1%) 2 (28.6%) 0 1 (14.3%) 7 (100%) 0 0 0

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Table 3 (continued) AS/AR (n=15)

AS (n=9)

AR (n=7)

9 (60%) 5 (33.4%) 1 (6.6%) 0 14 (93.4%) 1 (6.6%) 0 0

6 (66.7%) 2 (22.2%) 1 (11.1%) 0 7 (77.8%) 0 2 (22.2%) 0

5 (71.4%) 2 (28.6%) 0 0 4 (57.1%) 2 (28.6%) 1 (14.3%) 0

Intimal fibrosis/atherosclerosis Anterior—None 12 (80%) Mild 3 (20%) Moderate 0 Severe 0 Posterior—None 10 (66.6%) Mild 0 Moderate 5 (33.4%) Severe 0 Medial—None 13 (86.6%) Mild 2 (13.4%) Moderate 0 Severe 0 Lateral—None 8 (53.3%) Mild 1 (6.6%) Moderate 6 (40%) Severe 0

7 (77.8%) 1 (11.1%) 0 1 (11.1%) 5 (55.6%) 1 (11.1%) 2 (22.2%) 1 (11.1%) 6 (66.7%) 2 (22.2%) 1 (11.1%) 0 6 (66.7%) 2 (22.2%) 1 (11.1%) 0

7 (100%) 0 0 0 5 (71.4%) 2 (28.6%) 0 0 6 (85.7%) 1 (14.3%) 0 0 4 (57.1%) 1 (14.3%) 3 (42.8%) 0

Medial—None Mild Moderate Severe Lateral—None Mild Moderate Severe

aortic valvular malformation [18], and hence one would expect a greater degree of medial change. Contrary to our assumption, apart from the younger age at onset, we found medial changes to be comparable in the media of UAV, BAV, and TAV cases. Whether acommissural or unicommissural, UAV are hinged, to variable degrees, in an annular fashion, rather than in a semilunar or crescentic fashion (as is usual in trileaflet aortic valves); this inherently restricts the UAV leaflets' potential to open properly and even more from being able to close properly (with a greater tendency to incompetence) [19]. In all probability, the eccentric jets of these congenitally stenotic valves accelerate the degeneration of the intrinsically abnormal aortic media. Changes were generally mild to moderate; and medionecrosis was a consistent finding. In this study, associated aortic coarctation was noted in four patients, but only two of these cases showed marked changes in the wall. Cystic medial change was seen in 82.05% of cases and was severe in eight (20.5%). Thirty-three cases also showed absence of one or more of the four medial changes. This is not unexpected, as some authors have found lesser degree of abnormalities [20]. Additionally, when sections from different areas of the tubular aortic segments were studied in 31 cases, the changes were not uniform in the four quadrants of the aortic circumference. This allows speculation that even UAV can be associated with a variable location of maximum stress. In the BAV, there is greater stress at the anterolateral region and mid-portion of the ascending aorta [21,22].

Fig. 5. Significant medionecroses in the media affecting the (A) inner-third of the anterior wall and (B) mid-third of the lateral wall of the same aortic segment. (Movat pentachromeoriginal magnification ×5.0.)

This study demonstrates the presence of medial changes in the ascending aortic tissue in all patients of UAV with aneurysms. These changes were mild to moderate in degree with a similar pathogenetic mechanism seen with BAV disease. However, degenerative changes are complex and variable, affecting small segments of the vessels. Since the malformations are part of a developmental disease, they could have different phenotypic manifestations, could be more aggressive in one patient (young, with aortic regurgitation and ascending aortic aneurysm) or mild in the other (with aortic stenosis, no aneurysm, and older).

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