Keywords
aortic histopathology - aortic valve reimplantation - bicuspid aortic valve - connective
tissue disease
Introduction
For patients with bicuspid aortic valves (BAV) and connective tissue disease (CTD),
including Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome, a well-documented
association with aneurysms, dissections, and ruptures of the thoracic aorta is of
particular concern. More than 35% of patients with BAV will require interventions
due to complications of the aortic valve and ascending aorta, and dissection and rupture
of the aortic root are the leading cause of death among patients with Marfan syndrome.[1]
[2] Despite the clinical significance of this association, the exact mechanism by which
these conditions lead to thoracic aortic complications is not yet fully elucidated.[1] Filling the gaps in this knowledge may not only provide insight into the pathogenesis
of aortic dilatation in the setting of CTD, but also may suggest strategies for predicting
and managing the course of disease.
In this study, we examined the histopathologic findings of 559 patients who underwent
aortic valve reimplantation from 2006 to 2017. By comparing these findings between
patients with BAV, CTD, and those without either, we can suggest different mechanisms
for the development of aortic root aneurysms and seek to identify factors associated
with the long-term success of aortic valve reimplantation.
Materials and Methods
Between January 2006 and March 2017, 568 patients underwent aortic valve reimplantation
for repair of aortic root aneurysm, including patients with tricuspid aortic valves
with no CTD (TAV/NoCTD, n = 314/568; 55%), BAVs (n = 86/568; 15%), or CTD (n = 177/568; 31%). Patients who were documented to have both a BAV and a CTD accounted
for only 1.6% of the study sample (n = 9/568) and were consequently omitted from some analyses, as further described below.
All consecutive patients who received the reimplantation procedure during the above
time period were included in the study with informed consent waived, as approved by
the institutional review board. Data collection consisted of retrospective review
of patients' medical records, imaging studies, pathology studies, and operative reports.
The mean follow-up time among all patients was 2.97 years.
All pathology reports that were available from the Epic electronic health record and
corresponded to a patient's reimplantation procedure were included in the study, including
reports for 98.42% (n = 559/568) of patients. All reports were generated from two staff pathologists at
Cleveland Clinic, who were the sole cardiovascular pathologists for the institution
throughout the period of study, with histopathologic findings based on tissue samples
collected during surgery, most often from the noncoronary sinus of a patient's aorta.
All reported findings were tabulated into different description groups based on specific
phrases used by the pathologists, including findings such as “aortitis,” “cystic medial
degeneration,” “elastic laminae fragmentation,” etc. All significant phrases from
patients' pathology reports were included in initial analysis and then were ultimately
placed into appropriate categories in accordance with the Consensus Statement on Surgical Pathology of the Aorta from the Society for Cardiovascular
Pathology and the Association for European Cardiovascular Pathology: II.[3] Ultimately, the six histopathologic categories used for analysis included aortitis,
cystic medial degeneration, elastic lamellar fragmentation and loss without overt
cystic medical degeneration, medial fibrosis without smooth muscle cell loss, mucopolysaccharide
accumulation/increase without overt cystic medial degeneration, and smooth muscle
cell loss/laminar necrosis. For simplification of communication, these categories
will be referred to throughout this study as “aortitis,” “cystic medial degeneration,”
“elastic laminae fragmentation/loss,” “medial fibrosis,” “mucopolysaccharide increase,”
and “smooth muscle cell loss” ([Fig. 1]).
Fig. 1 Pathology slides of the six major histopathologic categories analyzed according to
the Consensus Statement on Surgical Pathology of the Aorta from the Society for Cardiovascular
Pathology and the Association for European Cardiovascular Pathology: II. Histopathology of the aorta is shown using Movat pentachrome stain in which the
smooth muscle cell cytoplasm is stained red, elastic lamellae black, mucopolysaccharide
matrix blue-green, and collagen yellow. (A) Mucopolysaccharide accumulation within elastic lamellar units. (B) Elastic lamellar fragmentation. (C) Medial fibrosis without smooth muscle cell loss. (D) Medial fibrosis with smooth muscle cell loss. (E) Cystic medial degeneration with elastic lamellar loss and marked accumulation of
mucopolysaccharides. (F) Aortitis with multinucleated giant cells.
Surgical Techniques
Overall, the vast majority of operations were performed on an elective basis (n = 544/568, 95.77%), with the remaining operations considered either emergency (n = 16/568, 2.82%) or urgent (n = 8/568, 1.41%). Major clinical indications for operation on these patients included
aortic root aneurysm and aortic insufficiency; however, Type A dissection was listed
as a surgical indication for 15 patients (2.64%), and Type B dissection was a comorbid
condition for 12 patients (2.11%).
Among all operations, redo sternotomies were performed on 27 patients (4.75%). Concomitant
operations included aortic valve repair (n = 204/568, 35.92%), mitral valve repair (n = 46/568, 8.10%), tricuspid valve repair (n = 12/568, 2.11%), coronary artery bypass grafting (n = 43/568, 7.57%), total aortic arch replacement (n = 28/568, 4.93%), hemiarch replacement (n = 53/568, 9.33%), conventional elephant trunk procedure (n = 15/568, 2.64%), and frozen elephant trunk procedure (n = 12/568, 2.11%). The figure-of-8 suturing technique was used for aortic valve repair
31.37% of the time (n = 64/204).
Statistical Analysis
Statistical analysis was performed using Microsoft Excel 2016 and R statistical software.
Comparisons among the three main patient groups (TAV/NoCTD, BAV, CTD) were conducted
primarily through chi-square analyses and analysis of variance with a significance
value of 0.05, unless otherwise specified. To accurately meet this p-value requirement of 0.05, a Bonferroni correction was applied for the six major
histopathologic groupings, making the level of significance for those comparisons
p < 0.0083. A p-value requirement of 0.01 after Bonferroni correction would require p < 0.0017. Post hoc analyses were then conducted by chi-square analyses and two-tailed
unequal variance Student's t-tests as appropriate. As noted earlier, the group with coexisting BAV and CTD was
excluded from these particular tests to avoid reduction in statistical power because
of its small sample size (n = 9).
Analyses related to late reintervention on the aortic valve were also conducted, with
comparisons being made between patients requiring some type of aortic valve reintervention
(AVReInt, n = 11/559, 1.97%) and patients not requiring a reintervention on the aortic valve
(NoReInt, n = 548/559, 98.03%). The group of nine patients with coexisting BAV and CTD was excluded
from analysis. Tests conducted for these analyses included chi-square analyses and
two-tailed unequal variance Student's t-tests with a significance value of 0.05, unless otherwise specified.
Results
Patient Demographics
Basic patient demographics, including age, sex, and comorbidities among the three
main groups of comparison (TAV/NoCTD, BAV, CTD), can be found in [Table 1]. Significant differences were found for age and sex, as well as comorbidities of
coronary artery disease, prior myocardial infarction, prior stroke, hypertension,
hyperlipidemia, and any type of cancer—and all of these differences remained significant
at a p-value level of 0.01 after Bonferroni correction (p < 0.0007 for the 15 comparisons made) except for prior myocardial infarction (p = 0.011) and prior stroke (p = 0.028).
Table 1
Basic demographics of patient population, tricuspid aortic valves with no connective
tissue disease versus bicuspid aortic valves versus connective tissue disease
|
TAV/NoCTD
|
BAV
|
CTD
|
p-Value
|
|
n = 314 (%)
|
n = 77 (%)
|
n = 168 (%)
|
|
Age
|
51.9 (range: 16–79)
|
46.2 (range: 17–70)
|
37.6 (range: 13–73)
|
< 0.01[b]
|
|
Male/Female
|
272 (86.6) / 42 (13.4)
|
69 (89.6) / 8(10.4)
|
119 (70.8) / 49 (29.2)
|
< 0.01[b]
|
|
Smoking
|
140 (44.6)
|
24 (31.2)
|
63 (37.5)
|
0.06
|
|
Comorbidities:
|
|
|
|
|
|
Congestive heart failure
|
23 (7.3)
|
5 (6.5)
|
5 (3.0)
|
0.15
|
|
Coronary artery disease
|
114 (36.3)
|
13 (16.9)
|
25 (14.9)
|
< 0.01[b]
|
|
Prior myocardial infarction
|
17 (5.4)
|
1 (1.3)
|
1 (0.6)
|
< 0.05[a]
|
|
Prior stroke
|
13 (4.1)
|
2 (2.6)
|
0 (0.0)
|
< 0.05[a]
|
|
Hypertension
|
221 (70.4)
|
53 (68.8)
|
89 (53.0)
|
< 0.01[b]
|
|
Diabetes mellitus
|
15 (4.8)
|
1 (1.3)
|
9 (5.4)
|
0.33
|
|
Hyperlipidemia
|
162 (51.6)
|
29 (37.7)
|
43 (25.6)
|
< 0.01[b]
|
|
Chronic obstructive pulmonary disease
|
17 (5.4)
|
1 (1.3)
|
8 (4.8)
|
0.31
|
|
Chronic kidney disease
|
10 (3.2)
|
1 (1.3)
|
1 (0.6)
|
0.15
|
|
Cancer (any)
|
36 (11.5)
|
0 (0)
|
6 (3.6)
|
< 0.01[b]
|
Abbreviations: BAV, bicuspid aortic valves; CTD, connective tissue disease; TAV/NoCTD,
tricuspid aortic valves with no connective tissue disease.
a Indicates that the comparison demonstrated significance (p < 0.05) after applying a Bonferroni correction.
b Indicates that the comparison demonstrated significance (p < 0.01) after applying a Bonferroni correction.
Aortic Histopathology
Initial chi-square analyses of the pathology reports among the three main groups of
comparison (TAV/NoCTD, BAV, and CTD) revealed that there was a significant difference
between these groups related to the histopathologic parameters of “aortitis” (p < 0.01), “cystic medial degeneration” (p < 0.01), “medial fibrosis” (p < 0.01), “mucopolysaccharide increase” (p < 0.01), and “smooth muscle cell loss” (p < 0.01). No difference was found between these groups for “elastic laminae fragmentation/loss”
(p = 0.75).
In applying a Bonferroni correction (at a level of p < 0.05 and p < 0.01) to all of these findings for the six main histopathologic comparisons made,
the p-value threshold for significance was adjusted to p < 0.0083 and p < 0.0017, respectively. In meeting these correction requirements, the findings for
“medial fibrosis” and “mucopolysaccharide increase” met the p < 0.0083 threshold, while the findings for “aortitis,” “cystic medial degeneration,”
and “smooth muscle cell loss” met the p < 0.0017 threshold. These findings are all summarized in [Table 2]. Ensuing post hoc analyses are presented in [Fig. 2] and will be described in the paragraphs below.
Fig. 2 Aortic histopathologic findings among tricuspid aortic valve with no connective tissue
disease (TAV/NoCTD), bicuspid aortic valve (BAV), and connective tissue disease (CTD).
Table 2
Aortic histopathology findings, tricuspid aortic valves with no connective tissue
disease versus bicuspid aortic valves versus connective tissue disease
|
TAV/NoCTD
|
BAV
|
CTD
|
p-Value
|
|
n = 314 (%)
|
n = 77 (%)
|
n = 168 (%)
|
|
Aortitis
|
23 (7.3)
|
0 (0.0)
|
2 (1.2)
|
< 0.01[b]
|
|
Cystic medial degeneration
|
165 (52.5)
|
20 (26.0)
|
111 (66.1)
|
< 0.01[b]
|
|
Elastic laminae fragmentation/loss
|
47 (15.0)
|
9 (11.7)
|
23 (13.7)
|
0.75
|
|
Medial fibrosis
|
32 (10.2)
|
2 (2.6)
|
5 (3.0)
|
< 0.01[a]
|
|
Mucopolysaccharide increase
|
116 (36.9)
|
48 (62.3)
|
55 (32.7)
|
< 0.01[a]
|
|
Smooth muscle cell loss
|
32 (10.2)
|
2 (2.6)
|
6 (3.6)
|
< 0.01[b]
|
a Indicates that the comparison demonstrated significance (p < 0.05) after applying a Bonferroni correction.
b Indicates that the comparison demonstrated significance (p < 0.01) after applying a Bonferroni correction.
Post hoc analyses demonstrated that the TAV/NoCTD group had a higher prevalence of
“aortitis” (7.3%), as compared with both the BAV (0%, p < 0.05) and CTD (1.2%, p < 0.01) groups. Additionally, the TAV/NoCTD group had a higher prevalence of “medial
fibrosis” (10.2%) as compared with the BAV (2.6%, p < 0.05) and CTD (3.0%, p < 0.01) groups, as well as a higher prevalence of “smooth muscle cell loss” (10.2%),
as compared with the BAV (2.6%, p < 0.05) and CTD (3.6%, p < 0.05) groups.
The BAV group was noted to have the highest prevalence of “mucopolysaccharide increase”
(62.3%), being significantly higher than both the TAV/NoCTD (36.9%, p < 0.01) and CTD groups (32.7%, p < 0.01).
Finally, prevalence of “cystic medial degeneration” was greatest in patients with
CTD (66.1%), then TAV/NoCTD (52.5%), and least in BAV (26.0%, p ≤ 0.01 for all comparisons). These major histopathologic findings are presented with
their associated conditions using a simplified schematic in [Fig. 3].
Fig. 3 Simplified schematic demonstrating the main aortic histopathologic findings associated
with tricuspid aortic valve with no connective tissue disease (TAV/NoCTD), bicuspid
aortic valve (BAV), and connective tissue disease (CTD) after analysis.
Morbidity and Mortality
In examining safety of reimplantation operations overall, death within 30 days of
operation occurred in only 3 patients (0.53%). Regarding complications, operative
stroke occurred in 8 patients (1.41%), operative paralysis occurred in 5 patients
(0.88%), operative paresthesia occurred in 12 patients (2.11%), myocardial infarction
occurred in 7 patients (1.23%), and reoperations for bleeding were performed in 40
patients (7.04%).
Aortic Valve Reinterventions
In our sampled population, 1.97% of patients (n = 11/559) had an unplanned reintervention on the aortic valve postreimplantation.
As summarized in [Table 3], there were no significant differences in age, sex, smoking status, or comorbidities
between the patients who underwent late aortic valve reintervention and those who
did not.
Table 3
Basic demographics of patient population, aortic valve (AV) reintervention versus
no AV reintervention
|
AV reintervention
|
No AV reintervention
|
p-Value
|
|
n = 11 (%)
|
n = 548 (%)
|
|
Age
|
38.3
|
47.0
|
0.07
|
|
Male/Female
|
10 (90.9)/1 (9.1)
|
450 (82.1)/98 (17.9)
|
0.45
|
|
Smoking
|
6 (54.5)
|
221 (40.3)
|
0.34
|
|
Comorbidities:
|
|
|
|
|
Bicuspid aortic valve
|
3 (27.3)
|
74 (13.5)
|
0.19
|
|
Connective tissue disease
|
2 (18.2)
|
166 (30.3)
|
0.39
|
|
Congestive heart failure
|
1 (9.1)
|
32 (5.8)
|
0.65
|
|
Coronary artery disease
|
3 (27.3)
|
149 (27.2)
|
1.00
|
|
Prior myocardial infarction
|
0 (0.0)
|
19 (3.5)
|
0.53
|
|
Prior stroke
|
1 (9.1)
|
14 (2.6)
|
0.18
|
|
Hypertension
|
5 (45.5)
|
358 (65.3)
|
0.17
|
|
Diabetes mellitus
|
0 (0.0)
|
25 (4.6)
|
0.47
|
|
Hyperlipidemia
|
3 (27.3)
|
231 (42.2)
|
0.32
|
|
Chronic obstructive pulmonary disease
|
0 (0.0)
|
26 (4.7)
|
0.46
|
|
Chronic kidney disease
|
0 (0.0)
|
12 (2.2)
|
0.62
|
|
Cancer (any type)
|
0 (0.0)
|
42 (7.7)
|
0.34
|
When analyzing for aortic histopathologic differences between these two groups, there
were no significant differences for any of the six categories of “aortitis” (p = 0.47), “cystic medial degeneration” (p = 0.27), “elastic laminae fragmentation/loss” (p = 0.63), “medial fibrosis” (p = 0.78), “mucopolysaccharide increase” (p = 0.67), or “smooth muscle cell loss” (p = 0.35) in relation to aortic valve reinterventions. A summary of these histopathologic
findings can be found in [Table 4].
Table 4
Aortic histopathology findings, aortic valve (AV) reintervention versus no AV reintervention
|
AV reintervention
|
No AV reintervention
|
p-Value
|
|
n = 11 (%)
|
n = 548 (%)
|
|
Aortitis
|
0 (0.0)
|
25 (4.6)
|
0.47
|
|
Cystic medial degeneration
|
4 (36.4)
|
292 (53.3)
|
0.27
|
|
Elastic laminae fragmentation/loss
|
1 (9.1)
|
78 (14.2)
|
0.63
|
|
Medial fibrosis
|
1 (9.1)
|
38 (6.9)
|
0.78
|
|
Mucopolysaccharide increase
|
5 (45.5)
|
214 (39.1)
|
0.67
|
|
Smooth muscle cell loss
|
0 (0.0)
|
40 (7.3)
|
0.35
|
Discussion
Normal histology of the ascending aorta reveals three layers: the tunica intima, tunica
media, and tunica adventitia, from the inside (luminal aspect) to the outside of the
vessel, respectively. The tunica media layer, the largest component of the aortic
wall, is composed of 60 to 70 layers of lamellar units, which are composed of smooth
muscle cells, collagen, and proteoglycans, between two sheets of elastic lamellae.[3] Disruption of lamellar units is routinely evaluated during pathologic examination,
and aortic aneurysms and dissections are specifically associated with medial degeneration.[4] Due to the potentially fatal outcomes of these conditions, it is imperative to investigate
the components of the medial layer of the aorta to understand the pathogenesis of
the degeneration.
Several studies have investigated the role of mucopolysaccharides, also known as proteoglycans,
in both the nonpathologic and pathologic states of the aorta. In the nonpathologic
state, for example, Azeloglu et al[5] verified their hypothesis that proteoglycans produce a Donnan osmotic pressure,
helping to provide residual stress to the aorta to allow for homeostatic maintenance
of uniform distribution of wall stress. Increasing the proteoglycan production, degradation,
and distribution is how vascular cells respond to changes in wall stress from blood
pressure or flow.[5] The negative charges on glycosaminoglycan side chains attract mobile counterions,
such as sodium; water then follows the sodium, creating pressure in the region.[6] This swelling changes the tension on the connections between the microfibrils and
the smooth muscle cells, facilitating the mechanosensory function of smooth muscle
cells.[6]
However, if proteoglycan levels accumulate to pathologic levels, they can generate
an osmotic pressure that can disrupt the extracellular matrix within the lamellar
unit.[6] This disruption has biochemical, electrochemical, and mechanobiological ramifications.[7] Specifically, Cikach et al[6] have discussed the characteristics of different proteoglycans, aggrecan and versican,
that belong to the proteoglycanomes of both nonpathologic and pathologic states of
the aorta. For example, glycosylated versican demonstrates antiadhesive properties.[6] Smooth muscle cells, endothelial cells, fibroblasts, and cardiac myocytes require
adhesion to structural glycoproteins for survival—and adhesion represses apoptotic
signals and allows for tensional integrity.[8] Therefore, antiadhesive properties play a role in the deterioration of smooth muscle
cells.[6] Furthermore, Michel[8] discussed how a loss of interactions between cells and the extracellular matrix
prompts smooth muscle cell apoptosis by a process known as anoikis. Thus, depending
on the degree, proteoglycan accumulation throughout the aorta might lead to pathologic
states.
For the case of thoracic aortic aneurysms and dissections (TAADs), Cikach et al[6] used ribonucleic acid in situ hybridization studies to demonstrate a rise in gene
expression of aggrecan and versican in humans and in mouse models. They also noted
reduced expression of ADAMTS5, a protease that contributes to the degradation of proteoglycans.[6] Thus, given increased production and decreased turnover of proteoglycans, proteoglycans
are able to accumulate. Cikach et al[6] speculated that the process of proteoglycan accumulation is accelerated in TAAD
because of genetic defects in the connections between cells and extracellular matrix
of lamellar units. It has been established that proteoglycans are present in states
of TAAD.[3] Nonetheless, the role that proteoglycans play in the pathogenesis of TAAD is currently
being investigated.[6]
Given our observations that the BAV group of aortic root biopsies exhibited an increased
frequency of “mucopolysaccharide increase,” we postulate that individuals with BAV
might develop aortopathy, such as TAAD, at a faster rate and/or to a greater degree
than patients who have a TAV and no coexisting CTD. Greater proteoglycan content or
distribution in the aortic wall could result in a greater Donnan osmotic swelling
pressure and loss of tensile stiffness, creating a microenvironment that facilitates
the development of stress concentrations.[9]
In our study, we did not observe any differences in the frequency of elastic laminae
fragmentation and loss among patients with TAV/NoCTD, BAV, or CTD. However, several
other studies have previously documented that the aortas in patients with BAV tend
to have well-organized elastic lamellae that are thinner and have a greater interlamellar
distance.[10]
[11] Some published literature has demonstrated disagreement with this finding, such
as a study from de Sa et al[12] that reported that elastic fragmentation, smooth muscle cell changes, and cystic
medial degeneration were significantly more severe in patients with BAV as compared
with patients with TAV. Other studies have identified possible biomarkers that suggest
an alternative mechanism for the development of aneurysm in patients with BAV, including
elevated levels of matrix metalloproteinases (MMP). In particular, the turbulent flow
and shear stress associated with BAV may activate MMP-2, which is predominantly expressed
in the outer curvature of the ascending aorta and cleaves numerous collagen subtypes
and fibrillin. On the other hand, elastic fragmentation in TAV may be driven by elevated
levels of MMP-13.[13]
[14] Seeing as we could not distinguish a difference in this parameter, the role of elastic
laminae fragmentation and loss remains unclear between these groupings.
The CTD group was noted to have greater amounts of “cystic medial degeneration” than
the BAV and TAV/NoCTD groups. This is consistent with multiple studies that have specifically
associated Marfan syndrome with more overall medial degeneration.[11]
[15] However, the graded effect seen with the BAV group having less frequent cystic medial
degeneration than the TAV/NoCTD group is somewhat in disagreement with the study from
de Sa et al[12]—though this may be more of a difference in sampling error and/or classification
between frequency and severity of cystic medial degeneration, as the present study
was only designed for frequencies of the pathology phrase.
While we have highlighted some histopathologic differences in this study, there may
be some overlap between the mechanism of aortic wall complications between patients
with BAV and CTD. In particular, a study by Grewal and Gittenberger-de Groot[16] examined specimens from the aortas of patients with Marfan syndrome and BAV and
found that a significant lack of differentiation of vascular smooth muscle cells (VSMCs)
appears to play a role in the disease process of both. This was highlighted by a lack
of smoothelin, a marker of highly differentiated VSMCs, and localization of fibrillin-1
that was intracellular, as opposed to the extracellular localization observed in aortas
with TAV and no CTD. This overlap, they hypothesized, may be attributed to the common
embryological origin of the semilunar valves and the VSMCs of the ascending aorta
and aortic root, both of which are derived from neural crest cells and second heart
field progenitor cells.
Finally, the TAV/NoCTD group was notably distinguished from the BAV and CTD groups
by its higher frequencies of “aortitis,” “medial fibrosis,” and “smooth muscle cell
loss.” Other preliminary analyses in preparation for this study discovered that common
phrases in the “aortitis” group also included “inflammation,” “neointimal hyperplasia,”
and “plasma cells.” These phrases all share an inflammatory and/or chronic disease
picture of pathogenesis that differs from the more congenital mechanisms at play in
BAV and CTD patients. Aortitis, including giant cell arteritis and clinically isolated
aortitis, are typically more common in older patients, and present as aortic aneurysms.
The findings of “medial fibrosis” and “smooth muscle cell loss” are also intuitively
consistent with the demographic findings that the TAV/NoCTD group tended to present
for surgery at older ages, and that these findings were at least in part related to
age-related changes.
In reintervention analyses, there were no statistically detectable differences in
either demographics of histopathology noted between patients who underwent an unplanned
reintervention on the aortic valve and those who did not. While this result may simply
be due to a lack of power (as this comparison was significantly unbalanced in population
sizes), this study's design ultimately could not identify any useful patient characteristics
or histopathologic factors in predicting need for a future procedure on the aortic
valve.
There were some limitations in this study that may have influenced some of our findings.
Broadly speaking, the design does revolve around a single-center, retrospective chart
review of many histological descriptions of aortic specimens spanning 11 years of
patients. While one concern with this could be that there were variations in phrasing
and/or interpretation of findings among pathology readings, this was controlled for
by including a range of dates for which there were only two staff cardiovascular pathologists
in charge of these reports. Additionally, initial data collection from patient charts
were tabulated with any and all descriptions from every pathology report first before
being sorted later into their representative categories to best reflect the recommendations
based on the Consensus Statement on Surgical Pathology of the Aorta from the Society for Cardiovascular
Pathology and the Association for European Cardiovascular Pathology: II.[3] Despite these efforts, it is understood that depending on the size and location
of a tissue sample that was retrieved from surgery, there may have been differing
amounts of findings on the histologic slides, which is a limitation of sampling error
that could not be addressed in this retrospective study.
Ultimately, this study was intended as a preliminary investigation into what histopathologies
are found in some of the major patient groups that we see presenting with thoracic
aortic aneurysms. Because the sample is drawn from consecutive patients, the results
of the study are representative of the patients who receive aortic valve reimplantation
procedures at our institution. Since there were no patient matching analyses performed,
there were a few notable, significant differences in patient demographics. This obviously
does not mean that all of our findings can be contributed to our defined groupings
alone, but this study does help describe how the groups that we see commonly present,
such as how patients with CTD tend to require surgical management at younger ages.
In recognition of these limitations, research on the development of thoracic aortic
aneurysms would certainly benefit from more prospective studies that specifically
examine the histopathologies of patient tissue samples. Some prospective research
has already been done in mouse models, such as in a study by Cikach et al,[6] which observed increased aggrecan staining in mice with Marfan syndrome; similar,
ongoing research at Cleveland Clinic using human aortic specimens will continue to
provide insight surrounding our understanding of the differing pathophysiologies of
aortic aneurysms.
Conclusions
This preliminary, single-center, retrospective study was designed to investigate the
histopathologic features of patients who present for aortic valve reimplantation procedures
to suggest different mechanisms for the pathogenesis of aortic root aneurysms and
to identify factors associated with long-term success of aortic valve reimplantation.
While there were many common histopathologic features among patients undergoing aortic
valve reimplantation, there were enough distinguishing features among aortic tissue
samples of TAV/NoCTD, BAV, and CTD patients to propose that these patient groups develop
aortic root aneurysms by different mechanisms. However, while these pathology report
findings may provide insight into the different ways that aortic root aneurysms develop,
there were no significant histopathologic findings that could predict the need for
late reintervention on the aortic valve.
