Statistics

Statistical analysis was performed using IBM SPSS Statistics, version 26, software. For the first study, which included 42 patients with HTAD with documented genetic variations, the Kruskal-Wallis test was used to compare the grade of medial degeneration among genes. The grade of medial degeneration was measured on an ordinal scale, with scores ranging from 1 (mild) to 3 (severe). A χ² test was used to compare the frequency of aortic dissection across the genes.

For the second study involving the detailed examination of histologic sections from all operative cases of thoracic aortic disease in a single year (2019), the Pearson χ² test was used to compare the frequency distributions of categorical data between groups. The Mann-Whitney test was used to compare variables across the dichotomous groups. The variables were measured on an ordinal scale.

HTAD With Documented Genetic Variations

Patients with HTAD were identified by querying the Division of Medical Genetics database.^6,9,10 Forty-two patients had positive genetic tests and surgical pathology material available that had been obtained during open surgical repair from 2012 to 2020. The 42 individuals had pathogenic variants in 1 of the following 10 established genetic aortopathies: FBN1,¹¹ACTA2,⁶TGFBR1,¹⁰TGFBR2,³TGFβ2,³SMAD3,³LOX,²MYLK,²PRKG1,² and COL3A1.^5,7-10

These aortic specimens were evaluated for intimal lesions, medial dissection, and medial degenerative lesions based on SCVP/AECP consensus criteria.¹ A spectrum of extent and severity of medial degenerative changes was observed: 8 patients (19%) had mild disease, 18 patients (43%) had moderate disease, and 16 patients (38%) had severe disease (Table II). Mucoid extracellular matrix accumulation was particularly prominent in patients with Marfan syndrome (Fig. 2). Of the 42 patients in this study, 17 had aortic dissection and 25 had nondissected aneurysms. When the data were analyzed according to the affected genes, neither the differences in the grade of medial degeneration nor the differences in the frequency of aortic dissection were statistically significant.

TABLE II. Medial Degeneration in Heritable Thoracic Aortic Aneurysm and Dissection (Genetic Aortopathies)

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Comparative Studies

In an analysis of 86 operative cases of thoracic aortic disease within 1 year, 34 cases were type A aortic dissection, and 52 cases were ascending thoracic aortic aneurysms without aortic dissection (Fig. 2 and Fig. 3). Notable differentiating features of the 86 cases were heritable aortopathy with known genetic variation (12/86) or sporadic disease (74/86), bicuspid aortic valve (BAV) (21/86) or tricuspid aortic valve (TAV) (65/86), and aortic root involvement (23/86) or aortic root spared (63/86). The grading of medial degeneration in the various categories is shown in Figure 3.

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Overall medial degeneration was significantly different between inherited and sporadic aortopathy groups, with the inherited group typically having higher severity levels than the sporadic group (P = .004). The extent of elastic fiber fragmentation and translamellar MEMA was significantly different between the inherited and sporadic aortopathy groups (elastic fiber fragmentation, P = .03; MEMA, P = .04), with greater severity observed in the inherited aortopathy group.

Medial degeneration scores were not significantly different between patients with type A aortic dissection and patients with nondissected aneurysms. Extent and severity of elastic fiber fragmentation were significantly lower for patients with BAV than for patients with TAV (P = .001 and P = .002, respectively). Age was not significantly different between patients with BAV and patients with TAV (mean [SD] age, 57.5 [11.5] years vs 58.2 [16] years; P = .8). Most patients with BAVs had a mild (1-5) to moderate (6-10) medial degeneration score. In contrast, most patients with TAVs had a moderate (6-10) to severe (11 to ≥20) medial degeneration score and more frequent type A aortic dissection.

Cases with and without aortic root involvement were also compared. Aortic root involvement was defined as involving the aortic sinuses (Table III). Of the 23 patients with aortic root involvement, 21 had an aneurysm of the sinus of Valsalva, and 2 patients had acute type A aortic dissection. In addition, 7 of the 23 patients had heritable aortopathy with a known genetic variation. The procedures patients underwent included valve-sparing aortic root replacement (David procedure; n = 13), aortic root replacement with a prosthetic aortic valve (n = 6), and reoperation with aortic root or valve replacement (n = 4). The overall medial degeneration severity was significantly different between patients with and without aortic root involvement, with the aortic root involvement group typically having more severe disease than the group with no aortic root involvement (P = .01).

TABLE III. Medial Degeneration in Patients With and Without Aortic Root Involvement^a

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Another focus of this investigation was sex differences among the cohort of 86 patients with proximal thoracic aortic disease (64 men and 22 women) (Table IV). The overall incidence of thoracic aortopathy was higher in men, accounting for 74.4% of individuals with proximal thoracic aortic disease; however, heritable aortopathy with known genetic variation was more prevalent in women than in men (27.2% vs 9.8%; P = .03). Histopathology data showed that women more frequently had translamellar MEMA (45.4% vs 21.8%; P = .04), extensive (54.5% vs 22.8%; P = .02) and severe (59% vs 32.8%; P = .04) elastic fiber fragmentation, extensive smooth muscle nuclei loss (13.6% vs 4.9%; P = .05), and focal laminar medial collapse (13.6% vs 1.6%; P = .01) than men. Overall histopathologic medial degenerative scores were higher in women than in men (P = .047). Among the 86 patients, women had a lower prevalence of thoracic aortic disease treated with open repair than men; however, women who developed thoracic aortic disease harbored a greater burden of aortic wall pathology.

TABLE IV. Assessment of Medial Degeneration in Women and Men With Thoracic Aortic Aneurysm and Dissection^a

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A separate analysis examined the incidence of type A aortic dissection in patients with heritable aortopathy and patients with sporadic etiology, primarily as a complication of hypertension. Of the 34 patients with type A aortic dissections, 10 had genetic aortopathy (group 1), and 24 had sporadic disease (group 2). The percentage of type A aortic dissections was not significantly different between groups 1 and 2 (23.8% vs 27.9%; P > .5). Patients in group 1 were significantly younger than patients in group 2 (group 1 mean [SD] age, 49.5 [14.9] years vs group 2 mean [SD] age, 61.9 [16.8] years; P = .048). Group 1 had no patients with atheromatous lesions, whereas group 2 had 5 patients with aortic atherosclerosis (P < .02). Regarding medial degeneration, no significant differences were observed between groups regarding elastic fiber fragmentation (mean [SD], 4.4 [1.7] points vs 4.0 [1.5] points; P = .5), smooth muscle cell nuclei loss (2.2 [2.3] points vs 1.9 [2.2] points; P = .70), or laminar medial collapse (1.1 [1.4] vs 0.5 [1.2] points; P = .20). Group 1, however, had a significantly higher level of MEMA than did group 2 (mean [SD], 4.7 [2.1] points vs 2.6 [3.4] points; P = .04) (Fig. 2). In both groups, medial degeneration lesions were concentrated on the outer one-third of the aortic media.

Comparative Analysis of Medial Degeneration Among Aortopathies

A particular focus of this study was comparatively assessing patients with sporadic aortopathies and documented heritable aortopathies. Among patients with heritable aortopathy and documented pathogenic genetic variants, considerable overlap in the various types of medial degeneration lesions and the overall severity of medial degeneration was observed (Table IV). Specific trends, however, were noted. Patients with Marfan syndrome frequently had prominent translamellar MEMA (Fig. 2). Some patients with Ehlers-Danlos syndrome had minimal histologic change, despite severe clinical manifestations. This finding can be explained by a basic genetic variation that leads to defective collagen and intact elastic fibers. As was previously reported, ACTA2 variations¹⁸ showed evidence of dysplasia of the vasa vasorum and disorganization and loss of smooth muscle cells in the aortic media.¹⁸

In this study’s analysis of cases within a single recent year (Fig. 3), overall medial degeneration was significantly different between patients with heritable aortopathy and patients with sporadic aortopathy, with significantly more elastic fiber fragmentation and translamellar MEMA in patients with heritable aortopathy. In both groups, the markers of medial degeneration were concentrated on the outer one-third of the aortic media.

The overall medial degeneration score was high in patients with aortic root aneurysm and HTAD. Most patients with BAVs had low medial degeneration scores, whereas patients with TAVs had moderate medial degeneration scores and a high incidence of type A aortic dissection. In this patient population, women had a lower prevalence of thoracic aortic disease treated with open repair; however, those women who developed thoracic aortic disease harbored a greater burden of aortic wall pathology and had a higher probability of worse outcomes. The adverse outcomes of women with thoracic aortic disease have been noted in other clinical studies.³

From this study’s findings, the authors posit that the extent and severity of individual pathologic lesions and overall medial degeneration reflect a final common pathway for aortic diseases of genetic and sporadic etiologies; however, the comprehensive analysis was useful in identifying certain features that may differentiate a sporadic from a genetic etiology of proximal thoracic aortic disease, such as more MEMA in patients with HTAD than in patients with sporadic disease (Fig. 3).

Consideration of Findings in the Broader Context of the Literature

Clinicians can gain a broad perspective by comparing these findings with those of other groups that have performed systematic histopathologic analysis of proximal thoracic aortic disease specimens.^11-17 Leone et al^15,16 performed a detailed histopathologic analysis of aortic specimens from patients with ascending thoracic aortic aneurysms and acute aortic syndromes. In a series that examined 158 patients, 2 histologic patterns were identified: medial degenerative alterations alone in 122 patients (77%) and mixed degenerative-atherosclerotic lesions in 36 patients (23%). Patients with mixed degenerative-atherosclerotic disease had a distinct clinical profile characterized by a clinical presentation that often mimics acute coronary syndrome.¹⁶ In another series of 255 patients with surgically treated ascending thoracic aortic aneurysms, the histopathologic lesion was most often a medial degenerative change (67.5%) but with a considerable prevalence of atherosclerotic lesions (18.8%) and aortitis (13.7%).¹⁵ The authors concluded that although degenerative histopathology is the most frequent type of lesion in ascending thoracic aortic aneurysm, atherosclerosis and inflammation also contribute to chronic thoracic aortic aneurysm disease development. This conclusion is in contrast with the current study’s findings of a low frequency of aortitis and minimal atherosclerosis in most patients with ascending thoracic aortic aneurysm or dissection.

In a study by Waters et al,¹¹ the SCVP/AECVP consensus criteria grading system was used to evaluate 148 surgically resected specimens. The authors found that overall patterns of histopathologic change could be used to distinguish patients with BAVs and nonsyndromic disease from patients with Marfan syndrome and Loeys-Dietz syndrome. Patients with Marfan syndrome had significantly more overall medial degeneration and MEMA than patients with other syndromes. This finding is in agreement with the current study’s findings regarding patients with Marfan syndrome.

In a retrospective study, Amemiya et al¹³ analyzed aortic specimens from a large cohort (N = 496) surgically treated for aortic diseases at a major European aortic center. Their findings revealed the following: (1) patients without BAVs have higher medial degeneration scores than patients with BAVs; (2) higher medial degeneration scores are correlated with increased aortic diameter; (3) thoracic aortic disease can occur frequently in small aortas associated with high medial degeneration scores; and (4) the clinical risk stratification of aortic dissection based on aortic dimensions is imperfect.

In another large retrospective study of 719 patients, Amemiya et al¹² examined the role of aging and other degenerative processes compared with inflammation in damaging the aortic wall. Using the SCVP/AECVP consensus criteria, they observed higher medial degeneration scores for all aortic sizes in a group of patients with aortitis than in a group of patients without aortitis, especially with respect to elastic fiber damage and smooth muscle cell loss. The authors concluded that aortitis is strongly associated with severe damage to the aortic wall, resulting in advanced medial degeneration scores, and that the inflammatory process induces greater medial degeneration in the aortic wall than aging or other degenerative processes.

In another study, Stejskal et al¹⁷ evaluated aortic dissection specimens using the SCVP/AECVP consensus criteria. They presented their results from 62 ascending aortic dissection biopsies during a 5-year period at a single institution. The most common finding was medial degeneration in 61 patients (98.4%). Atherosclerosis was identified in 19 patients (30.6%), and a chronic giant cell aortitis pattern was seen in 1 patient (1.6%). The results were compared between subgroups of patients with BAVs (n = 7 [11.3%]) and patients with TAVs (n = 55 [88.7%]). No significant differences were observed, except for more severe (P = .04) translamellar fibrosis in the BAV group than in the TAV group (P = .04). These findings contrast with the current study’s finding that patients with TAVs had more severe medial degeneration changes than patients with BAVs.

In summary, studies from several centers, including the current study, have reported histopathologic data generated by applying the SCVP/AECVP consensus criteria for systematically assessing thoracic aortic disease pathogenesis. A particular contribution of the study by Amemiya et al¹³ was the reporting of aortic size in relationship to the histopathologic findings.

A consistent finding from most of the studies that applied the consensus criteria was that aortic medial degenerative changes are less severe in patients with BAVs than in patients with TAVs. This finding has been reported by others, as well.¹⁴ Grewal and colleagues¹⁹ further characterized the aortic wall in patients with BAVs and found a vascular smooth muscle differentiation defect in ascending aorta with BAVs before the development of medial degenerative changes and aneurysm formation.¹⁹ They described a significantly thinner intimal layer without features of atherosclerosis (P < .001) and a significantly thicker medial layer (P < .001) with more MEMA (P < .001) in nondilated ascending aortic walls with BAVs than in aortic walls with TAVs. The aortic media had significantly fewer differentiated vascular smooth muscle cells in the BAV group than in the TAV group (P < .0001), with reduced expression of α-smooth muscle actin, SM22-α, and smoothelin (P < .001) between the neatly regulated elastic lamellae in the BAV group. The findings of Grewal et al¹⁹ are consistent with a vascular smooth muscle differentiation defect in the ascending aorta of patients with BAVs before the development of medial degenerative changes and aneurysm formation.¹⁹

The Role of Genetic Variants in Thoracic Aortic Disease

Underlying genetic variants strongly influence the risk of thoracic aortic disease.^7-10 To date, pathogenic variants in at least 11 genes have been found to predispose individuals to either syndromic or nonsyndromic heritable thoracic aortic aneurysm and dissection.^7-10 An estimated 30% of patients with HTAD, which is typically inherited in an autosomal dominant manner, also have a pathogenic variant in 1 of these genes. Saxon and colleagues²⁰ identified pathogenic variants in these 11 genes by analyzing the postmortem tissue or blood in 23.5% of the study’s population, individuals who died suddenly of thoracic aortic disease. These gene variants predispose individuals to aneurysms and dissections of the thoracic aorta and, in some cases, to vascular complications throughout the arterial tree.^7-10 These genes are involved in vascular smooth muscle cell contraction and metabolism, extracellular matrix integrity, and transforming growth factor-β signaling.^7-10 The gene mutation creates an altered milieu, which leads to activation of local inflammation, cytokine activation, increased proteolysis of extracellular matrix components, and deficient smooth muscle cell function.^7-10 Further study is ongoing to correlate the extent and type of medial degenerative lesions with specific gene variations. Research is also in progress to identify other genes that predispose individuals to thoracic aortic disease. In 60% of cases, the gene variation is currently unknown.

Genetic factors are also believed to be important in the pathogenesis of sporadic or late-onset thoracic aortic diseases—specifically, genes that predispose the individual to the disease in combination with other risk factors, such as hypertension. Single-cell transcriptome analysis has revealed dynamic cell populations and differential gene expression patterns that control aneurysmal aortic tissue.²¹ Proteomic analysis has shown some overlapping differentially expressed proteins between aneurysmal and nonaneurysmal descending thoracic aortas at risk of dissection compared with normal aortas as well as uniquely altered molecular pathways that may represent mechanisms for dissection.²² These findings imply that selective gene activation is integral to developing different types of aortic pathology.

A unifying hypothesis to explain the spectrum of thoracic aortic disease is that variant genes and the selective activation of genes in sporadic disease cause vasculopathy by producing alterations in the functional integrity of the lamellar units.^23-25 Ultrastructural analyses have identified impaired connections between vascular smooth muscle cells and elastic fiber extensions and the loss of interconnecting elastic fibers that bind the longitudinal elastic fibers across lamellar units, particularly in the outer media.^23,25 These alterations have been postulated to lead to altered mechanotransduction and the progressive impairment of aortic smooth muscle function and structure, followed by the accumulation of MEMA and degeneration of the longitudinal elastic fibers of the lamellae.^9,24 This process, in turn, leads to the various lesions of medial degeneration identified by using the SCVP/AECVP consensus criteria.¹

Although the literature has shown the importance of genetic factors in the pathogenesis of thoracic aortic aneurysm and dissection, this study has shown that formal genetic analytical data are often unavailable in everyday practice. This finding has led to the development of a proposed scheme for assigning a genetic component to cases of thoracic aortic disease (Table V).

TABLE V. Proposed Paradigm for Assessing the Genetic Contribution to Thoracic Aortic Disease

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Limitations

This study had limitations. Most notably, the number of patients in both substudies was relatively small. Also, the obtained pathologic information was available only after the surgeries were complete and was unavailable for making intraoperative decisions.