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Original article
Type A aortic dissection in patients with bicuspid aortic valves: clinical and pathological comparison with tricuspid aortic valves
  1. Mackram F Eleid1,
  2. Inga Forde1,
  3. William D Edwards2,
  4. Joseph J Maleszewski2,
  5. Rakesh M Suri3,
  6. Hartzell V Schaff3,
  7. Maurice Enriquez-Sarano1,
  8. Hector I Michelena1
  1. 1Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
  2. 2Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA
  3. 3Division of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Hector I Michelena, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; michelena.hector{at}mayo.edu

Abstract

Objective Bicuspid aortic valve (BAV) is associated with a higher risk of type A aortic dissection (AD) compared with tricuspid aortic valve (TAV). We sought to study differences between patients with BAV and TAV with AD.

Design and setting Observational descriptive analysis of clinical, imaging and pathological characteristics of all patients with confirmed BAV and AD from 1980–2010, compared with a consecutive TAV group with AD.

Results Of 47 patients with BAV (mean age 58±14, 77% male), 31 (66%) had acute AD, 16 (34%) had chronic AD, 40 (85%) had typical BAV, 32 (68%) had hypertension and 11 (23%) had previous aortic coarctation repair. Of 53 patients with TAV (mean age 66±13 (p=0.007), 76% male), 34 (66%) had acute AD (p=1.0) and 46 (87%) had hypertension (p=0.03). More patients with BAV had known aortic dilatation prior to AD (49% versus 17%, p=0.001). Presentation symptoms were identical between groups (p=NS). Maximal ascending aortic diameter at AD was higher in patients with BAV (66±15 mm vs 56±11 mm, p=0.0004). Previous aortic valve replacement (AVR) was more common in BAV (23% vs 6%, p=0.02). Of 11 patients with BAV with previous isolated AVR, 7 had ≥moderate ascending aorta dilatation at the time of surgery. Patients with BAV had increased aortic jet velocity (28% vs 10%) and more severe aortic stenosis (19% vs 0%) at presentation (p=0.04 and 0.002, respectively). In acute AD, aortic medial degeneration affected 75% of BAV specimens and 41% TAV specimens (p=0.01) while aortic atherosclerosis was more frequent in TAV (56% vs 26%, p=0.02).

Conclusions Compared with patients with TAV, patients with BAV with type A AD are younger, have less hypertension, more valve stenosis and previous AVR, higher maximal aortic dimension, worse aortic medial degeneration, high prevalence of aortic coarctation, and 1 out of 2 have known aortic dilatation prior to AD. Implementation of current guidelines could have theoretically prevented AD in several patients with BAV.

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Introduction

Bicuspid aortic valve (BAV) is a valvular aortopathy affecting 1.3% of the general population.1 Aortic valve replacement (AVR) is the most frequent complication incurred by these patients.2 ,3 However, aortic dissection (AD), despite its low contemporary incidence, is approximately eight times more common in patients with BAV compared with the general population4 and remains the most feared complication, owing to its high mortality.5 Aortic aneurysm, defined as an ascending aorta ≥45 mm,4 is approximately 86 times more frequent in BAV than the general population, and is associated with a higher incidence of AD.4

In the general population with predominantly tricuspid aortic valve (TAV), severe dilatation of the ascending aorta beyond 55–60 mm is a risk factor for AD,6 and although AD may occur in patients with only mild or moderate dilatation,7 prophylactic surgical aorta repair based on a 55 mm cut-off has been adopted for patients with TAV. 8 ,9 For patients with BAV, this cut-point has been arbitrarily set at 50 mm. Based on scant clinical data, concomitant elective aorta repair is also recommended for patients with BAV undergoing AVR if the ascending aorta is ≥45 mm.8 Despite these different thresholds, the differences between patients with BAV and TAV who develop AD remain unexplored. Our objective was to describe the clinical characteristics, aortic imaging, and pathological findings in a population of patients with Type A AD and pathologically or surgically-confirmed BAV, and compare them to a group of patients with AD with TAV who underwent surgery.

Methods

Patients

We identified all patients with a pathologically and/or surgically-confirmed congenital BAV and Stanford type A AD10 ,11 at our institution from December 1980 to December 2010. To ensure complete capture of all patients, we performed a systematic search and cross-linkage of all electronic databases including medical records, surgical procedures, pathology and echocardiography reports. The study group included all patients with either acute (<2 weeks of symptoms) or chronic (≥2 weeks of symptoms or asymptomatic/incidentally found) AD with confirmed BAV. Patients with heritable connective tissue disease were excluded (n=4). Patients with vasculitis-associated AD were also excluded (n=2). A control group of all consecutive patients with TAV with acute or chronic Stanford type A AD who underwent surgery at our institution from May 2005 to January 2010 was used for comparison. Baseline clinical characteristics were obtained from the medical records. AD was diagnosed by detection of an ascending aortic intimal flap using either echocardiography or CT or by one or more intimal tears identified by pathologists.5 The protocol was approved by the institutional review board.

Echocardiography

Left ventricular ejection fraction was assessed with two-dimensional echocardiography12 and visual estimation.13 Initial diagnosis of BAV was based on transthoracic short-axis imaging of the aortic valve demonstrating only two commissures delimiting only two aortic valve cusps.2 ,3 Bicuspid valves were classified as typical (right-left coronary cusp fusion) if the commissures were at 4–10, 5–11 or 3–9 o'clock (anterior-posterior cusps) and atypical (right-non-coronary cusp fusion) if the commissures were at 1–7 or 12–6 o'clock (right-left cusps).14–16 Equivalent mid-esophageal short-axis views determined the presence and type of BAV by transoesophageal echocardiography. Doppler was used to measure blood velocity, with pulsed and colour Doppler assessing subaortic flow and degree of aortic regurgitation,17 with assessment of flow reversal in the aortic arch, and with continuous-wave Doppler measurement of maximal jet velocity.18 A mean transaortic pressure gradient ≥40 mm Hg defined severe valvular stenosis while aortic peak velocity ≥2 m/s defined any aortic stenosis. Aortic regurgitation was classified as mild, moderate or severe. Aortic dimensions were obtained from echocardiograms, CT or MRI. Transthoracic two-dimensional ascending aorta measurements were obtained in the parasternal long-axis view. Sinuses of Valsalva (root) and ascending aorta diameters were measured by the leading-edge-to-leading-edge technique, at end of diastole.19 For transoesophageal echocardiography, measurements were made at mid and upper oesophageal levels. For CT and MRI, the maximal aortic diameter was measured in an axial plane by image reconstruction. The largest diameter between the root and ascending aorta for each patient was used for analysis.4

For patients with BAV with previous AVR (n=11), the ascending aorta dimension at the time of AVR was considered significantly dilated if maximal dimension was ≥45 mm8 and/or qualitatively described as ≥moderately dilated by the surgeon's report. Aortic dimensions were measured de novo (MFE) on preoperative or intraoperative echocardiograms when stored images were available (five patients), by echo report in one, by echo report and surgeon's visual assessment in two, by aortic angiography and surgeon's visual assessment in one and by surgeon's visual assessment alone in two.

Pathological evaluation

All BAVs and ADs were confirmed by pathology and/or direct surgical inspection. All aortic available tissue specimens were evaluated de novo (WDE, JJM) by light microscopy with H&E and Verhoeff's-Van Geison stains. Specimens were evaluated for the presence of dissection, intimal tear, haemorrhage, rupture and for the presence and severity of atherosclerosis, intimal thickening, medial degeneration, laminar medial necrosis and aortitis. The degree of medial degeneration was graded as minimal, mild, moderate or severe.

Statistical analysis

Continuous variables are expressed as mean±SD and percentage for categorical variables. Student t test and Fisher's exact test were used to compare variables between study and control groups. Values of p<0.05 were considered statistically significant.

Results

Baseline patient characteristics

Baseline clinical characteristics of patients with BAV and TAV are contrasted in tables 1 and 2. We identified 47 patients (mean age 58±14 years, 36 (77%) male) with pathologically or surgically confirmed BAV who presented with acute (31, 66%) or chronic (16, 34%) Stanford type A AD. Twelve patients with BAV were identified between 1980 and 1989, 10 patients between 1990 and 1999, and 25 between 2000 and 2010. Forty-five patients (96%) underwent surgery for AD, while the remaining two (4%) died before undergoing surgery and were diagnosed at autopsy. Forty (85%) patients with BAV had a typical BAV. Eleven patients with BAV (23%) had a history of previously repaired coarctation. Two patients had Shone's syndrome (4%) and one (2%) had Turner's syndrome.

Table 1

Aortic dissection patient characteristics

Table 2

Clinical characteristics on presentation

Fifty-three consecutive patients (mean age 66±13 years, 41 (77%) male) with TAV who presented with acute (35, 66%, p=1.0) or chronic (18, 34%) type A AD and underwent surgery were identified for comparison. Patients with TAV were almost a decade older than patients with BAV (p=0.007) at AD diagnosis. Although measured systolic blood pressure was not different at baseline (table 2), 87% of patients with TAV had a clinical history of hypertension versus 68% of patients with BAV (p=0.03). Atrial fibrillation was also more common in patients with TAV (17% vs 2%, p=0.02). Prior total cardiac surgery was not different between groups, but prior AVR was significantly more common in patients with BAV (23% vs 6%, p=0.02). Presenting AD symptoms were similar between groups. Left ventricular ejection fraction was similar between groups (55±15% vs 57±11%, p=0.36).

Seven patients (two BAV and five TAV, table 1) with chronic AD had had previous surgery for AD. One patient with BAV with Turner's syndrome and coarctation had a previous repair of type B AD. The rest had previous partial ascending aorta graft repairs for type A AD, and were reintervened for aneurysmal dilatation of the unrepaired ascending aorta portion, where chronic AD was found.

Baseline aortic valve dysfunction

Native aortic valve function at the time of AD is presented in table 3. Moderate or more native aortic valve dysfunction was significantly prevalent in patients with BAV than in patients with TAV (58% vs 32%, p=0.02), driven primarily by severe stenosis (19% vs 0%, p=0.002) and any degree of stenosis (28% vs 10%, p=0.04) in the BAV group. Conversely, aortic regurgitation was not different between groups.

Table 3

Aortic valve dysfunction at presentation

Ascending aorta dimensions

In patients with BAV, aortic dimensions at AD were measured by echocardiography in 34 (72%), CT in 9 (19%) and magnetic resonance in 4 (9%) patients. In patients with TAV, aortic dimensions at AD were measured by echocardiography in 43 (81%) and CT in 8 (19%) patients. Ascending aorta diameter at the time of dissection was larger in patients with BAV (66±15 mm vs 56±11 mm, p=0.0004, table 1, figure 1). In addition, patients with BAV were more likely to have had known aortic dilatation prior to AD than patients with TAV (49% vs 17%, p=0.001), and maximal aortic dimension in patients with previously recognised aortic dilatation was significantly larger in patients with BAV than patients with TAV (53±11 mm vs 44±1 mm, p=0.002, figure 2). Of the 23 patients with BAV with previously recognised aortic dilatation, maximal diameters were ≥55 mm in 5 patients (22%), 50–54 mm in 6 (26%) and <50 mm in 12 (52%). The mean number of days aortic measurement was taken prior to AD was 1124±1261 (median 1915) in patients with BAV and 61±64 (median 17) in patients with TAV.

Figure 1

Maximum aortic dimensions at the time of dissection. Patients with bicuspid aortic valve had higher maximum aortic dimensions at the time of dissection compared with patients with tricuspid aortic valve (p=0.0001). Access the article online to view this figure in colour.

Figure 2

Maximum aortic dimension prior to dissection in patients with previously recognised aortic dilatation. Patients with bicuspid aortic valve had higher maximum aortic dimension compared with patients with tricuspid aortic valve (p=0.002). Access the article online to view this figure in colour.

Eleven patients with BAV had AVR before presenting with AD. Seven of them had significant aorta dilatation at the time of AVR; an ascending aorta diameter ≥45 mm and/or ≥moderate aortic dilatation by direct surgical inspection (table 4).

Table 4

Aortic dimensions in patients with bicuspid aortic valve prior to aortic valve replacement

Pathology findings

Pathological findings are contrasted between groups in table 5. In the BAV group, 42 (89%) had an available aortic specimen for pathological analysis. Medial degeneration was found in 28 (67%) of aortic specimens, with severe (grade 4 of 4) disease in 13 (31%) (figure 3). There was no significant relationship between maximal ascending aorta dimension and medial degeneration (p=0.55). Aortic specimens were available in all patients with TAV. In the TAV group, 21 (40%) had evidence of medial degeneration (p=0.01 vs BAV) and 6 (11%) had severe medial degeneration (p=0.02 vs BAV). In contrast, aortic intimal atherosclerosis was more frequent in TAV (51% vs 24%, p=0.01).

Table 5

Aortic pathological findings

Figure 3

Aortic histopathology. Photomicrograph of normal aortic histology with uniform and parallel arrangement of elastic lamellae ((A) H&E; (B) Verhoeff's-Van Gieson). Medial degeneration, characterised by elastic fibres with intramedial glycoprotein pooling ((C) H&E; (D) Verhoeff's-Van Gieson). Laminar medial necrosis, characterised by band-like smooth muscle nuclear loss (between arrowheads) with concomitant elastic lamellar collapse ((E) H&E; (F) Verhoeff's-Van Gieson). Access the article online to view this figure in colour.

Acute versus chronic AD

Twenty-five (81%) patients with BAV with acute AD had a typical BAV versus 15 (94%) with chronic AD (p=0.4). There were no differences in presenting symptoms between BAV and TAV for acute AD (table 6). In patients with BAV presenting with acute AD, 75% had some degree of medial degeneration with 36% having severe medial degeneration, compared with 41% and 9%, respectively for patients with TAV (p=0.01 for both, table 6). In contrast, for patients with chronic AD there was no difference in the prevalence or severity of aortic medial degeneration between the two groups (table 6). Aortic atherosclerosis was present in 8 (26%) patients with BAV with acute AD versus 19 (56%) patients with TAV (p=0.02). In contrast, presence of atherosclerosis in chronic AD was not statistically different between groups.

Table 6

Acute versus chronic dissection

Discussion

To our knowledge, this is the first study comparing clinical, imaging and pathological characteristics between pathologically/surgically-proven patients with BAV and patients with TAV with Stanford type A AD. We find similarities between groups; in particular, there was no difference in presenting symptoms of AD and identical prevalence of chronic AD. Nonetheless, several clinical, imaging and pathological hypothesis-generating differences are reported for the first time. In addition, guideline-pertinent observations are presented. The BAV condition is highly heterogeneous and may be associated with other congenital abnormalities (ie, Shone's complex and aortic coarctation) or be part of syndromic diseases (ie, Turner's syndrome). By isolating patients with BAV with AD, we find prior aortic dilatation, aortic stenosis and aortic coarctation to be the most commonly associated features with these patients.

Clinical features

Our study is consistent with demographic observations from larger studies in regards to the male predominance in general population patients with AD,5 ,20 and thus, there was no gender difference between patients with TAV and BAV with AD, as BAV also affects men predominantly. In addition, pain as a presenting symptom5 was predominant in both groups. However, patients with BAV were almost a decade younger than patients with TAV, and a history of hypertension was significantly more prevalent in patients with TAV. The 23% prevalence of aortic coarctation in patients with BAV with AD is higher than reported for the general BAV community (∼7%),2 ,4 in keeping with a large BAV outcomes study21 where coarctation was the only significant predictor of aortic complications, thus, patients with BAV with coarctation appear to be a higher risk subgroup.

The prevalence of severe aortic stenosis at the time of AD was significantly higher in patients with BAV, despite their younger age at AD presentation. Aortic stenosis has been reported an independent predictor of aneurysm formation in patients with BAV,4 suggesting a haemodynamic association between BAV stenosis and aortic complications. Furthermore, the presence of aortic stenosis was the only independent predictor of aortic catastrophes and death in a cohort of 70 patients with BAV with aneurysms followed for a mean of 63 months.22 Conversely, aortic regurgitation, likely the result of the dissection itself for patients with BAV and TAV, was not different between groups. Previous AVR was significantly more prevalent in patients with BAV. A high incidence of early aortic valve dysfunction in patients with BAV is the likely explanation, and highlights the importance of careful qualitative and quantitative evaluation of the aorta during AVR, as well as the importance of continued interval aortic imaging surveillance after isolated AVR. An alternative explanation would implicate previous aortotomy for AVR as a predisposing factor for dissection, however, we reported on 1286 patients with BAV who underwent AVR without aorta repair, and the 25-year freedom from AD was 97%,23 rendering this hypothesis improbable. Nevertheless, both groups had a high prevalence of total previous cardiac surgery, suggesting a potential association between previous surgical aortic cannulation/manipulation and AD, which merits further study.

Aortic imaging and aortic pathology

At the time of AD, the ascending aorta in patients with BAV was significantly larger than in patients with TAV. The most plausible explanation for this difference is that patients with BAV have baseline structural abnormalities of the aorta,24–26 leading to medial degeneration. AD causes expansion of the aortic media and/or adventitia, and this expansion can be expected to be more severe in patients with BAV who have pre-existing medial degeneration, laminar medial necrosis and overall medial weakness. In both groups, it is likely that the aortic diameter at the time of AD was higher than the diameter immediately before dissection. For the first time we show that aortic medial degeneration is more common in patients with BAV with acute AD compared with patients with TAV. This is evidenced by 75% of patients with BAV with acute AD and having medial degeneration (36% severe medial degeneration) compared with 41% of patients with TAV (9% severe medial degeneration) (p=0.01 for both). Thus, it appears that medial degeneration progression is likely a factor related to acute AD in BAV. However, 25% of our patients with BAV had no evidence of medial degeneration and severe medial degeneration has been found in patients with BAV without AD.27 Therefore, just as aortic size is not an infallible predictor of AD since AD can occur in patients with smaller aortas,7 the presence and severity of medial degeneration would also be an imperfect risk-stratifying tool. Nonetheless, our study suggests that developing technology to image medial degeneration would likely aid in AD risk stratification for BAV.

Conversely, atherosclerosis of aorta was significantly more prevalent in patients with TAV, particularly those with acute AD. This pathological finding, together with a higher hypertension prevalence and older age in TAV, suggest different pathogenic mechanisms involved in patients with TAV with acute AD. It must be acknowledged however, that the presence of intimal atherosclerosis rather than a risk for AD,28 likely represents a marker of increased age.

The BAV aorta prior to AD

A unique feature of our study was gaining insight into the potential utility of quantitative and/or qualitative aortic evaluations prior to AD in patients with BAV. One out of two patients with BAV with AD had previously recognised aortic dilatation compared with one in every five with TAV. This presents a window of opportunity for risk stratification to prevent AD in patients with BAV with dilated aortas. Since many patients with BAV with dilated aortas will never dissect,4 this risk stratification must include at least one other yet unknown feature.

Notably, of 11 patients with BAV who underwent AVR prior to AD, elective aortic repair at the time of AVR could have prevented subsequent type A AD in 7 of them, according to current guidelines, since their aortas were dilated ≥45 mm and/or were deemed moderately dilated by direct surgical inspection. Furthermore, of 23 patients with aortic measurements prior to AD, 11 were ≥50 mm, a current guideline indication for elective repair. Therefore, with guideline implementation, several ADs could have theoretically been prevented, an observation in need of ascertainment in quality cohorts of centres that implement guidelines consistently. Importantly, a recent large tertiary centre experience revealed no 30-day postoperative mortality penalty incurred by patients with BAV in whom elective aorta repair was performed with AVR when aortic size was >45 mm.29

Strengths and limitations

Given the tertiary referral practice of Mayo Clinic, there was a high prevalence of previous cardiac surgery, potentially related to selection bias. However, the groups studied represent ‘real world’ patients since AD is surgically managed exclusively in tertiary referral centres. This is a single-centre retrospective study with a relatively small number of patients with BAV AD (47). Notwithstanding, differences between groups were striking, and this is the largest group of patients with proven BAV AD with clinical, imaging and pathological data available in the literature to date. The exhaustive ascertainment of AD including all possible sources, and the catastrophic nature of AD makes the possibility of unrecognised acute BAV AD cases unlikely. In addition, pathological/surgical congenital BAV confirmation eliminates the well-known bias of including misdiagnosed patients without BAV. Given the sudden and unpredictable nature of AD, aortic dimension measurements immediately before AD were unavailable. Direct aortic diameter measurements were not available for all patients with BAV undergoing prior AVR. However, only 2 of 11 patients relied on surgical-inspection size estimation alone and only one of those was deemed to have moderate aortic dilatation. Finally, CT imaging may enhance detection of aortic dilatation, particularly when present in the distal ascending aorta,30 and most of the aortic diameters before dissection were obtained by echocardiography in this study.

Conclusions

There are significant differences between patients with BAV and TAV presenting with type A AD. Compared with patients with TAV, patients with BAV are younger, have less hypertension, have increased maximal aortic dimension pre-AD and at AD presentation with one of every two patients having a known dilated aorta before AD, and bear a higher degree of medial degeneration at the time of AD, particularly in the acute form. In addition, patients with BAV presenting with AD have a high prevalence of aortic stenosis and aortic coarctation, thus, these subpopulations need further study and stringent follow-up, since their risk appears higher. Conversely, patients with TAV are older and have a higher prevalence of hypertension, and less medial degeneration, suggesting different pathogenic mechanisms leading to AD. Despite these differences, risk stratification based on aortic size and medial degeneration appears insufficient, setting the stage for scientific examination of alternative risk-stratification tools, such as special aortic imaging and individual genetic make-up. Finally, our study suggests that implementation of size-based risk-stratification guidelines could have theoretically prevented several AD cases, an observation in need of ascertainment in quality cohorts of centres that implement guidelines consistently.

References

Footnotes

  • Contributors All authors contributed significantly to one or more of the following: design, data collection, analysis, drafting, revision and final approval of the manuscript. MFE and HIM had full access to all of the data and take full responsibility for the integrity of the data and the accuracy of the data analysis.

  • Funding Partially funded by a development grant awarded to Dr Michelena by the Department of Medicine of the Mayo Clinic.

  • Competing interests None.

  • Ethics approval IRB.

  • Provenance and peer review Not commissioned; externally peer reviewed.