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Impact of Aortic Insufficiency on Ascending Aortic Dilatation and Adverse Aortic Events After Isolated Aortic Valve Replacement in Patients With a Bicuspid Aortic Valve
Impact of Aortic Insufficiency on Ascending Aortic Dilatation and Adverse Aortic Events After Isolated Aortic Valve Replacement in Patients With a Bicuspid Aortic Valve Yongshi Wang, MD,* Boting Wu, MD,* Jun Li, MD, Lili Dong, MD, Chunsheng Wang, MD, and Xianhong Shu, MD, PhD Shanghai Institute of Cardiovascular Diseases, Shanghai Institute of Medical Imaging, and Department of Transfusion, Zhongshan Hospital Fudan University, Shanghai, China
Background. Aberrant flow pattern and congenital fragility bestows bicuspid aortic valve (BAV) with a propensity toward ascending aorta dilatation, aneurysm, and dissection. Whether isolated aortic valve replacement (AVR) can prevent further dilatation in BAV ascending aorta and what indicates concurrent aortic intervention in the case of valve operation remain controversial. Methods. From June 2006 to January 2009, patients with a BAV who underwent isolated AVR were consecutively included and categorized into aortic insufficiency (BAV-AI, n [ 84) and aortic stenosis (n [ 112) groups, and another population of patients with a tricuspid aortic valve with aortic insufficiency (n [ 149) was also recruited during the same period for comparison of annual aortic dilatation rate and adverse aortic events after isolated AVR. Results. With a median follow-up period of 72 months (interquartile range, 66 to 78 months), ascending aorta dilatation rates were faster in the BAV-AI group than the BAV plus aortic stenosis and tricuspid aortic valve with aortic insufficiency groups (both p < 0.001). The BAV-AI
group showed a higher risk for adverse aortic events compared with both the BAV plus aortic stenosis (15.5% versus 4.5%; p [ 0.008) and tricuspid aortic valve with aortic insufficiency (15.5% versus 6.0%; p [ 0.018) groups. Cox regression analysis identified aortic insufficiency (hazard ratio, 3.7; 95% confidence interval, 1.2 to 11.1; p [ 0.019) as an independent risk factor for adverse aortic events among patients with BAV in general, whereas preoperative ascending aortic diameter larger than 45 mm (hazard ratio, 13.8; 95% confidence interval, 3.0 to 63.3; p [ 0.001) served as a prognostic indicator in the BAV-AI group. Conclusions. An aggressive policy of preventive aortic interventions seemed appropriate in patients with BAVAI during AVR, and BAV phenotype presenting as either insufficiency or stenosis should be taken into consideration when contemplating optimal surgical strategies for BAV aortopathy.
B
should be considered when aortic diameter is between 40 and 50 mm in patients with BAV, and the threshold for concomitant aortic operation should be 45 mm in the case of an aortic valve operation [7]. Recent studies have emphasized the aberrant eccentric and spiral flow patterns in BAV, as well as increased wall shear stress especially in those with aortic valve dysfunction, both of which may serve as major contributors to aortic dilatation [8–10]. Therefore, a long-standing controversy over the prophylactic value of aortic valve replacement (AVR) for BAV aortopathy has arisen. Several studies have argued the impact of aortic valve dysfunction on annual aortic dilatation rate and adverse aortic events in the BAV scenario [11, 12], although additional data stratified as to type of aortic valve dysfunction are still needed to better address this issue. The present study compared long-term outcomes for aortic dilatation and adverse aortic events after isolated AVR between patients with BAV with aortic insufficiency and aortic stenosis, and evaluated the
icuspid aortic valve (BAV), a congenital cardiac malformation previously acknowledged for causing valve dysfunction, has become the focus of intense academic arguments over its elevated risk for aortic dilatation, aneurysm, and dissection [1–3]. Various genetic and hemodynamic theories have been developed to address the mechanism and risk stratification of BAV aortopathy [4–6]. It has been generally speculated that BAV may represent a disorder bestowed with intrinsic propensity toward aortic wall tissue matrix degradation. According to the 2010 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines for thoracic aortic management, surgical intervention
Accepted for publication Oct 12, 2015. *Drs Y Wang and Wu contributed equally to this manuscript. Address correspondence to Dr Dong, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai 200032, China; email: [email protected].
Ó 2016 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2016;-:-–-) Ó 2016 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.10.047
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rationale for prophylactic aortic interventions during valve operation.
Material and Methods Study Population We reviewed patients undergoing AVR from June 2006 to January 2009 at our institute. Details of the screening process are depicted in Figure 1. Briefly, 332 patients with BAV and 636 with tricuspid aortic valve (TAV) identified by preoperative echocardiography and confirmed by surgical inspection were initially screened. Patients with mixed aortic valve dysfunction were included only if either stenosis or insufficiency was predominant. The aortic insufficiency group (BAV-AI group) comprised patients with BAV with moderate to severe aortic insufficiency but no more than moderate aortic stenosis; the aortic stenosis group (BAV-AS group) comprised those with severe aortic stenosis defined as mean transaortic pressure gradient greater than 40 mm Hg but no more than moderate aortic insufficiency [13, 14]. Patients with TAV with aortic insufficiency (TAV-AI group) were used as a control group. All patients with ascending aorta diameter larger than 50 mm routinely underwent aortic operation and were excluded from this study. Additional exclusion criteria were previous cardiac operation, infective endocarditis, acute aortic dissection, Marfan syndrome, connective tissue disease, or other severe congenital heart defects (namely coarctation of the aorta, tetralogy of Fallot, ventricular septal defect, and supraaortic stenosis). In-hospital death occurred in 2 patients with BAV and 3 patients with TAV, who were then excluded from the study. The leading cause for
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postoperative in-hospital death was cardiac failure (4 of 5 patients, 80.0%), followed by stroke (1 of 5 patients, 20.0%). Eventually, a total of 345 patients undergoing isolated AVR during the referring period were recruited to form the study population, of which 84 patients made up the BAV-AI group, 112 patients, the BAV-AS group, and 149 patients, the TAV-AI group. In the study population, 42 patients with BAV and 27 patients with TAV had an ascending aorta diameter at or greater than 45 mm.
Data Collection Clinical features, laboratory data, and demographic characteristics were collected and abstracted in standardized data collection sheets. The diagnosis of BAV was confirmed according to the classification by Sievers and Schmidtke [15] based on intraoperative observation. Echocardiography was performed using commercially available machines followed by a uniform and standardized protocol based on the American College of Cardiology (ACC)/AHA practice guidelines and American Society of Echocardiography (ASE) recommendations [13, 16]. The diameters of the aortic annulus, aortic root (at the sinus of Valsalva), and ascending aorta (at the level of the bifurcation of the pulmonary artery) were measured perpendicular to the long axis of the aorta, during systole, from leading edge to leading edge. Because patients with suspected dilatation of the ascending aorta underwent preoperative computed tomographic angiography, we consecutively selected 50 patients to assess the agreement of transthoracic echocardiography and computed tomographic angiography for measuring the aortic diameters with the Bland-Altman method. The consistency of both
Fig 1. Schematic representation of the patient screening process. (BAV ¼ bicuspid aortic valve; TAV ¼ tricuspid aortic valve.)
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techniques was excellent, with an average difference of 0.16 1.18 mm for the aortic root and 0.20 1.24 mm for the proximal ascending aorta.
Statistical significance was defined as a two-sided probability value of less than 0.05.
Surgical Procedures
Results
Under general anesthesia, median sternotomy, and total cardiopulmonary bypass, AVR was performed by the standard technique [17] using mechanical valves in 81.2% of patients and stented tissue valves in the rest (18.8%). The labeled valve prosthesis size was 17 mm in 1.4%, 19 mm in 7.0%, 21 mm in 25.2%, 23 mm in 28.7%, 25 mm in 26.4%, 27 mm in 7.5%, and 29 mm in 3.8% of patients.
Baseline and Surgical Characteristics
Follow-Up Clinical indicators and echocardiographic variables of all 345 enrolled patients were followed up annually in our institute. Follow-up data including postoperative blood pressure, medication, morbidity, and mortality were obtained from a review of patients’ clinic records or a telephone interview with patients or their family members. The diameters of the aortic root or ascending aorta were routinely evaluated by transthoracic echocardiography during follow-up. The difference between aortic diameters before AVR and at latest follow-up was calculated and divided by the duration of follow-up to yield the annual dilatation rate. Adverse aortic events were defined as occurrence of aortic dissection or rupture, aorticrelated death, or the need for proximal aortic operation that was indicated by symptoms suggestive of aortic expansion, aortic diameter of more than 55 mm, or aortic growth rate of more than 5 mm/y [7]. The study conformed to the principles outlined in the Declaration of Helsinki and was approved by the ethics committee of Zhongshan Hospital, Fudan University, Shanghai, China.
Statistical Analysis Analysis was performed with the SPSS 12.0 software (SPSS, Inc, Chicago, IL). Data were reported as mean standard deviation or medians (interquartile ranges) for continuous variables and as frequencies (percentages) for categorical variables. Continuous variables among groups were assessed by one-way analysis of variance or MannWhitney U test as appropriate. Aortic diameters at latest follow-up were compared among groups by covariance analysis with adjustment for baseline values. Differences in percentages were evaluated using c2 or Fisher’s exact tests. The level of significance for pairwise comparisons was adjusted when multiple comparisons were performed (p ¼ 0.05/2 ¼ 0.025). Aortic event-free survival curves were constructed using the Kaplan-Meier estimator and compared using log-rank tests. Multiple linear stepwise regression analysis was used to identify independent predictors related to annual dilatation rate. The risks for adverse outcomes were compared using Cox regression models. The variables taken into account for multivariate analysis included age at admission, sex, body surface area, smoking, comorbid conditions, baseline aortic diameter, baseline echocardiographic variables, treatment modalities, blood pressure, and medication during follow-up.
Baseline and surgical characteristics are summarized in Table 1. Patients in the BAV-AI group demonstrated younger age (p < 0.001 versus both BAV-AS and TAV-AI groups) and male preference (p ¼ 0.047, BAV-AI versus BAV-AS group; p < 0.001 BAV-AI versus TAV-AI group). Among patients with BAV in general, the right and left coronary leaflet fusion type (57.7%) was the most frequent, followed by right and noncoronary leaflet fusion type (37.8%) and left and noncoronary leaflet fusion type (4.5%). Compared with the BAV-AS group, the BAV-AI group demonstrated a higher prevalence of the right and left coronary leaflet fusion type (73.8% versus 45.5%; p < 0.001), wider aortic roots (38.1 4.6 mm versus 34.0 3.9 mm; p < 0.001), and larger diameter of the aortic annulus (24.3 2.5 mm versus 21.7 2.3 mm; p < 0.001), which then contributed to larger prosthesis sizes (25 mm [23 to 25 mm] versus 21 mm [21 to 23 mm]; p < 0.001). In the TAV-AI group, degenerative valvulopathy was the predominant cause (65.8%), followed by rheumatic causes (34.2%), and the incidence of accompanying coronary artery disease (18.1% versus 3.6%; p ¼ 0.001) was much higher than in the BAV-AI group. Mechanical valve prosthesis was preferred (p < 0.005 versus both the BAV-AS and TAV-AI groups) in the BAVAI group, in accordance with their younger age. Cardiopulmonary bypass and aortic cross-clamp times were similar between the BAV-AI and BAV-AS groups, whereas the TAV-AI group showed prolongation in both (p ¼ 0.006 and p < 0.001, respectively) owing to a higher incidence of accompanying procedures such as coronary artery bypass grafting (p ¼ 0.016) and mitral valve intervention (p < 0.001) than their BAV counterparts.
Long-Term Outcomes After Aortic Valve Replacement The median follow-up period for all patients was 72 months (interquartile range, 66 to 78 months). Blood pressure and medication during follow-up were similar among all patient groups, except for a preference for statin administration in the TAV-AI group (p ¼ 0.001). We found that AVR could prevent the aortic root from further dilatation (p > 0.05 in all groups), but not the ascending aorta (p < 0.001 in all groups). Ascending aortic dilatation rate seemed to be much faster in the BAV-AI group than in the other two groups (both p < 0.001), resulting in greater ascending aorta diameters at latest follow-up in patients with BAV-AI after adjustments for baseline index (Table 2, Fig 2). During follow-up, the BAV-AI group showed a higher risk for adverse aortic events compared with both the BAV-AS (15.5% versus 4.5%; p ¼ 0.008) and the TAV-AI (15.5% versus 6.0%; p ¼ 0.018) groups. Eleven patients (13.1%) in the BAV-AI group experienced progression to ascending aortic aneurysm and needed proximal aortic
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operation, whereas only 5 patients in the BAV-AS and 8 in the TAV-AI group did. Among patients requiring proximal aortic operation, the annual aortic progression rate was 1.49 0.55 mm in the BAV-AI group, 0.86 0.33 mm in the BAV-AS group, and 1.43 0.45 mm in the TAV-AI group. Acute type A aortic dissection occurred in 3 patients after a mean follow-up of 71 13 months, and 1 patient in the BAV-AI group died of postoperative cardiac failure and brain damage. Among patients with BAV with ascending aorta diameter between 40 and 45 mm, 3 experienced adverse aortic complications, 1 in the BAV-AS group and 2 in the BAV-AI group. Kaplan-Meier survival analysis showed inferior aortic event-free survival in patients with BAV-AI compared with the BAVAS (p ¼ 0.005) and the TAV-AI (p ¼ 0.089) groups, albeit with borderline statistical significance in the latter (Table 2, Fig 3).
Multivariate Analyses of Adverse Aortic Events in Patients With Bicuspid Aortic Valve Multivariate linear regression analysis revealed aortic insufficiency (b ¼ 0.317; p < 0.001) and ascending aorta diameters (b ¼ 0.271; p < 0.001) as major factors
associated with the annual ascending aortic dilatation rate in patients with BAV after AVR (Table 3). Cox regression analysis identified aortic insufficiency (hazard ratio, 3.7; 95% confidence interval, 1.2 to 11.1; p ¼ 0.019) and preoperative ascending aortic diameter greater than 45 mm (hazard ratio, 16.8; 95% confidence interval, 5.3 to 53.6; p < 0.001) as independent risk factors for adverse aortic events among patients with BAV in general. In patients with BAV-AI, those with an ascending aortic diameter greater than 45 mm at the time of AVR (hazard ratio, 13.8; 95% confidence interval, 3.0 to 63.3; p ¼ 0.001) were more likely to experience adverse aortic events, whereas both preoperative ascending aortic diameter and follow-up systolic blood pressure were indicators for adverse aortic events in the BAV-AS group (Table 4).
Comment As the most common congenital cardiac abnormality, BAV occurs in 1% to 2% of the general population [18, 19], and the incidence of a normally functioning aortic valve is reported to be 15% to 30% [20, 21], which means that the majority of patients with BAV are likely to have an aortic
Table 1. Baseline Characteristics and Surgical Features of Patients Undergoing Aortic Valve Replacement
Variable Age, y Male sex BSA, m2 NYHA class III/IV Smoking Comorbid conditions Hypertension Diabetes Dyslipidemia History of coronary artery disease History of cerebrovascular disease Echocardiographic findings Left ventricular ejection fraction <0.55 RL fusion Rheumatic valve disease Aortic annulus, mm Aortic root, mm Ascending aorta, mm Surgical features Mechanical valve prosthesis Prosthesis size, mm Cardiopulmonary bypass time, min Cross-clamp time, min Lowest body temperature, C Mitral valve repair/replacement Coronary artery bypass grafting
BAV-AI (n ¼ 84)
BAV-AS (n ¼ 112)
TAV-AI (n ¼ 149)
p Value (BAV-AI Versus BAV-AS)
p Value (BAV-AI Versus TAV-AI)
46 13 67 (79.8) 1.81 0.17 57 (67.9) 25 (29.8)
56 14 75 (67.0) 1.81 0.17 69 (61.6) 21 (18.8)
56 11 81 (54.4) 1.83 0.14 103 (69.1) 34 (22.8)
<0.001 0.047 0.931 0.366 0.072
<0.001 <0.001 0.920 0.841 0.242
26 2 8 3 3
37 9 11 9 2
0.757 0.120 0.944 0.197 0.653
0.820 0.494 0.202 0.001 0.181
(31.0) (2.4) (9.5) (3.6) (3.6)
(33.0) (8.0) (9.8) (8.0) (1.8)
44 7 23 27 12
(29.5) (4.7) (15.4) (18.1) (8.1)
19 (22.6) 62 (73.8) . 24.3 2.5 38.1 4.6 40.5 4.5
25 (22.3) 51 (45.5) . 21.7 2.3 34.0 3.9 39.6 4.7
19 (12.8) . 51 (34.2) 23.8 2.3 37.2 3.9 39.4 5.1
0.961 <0.001 . <0.001 <0.001 0.213
0.052 . . 0.134 0.104 0.115
79 (94.0) 25 (23–25) 85.0 27.1 56.1 19.5 30.1 1.6 13 (15.5) 2 (2.4)
83 (74.1) 21 (21–23) 86.0 27.8 56.5 19.8 29.8 1.4 12 (10.7) 6 (5.4)
118 (79.2) 23 (21–25) 93.6 20.4 65.0 15.3 29.7 1.5 58 (38.9) 17 (11.4)
<0.001 <0.001 0.805 0.877 0.319 0.323 0.470
0.003 0.031 0.006 <0.001 0.097 <0.001 0.016
Data are presented as the mean SD, as number (percentage), or as median (interquartile range). AI ¼ aortic insufficiency; AS ¼ aortic stenosis; BAV ¼ bicuspid aortic valve; BSA ¼ body surface area; NYHA ¼ New York Heart Association; RL fusion ¼ right and left coronary leaflet fusion; SD ¼ standard deviation; TAV ¼ tricuspid aortic valve.
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Table 2. Long-Term Follow-Up in Patients After Aortic Valve Replacement
Variable Follow-up, mo SBP during follow-up, mm Hg DBP during follow-up, mm Hg Postoperative b-blocker therapy Postoperative ACEI/ARB therapy Postoperative statin therapy Mean gradient of aortic prosthesis, mm Hg Peak velocity of aortic prosthesis, m/s Aortic root, mm Ascending aorta, mm Rate of aortic root dilatation, mm/y Rate of ascending aorta dilatation, mm/y Adverse aortic events Aortic dissection/rupture Aortic-related death Need for proximal aortic surgery Cardiac mortality Congestive heart failure Endocarditis Noncardiovascular mortality
BAV-AI (n ¼ 84)
BAV-AS (n ¼ 112)
TAV-AI (n ¼ 149)
73 (65–78) 123 (112–142) 77 (66–88) 39 (46.4) 12 (14.3) 4 (4.8) 13.6 4.6
71 (62–78) 123 (112–138) 81 (72–86) 42 (37.5) 20 (17.9) 9 (8.0) 15.2 5.2
73 (68–77) 120 (110–135) 75 (70–82) 61 (40.9) 30 (20.1) 32 (21.5) 14.1 4.6
2.66 0.42 38.5 5.1 43.2 6.5 0.02 (0.19–0.23) 0.29 (0.19–0.79) 13 (15.5) 2 (2.4) 1 (1.2) 11 (13.1) 1 (1.2) 1 (1.2) 0 0
2.72 0.46 34.2 3.7 40.8 4.9 0.05 (0.10–0.21) 0.18 (0.10–0.29) 5 (4.5) 0 0 5 (4.5) 2 (1.8) 1 (0.9) 1 (0.9) 1 (0.9)
2.62 0.43 37.1 3.7 40.6 6.2 0.03 (0.20–0.27) 0.05 (0.20–0.48) 9 (6.0) 1 (0.7) 0 8 (5.4) 2 (1.3) 2 (1.3) 0 (0.5) 2 (0.5)
p Value (BAV-AI versus BAV-AS)
p Value (BAV-AI versus TAV-AI)
0.825 0.070 0.146 0.209 0.503 0.362 0.055
0.286 0.067 0.240 0.416 0.265 0.001 0.419
0.472 0.223 <0.001 0.215 <0.001 0.008 0.182 0.429 0.029 1.000 1.000 1.000 1.000
0.540 0.521 0.001 0.105 <0.001 0.018 0.295 0.361 0.039 1.000 1.000 1.000 0.537
Data are presented as the mean standard deviation, as number (percentage), or as median (interquartile range). ACEI/ARB ¼ angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; AI ¼ aortic insufficiency; AS ¼ aortic stenosis; bicuspid aortic valve; DBP ¼ diastolic blood pressure; SBP ¼ systolic blood pressure; TAV ¼ tricuspid aortic valve.
valve operation within their life. Until now, the guidelines of the optimal surgical strategy for patients with BAV with valve dysfunction and concomitant aortic dilatation were still based on expert opinions and remained an open debate. Both the 2010 ACCF/AHA and 2014 European Society of Cardiology (ESC) guidelines recommended 45 mm as the threshold for ascending aorta replacement
Fig 2. Annual aortic root and ascending aortic dilatation rate after aortic valve replacement in three groups. Ascending aorta dilatation rate was faster in patients with bicuspid aortic valve with aortic insufficiency (BAV-AI group) than in patients with bicuspid aortic valve with aortic stenosis (BAV-AS group) and patients with tricuspid aortic valve with aortic insufficiency (TAV-AI group; both p < 0.001).
BAV ¼
in patients undergoing valve operation, whereas the 2014 Canadian guidelines favored a more conservative strategy with the surgical indication as 50 mm [7, 22, 23].
Fig 3. Kaplan-Meier curves of adverse aortic events after aortic valve replacement in three groups. (BAV-AI ¼ patients with bicuspid aortic valve with aortic insufficiency; BAV-AS ¼ patients with bicuspid aortic valve with aortic stenosis; TAV-AI ¼ patients with tricuspid aortic valve with aortic insufficiency.)
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Table 3. Multivariate Linear Regression Analysis of Annual Ascending Aortic Dilatation Rate Among Patients With Bicuspid Aortic Valve After Aortic Valve Replacement Variables Aortic insufficiency Ascending aorta diameters, mm
Unstandardized B
Standard Error
Standardized b
p Value
0.190 0.018
0.040 0.004
0.317 0.271
<0.001 <0.001
Moreover, the current recommendation for aortic intervention in the setting of valve operation lacks at-length stratification on the BAV phenotype because the severity of vessel wall matrix degradation has proved to be different between patients with aortic stenosis and those with aortic insufficiency, probably as a result of the long-term impact of hemodynamic abnormality [24]. The present study was performed during a 5-year follow-up and looked at aortic dilatation rate and adverse aortic events after isolated AVR in a large cohort of patients with BAV, thus assessing clinical outcomes and risk stratification for BAV aortopathy. A conservative institutional policy of 50 mm as the threshold for proximal aorta intervention in patients requiring valve operation was in place throughout the study period, and all relevant data were obtained at baseline and after isolated AVR in the 345 patients enrolled. We demonstrated an astoundingly elevated hazard toward adverse aortic events after AVR in patients with BAV-AI, which advocated the heterogeneity of BAV aortopathy with a root phenotype (aortic valve insufficiency and dilatation at aortic sinus) proposed by Girdauskas and colleagues [12] as well as accelerated matrix elastic fiber loss in patients with aortic insufficiency dominance argued by Roberts and associates [25] and Girdauskas and coworkers [26]. The combination of BAV and aortic insufficiency seemed to be decisive, as the 7year aortic event-free rate was 65.5% in the BAV-AI group, inferior to both the BAV-AS and TAV-AI groups, which demonstrated 7-year aortic event-free rates of 92.3% and 85.8%, respectively. Based on the observation that only patients with BAV-AI were susceptible to ascending aorta dilatation after AVR, some mechanism other than mere hemodynamic forces was probably at work. However, it was hard to determine whether aortic insufficiency was the driving force for ascending aorta
dilatation or vice versa. A third, and more likely, explanation was that both aortic insufficiency and proximal aortopathy represented different phenotypic aspects of the same BAV subgroup. In other words, some common intrinsic traits that made certain patients with BAV prone to aortic complications might also render them prone to an aortic insufficiency phenotype. Our data validated the consensus of ascending aorta diameter greater than 45 mm as the threshold to consider concurrent aortic operation during AVR as well as the rationale for the surgical option of an aortic root-sparing procedure [27, 28], as we demonstrated that isolated AVR was capable of preventing the aortic root but not the ascending aorta from further dilatation in patients with BAV. On the other hand, patients with BAV may further benefit from individualized surgical strategies according to their valve dysfunction type [29]. By changing the threshold for aortic intervention to 45 mm, the expected reduction of adverse aortic events was 11.9% (10 of 84 patients; two acute aortic dissections included) in the BAV-AI group, but merely 3.6% (no acute aortic dissection included) in the BAV-AS group. If a further leap to use 40 mm as the cutoff value for ascending aorta intervention was taken, 3 more patients (1 in the BAV-AS group and 2 in the BAV-AI group) experiencing future adverse aortic events among 53 patients with BAV with an ascending aorta diameter between 40 and 45 mm in our cohort would have be included, but the potential benefit could not compensate for the markedly increased number of surgical candidates as well as elevated procedural risks and medical expenses. Therefore, it was reasonable to advocate the 45-mm threshold in patients with BAV-AI, who tended to be younger and have a longer life expectancy and lower surgical-related mortality, as also mentioned by Sievers and colleagues [30] in a retrospective study of 1,362 patients with BAV undergoing
Table 4. Cox Regression Analysis of Adverse Aortic Events Among Patients With Bicuspid Aortic Valve After Aortic Valve Replacement Variables All patients with BAV Aortic insufficiency Ascending aorta dimension >45 mm Patients with BAV with aortic insufficiency Ascending aorta dimension >45 mm Patients with BAV with aortic stenosis Ascending aorta dimension >45 mm Follow-up SBP >140 mm Hg BAV ¼ bicuspid aortic valve;
SBP ¼ systolic blood pressure.
Hazard Ratio
95% Confidence Interval
p Value
3.7 16.8
1.2–11.1 5.3–53.6
0.019 <0.001
13.8
3.0–63.3
0.001
38.7 11.4
2.5–588.6 1.2–113.0
0.009 0.037
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aortic valve operation with and without aortic intervention. Isolated AVR might be an option for patients with BAV-AS with aortic diameter of 45 to 50 mm, and optimized control of postoperative blood pressure could be beneficial because follow-up systolic blood pressure greater than 140 mm Hg served as a risk factor for adverse aortic events in the BAV-AS group compared with the BAV-AI group [30, 31].
Study Limitations Several limitations should be noted concerning the retrospective and single-centered nature of this study. A prolonged follow-up period would be a benefit, although distinct prognostic features were already revealed. Additional imaging techniques such as computed tomographic angiography could help to illustrate various aortic segments including the mid and distal ascending aorta, the aortic arch, and the descending aorta for a better description of different types of aortopathy. The lack of a TAV-AS group might be a problem, but these patients with degenerating aortic valves were usually older, which could contribute additional bias to the follow-up and survival analysis. Last but not least, the causative association between aortic insufficiency and aortic dilatation is still far from clear and requires further well-designed studies evaluating histologic, enzymatic, and gene expression data.
Conclusions Patients with BAV-AI demonstrated a faster ascending aorta dilatation rate and a higher risk for adverse aortic events than did patients with BAV-AS after isolated AVR. An aggressive policy of preventive aortic interventions is optional in patients with BAV-AI in whom the aortic diameter is larger than 45 mm, whereas those with BAVAS were at a lower risk for adverse aortic events with an aortic diameter of less than 50 mm. The study was supported by the National Natural Science Foundation of China (No. 81300232) and Shanghai Municipal Health Bureau (No. 20154Y0030).
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7. Hiratzka LF, Bakris GL, Beckman JA, et al, American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; American Association for Thoracic Surgery; American College of Radiology; American Stroke Association; Society of Cardiovascular Anesthesiologists; Society for Cardiovascular Angiography and Interventions; Society of Interventional Radiology; Society of Thoracic Surgeons; Society for Vascular Medicine. 2010 ACCF/AHA/AATS/ACR/ASA/ SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation 2010;121: e266–369. 8. Bissell MM, Hess AT, Biasiolli L, et al. Aortic dilation in bicuspid aortic valve disease: flow pattern is a major contributor and differs with valve fusion type. Circ Cardiovasc Imaging 2013;6:499–507. 9. Mahadevia R, Barker AJ, Schnell S, et al. Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy. Circulation 2014;129:673–82. 10. Benedik J, Dohle DS, Wendt D, et al. Comparison of ascending aortic cohesion between patients with bicuspid aortic valve stenosis and regurgitation. Eur J Cardiothorac Surg 2014;46:e89–93. 11. Yasuda H, Nakatani S, Stugaard M, et al. Failure to prevent progressive dilation of ascending aorta by aortic valve replacement in patients with bicuspid aortic valve: comparison with tricuspid aortic valve. Circulation 2003;108(Suppl 1):II291–4. 12. Girdauskas E, Disha K, Raisin HH, Secknus MA, Borger MA, Kuntze T. Risk of late aortic events after an isolated aortic valve replacement for bicuspid aortic valve stenosis with concomitant ascending aortic dilation. Eur J Cardiothorac Surg 2012;42:832–8. 13. Bonow RO, Carabello BA, Chatterjee K, et al, American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease); Society of Cardiovascular Anesthesiologists. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006;48:e1–148. 14. Perry GJ, Helmcke F, Nanda NC, Byard C, Soto B. Evaluation of aortic insufficiency by Doppler color flow mapping. J Am Coll Cardiol 1987;9:952–9. 15. Sievers HH, Schmidtke C. A classification system for the bicuspid aortic valve from 304 surgical specimens. J Thorac Cardiovasc Surg 2007;133:1226–33. 16. Lang RM, Bierig M, Devereux RB, et al, Chamber Quantification Writing Group; American Society of Echocardiography’s Guidelines and Standards Committee; European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–63.
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17. Czer LS, Chaux A, Matloff JM, et al. Ten-year experience with the St. Jude Medical valve for primary valve replacement. J Thorac Cardiovasc Surg 1990;100:44–55. 18. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol 2002;39:1890–900. 19. Wang Y, Wu B, Dong L, Wang C, Shu X. Type A aortic dissection in patients with bicuspid or tricuspid aortic valves: a retrospective comparative study in 288 Chinese patients. Eur J Cardiothorac Surg 2013;44:172–7. 20. Ward C. Clinical significance of the bicuspid aortic valve. Heart 2000;83:81–5. 21. Kim YG, Sun BJ, Park GM, et al. Aortopathy and bicuspid aortic valve: haemodynamic burden is main contributor to aortic dilatation. Heart 2012;98:1822–7. 22. Erbel R, Aboyans V, Boileau C, et al, The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. Eur Heart J 2014;35:2873–926. 23. Boodhwani M, Andelfinger G, Leipsic J, et al, Canadian Cardiovascular Society. Canadian Cardiovascular Society position statement on the management of thoracic aortic disease. Can J Cardiol 2014;30:577–89. 24. Girdauskas E, Rouman M, Disha K, et al. Correlation between systolic transvalvular flow and proximal aortic wall changes in bicuspid aortic valve stenosis. Eur J Cardiothorac Surg 2014;46:234–9. 25. Roberts WC, Vowels TJ, Ko JM, et al. Comparison of the structure of the aortic valve and ascending aorta in adults
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26.
27.
28.
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31.
having aortic valve replacement for aortic stenosis versus for pure aortic regurgitation and resection of the ascending aorta for aneurysm. Circulation 2011;123: 896–903. Girdauskas E, Rouman M, Borger MA, Kuntze T. Comparison of aortic media changes in patients with bicuspid aortic valve stenosis versus bicuspid valve insufficiency and proximal aortic aneurysm. Interact Cardiovasc Thorac Surg 2013;17:931–6. Borger MA, Preston M, Ivanov J, et al. Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease? J Thorac Cardiovasc Surg 2004;128: 677–83. Dayan V, Cura L, Mu~ noz L, Areco D, Ferreiro A, Pizzano N. Risk of subsequent aortic dilatation is low in patients with bicuspid aortic valve and normal aortic root diameter at the time of aortic valve replacement. Interact Cardiovasc Thorac Surg 2010;10:535–8. Kallenbach K. Editorial comment: moderate aneurysms of the ascending aorta in stenotic bicuspid aortic valve—life threatening or merely an epiphenomenon? Eur J Cardiothorac Surg 2012;42:838–9. Sievers HH, Stierle U, Mohamed SA, et al. Toward individualized management of the ascending aorta in bicuspid aortic valve surgery: the role of valve phenotype in 1362 patients. J Thorac Cardiovasc Surg 2014;148:2072–80. Girdauskas E, Disha K, Borger MA, Kuntze T. Long-term prognosis of ascending aortic aneurysm after aortic valve replacement for bicuspid versus tricuspid aortic valve stenosis. J Thorac Cardiovasc Surg 2014;147:276–82.
Background. Aberrant flow pattern and congenital fragility bestows bicuspid aortic valve (BAV) with a propensity toward ascending aorta dilatation, aneurysm, and dissection. Whether isolated aortic valve replacement (AVR) can prevent further dilatation in BAV ascending aorta and what indicates concurrent aortic intervention in the case of valve operation remain controversial. Methods. From June 2006 to January 2009, patients with a BAV who underwent isolated AVR were consecutively included and categorized into aortic insufficiency (BAV-AI, n [ 84) and aortic stenosis (n [ 112) groups, and another population of patients with a tricuspid aortic valve with aortic insufficiency (n [ 149) was also recruited during the same period for comparison of annual aortic dilatation rate and adverse aortic events after isolated AVR. Results. With a median follow-up period of 72 months (interquartile range, 66 to 78 months), ascending aorta dilatation rates were faster in the BAV-AI group than the BAV plus aortic stenosis and tricuspid aortic valve with aortic insufficiency groups (both p < 0.001). The BAV-AI
group showed a higher risk for adverse aortic events compared with both the BAV plus aortic stenosis (15.5% versus 4.5%; p [ 0.008) and tricuspid aortic valve with aortic insufficiency (15.5% versus 6.0%; p [ 0.018) groups. Cox regression analysis identified aortic insufficiency (hazard ratio, 3.7; 95% confidence interval, 1.2 to 11.1; p [ 0.019) as an independent risk factor for adverse aortic events among patients with BAV in general, whereas preoperative ascending aortic diameter larger than 45 mm (hazard ratio, 13.8; 95% confidence interval, 3.0 to 63.3; p [ 0.001) served as a prognostic indicator in the BAV-AI group. Conclusions. An aggressive policy of preventive aortic interventions seemed appropriate in patients with BAVAI during AVR, and BAV phenotype presenting as either insufficiency or stenosis should be taken into consideration when contemplating optimal surgical strategies for BAV aortopathy.
B
should be considered when aortic diameter is between 40 and 50 mm in patients with BAV, and the threshold for concomitant aortic operation should be 45 mm in the case of an aortic valve operation [7]. Recent studies have emphasized the aberrant eccentric and spiral flow patterns in BAV, as well as increased wall shear stress especially in those with aortic valve dysfunction, both of which may serve as major contributors to aortic dilatation [8–10]. Therefore, a long-standing controversy over the prophylactic value of aortic valve replacement (AVR) for BAV aortopathy has arisen. Several studies have argued the impact of aortic valve dysfunction on annual aortic dilatation rate and adverse aortic events in the BAV scenario [11, 12], although additional data stratified as to type of aortic valve dysfunction are still needed to better address this issue. The present study compared long-term outcomes for aortic dilatation and adverse aortic events after isolated AVR between patients with BAV with aortic insufficiency and aortic stenosis, and evaluated the
icuspid aortic valve (BAV), a congenital cardiac malformation previously acknowledged for causing valve dysfunction, has become the focus of intense academic arguments over its elevated risk for aortic dilatation, aneurysm, and dissection [1–3]. Various genetic and hemodynamic theories have been developed to address the mechanism and risk stratification of BAV aortopathy [4–6]. It has been generally speculated that BAV may represent a disorder bestowed with intrinsic propensity toward aortic wall tissue matrix degradation. According to the 2010 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines for thoracic aortic management, surgical intervention
Accepted for publication Oct 12, 2015. *Drs Y Wang and Wu contributed equally to this manuscript. Address correspondence to Dr Dong, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai 200032, China; email: [email protected].
Ó 2016 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2016;-:-–-) Ó 2016 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.10.047
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rationale for prophylactic aortic interventions during valve operation.
Material and Methods Study Population We reviewed patients undergoing AVR from June 2006 to January 2009 at our institute. Details of the screening process are depicted in Figure 1. Briefly, 332 patients with BAV and 636 with tricuspid aortic valve (TAV) identified by preoperative echocardiography and confirmed by surgical inspection were initially screened. Patients with mixed aortic valve dysfunction were included only if either stenosis or insufficiency was predominant. The aortic insufficiency group (BAV-AI group) comprised patients with BAV with moderate to severe aortic insufficiency but no more than moderate aortic stenosis; the aortic stenosis group (BAV-AS group) comprised those with severe aortic stenosis defined as mean transaortic pressure gradient greater than 40 mm Hg but no more than moderate aortic insufficiency [13, 14]. Patients with TAV with aortic insufficiency (TAV-AI group) were used as a control group. All patients with ascending aorta diameter larger than 50 mm routinely underwent aortic operation and were excluded from this study. Additional exclusion criteria were previous cardiac operation, infective endocarditis, acute aortic dissection, Marfan syndrome, connective tissue disease, or other severe congenital heart defects (namely coarctation of the aorta, tetralogy of Fallot, ventricular septal defect, and supraaortic stenosis). In-hospital death occurred in 2 patients with BAV and 3 patients with TAV, who were then excluded from the study. The leading cause for
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postoperative in-hospital death was cardiac failure (4 of 5 patients, 80.0%), followed by stroke (1 of 5 patients, 20.0%). Eventually, a total of 345 patients undergoing isolated AVR during the referring period were recruited to form the study population, of which 84 patients made up the BAV-AI group, 112 patients, the BAV-AS group, and 149 patients, the TAV-AI group. In the study population, 42 patients with BAV and 27 patients with TAV had an ascending aorta diameter at or greater than 45 mm.
Data Collection Clinical features, laboratory data, and demographic characteristics were collected and abstracted in standardized data collection sheets. The diagnosis of BAV was confirmed according to the classification by Sievers and Schmidtke [15] based on intraoperative observation. Echocardiography was performed using commercially available machines followed by a uniform and standardized protocol based on the American College of Cardiology (ACC)/AHA practice guidelines and American Society of Echocardiography (ASE) recommendations [13, 16]. The diameters of the aortic annulus, aortic root (at the sinus of Valsalva), and ascending aorta (at the level of the bifurcation of the pulmonary artery) were measured perpendicular to the long axis of the aorta, during systole, from leading edge to leading edge. Because patients with suspected dilatation of the ascending aorta underwent preoperative computed tomographic angiography, we consecutively selected 50 patients to assess the agreement of transthoracic echocardiography and computed tomographic angiography for measuring the aortic diameters with the Bland-Altman method. The consistency of both
Fig 1. Schematic representation of the patient screening process. (BAV ¼ bicuspid aortic valve; TAV ¼ tricuspid aortic valve.)
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techniques was excellent, with an average difference of 0.16 1.18 mm for the aortic root and 0.20 1.24 mm for the proximal ascending aorta.
Statistical significance was defined as a two-sided probability value of less than 0.05.
Surgical Procedures
Results
Under general anesthesia, median sternotomy, and total cardiopulmonary bypass, AVR was performed by the standard technique [17] using mechanical valves in 81.2% of patients and stented tissue valves in the rest (18.8%). The labeled valve prosthesis size was 17 mm in 1.4%, 19 mm in 7.0%, 21 mm in 25.2%, 23 mm in 28.7%, 25 mm in 26.4%, 27 mm in 7.5%, and 29 mm in 3.8% of patients.
Baseline and Surgical Characteristics
Follow-Up Clinical indicators and echocardiographic variables of all 345 enrolled patients were followed up annually in our institute. Follow-up data including postoperative blood pressure, medication, morbidity, and mortality were obtained from a review of patients’ clinic records or a telephone interview with patients or their family members. The diameters of the aortic root or ascending aorta were routinely evaluated by transthoracic echocardiography during follow-up. The difference between aortic diameters before AVR and at latest follow-up was calculated and divided by the duration of follow-up to yield the annual dilatation rate. Adverse aortic events were defined as occurrence of aortic dissection or rupture, aorticrelated death, or the need for proximal aortic operation that was indicated by symptoms suggestive of aortic expansion, aortic diameter of more than 55 mm, or aortic growth rate of more than 5 mm/y [7]. The study conformed to the principles outlined in the Declaration of Helsinki and was approved by the ethics committee of Zhongshan Hospital, Fudan University, Shanghai, China.
Statistical Analysis Analysis was performed with the SPSS 12.0 software (SPSS, Inc, Chicago, IL). Data were reported as mean standard deviation or medians (interquartile ranges) for continuous variables and as frequencies (percentages) for categorical variables. Continuous variables among groups were assessed by one-way analysis of variance or MannWhitney U test as appropriate. Aortic diameters at latest follow-up were compared among groups by covariance analysis with adjustment for baseline values. Differences in percentages were evaluated using c2 or Fisher’s exact tests. The level of significance for pairwise comparisons was adjusted when multiple comparisons were performed (p ¼ 0.05/2 ¼ 0.025). Aortic event-free survival curves were constructed using the Kaplan-Meier estimator and compared using log-rank tests. Multiple linear stepwise regression analysis was used to identify independent predictors related to annual dilatation rate. The risks for adverse outcomes were compared using Cox regression models. The variables taken into account for multivariate analysis included age at admission, sex, body surface area, smoking, comorbid conditions, baseline aortic diameter, baseline echocardiographic variables, treatment modalities, blood pressure, and medication during follow-up.
Baseline and surgical characteristics are summarized in Table 1. Patients in the BAV-AI group demonstrated younger age (p < 0.001 versus both BAV-AS and TAV-AI groups) and male preference (p ¼ 0.047, BAV-AI versus BAV-AS group; p < 0.001 BAV-AI versus TAV-AI group). Among patients with BAV in general, the right and left coronary leaflet fusion type (57.7%) was the most frequent, followed by right and noncoronary leaflet fusion type (37.8%) and left and noncoronary leaflet fusion type (4.5%). Compared with the BAV-AS group, the BAV-AI group demonstrated a higher prevalence of the right and left coronary leaflet fusion type (73.8% versus 45.5%; p < 0.001), wider aortic roots (38.1 4.6 mm versus 34.0 3.9 mm; p < 0.001), and larger diameter of the aortic annulus (24.3 2.5 mm versus 21.7 2.3 mm; p < 0.001), which then contributed to larger prosthesis sizes (25 mm [23 to 25 mm] versus 21 mm [21 to 23 mm]; p < 0.001). In the TAV-AI group, degenerative valvulopathy was the predominant cause (65.8%), followed by rheumatic causes (34.2%), and the incidence of accompanying coronary artery disease (18.1% versus 3.6%; p ¼ 0.001) was much higher than in the BAV-AI group. Mechanical valve prosthesis was preferred (p < 0.005 versus both the BAV-AS and TAV-AI groups) in the BAVAI group, in accordance with their younger age. Cardiopulmonary bypass and aortic cross-clamp times were similar between the BAV-AI and BAV-AS groups, whereas the TAV-AI group showed prolongation in both (p ¼ 0.006 and p < 0.001, respectively) owing to a higher incidence of accompanying procedures such as coronary artery bypass grafting (p ¼ 0.016) and mitral valve intervention (p < 0.001) than their BAV counterparts.
Long-Term Outcomes After Aortic Valve Replacement The median follow-up period for all patients was 72 months (interquartile range, 66 to 78 months). Blood pressure and medication during follow-up were similar among all patient groups, except for a preference for statin administration in the TAV-AI group (p ¼ 0.001). We found that AVR could prevent the aortic root from further dilatation (p > 0.05 in all groups), but not the ascending aorta (p < 0.001 in all groups). Ascending aortic dilatation rate seemed to be much faster in the BAV-AI group than in the other two groups (both p < 0.001), resulting in greater ascending aorta diameters at latest follow-up in patients with BAV-AI after adjustments for baseline index (Table 2, Fig 2). During follow-up, the BAV-AI group showed a higher risk for adverse aortic events compared with both the BAV-AS (15.5% versus 4.5%; p ¼ 0.008) and the TAV-AI (15.5% versus 6.0%; p ¼ 0.018) groups. Eleven patients (13.1%) in the BAV-AI group experienced progression to ascending aortic aneurysm and needed proximal aortic
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operation, whereas only 5 patients in the BAV-AS and 8 in the TAV-AI group did. Among patients requiring proximal aortic operation, the annual aortic progression rate was 1.49 0.55 mm in the BAV-AI group, 0.86 0.33 mm in the BAV-AS group, and 1.43 0.45 mm in the TAV-AI group. Acute type A aortic dissection occurred in 3 patients after a mean follow-up of 71 13 months, and 1 patient in the BAV-AI group died of postoperative cardiac failure and brain damage. Among patients with BAV with ascending aorta diameter between 40 and 45 mm, 3 experienced adverse aortic complications, 1 in the BAV-AS group and 2 in the BAV-AI group. Kaplan-Meier survival analysis showed inferior aortic event-free survival in patients with BAV-AI compared with the BAVAS (p ¼ 0.005) and the TAV-AI (p ¼ 0.089) groups, albeit with borderline statistical significance in the latter (Table 2, Fig 3).
Multivariate Analyses of Adverse Aortic Events in Patients With Bicuspid Aortic Valve Multivariate linear regression analysis revealed aortic insufficiency (b ¼ 0.317; p < 0.001) and ascending aorta diameters (b ¼ 0.271; p < 0.001) as major factors
associated with the annual ascending aortic dilatation rate in patients with BAV after AVR (Table 3). Cox regression analysis identified aortic insufficiency (hazard ratio, 3.7; 95% confidence interval, 1.2 to 11.1; p ¼ 0.019) and preoperative ascending aortic diameter greater than 45 mm (hazard ratio, 16.8; 95% confidence interval, 5.3 to 53.6; p < 0.001) as independent risk factors for adverse aortic events among patients with BAV in general. In patients with BAV-AI, those with an ascending aortic diameter greater than 45 mm at the time of AVR (hazard ratio, 13.8; 95% confidence interval, 3.0 to 63.3; p ¼ 0.001) were more likely to experience adverse aortic events, whereas both preoperative ascending aortic diameter and follow-up systolic blood pressure were indicators for adverse aortic events in the BAV-AS group (Table 4).
Comment As the most common congenital cardiac abnormality, BAV occurs in 1% to 2% of the general population [18, 19], and the incidence of a normally functioning aortic valve is reported to be 15% to 30% [20, 21], which means that the majority of patients with BAV are likely to have an aortic
Table 1. Baseline Characteristics and Surgical Features of Patients Undergoing Aortic Valve Replacement
Variable Age, y Male sex BSA, m2 NYHA class III/IV Smoking Comorbid conditions Hypertension Diabetes Dyslipidemia History of coronary artery disease History of cerebrovascular disease Echocardiographic findings Left ventricular ejection fraction <0.55 RL fusion Rheumatic valve disease Aortic annulus, mm Aortic root, mm Ascending aorta, mm Surgical features Mechanical valve prosthesis Prosthesis size, mm Cardiopulmonary bypass time, min Cross-clamp time, min Lowest body temperature, C Mitral valve repair/replacement Coronary artery bypass grafting
BAV-AI (n ¼ 84)
BAV-AS (n ¼ 112)
TAV-AI (n ¼ 149)
p Value (BAV-AI Versus BAV-AS)
p Value (BAV-AI Versus TAV-AI)
46 13 67 (79.8) 1.81 0.17 57 (67.9) 25 (29.8)
56 14 75 (67.0) 1.81 0.17 69 (61.6) 21 (18.8)
56 11 81 (54.4) 1.83 0.14 103 (69.1) 34 (22.8)
<0.001 0.047 0.931 0.366 0.072
<0.001 <0.001 0.920 0.841 0.242
26 2 8 3 3
37 9 11 9 2
0.757 0.120 0.944 0.197 0.653
0.820 0.494 0.202 0.001 0.181
(31.0) (2.4) (9.5) (3.6) (3.6)
(33.0) (8.0) (9.8) (8.0) (1.8)
44 7 23 27 12
(29.5) (4.7) (15.4) (18.1) (8.1)
19 (22.6) 62 (73.8) . 24.3 2.5 38.1 4.6 40.5 4.5
25 (22.3) 51 (45.5) . 21.7 2.3 34.0 3.9 39.6 4.7
19 (12.8) . 51 (34.2) 23.8 2.3 37.2 3.9 39.4 5.1
0.961 <0.001 . <0.001 <0.001 0.213
0.052 . . 0.134 0.104 0.115
79 (94.0) 25 (23–25) 85.0 27.1 56.1 19.5 30.1 1.6 13 (15.5) 2 (2.4)
83 (74.1) 21 (21–23) 86.0 27.8 56.5 19.8 29.8 1.4 12 (10.7) 6 (5.4)
118 (79.2) 23 (21–25) 93.6 20.4 65.0 15.3 29.7 1.5 58 (38.9) 17 (11.4)
<0.001 <0.001 0.805 0.877 0.319 0.323 0.470
0.003 0.031 0.006 <0.001 0.097 <0.001 0.016
Data are presented as the mean SD, as number (percentage), or as median (interquartile range). AI ¼ aortic insufficiency; AS ¼ aortic stenosis; BAV ¼ bicuspid aortic valve; BSA ¼ body surface area; NYHA ¼ New York Heart Association; RL fusion ¼ right and left coronary leaflet fusion; SD ¼ standard deviation; TAV ¼ tricuspid aortic valve.
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Table 2. Long-Term Follow-Up in Patients After Aortic Valve Replacement
Variable Follow-up, mo SBP during follow-up, mm Hg DBP during follow-up, mm Hg Postoperative b-blocker therapy Postoperative ACEI/ARB therapy Postoperative statin therapy Mean gradient of aortic prosthesis, mm Hg Peak velocity of aortic prosthesis, m/s Aortic root, mm Ascending aorta, mm Rate of aortic root dilatation, mm/y Rate of ascending aorta dilatation, mm/y Adverse aortic events Aortic dissection/rupture Aortic-related death Need for proximal aortic surgery Cardiac mortality Congestive heart failure Endocarditis Noncardiovascular mortality
BAV-AI (n ¼ 84)
BAV-AS (n ¼ 112)
TAV-AI (n ¼ 149)
73 (65–78) 123 (112–142) 77 (66–88) 39 (46.4) 12 (14.3) 4 (4.8) 13.6 4.6
71 (62–78) 123 (112–138) 81 (72–86) 42 (37.5) 20 (17.9) 9 (8.0) 15.2 5.2
73 (68–77) 120 (110–135) 75 (70–82) 61 (40.9) 30 (20.1) 32 (21.5) 14.1 4.6
2.66 0.42 38.5 5.1 43.2 6.5 0.02 (0.19–0.23) 0.29 (0.19–0.79) 13 (15.5) 2 (2.4) 1 (1.2) 11 (13.1) 1 (1.2) 1 (1.2) 0 0
2.72 0.46 34.2 3.7 40.8 4.9 0.05 (0.10–0.21) 0.18 (0.10–0.29) 5 (4.5) 0 0 5 (4.5) 2 (1.8) 1 (0.9) 1 (0.9) 1 (0.9)
2.62 0.43 37.1 3.7 40.6 6.2 0.03 (0.20–0.27) 0.05 (0.20–0.48) 9 (6.0) 1 (0.7) 0 8 (5.4) 2 (1.3) 2 (1.3) 0 (0.5) 2 (0.5)
p Value (BAV-AI versus BAV-AS)
p Value (BAV-AI versus TAV-AI)
0.825 0.070 0.146 0.209 0.503 0.362 0.055
0.286 0.067 0.240 0.416 0.265 0.001 0.419
0.472 0.223 <0.001 0.215 <0.001 0.008 0.182 0.429 0.029 1.000 1.000 1.000 1.000
0.540 0.521 0.001 0.105 <0.001 0.018 0.295 0.361 0.039 1.000 1.000 1.000 0.537
Data are presented as the mean standard deviation, as number (percentage), or as median (interquartile range). ACEI/ARB ¼ angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; AI ¼ aortic insufficiency; AS ¼ aortic stenosis; bicuspid aortic valve; DBP ¼ diastolic blood pressure; SBP ¼ systolic blood pressure; TAV ¼ tricuspid aortic valve.
valve operation within their life. Until now, the guidelines of the optimal surgical strategy for patients with BAV with valve dysfunction and concomitant aortic dilatation were still based on expert opinions and remained an open debate. Both the 2010 ACCF/AHA and 2014 European Society of Cardiology (ESC) guidelines recommended 45 mm as the threshold for ascending aorta replacement
Fig 2. Annual aortic root and ascending aortic dilatation rate after aortic valve replacement in three groups. Ascending aorta dilatation rate was faster in patients with bicuspid aortic valve with aortic insufficiency (BAV-AI group) than in patients with bicuspid aortic valve with aortic stenosis (BAV-AS group) and patients with tricuspid aortic valve with aortic insufficiency (TAV-AI group; both p < 0.001).
BAV ¼
in patients undergoing valve operation, whereas the 2014 Canadian guidelines favored a more conservative strategy with the surgical indication as 50 mm [7, 22, 23].
Fig 3. Kaplan-Meier curves of adverse aortic events after aortic valve replacement in three groups. (BAV-AI ¼ patients with bicuspid aortic valve with aortic insufficiency; BAV-AS ¼ patients with bicuspid aortic valve with aortic stenosis; TAV-AI ¼ patients with tricuspid aortic valve with aortic insufficiency.)
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Table 3. Multivariate Linear Regression Analysis of Annual Ascending Aortic Dilatation Rate Among Patients With Bicuspid Aortic Valve After Aortic Valve Replacement Variables Aortic insufficiency Ascending aorta diameters, mm
Unstandardized B
Standard Error
Standardized b
p Value
0.190 0.018
0.040 0.004
0.317 0.271
<0.001 <0.001
Moreover, the current recommendation for aortic intervention in the setting of valve operation lacks at-length stratification on the BAV phenotype because the severity of vessel wall matrix degradation has proved to be different between patients with aortic stenosis and those with aortic insufficiency, probably as a result of the long-term impact of hemodynamic abnormality [24]. The present study was performed during a 5-year follow-up and looked at aortic dilatation rate and adverse aortic events after isolated AVR in a large cohort of patients with BAV, thus assessing clinical outcomes and risk stratification for BAV aortopathy. A conservative institutional policy of 50 mm as the threshold for proximal aorta intervention in patients requiring valve operation was in place throughout the study period, and all relevant data were obtained at baseline and after isolated AVR in the 345 patients enrolled. We demonstrated an astoundingly elevated hazard toward adverse aortic events after AVR in patients with BAV-AI, which advocated the heterogeneity of BAV aortopathy with a root phenotype (aortic valve insufficiency and dilatation at aortic sinus) proposed by Girdauskas and colleagues [12] as well as accelerated matrix elastic fiber loss in patients with aortic insufficiency dominance argued by Roberts and associates [25] and Girdauskas and coworkers [26]. The combination of BAV and aortic insufficiency seemed to be decisive, as the 7year aortic event-free rate was 65.5% in the BAV-AI group, inferior to both the BAV-AS and TAV-AI groups, which demonstrated 7-year aortic event-free rates of 92.3% and 85.8%, respectively. Based on the observation that only patients with BAV-AI were susceptible to ascending aorta dilatation after AVR, some mechanism other than mere hemodynamic forces was probably at work. However, it was hard to determine whether aortic insufficiency was the driving force for ascending aorta
dilatation or vice versa. A third, and more likely, explanation was that both aortic insufficiency and proximal aortopathy represented different phenotypic aspects of the same BAV subgroup. In other words, some common intrinsic traits that made certain patients with BAV prone to aortic complications might also render them prone to an aortic insufficiency phenotype. Our data validated the consensus of ascending aorta diameter greater than 45 mm as the threshold to consider concurrent aortic operation during AVR as well as the rationale for the surgical option of an aortic root-sparing procedure [27, 28], as we demonstrated that isolated AVR was capable of preventing the aortic root but not the ascending aorta from further dilatation in patients with BAV. On the other hand, patients with BAV may further benefit from individualized surgical strategies according to their valve dysfunction type [29]. By changing the threshold for aortic intervention to 45 mm, the expected reduction of adverse aortic events was 11.9% (10 of 84 patients; two acute aortic dissections included) in the BAV-AI group, but merely 3.6% (no acute aortic dissection included) in the BAV-AS group. If a further leap to use 40 mm as the cutoff value for ascending aorta intervention was taken, 3 more patients (1 in the BAV-AS group and 2 in the BAV-AI group) experiencing future adverse aortic events among 53 patients with BAV with an ascending aorta diameter between 40 and 45 mm in our cohort would have be included, but the potential benefit could not compensate for the markedly increased number of surgical candidates as well as elevated procedural risks and medical expenses. Therefore, it was reasonable to advocate the 45-mm threshold in patients with BAV-AI, who tended to be younger and have a longer life expectancy and lower surgical-related mortality, as also mentioned by Sievers and colleagues [30] in a retrospective study of 1,362 patients with BAV undergoing
Table 4. Cox Regression Analysis of Adverse Aortic Events Among Patients With Bicuspid Aortic Valve After Aortic Valve Replacement Variables All patients with BAV Aortic insufficiency Ascending aorta dimension >45 mm Patients with BAV with aortic insufficiency Ascending aorta dimension >45 mm Patients with BAV with aortic stenosis Ascending aorta dimension >45 mm Follow-up SBP >140 mm Hg BAV ¼ bicuspid aortic valve;
SBP ¼ systolic blood pressure.
Hazard Ratio
95% Confidence Interval
p Value
3.7 16.8
1.2–11.1 5.3–53.6
0.019 <0.001
13.8
3.0–63.3
0.001
38.7 11.4
2.5–588.6 1.2–113.0
0.009 0.037
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aortic valve operation with and without aortic intervention. Isolated AVR might be an option for patients with BAV-AS with aortic diameter of 45 to 50 mm, and optimized control of postoperative blood pressure could be beneficial because follow-up systolic blood pressure greater than 140 mm Hg served as a risk factor for adverse aortic events in the BAV-AS group compared with the BAV-AI group [30, 31].
Study Limitations Several limitations should be noted concerning the retrospective and single-centered nature of this study. A prolonged follow-up period would be a benefit, although distinct prognostic features were already revealed. Additional imaging techniques such as computed tomographic angiography could help to illustrate various aortic segments including the mid and distal ascending aorta, the aortic arch, and the descending aorta for a better description of different types of aortopathy. The lack of a TAV-AS group might be a problem, but these patients with degenerating aortic valves were usually older, which could contribute additional bias to the follow-up and survival analysis. Last but not least, the causative association between aortic insufficiency and aortic dilatation is still far from clear and requires further well-designed studies evaluating histologic, enzymatic, and gene expression data.
Conclusions Patients with BAV-AI demonstrated a faster ascending aorta dilatation rate and a higher risk for adverse aortic events than did patients with BAV-AS after isolated AVR. An aggressive policy of preventive aortic interventions is optional in patients with BAV-AI in whom the aortic diameter is larger than 45 mm, whereas those with BAVAS were at a lower risk for adverse aortic events with an aortic diameter of less than 50 mm. The study was supported by the National Natural Science Foundation of China (No. 81300232) and Shanghai Municipal Health Bureau (No. 20154Y0030).
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