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Fate of remnant sinuses of Valsalva in patients with bicuspid and trileaflet valves undergoing aortic valve, ascending aorta, and aortic arch replacement

Open ArchivePublished:April 28, 2017DOI:https://doi.org/10.1016/j.jtcvs.2017.03.150

      Abstract

      Objective

      In patients presenting with aortic valvulopathy with concomitant ascending aortic aneurysm, surgical management of the sinus of Valsalva segment remains undefined, especially for moderately dilated aortic roots. In patients with this pathology undergoing aortic valve replacement with supracoronary ascending aorta replacement, we assessed the fate of the remnant preserved sinus of Valsalva segment stratified by aortic valve morphology and pathology.

      Methods

      From 2002 to 2015, 428 patients underwent elective aortic valve replacement with supracoronary ascending aorta replacement. Patients were stratified on the basis of valvular morphology (bicuspid aortic valve [n = 254] and tricuspid aortic valve [n = 174]), valvular pathology (bicuspid aortic valve with aortic stenosis [n = 178], bicuspid aortic valve with aortic insufficiency [n = 76], tricuspid aortic valve with aortic stenosis [n = 61], tricuspid aortic valve with aortic insufficiency [n = 113]), and preoperative sinus of Valsalva dimensions (<40, 40-45, >45 mm).

      Results

      Kaplan–Meier analysis revealed no significant difference in freedom from reoperation in tricuspid aortic valve versus bicuspid aortic valve (P = .576). Multivariable Cox regression model performed with sinus of Valsalva dimensions at baseline and follow-up as time-varying covariates did not adversely affect survival. A repeated-measure, mixed-effects model constructed to assess longitudinal sinus of Valsalva trends revealed that the retained sinus of Valsalva dimensions remain stable over long-term follow-up (discharge to ≥10 years), irrespective of valvular morphology/pathology (bicuspid aortic valve with aortic insufficiency, tricuspid aortic valve with aortic insufficiency, tricuspid aortic valve with aortic stenosis) and preoperative sinus of Valsalva groups (<40, 40-45, >45 mm).

      Conclusions

      In patients with nonaneurysmal sinuses of Valsalva undergoing aortic valve replacement with supracoronary ascending aorta replacement, the sinus segment can be preserved irrespective of the type of valvular pathology (aortic stenosis vs aortic insufficiency) or valvular morphology (bicuspid aortic valve vs tricuspid aortic valve). Aortic valve replacement with supracoronary ascending aorta replacement may have a stabilizing effect on the sinus segment over long-term follow-up in patients with tricuspid aortic valves or bicuspid aortic valves.

      Key Words

      Abbreviations and Acronyms:

      AI (aortic insufficiency), AS (aortic stenosis), AVRSCAAR (aortic valve and supracoronary ascending aortic replacement), BAV (bicuspid aortic valve), CI (confidence interval), HR (hazard ratio), NYHA (New York Heart Association), SOV (sinus of Valsalva), STJ (sinotubular junction), TAV (tricuspid aortic valve)
      Figure thumbnail fx1
      Aortic valve replacement and supracoronary ascending aortic replacement/hemiarch procedure.
      An aortic valve with supracoronary aortic replacement provides long-term stability to the remnant SOV segment in patients with bicuspid and tricuspid aortopathies.
      In patients undergoing aortic valve and supracoronary aortic replacement, a direct comparative analysis of the retained sinus segment in patients with BAV and TAV is lacking. We assess the long-term stability of the preserved sinus stratified by aortic valve morphology (bicuspid vs tricuspid) and pathology (AS or AI) and sinus dimensions to create evidence-based guidelines for the management of the sinus segment in patients with BAV or TAV aortopathies.
      See Editorial Commentary page 433.
      See Editorial page 419.
      Bicuspid aortic valve (BAV) is the most common congenital valvular pathology with an incidence of 1% to 2% and a known association with aortopathies.
      • Fedak P.W.
      • Verma S.
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      Clinical and pathophysiological implications of a bicuspid aortic valve.
      • Hahn R.T.
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      Association of aortic dilation with regurgitant, stenotic and functionally normal bicuspid aortic valves.
      • Michelena H.I.
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      Bicuspid aortic valve aortopathy in adults: incidence, etiology, and clinical significance.
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      Bicuspid aortic valve disease.
      The incidence of ascending aortic aneurysms in patients with BAV is 30% to 50%.
      • Hahn R.T.
      • Roman M.J.
      • Mogtader A.H.
      • Devereux R.B.
      Association of aortic dilation with regurgitant, stenotic and functionally normal bicuspid aortic valves.
      • Michelena H.I.
      • Della Corte A.
      • Prakash S.K.
      • Milewicz D.M.
      • Evangelista A.
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      Bicuspid aortic valve aortopathy in adults: incidence, etiology, and clinical significance.
      • Siu S.C.
      • Silversides C.K.
      Bicuspid aortic valve disease.
      Tricuspid aortic valve (TAV) idiopathic aortopathies are primarily associated with older age, smoking, hypertension, and higher atherosclerotic burden.
      It is well recognized that the presence of severe aortic root dilation with aortic valve disease requires root replacement in patients with TAV and BAV. What is less clear are the long-term characteristics and risk of aortic events for the retained sinus of Valsalva (SOV) in both BAV and TAV patients. An aortic valve replacement and supracoronary ascending aorta replacement (AVRSCAAR) procedure has been used for patients with a mild to moderately dilated sinus segment. This procedure has been used for patients with both TAV and BAV aortopathies and has the advantage of retaining the SOV and preserving the intact coronary ostia. On the basis of studies of the ascending aorta, it has been postulated that patients with BAV have a higher rate of complications
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      Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease?.
      of the remaining aorta and dilation of the proximal aorta and retained sinus segment.
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      • Kobayashi J.
      • 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.
      It has been shown that a nondilated BAV ascending aorta has degraded elastic lamella fibers compared with nondilated TAV ascending aorta.
      • Tadros T.M.
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      Ascending aortic dilatation associated with bicuspid aortic valve: pathophysiology, molecular biology, and clinical implications.
      However, a study by Heng and colleagues
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      Comparative histology of aortic dilatation associated with bileaflet versus trileaflet aortic valves.
      has suggested a more severe histologic abnormality in dilated TAV versus BAV aortas. Further extending these concepts, it has been suggested that the cause of aortic dilation is different in patients with aortic stenosis (AS) and aortic insufficiency (AI) and is based on TAV and BAV morphology, histology, and hemodynamic flow patterns.
      • Hahn R.T.
      • Roman M.J.
      • Mogtader A.H.
      • Devereux R.B.
      Association of aortic dilation with regurgitant, stenotic and functionally normal bicuspid aortic valves.
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      These findings prompted our investigation of the potential differential stability of the SOV between those with TAV and BAV with AS or AI.
      To date, a direct comparative longitudinal study of the stability of the retained mildly to moderately dilated sinus segment in patients with BAV and TAV stratified by AS or AI valve pathology is lacking. We investigated the midterm outcomes of the preserved SOV segment stratified by aortic valve type and pathology.

      Materials and Methods

       Patients

      This study was approved by the Institutional Review Board of the University of Pennsylvania. A prospectively maintained institutional database was retrospectively reviewed to stratify all patients by BAV or TAV valvular pathology with concomitant ascending aortic aneurysm who underwent AVRSCAAR. From 2002 to 2015, 428 patients underwent an elective AVRSCAAR for valvular and aneurysmal pathology. To maintain homogeneity within each group, patients with known connective tissue disorders, acute type A dissection, endocarditis, or reoperative procedures, and emergency cases were excluded. All aortoplasty procedures were excluded. An ascending hemiarch/total arch replacement procedure was performed in 100% of the cases included in this study.
      To account for the heterogeneous disease processes of patients with BAV and TAV with aortic valvulopathy and ascending aneurysm, we stratified the patient population by 4 variables, including valve morphology (BAV vs TAV), valve pathology (AS vs AI), baseline SOV dimensions (mild [<40 mm], moderate [40-45 mm], severe [>45 mm]), and time relation to the procedure (preoperative, discharge, and longitudinal follow-up to >10 years). To eliminate the variable of a third cohort, all patients with AS and AI pathology were grouped into the AS subcategory. Our institutional algorithm for AVRSCAAR based on the dimension of the aortic root, the valvular pathology, and the degree of effacement (STJ/annular ratio) is delineated in Figure 1. The final decision on the procedure performed was based on intraoperative findings and the operating surgeon's decision in cases of STJ/annular ratio greater than 1.5 or thinning of the sinus segment. The distribution of the 428 patients meeting inclusion criteria by subgroups was as follows: BAV group = 254 patients (BAV AS = 178, BAV AI = 76); TAV group = 174 patients (TAV AS = 61, TAV AI = 113).
      Figure thumbnail gr1
      Figure 1Institutional algorithm for ascending aortic aneurysm disease and AVRSCAAR procedure. AS, Aortic stenosis; AI, aortic insufficiency; STJ, sinotubular junction; AVRSCAAR, aortic valve and supracoronary ascending aortic replacement; VSRR, valve-sparing root reimplantation.

       Surgical Procedure

      In all cases, aortic valve replacement, ascending aorta replacement, and aortic arch reconstruction under hypothermic circulatory arrest were performed (Central Image).

       Ascending aorta replacement

      Figure thumbnail fx2
      Video 1Intraoperative video demonstrating aortic valve repair with subvalvular aortic ring annuloplasty and supracoronary ascending aorta replacement with a Dacron graft using a hemiarch approach. Video available at: http://www.jtcvsonline.org/article/S0022-5223(17)30870-X/addons.

       Aortic arch replacement

      Deep hypothermic circulatory arrest was initiated using retrograde cerebral perfusion via the superior vena cava or antegrade cerebral perfusion via the axillary artery. An aggressive transverse hemiarch was tailored by resecting the majority of the lesser curvature of the aortic arch, and a straight Dacron graft was beveled and anastomosed to the remnant aortic arch with a running Prolene stitch as an open distal anastomosis. The aortic graft was cannulated to reinitiate cardiopulmonary bypass.
      Total arch replacement was performed using deep hypothermic circulatory arrest with antegrade cerebral perfusion via the axillary artery or direct ostial arch vessel perfusion. The proximal descending thoracic aorta was anastomosed first to a 3- or 4-branch graft, and each head vessel was individually reimplanted to a branch of the graft. Typically, on completion of the distal aortic anastomosis and the left subclavian artery anastomosis, cardiopulmonary bypass was reinitiated and the left common carotid and innominate arteries were anastomosed individually.

       Aortic valve replacement

      On aggressive debridement of the valve and the annulus, valve replacement was performed by placing interrupted annular stitches circumferentially (Central Image).

       Clinical and Echocardiographic Follow-up

      Patients were seen in the Aorta Clinic and in individual surgeon clinics. In these patients, imaging and clinical follow-up were readily available. For patients not being followed routinely at our institution, phone calls were made to patients, their primary care physicians, and cardiologists to bring patients to the Aorta Clinic for follow-up evaluation. If patients were unable to return to clinic for personal reasons, with their permission, echocardiographic and clinical follow-up data were obtained from their primary care physicians and cardiologists. All patients with BAV and TAV were followed in the outpatient Aorta Clinic using transthoracic echocardiography exclusively.

       Statistical Analysis

      General statistics were analyzed using STATA/MP v14.2 (StataCorp LP, College Station, Tex) and SPSS v.23 (SPSS Inc, Armonk, NY). Predictive multivariate models and mixed-effect models for repeated measures were computed in STATA/MP v14.2, and R. Graphs were drawn in STATA/MP v14.2. First, data were checked for normality. Descriptive statistics were presented as means ± standard deviation for continuous variables, median (interquartile range) for continuous variables in cases of non-normality, and percentage (frequency) for categoric variables. Continuous variables were compared using the unpaired t test, paired dependent sample t test in cases of repeated measures (preoperative vs early postoperative SOV diameters), 1-way analysis of variance, and Wilcoxon signed-rank test in cases of non-normality. Fisher exact and chi-square statistics were used to compare categoric variables. All tests were 2 sided with the alpha level set at .05 for statistical significance.
      A linear mixed-effects regression for repeated measures was fitted to validate predictors of SOV diameters over time and to analyze SOV trends over a longitudinal follow up. Preoperative valve morphology (TAV, BAV), valve pathology (AI, AS), preoperative SOV diameters (continuous variable), and postoperative measurement time points (continuous variable) were included as fixed effects, with the unique patient identification number as random effect. Measurement time points were included as repeated-measure time points. In addition, an interaction term of preoperative SOV diameters and postoperative measurement time points was introduced as a separate fixed effect covariate. A generalized linear model was used to describe predictors of the continuous response variable discharge/1-month SOV diameter.
      Multivariable Cox regression was used to determine independent predictors of overall mortality. Factors included in the model were age, ascending aorta diameter (millimeters), time period of surgery (before or after 2009), gender, hypertension, New York Heart Association (NYHA) class III/IV, SOV greater than 45 mm, and valve morphology (TAV, BAV). To further determine the impact of longitudinal retained SOV trends on long-term outcome, follow-up SOV dimensions were added to the existing time-to-event model as a time-varying covariate. Kaplan–Meier method and log-rank statistics were used to determine and compare freedom from reoperation and reoperation-free survival (censoring for reoperation and death). Kaplan–Meier estimates and mean SOV diameters over long-term follow-up were homogenously plotted with 95% confidence interval (CI) bands/bars.

      Results

       Demographics, Preoperative Parameters, and Intraoperative and Postoperative Outcomes

      Demographics and preoperative parameters are listed in Table 1. Mean age was 59.4 ± 11.6 years and 71.9 ± 8.8 years (P < .001) for patients with BAV and TAV, respectively (77.6% vs 56.9% male gender). There was a significantly higher subpopulation of AS in the BAV cohort (BAV AS = 70.1% vs TAV AS = 35.1%, P < .001). The TAV cohort of patients had a higher incidence of heart failure (NYHA III/IV = 33.3% vs 18.1%, P < .001) and an increased incidence of dyslipidemia (67.2% vs 54.7%, P = .008). There was increased atherosclerotic burden noted in the ascending aorta at operation and increased incidence of diseased coronary vessels in patients with TAV (P < .001) (Table 1). Preoperative root diameters and stratification of patients with BAV and TAV by SOV dimensions are shown in Table 2. Overall, the preoperative SOV dimensions for TAV and BAV cases were similar.
      Table 1Demographics and preoperative parameters
      VariableTAV (n = 174)BAV (n = 254)P value
      AI (n = 113)AS (n = 61)AI (n = 76)AS (n = 178)
      Demographics
       Age, y71.8 ± 9.172.1 ± 8.354.3 ± 11.961.6 ± 10.8<.001
       Sex (male)60 (53.1%)39 (63.9%)65 (85.5%)132 (74.2%)<.001
       Hypertension95 (84.1%)52 (85.2%)50 (65.8%)118 (66.3%)<.001
       Smoking17 (15.0%)14 (23.0%)12 (15.8%)23 (12.3%).256
       Dyslipidemia70 (61.9%)47 (77.0%)33 (43.4%)106 (59.6%).008
       Diabetes mellitus17 (15.0%)12 (19.7%)3 (3.9%)24 (13.5%).065
      No. of diseased vessels
       1-vessel disease16 (14.2%)11 (18.0)4 (5.3%)25 (14.0%)
       2-vessel disease13 (11.5)10 (16.4%)3 (3.9%)12 (6.7%)<.001
       3-vessel disease16 (14.2)17 (27.9)2 (2.6)8 (4.5%)
       Aortic coarctation0 (-)0 (-)0 (-)4 (2.2%).096
      LVEF <40%14 (12.4%)8 (13.1%)4 (5.3%)10 (5.6%).010
      LVEF %53.8 ± 13.655.1 ± 16.255.8 ± 12.660.2 ± 12.2.002
      NYHA class III/IV33 (29.2%)25 (41.0%)9 (11.8%)37 (20.8%)<.001
      Echocardiographic data
       Stenotic valve pathology61 (35.1%)178 (70.1%)<.001
       Insufficiency valve pathology113 (64.9%)76 (29.9%)<.001
      Data are presented as mean ± standard deviation (SD) and n (%). TAV, Tricuspid aortic valve; BAV, bicuspid aortic valve; AI, aortic insufficiency; AS, aortic stenosis; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.
      Table 2Subgroup stratification by preoperative sinus of Valsalva dimensions and valve morphology
      VariableTAV (n = 174)BAV (n = 254)P value
      Aortic root diameter (mm)37.8 ± 5.9 (n = 155)37.4 ± 4.6 (n = 199).531
      Group A (<40 mm)34.1 ± 3.7 (n = 93)34.8 ± 3.4 (n = 129).128
      Group B (40-45 mm)41.7 ± 1.9 (n = 48)41.9 ± 1.5 (n = 66).519
      Group C (>45 mm)48.8 ± 3.5 (n = 14)46.8 ± 1.5 (n = 4).289
      Data are presented as mean ± SD. TAV, Tricuspid aortic valve; BAV, bicuspid aortic valve.

       Intraoperative results

      Intraoperative data are detailed in Table 3. AVRSCAAR was performed using a straight Dacron graft in 100% of cases. Mechanical valves were used in 2.3% of TAV cases (97.7% biologic) and 5.1% of BAV cases (94.9% biologic). Cardiopulmonary bypass times (219.8 ± 64.0 minutes vs 195.6 ± 54.9 minutes, P < .001) and aortic crossclamp times (159.2 ± 51.4 minutes vs 143.1 ± 39.9 minutes, P < .001) were significantly longer in the TAV cohort, most likely because of the increased number of diseased coronary vessels in those with TAV.
      Table 3Intraoperative data
      VariableTAV (n = 174)BAV (n = 254)P value
      Cardiopulmonary bypass (min)219.8 ± 64.0195.6 ± 54.9<.001
      Aortic crossclamp (min)159.2 ± 51.4143.1 ± 39.9<.001
      Mechanical valve4 (2.3%)13 (5.1%).142
      Biological valve170 (97.7%)241 (94.9%).142
      Valve prosthesis size (mm)24.5 ± 2.225.9 ± 2.1<.001
      Data are presented as mean ± SD and n (%). TAV, Tricuspid aortic valve; BAV, bicuspid aortic valve.

       Postoperative outcomes

      Postoperative outcomes are listed in Table 4. In-hospital/30-day mortality was higher in patients with TAV (5.2% [9/174] vs 1.6% in patients with BAV [4/254], P = .033). The incidence of transient ischemic attack/stroke was higher in the TAV group (3.4% [6/174] vs 0.8% [2/254], P = .04). In patients from both groups presenting with AI, significant left ventricular remodeling was noted on postoperative echocardiographic assessments compared with preoperative dimensions. Left ventricular end-diastolic dimension decrease of 7.4 ± 1.0 mm (P < .001) was noted for those with TAV AI, and a mean decrease of 6.1 ± 1.0 mm (P < .001) was noted in the BAV AI subgroup (data not shown).
      Table 4Postoperative outcomes
      VariableTAV (n = 174)BAV (n = 254)P value
      Stroke/transient ischemic attack6 (3.4%)2 (0.8%).046
      Renal failure6 (3.4%)1 (0.4%).014
      Renal failure requiring dialysis3 (1.7%)1 (0.4%).160
      Prolonged ventilation (>24 h)50 (28.7%)27 (10.6%)<.001
      In-hospital/30-d mortality9 (5.2%)4 (1.6%).033
      Data are presented as mean ± SD and n (%). TAV, Tricuspid aortic valve; BAV, bicuspid aortic valve.

       Longitudinal Follow-up

      In total, 428 patients met inclusion criteria with total follow-up of 1672 patient-years.

       Sinus of Valsalva measurement

      There was no significant difference in mean preoperative aortic root diameters between BAV and TAV cohorts for the AS or AI subpopulations: TAV AS 36.0 ± 6.1 mm, TAV AI 38.7 ± 5.6 mm, BAV AS 36.6 ± 4.7 mm, and BAV AI 39.2 ± 3.9 mm (P = .531 on analysis of variance) (Table 2). The number of patients remaining in the analysis for every follow-up time point is shown in Figure 2. Longitudinal follow-up data for SOV dimensions stratified into 12 subgroups based on valve morphology (BAV vs TAV), valve pathology (AS vs AI), and preoperative SOV dimension (<40 mm vs 40-45 mm vs >45 mm) are delineated in Figure 2.
      Figure thumbnail gr2
      Figure 2Long-term follow-up of SOV dimensions in patients with BAV and TAV disease with ascending aneurysm undergoing AVRSCAAR stratified by preoperative SOV dimensions. TAVAI, Tricuspid aortic valve with aortic insufficiency; TAVAS, tricuspid aortic valve with aortic stenosis; BAVAI, bicuspid aortic valve with aortic insufficiency; BAVAS, bicuspid aortic valve with aortic stenosis; CI, confidence interval; SOV, sinus of Valsalva.
      A dependent-sample paired t test for the stratified TAV AS, TAV AI, BAV AS, and BAV AI subpopulations comparing preoperative with early postoperative (discharge to 1 month) echocardiographic assessments of SOV diameters revealed an early, significant decrease in retained sinus dimensions (38.2 ± 5.3 mm vs 35.1 ± 5.8 mm, P < .001). Results of a generalized linear model to determine the predictors of early postoperative reduction in SOV dimensions are shown in Table 5. Although patient age and aortic valvular morphology/pathology had no discernible effect on early SOV dimensions, larger preoperative SOV diameters were associated with greater early postoperative reduction in SOV dimensions (P = .030).
      Table 5Generalized linear model showing predictors of postoperative reduction in sinus of Valsalva dimensions
      CoefficientSEP value
      Age−0.0050.009.573
      AI−0.1170.213.583
      TAV−0.3420.240.155
      Preoperative SOV diameter−0.4200.194.030
      SE, Standard error; AI, aortic insufficiency; TAV, tricuspid aortic valve; SOV, sinus of Valsalva.

       Repeated-measure mixed effects model for longitudinal echocardiographic assessment of sinus of Valsalva

      To achieve a statistically comprehensive interpretation incorporating long-term echocardiography data, we modeled a mixed-effects regression based on a repeated-measure approach in a longitudinal fashion. Valvular morphology and pathology at baseline, preoperative SOV diameter, postoperative time course, and interaction effect of preoperative SOV diameters and postoperative time course were used as covariates. Within-subject and within-stratified subgroup comparison failed to show main effects for follow-up time on the postoperative SOV pattern (P = .935) (Table 6 and Figure 2), implying that the pattern in SOV trends was stable and sustained (discharge to ≥10 years) irrespective of valvular morphology and pathology (BAV AI, BAV AS, TAV AI, and TAV AS) (Table 6 and Figure 2). This was statistically supported by the additional introduction of an interaction term (preoperative SOV diameter with postoperative time course), which also failed to show significant effects (P = .783). Not surprisingly, preoperative SOV dimensions significantly affected the retained postoperative sinus dimensions (P < .001). Taken together, the longitudinal data assessment implies that an initial and pronounced postoperative decrease in SOV dimensions occurs with AVRSCAAR independently of aortic valve morphology (P = .155), aortic valve pathology (P = .583), and age (P = .573). This is then followed by a sustained and stable pattern of SOV dimension throughout the postoperative time course of 10 years or more in all the subgroups.
      Table 6Repeated-measures, mixed-effect longitudinal model
      CoefficientSEP value
      Valve geometry and pathology
       BAV AIReference
       BAV AS−1.0610.804.187
       TAV AI−0.6920.808.391
       TAV AS−0.980.925.290
      Preoperative SOV diameter
       (continuous)0.6540.567<.001
      Postoperative time course
       (continuous)0.030.367.935
      Interaction term
       (preoperative SOV diameter with time)0.0030.009.783
      SE, Standard error; BAV, bicuspid aortic valve; AI, aortic insufficiency; AS, aortic stenosis; TAV, tricuspid aortic valve; SOV, sinus of Valsalva.

       Multivariable Cox regression

      The results of the Cox regression model to determine factors associated with mortality over long-term follow-up are shown in Table 7. Only increased age (hazard ratio [HR], 1.061; 95% CI, 1.008-1.117; P = .022) and advanced heart failure (NYHA classes III and IV; HR, 3.220; 95% CI, 1.463-7.084; P = .004) were independently predictive of increased mortality. Of note, neither a dilated sinus segment at baseline (>45 mm) nor the type of valvular morphology (TAV vs BAV) had a discernible association with mortality (HR, 1.040; 95% CI, 0.286-3.780; P = .952 and HR, 2.307; 95% CI, 0.946-6.124; P = .065). There was an inverse effect for the year of surgical intervention, with a better survival for procedures performed during and after the year 2009 (HR, 0.275; 95% CI, 0.113-0.672; P = .005). A 10% increase (nonsignificant) in SOV dimensions as a time-varying covariate for the time-to-event model proved to have no predictive effect in terms of overall mortality.
      Table 7Cox regression model: Factors associated with mortality over long-term follow-up
      VariableHR95% CIP value
      Age1.0611.008-1.117.022
      Ascending aorta (mm)1.1950.830-1.719.338
      Surgical period ≥20090.2750.113-0.672.005
      Gender (male)1.2010.524-2.755.665
      Hypertension1.0580.377-2.969.915
      NYHA III/IV3.2201.463-7.084.004
      SOV >45 mm1.0400.286-3.780.952
      Valve morphology (TAV/BAV)2.4070.946-6.124.065
      Day 3: Fate of remnant SOV in patients undergoing aortic valve replacement, ascending aorta replacement, and aortic arch replacement. HR, Hazard ratio; CI, confidence interval; NYHA, New York Heart Association; SOV, sinus of Valsalva; TAV, tricuspid aortic valve; BAV, bicuspid aortic valve.

       Aortic Reoperation and Long-Term Survival in Patients Undergoing Aortic Valve Replacement and Supracoronary Ascending Aorta Replacement

      Freedom from aortic reoperation in the BAV and TAV cohorts is delineated in Figure 3. Overall, both cohorts showed excellent long-term durability of the AVRSCAAR procedure, with 10-year freedom from aortic reoperation rates of 97% and 95% in the BAV and TAV subgroups, respectively. Reoperation-free survival, defined by freedom from aortic reoperation events and death, is shown for the BAV and TAV cohorts in Figure 4. This showed that the BAV group had improved reoperation-free survival compared with the TAV group (P < .001 by log rank). The type of valvular pathology within each group did not show a significant difference in reoperation-free survival (BAV AI vs BAV AS: log rank P = .163; TAV AI vs TAV AS: log rank P = .285) (Figure 4).
      Figure thumbnail gr3
      Figure 3Kaplan–Meier freedom from reoperation in BAV and TAV groups. BAV, Bicuspid aortic valve; TAV, tricuspid aortic valve; AVRSCAAR, aortic valve and supracoronary ascending aortic replacement.
      Figure thumbnail gr4
      Figure 4Reoperation-free Kaplan–Meier survival in BAV versus TAV groups, and reoperation-free survival within each group by valve pathology (AS vs AI). BAV, Bicuspid aortic valve; TAV, tricuspid aortic valve; AVRSCAAR, aortic valve and supracoronary ascending aortic replacement; AI, aortic insufficiency; AS, aortic stenosis.

      Discussion

      In patients with critical aortic valve disease and ascending aortic aneurysm, the management of the SOV segment for patients with a moderately dilated aortic root remains unresolved. Multiple studies have advocated AVRSCAAR as a treatment, thereby preserving the intact moderately dilated sinus segment and coronary ostia,
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      • Deroma L.
      • Cimarosti R.
      • Lutman C.
      • et al.
      Bicuspid aortic valve disease and ascending aortic aneurysm: should an aortic root replacement be mandatory dagger.
      whereas others suggest removal of the sinus segment and a Bentall root replacement procedure.
      • Etz C.D.
      • Homann T.M.
      • Silovitz D.
      • Spielvogel D.
      • Bodian C.A.
      • Luehr M.
      • et al.
      Long-term survival after the Bentall procedure in 206 patients with bicuspid aortic valve.
      • Reece T.B.
      • Singh R.R.
      • Stiles B.M.
      • Peeler B.B.
      • Kern J.A.
      • Tribble C.G.
      • et al.
      Replacement of the proximal aorta adds no further risk to aortic valve procedures.
      However, most investigations have limited their analysis to the retention or replacement of the sinus segment of known congenital BAV aortopathies. There is limited direct comparative analysis regarding the stability of the remnant SOV segment between BAV and TAV cases. In this study, we assessed the fate of the remnant, preserved SOV segment in patients undergoing AVRSCAAR (Central Image).
      Clinical reports on comparative histologic analysis of the aortic specimen have shown that the bicuspid aorta is abnormal even if it is not aneurysmal. It is known that BAV is a multifaceted heterogeneous disease with an underlying genetic and developmental foundation.
      • Michelena H.I.
      • Della Corte A.
      • Prakash S.K.
      • Milewicz D.M.
      • Evangelista A.
      • Enriquez-Sarano M.
      Bicuspid aortic valve aortopathy in adults: incidence, etiology, and clinical significance.
      • Girdauskas E.
      • Disha K.
      • Borger M.A.
      • Kuntze T.
      Long-term prognosis of ascending aortic aneurysm after aortic valve replacement for bicuspid versus tricuspid aortic valve stenosis.
      • Jiao J.
      • Xiong W.
      • Wang L.
      • Yang J.
      • Qiu P.
      • Hirai H.
      • et al.
      Differentiation defect in neural crest-derived smooth muscle cells in patients with aortopathy associated with bicuspid aortic valves.
      • Waldo K.L.
      • Hutson M.R.
      • Ward C.C.
      • Zdanowicz M.
      • Stadt H.A.
      • Kumiski D.
      • et al.
      Secondary heart field contributes myocardium and smooth muscle to the arterial pole of the developing heart.
      • Keane M.G.
      • Wiegers S.E.
      • Plappert T.
      • Pochettino A.
      • Bavaria J.E.
      • Sutton M.G.
      Bicuspid aortic valves are associated with aortic dilatation out of proportion to coexistent valvular lesions.
      We now believe that both BAV and TAV aortopathies are heterogeneous disease processes with a common clinical presentation of a bicuspid or trileaflet aortic valve. Therefore, to understand the impact of a common therapeutic surgical procedure such as AVRSCAAR on the clinically important aspects of sinus segment size and geometry, it is important to understand the behavior of the retained SOV in the subpopulations of patients within these diagnoses: AS versus AI in both BAV and TAV cases. For this reason, we stratified the study population into 4 groups to obtain definitive assessment of potential dilatation of the SOV segment in the context of a defined surgical repair. The overall results of our study strongly support that AVRSCAAR maintains SOV stability over long-term follow-up irrespective of aortic valvular pathology or anatomic valve type.
      The majority of investigations on the behavior of the sinus segment have been in patients with BAV. Previous studies have proposed that the sinus segment in BAV aortopathies is at risk for aortic events
      • Etz C.D.
      • Homann T.M.
      • Silovitz D.
      • Spielvogel D.
      • Bodian C.A.
      • Luehr M.
      • et al.
      Long-term survival after the Bentall procedure in 206 patients with bicuspid aortic valve.
      • Reece T.B.
      • Singh R.R.
      • Stiles B.M.
      • Peeler B.B.
      • Kern J.A.
      • Tribble C.G.
      • et al.
      Replacement of the proximal aorta adds no further risk to aortic valve procedures.
      and suggested removal of the sinus segment in patients with aortopathies with moderate sinus dilation.
      • Etz C.D.
      • Homann T.M.
      • Silovitz D.
      • Spielvogel D.
      • Bodian C.A.
      • Luehr M.
      • et al.
      Long-term survival after the Bentall procedure in 206 patients with bicuspid aortic valve.
      • Reece T.B.
      • Singh R.R.
      • Stiles B.M.
      • Peeler B.B.
      • Kern J.A.
      • Tribble C.G.
      • et al.
      Replacement of the proximal aorta adds no further risk to aortic valve procedures.
      Recently, a slower growth rate for the sinus segment and a less-aggressive aortic event rate have been recognized.
      • Michelena H.I.
      • Della Corte A.
      • Prakash S.K.
      • Milewicz D.M.
      • Evangelista A.
      • Enriquez-Sarano M.
      Bicuspid aortic valve aortopathy in adults: incidence, etiology, and clinical significance.
      • Gagne-Loranger M.
      • Dumont E.
      • Voisine P.
      • Mohammadi S.
      • Dagenais F.
      Natural history of 40-50 mm root/ascending aortic aneurysms in the current era of dedicated thoracic aortic clinics.
      A recent investigation reported no significant change in the sinus segment less than 40 mm and no difference in survival in patients with BAV between those in whom the sinus segment is removed (Bentall) and those in whom the sinus segment is retained (AVRSCAAR).
      • Vendramin I.
      • Meneguzzi M.
      • Sponga S.
      • Deroma L.
      • Cimarosti R.
      • Lutman C.
      • et al.
      Bicuspid aortic valve disease and ascending aortic aneurysm: should an aortic root replacement be mandatory dagger.
      In this study, analysis of the sinus segment showed a significant decrease in size in patients with a preoperative sinus segment greater than 40 mm. However, this study did not account for time bias.
      • Vendramin I.
      • Meneguzzi M.
      • Sponga S.
      • Deroma L.
      • Cimarosti R.
      • Lutman C.
      • et al.
      Bicuspid aortic valve disease and ascending aortic aneurysm: should an aortic root replacement be mandatory dagger.
      A novel concept postulated by Della Corte and colleagues
      • Della Corte A.
      • Bancone C.
      • Buonocore M.
      • Dialetto G.
      • Covino F.E.
      • Manduca S.
      • et al.
      Pattern of ascending aortic dimensions predicts the growth rate of the aorta in patients with bicuspid aortic valve.
      • Della Corte A.
      • Bancone C.
      • Dialetto G.
      • Covino F.E.
      • Manduca S.
      • D'Oria V.
      • et al.
      Towards an individualized approach to bicuspid aortopathy: different valve types have unique determinants of aortic dilatation.
      advocates a therapeutic approach to the sinus segment based on BAV leaflet fusion morphology as a method of risk stratification for sinus or ascending aortopathies. A group from the Massachusetts General Hospital recently compared the ascending aorta of patients with BAV and TAV. Their results indicated that TAV ascending aortic segments have more severe histologic changes than BAV, including atherosclerotic changes, elastic fiber and vascular smooth muscle cell loss, as well as medial fibrosis.
      • Heng E.
      • Stone J.R.
      • Kim J.B.
      • Lee H.
      • MacGillivray T.E.
      • Sundt T.M.
      Comparative histology of aortic dilatation associated with bileaflet versus trileaflet aortic valves.
      These findings advocate for a more moderate approach to BAV aortopathies.
      • Heng E.
      • Stone J.R.
      • Kim J.B.
      • Lee H.
      • MacGillivray T.E.
      • Sundt T.M.
      Comparative histology of aortic dilatation associated with bileaflet versus trileaflet aortic valves.
      A similar investigation comparing the ascending aorta of patients with BAV and TAV found a correlation between root parameters and ascending aortopathies. These ascending aortopathies demonstrated that in the subpopulation of AS, the proximal aorta of TAV had similar behavior as the proximal aorta of BAV.
      • Girdauskas E.
      • Rouman M.
      • Disha K.
      • Fey B.
      • Dubslaff G.
      • Theis B.
      • et al.
      Functional aortic root parameters and expression of aortopathy in bicuspid versus tricuspid aortic valve stenosis.
      Overall, the pendulum seems to swing increasingly toward preservation of the moderately dilated sinus segment in BAV and TAV cases.
      The results of our study support these investigations, advocating for a more moderate approach to the SOV in bicuspid and tricuspid aortopathies. To validate this strategy, our results suggest an early significant reduction in SOV diameter from preoperative baseline to early postoperative for all patient subgroups (P < .001). Furthermore, unlike other investigations,
      • Park C.B.
      • Greason K.L.
      • Suri R.M.
      • Michelena H.I.
      • Schaff H.V.
      • Sundt III, T.M.
      Fate of nonreplaced sinuses of Valsalva in bicuspid aortic valve disease.
      • Vendramin I.
      • Meneguzzi M.
      • Sponga S.
      • Deroma L.
      • Cimarosti R.
      • Lutman C.
      • et al.
      Bicuspid aortic valve disease and ascending aortic aneurysm: should an aortic root replacement be mandatory dagger.
      our study used a repeated-measure, mixed-effects model for longitudinal echocardiographic data assessment. This mixed-effects model, which includes aortic valve pathology and morphology, preoperative SOV diameters, postoperative measurement time points, and an interaction term of preoperative SOV with postoperative time as covariates to the longitudinal dataset, suggests that for all follow-up time points (discharge to ≥10 years), the retained SOV dimensions remain stable (within-subject comparison) over long-term follow-up, irrespective of valvular morphology and pathology (Table 6 and Figure 2). We believe that using these results in combination with the decision algorithm detailed in Figure 1 might provide guidance in the decision to retain or resect the sinus segment (AVRSCAAR vs Bentall procedure) in patients with ascending aortopathies with valvular disease.
      Also, in concordance with the findings of others, the BAV and TAV subpopulations had a high freedom from reoperation. No difference in subgroups was discernible on log-rank statistics. There were no surgical aortic events in the sinus segment throughout the follow-up period. Although survival estimates suggested a significant difference in outcomes (P < .001), this most likely indicates a statistical artifact because both groups were not different on attempted propensity score matching after adjusting for age, gender, and renal function (P = .934; data not shown). Our cohort size prevented a full propensity score matching. Likewise, we also noted excellent midterm to long-term survival in BAV and TAV cases undergoing AVRSCAAR. Cox regression identified advanced age and advanced heart failure as predictors for mortality. When era of surgery was introduced as a covariate, better survival outcomes were seen in patients undergoing AVRSCAAR after 2009, compared with the period before. Although the surgical technique and the principal surgeons performing the procedure have not changed during the study period, we believe that the mortality difference noted may be a reflection of the increasing experience and volume of AVRSCAAR procedures at our institution. Furthermore, significant advances have been made in the past decade in the postoperative care of patients undergoing cardiac surgery. Our group is looking into this in greater detail to better understand the factors associated with improved outcomes at our center during the more recent time period of the study.
      The overall findings in our study may be rationalized by 3 concepts in relation to the SOV: (1) developmental differences between SOV and ascending aorta; (2) pressure/flow changes associated with AVRSCAAR; and (3) changes in aortic root geometry associated with AVRSCAAR. Sinus segment stabilization may be facilitated because of its different embryologic origin compared with the ascending aorta. It has been shown by cell fate mapping studies that the vascular smooth muscle cells of the ascending aorta are of neural crest origin, whereas studies suggest the aortic root develops from contributions of vascular smooth muscle cells from the secondary heart field.
      • Jiao J.
      • Xiong W.
      • Wang L.
      • Yang J.
      • Qiu P.
      • Hirai H.
      • et al.
      Differentiation defect in neural crest-derived smooth muscle cells in patients with aortopathy associated with bicuspid aortic valves.
      • Waldo K.L.
      • Hutson M.R.
      • Ward C.C.
      • Zdanowicz M.
      • Stadt H.A.
      • Kumiski D.
      • et al.
      Secondary heart field contributes myocardium and smooth muscle to the arterial pole of the developing heart.
      • Majesky M.W.
      Developmental basis of vascular smooth muscle diversity.
      The STJ is the potential interdigitation transition area of the developmental field boundaries of the vascular smooth muscle cells from the secondary heart field and neural crest origin.
      • Waldo K.L.
      • Hutson M.R.
      • Ward C.C.
      • Zdanowicz M.
      • Stadt H.A.
      • Kumiski D.
      • et al.
      Secondary heart field contributes myocardium and smooth muscle to the arterial pole of the developing heart.
      • Majesky M.W.
      Developmental basis of vascular smooth muscle diversity.
      • Lindsay M.E.
      • Dietz H.C.
      Lessons on the pathogenesis of aneurysm from heritable conditions.
      The different origin of vascular smooth muscle cells in the SOV may enable better sinus segment stabilization even for the moderately dilated aortic root, compared with the ascending aorta. The second concept for sinus segment stabilization invokes the role of transvalvular flow jets and potential rheology-associated hemodynamic shear stress eliciting possible endothelial mechanotransduction, which contributes to aneurysm formation.
      • Barker A.J.
      • Markl M.
      • Burk J.
      • Lorenz R.
      • Bock J.
      • Bauer S.
      • et al.
      Bicuspid aortic valve is associated with altered wall shear stress in the ascending aorta.
      • Humphrey J.D.
      • Schwartz M.A.
      • Tellides G.
      • Milewicz D.M.
      Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections.
      • Azadani A.N.
      • Chitsaz S.
      • Matthews P.B.
      • Jaussaud N.
      • Leung J.
      • Tsinman T.
      • et al.
      Comparison of mechanical properties of human ascending aorta and aortic sinuses.
      • Katayama S.
      • Umetani N.
      • Sugiura S.
      • Hisada T.
      The sinus of Valsalva relieves abnormal stress on aortic valve leaflets by facilitating smooth closure.
      This shear stress may be reduced with removal of the dysfunctional aortic valve with AVRSCAAR, and in turn may stabilize the sinus segment.
      • Barker A.J.
      • Markl M.
      • Burk J.
      • Lorenz R.
      • Bock J.
      • Bauer S.
      • et al.
      Bicuspid aortic valve is associated with altered wall shear stress in the ascending aorta.
      • Humphrey J.D.
      • Schwartz M.A.
      • Tellides G.
      • Milewicz D.M.
      Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections.
      • Azadani A.N.
      • Chitsaz S.
      • Matthews P.B.
      • Jaussaud N.
      • Leung J.
      • Tsinman T.
      • et al.
      Comparison of mechanical properties of human ascending aorta and aortic sinuses.
      • Katayama S.
      • Umetani N.
      • Sugiura S.
      • Hisada T.
      The sinus of Valsalva relieves abnormal stress on aortic valve leaflets by facilitating smooth closure.
      The third concept, root geometry, may be a factor in the stability of the retained sinus segment in patients undergoing AVRSCAAR by affecting the mechanical properties of the aortic root.
      • Azadani A.N.
      • Chitsaz S.
      • Matthews P.B.
      • Jaussaud N.
      • Leung J.
      • Tsinman T.
      • et al.
      Comparison of mechanical properties of human ascending aorta and aortic sinuses.
      • Katayama S.
      • Umetani N.
      • Sugiura S.
      • Hisada T.
      The sinus of Valsalva relieves abnormal stress on aortic valve leaflets by facilitating smooth closure.
      • David T.E.
      • Feindel C.M.
      • Armstrong S.
      • Maganti M.
      Replacement of the ascending aorta with reduction of the diameter of the sinotubular junction to treat aortic insufficiency in patients with ascending aortic aneurysm.
      Stabilization of the aortic annulus with a normally functioning aortic valve and reestablishing a STJ/annular ratio with the supracoronary tube graft might restore a more stable geometry of the SOV. This “normalization” of the STJ to annular ratio may stabilize the aortic sinus segment hemodynamics and geometry, and reduce shear stress.
      • Azadani A.N.
      • Chitsaz S.
      • Matthews P.B.
      • Jaussaud N.
      • Leung J.
      • Tsinman T.
      • et al.
      Comparison of mechanical properties of human ascending aorta and aortic sinuses.
      • Katayama S.
      • Umetani N.
      • Sugiura S.
      • Hisada T.
      The sinus of Valsalva relieves abnormal stress on aortic valve leaflets by facilitating smooth closure.
      • David T.E.
      • Feindel C.M.
      • Armstrong S.
      • Maganti M.
      Replacement of the ascending aorta with reduction of the diameter of the sinotubular junction to treat aortic insufficiency in patients with ascending aortic aneurysm.
      • Kunzelman K.S.
      • Grande K.J.
      • David T.E.
      • Cochran R.P.
      • Verrier E.D.
      Aortic root and valve relationships. Impact on surgical repair.
      • Northrup III, W.F.
      • Rollins S.D.
      Aortic annuloplasty.

       Study Limitations

      Although extensive work was performed to obtain echocardiographic data for long-term outcome analysis of the SOV, insufficient data were available for patients with preoperative SOV greater than 45 mm because of cardiology referral patterns and patient and cardiologist preference for local echocardiographic follow-up. Echocardiograms were not read by one individual, which may introduce operator and reader bias. However, we did make every possible attempt to reach out to all patients and their primary care physicians and cardiologists to obtain complete follow-up data. Missing data were addressed by fitting a mixed-effects, repeated-measure model for longitudinal data assessment and by carefully validating that data were missing at random. Finally, the overall cohort size was not large enough to perform reliable propensity score matching, which we hope to perform in the future with a larger sample size.

      Conclusions

      Our results have shown that for patients undergoing AVRSCAAR, the sinus segment remains stable in all TAV (TAV AS/TAV AI) and BAV (BAV AS/BAV AI) subpopulations. Therefore, irrespective of the aortic valve morphology or valve pathology, in patients with mild to moderate aortic root dilatation (<45 mm), preservation of the SOV segment in the context of an AVRSCAAR procedure is justified. Continued further follow-up will be important to understand the long-term outcomes of sinus preservation, especially in the younger population with BAVs.

       Conflict of Interest Statement

      Authors have nothing to disclose with regard to commercial support.

      Supplementary Data

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      Linked Article

      • Noncoronary sinus replacement in bicuspid valve: The other fate?
        The Journal of Thoracic and Cardiovascular SurgeryVol. 155Issue 2
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          We read with interest the article by Milewski and colleagues,1 which demonstrated that supracoronary ascending aortic replacement in patients with concomitant aortic valve disease (either insufficiency or stenosis) may positively affect aortic root fate in the long term (≥10 years of follow-up) irrespective of valve morphology (bicuspid or tricuspid aortic valve).
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