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Survival and reoperation pattern after 20 years of experience with aortic valve–sparing root replacement in patients with tricuspid and bicuspid valves
Accepted Manuscript Survival and reoperation pattern after 20 years of experience with aortic valve sparing root replacement in patients with tricuspid and bicuspid valves Stefan Klotz, MD, Sina Stock, MD, Hans-Hinrich Sievers, MD, Michael Diwoky, Michael Petersen, MD, Ulrich Stierle, MD, Doreen Richardt, MD PII:
S0022-5223(17)32847-7
DOI:
10.1016/j.jtcvs.2017.12.039
Reference:
YMTC 12366
To appear in:
The Journal of Thoracic and Cardiovascular Surgery
Received Date: 5 July 2017 Revised Date:
15 November 2017
Accepted Date: 5 December 2017
Please cite this article as: Klotz S, Stock S, Sievers H-H, Diwoky M, Petersen M, Stierle U, Richardt D, Survival and reoperation pattern after 20 years of experience with aortic valve sparing root replacement in patients with tricuspid and bicuspid valves, The Journal of Thoracic and Cardiovascular Surgery (2018), doi: 10.1016/j.jtcvs.2017.12.039. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Survival and reoperation pattern after 20 years of experience with aortic valve sparing
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root replacement in patients with tricuspid and bicuspid valves
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Stefan Klotz1, MD; Sina Stock1, MD; Hans-Hinrich Sievers, MD; Michael Diwoky; Michael
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Petersen, MD; Ulrich Stierle, MD; Doreen Richardt, MD
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Both authors contributed equally to this work
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Department of Cardiac and Thoracic Vascular Surgery, University Medical Center Schleswig-
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Holstein, Campus Lübeck, Germany
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Funding statement: This work received no funding
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Conflict of interest: none declared
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Corresponding author: Prof. Dr. Hans-H. Sievers, MD
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University Medical Center Schleswig-Holstein
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Department of Cardiac and Thoracic Vascular Surgery
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Ratzeburger Allee 160
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23538 Luebeck, Germany
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Tel: +49-451-500-42301
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Fax: +49-451-500-42304
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E-mail: [email protected]
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Total word count: 4045 1
Glossary of Abbreviations
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BAV: Bicuspid aortic valve
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CTD: Connective tissue disease
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HR: Hazard ratio
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TAV: Tricuspid aortic valve
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Central Picture Legend
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Cumulative incidence of reoperation after aortic valve sparing root replacement.
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(80 / 90 characters incl. spaces)
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Central Message
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Aortic valve sparing root replacement offers near normal survival. However, the risk of
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reoperation is increased in the second postoperative decade especially in patients with a
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bicuspid valve.
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(193 / 200 characters incl. spaces)
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Perspective statement
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Aortic valve sparing root replacement techniques are appealing options to treat aortic root
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dilatation with or without aortic valve disease. Data of other groups regarding reoperation in
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the second decade after the operation in patients with a bicuspid aortic valve are required to
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get further inside in the probably more complex issue of bicuspid aortic valve and surgical
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treatment.
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(384 / 405 characters incl. spaces)
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ACCEPTED MANUSCRIPT Abstract
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Objective. Remodeling or reimplantation are established operative techniques of aortic valve
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sparing root replacement. Long-term follow-up is necessary comparing tricuspid and bicuspid
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aortic valves.
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Methods. A total of 315 patients (tricuspid n=225, bicuspid n=89, quadricuspid n=1;
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remodeling n=101, reimplantation n=214) were evaluated. Mean follow-up was 10.1±5.6 and
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6.4±4.2 years for the remodeling and reimplantation group, respectively. Longest follow-up
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was 21.9 years with 99.2% completeness. Mean age of the patients was 55.9±14.3 for the
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remodeling group and 48.9±14.5 years for the reimplantation group.
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Results. There was no significant difference in survival between the remodeling and
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reimplantation group (p=0.11). Survival was comparable to the normal population in the
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reimplantation group (p=0.33). Risk factors for late death were age, diabetes and a higher
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NYHA classification. Cumulative incidence of reoperation at 10 years was 5.8% for the
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reimplantation and 11.7% for the remodeling group. (p=0.65). Overall there was no difference
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in the cumulative incidence of reoperation between tricuspid and bicuspid aortic valve
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patients (p=0.13), however a landmark analysis showed that in the second decade the
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cumulative incidence of reoperation was higher in bicuspid aortic valve patients (p<0.001). 10
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of 11 reoperated bicuspid aortic valves were degenerated.
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Conclusions. The remodeling and reimplantation aortic valve sparing root replacement
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techniques provided excellent long-term survival. Although the number of patients was
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relatively small we provide some hints that in the second decade after the operation especially
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in bicuspid aortic valve patients the risk of reoperation may be increased needing further
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evaluation. (Abstract word count: 243 / 250)
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Introduction In patients with aortic root aneurysm and macroscopic intact aortic valve leaflets a
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valve sparing root replacement may be indicated to prevent shortcomings of replacement
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substitutes like bioprostheses and mechanical valves. Such repair operations are performed in
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two different techniques: the remodeling (Yacoub) [1] and the reimplantation (David) [2]
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technique.
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hemodynamics, low thromboembolism and bleeding complications without the need for
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anticoagulation. The remodeling technique preserves more physiologically the aortic root
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distensibility and movement of the aortic cusps [3;4]. The clinical relevance of it however is
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unclear and may surface after decades only. Midterm results after both valve sparing
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techniques were reported to be excellent [5-9]. For further judgement of this surgical
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principle, however, results of long-term, preferably life-long follow-up are essential [10].
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Since survival and reoperation are the most relevant determinants for treatment quality we
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present survival and reoperation pattern in patients after aortic valve sparing root replacement
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comparing the remodeling and reimplantation technique including BAV and TAV.
are
aortic
valve
reconstructions
warranting
excellent
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Materials and methods
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appealing
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From March 1994 to December 2016 434 patients were consecutively operated on
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with the valve sparing root replacement technique. After exclusion of patients with acute type
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A dissection 315 patients (240 males, 51.1 ± 14.8 years, mean follow-up: 7.5 ± 5.0 years,
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reverse Kaplan-Meier method: median follow-up = 7.9 years (95% CI 7.6-8.2 years), 2377.99
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patient*years) were left for the study. The remodeling technique was performed in 101
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patients; the reimplantation technique in 214 patients. A histogram with the annual number of
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the two procedures is depicted in Figure e1. After approval by the ethical committee patients’
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consent was obtained. Follow-up data were gained between 2015 and 2017 via written
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questionnaires to the patients or their family doctors and via outpatient visits. Longest follow-
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colleagues [11] - was 99.2%. Preoperative data are presented in Table 1. The choice for either
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of the two techniques at early days of valve sparing surgery was related to the surgeon’s
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preference, not to dimensions of the annulus or other pathologies. Only if the annulus appears
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enlarged (>28-30 mm) a David annuloplasty [12] was performed in the remodeling group
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(n=16). When we evaluated our results in 2008 we found that best hemodynamic results were
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obtained with the remodeling technique at lower annulus diameters and vice versa with the
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reimplantation technique [13]. Since then we used both the techniques according to annulus
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diameter. In patients with an annulus diameter of 28 – 30 mm the remodeling technique and in
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those with an annulus diameter > 30 mm the reimplantation technique was applied. Our
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operative technique was reported in detail previously [3]. Only leaflets which had a normal or
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near normal macroscopic appearance with good pliability were accepted for repair. Additional
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cusp intervention was performed in 137 patients (Table 2). A central leaflet stich was
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performed after root replacement in both remodeling and reimplantation. By this technique
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the absolute parallelism of the leaflets with respect to the normal appearing reference leaflet
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was judged and if additional length, which means some kind of prolapse, was present this
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amount of additional length was centrally plicated with 6/0 U-stiches. In some cases the
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thickened raphe of BAV type 1 LR was resected and replaced with a triangular autologous
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glutaraldehyde preserved pericardial patch with 6/0 running suture.
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Intraoperative or pre-discharge echocardiography revealed aortic insufficiency of
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grade none/trace in 287 patients (none n=230, trace n=57), mild in 20 patients, mild to
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moderate in 1 patient and unknown in 7 patients.
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Statistical analysis
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For statistical analysis the chi-square test, Fisher exact test, the Mann-Whitney U test,
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and the Student's t-test were used where appropriate. Nominal and ordinal data are presented 6
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deviations. Standardized differences were calculated using the definition recommended by
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Austin [14]. The method of Benjamini and Hochberg [15] was used to control the false
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discovery rate, resulting in a corrected significance level of 0.008. The calculations were
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performed using IBM SPSS Statistics (IBM Corp. Released 2013. IBM SPSS Statistics for
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Windows, Version 22.0. Armonk, NY: IBM Corp.) and SAS software (Version 9.4, SAS
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Institute Inc., Cary, NC, USA).
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Patient survival rates were analyzed by the Kaplan-Meier method and the log rank test
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and reoperation by the cumulative incidence function adjusting reoperation for the competing
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risk of death and Gray’s log-rank test. For patients living more than 10 years the reoperation
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rates in the remodeling and in the reimplantation group was calculated by the landmark
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analysis that is competing risk analysis considering only patients with the occurrence with
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reoperation or death conditional on neither having occurred in the first 10 years. The Cox
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proportional hazards model was used to compare survival for the two procedures while also
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allowing for other variables. The aim of the Cox models was to allow for potential imbalances
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between the groups when comparing the reimplantation and remodeling procedures. We
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started by just allowing for differences between the reimplantation and remodeling procedures
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and then also included age and then we looked at models including both the procedures, age
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and one other variable. The survival of patients in the study was compared with the predicted
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survival experience for equivalent members of the general population with respect to age and
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gender. The latter was determined using the German life-table, 2010/2012 (www.destatis.de).
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The subject-years method was used to compare the numbers of deaths for the two procedures
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with the expected (i.e. average) numbers of deaths in the general population with the same age
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and sex profile. The standardized mortality ratio was calculated by the actual number of
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deaths divided by expected number of deaths based on life tables.
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Clinical characteristics
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Clinical characteristics are presented in Table 3 and 4. Follow-up in the reimplantation group
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was 6.4+-4.2 years (range 0-21.9 years) and 10.1 +- 5.6 (range 0-19.8 years) in the
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remodeling group (p<0.001).
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Early mortality
There were 5 early deaths overall (Table 4). In the reimplantation group the causes for
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early death were sudden cardiac death, cardiac arrest with hemorrhagic shock and hypoxic
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brain injury and in the remodeling the causes were septic shock with multi-organ failure and
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cardiogenic shock.
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Late mortality
38 late deaths occurred during the study time (Table 4). There were 6 late cardiac
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deaths in the remodeling group (3 patients with sudden cardiac death, 1 patient with heart
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failure, 1 patient with cardiac arrest after suspected myocardial infarction, and 1 patient with
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cardiac decompensation after pulmonary embolism). In the remodeling group 9 late cardiac
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deaths occurred (2 patients with myocardial infarction, 2 patients with heart failure, 2 patients
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with acute aortic dissection, 1 patient with sudden cardiac death, 1 patient with cardiac arrest
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after descending aorta replacement and multiple bleedings, and 1 patient with cardiac
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decompensation after systemic inflammatory response syndrome.
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Overall mortality
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The
Cox
proportional
hazards
model
revealed
a
hazard
ratio
(HR)
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remodeling/reimplantation of 1.68 (95% CI 0.89-3.19, p=0.111), indicating no significant
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evidence of a difference in survival times (Figure 1). When age and gender were adjusted for, 8
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the estimated HR remodeling/reimplantation was smaller (HR: 1.23, 95% CI 0.63-2.41,
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p=0.549) and age was a significant risk factor for survival (HR per year: 1.04, 95% CI 1.02-
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1.07, p=0.001). Also including other imbalances between groups (Table 1) in the multivariate
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Cox model did not reveal a difference in survival between the groups. Survival was comparable to the normal population in the reimplantation group
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(Standardized mortality ratio: 1.26 ± 0.60, p=0.39) but was lower in the remodeling group
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(Standardized mortality ratio: 1.64 ± 0.63, p=0.047).
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A multivariable Cox proportional hazards model using backward elimination
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including the variables listed in Table 1 revealed age (HR 1.03, 95% CI 1.01-1.06, p=0.02),
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diabetes (HR 3.04, 95% CI 1.06-8.73, p=0.039) and higher NYHA classification (HR per
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increment 1.48, 95% CI 1.04-2.12, p=0.032) as risk factors for shorter survival time.
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There was not significant evidence of a difference in survival time between TAV and BAV patients (p=0.095, Figure e2).
2 (4.3%) patients with connective tissue disease (CTD) died in comparison to 41
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(15.3%) patients of the non-CTD group. In the remodeling group 2 (15.5%) patients with
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annuloplasty and 24 (28.2%) patients without annuloplasty died.
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Reoperation
There was no statistically significant difference regarding reoperation in both groups
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(p=0.65, Figure 2). The cumulative incidence of reoperation at 10 years was 5.8% (95%CI
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2.8-12.0) for the reimplantation group and 11.7% (95%CI 6.5-20.7) for the remodeling group.
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27 patients (BAV: n=11; TAV: n=16) needed a reoperation. The cumulative incidence of
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reoperation at 10 and 16 years was 5.3% (95% CI 1.7 - 15.4) and 48.4% (95% CI 27.7 - 74.1)
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in BAV patients and 9.8% (95% CI 5.9 - 16.0) and 10.9% (95% CI 6.6 - 17.5) for TAV
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patients respectively (p=0.13) (Figure 3). The landmark analysis showed that the difference
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regarding reoperation between the BAV and TAV patients was only significant considering 9
ACCEPTED MANUSCRIPT patients living more than 10 years (p<0.001) (Figure 3). Causes for reoperation were different
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(Table 4). 5 (10.6%) reoperations had to be performed in patients with CTD compared to 22
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(8.2%) patients without CTD. 7 BAV and 2 Marfan patients needed reoperation in the
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reimplantation group and 4 BAV and 3 Marfan patients in the remodeling group. 10 of 11
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reoperated BAV patients developed fibrotic tissue shrinkage or calcification of the leaflets
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causing predominantly aortic insufficiency with a lesser degree of stenosis. In the remodeling
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group 3 (18.8%) patients with annuloplasty were reoperated and 11 (12.9%) patients without
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annuloplasty. Two patients were reoperated due to aortic valve endocarditis.
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Morbidity
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A stroke occurred in 8 (3.7%) patients of the reimplantation group and 2 (2.0%)
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patients of the remodeling group. Major bleeding events were reported by 10 (4.7%) patients
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of the reimplantation group and 4 (4.0%) patients of the remodeling group. 2 (0.9%) of the
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reimplantation group and 2 (2.0%) patients of the remodeling group reported non-cerebral
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embolic events.
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Discussion
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In this retrospective study we found that the survival and cumulative incidence of
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reoperation after the remodeling and reimplantation aortic valve sparing root replacement
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techniques did not differ significantly. The same holds true for the probability of survival in
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TAV and BAV patients. However, more reoperations were necessary in BAV patients in the
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second decade after the reoperation especially in the reimplantation group.
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Normal anatomy warrants optimal function. Keeping this maxim in mind the
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restoration of normal anatomy in general is appealing if the tissue is of favorable quality to
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expect long-term function and durability. This is particularly important for the aortic valve
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which plays a crucial role for left-ventricular to aortic coupling allowing for passage of blood 10
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at rest and exercise with low energy loss [16]. To achieve this goal the aortic valve performs
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complex movements. It follows sophisticated 3D deformational dynamics thereby reducing
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stress on the aortic cusps, minimizing transvalvular energy loss and optimizing coronary flow
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[17-19]. Preserving the aortic leaflets and restoring physiological root dynamics theoretically
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bear the potential to favorably influence long-term outcome of the patients. The remodeling
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technique includes the resection of the sinuses only and does not touch the interleaflet
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trigones and the annulus of the aortic valve which seems to restore some kind of distensibility
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in this area in contrast the reimplantation technique which incorporates the aortic valve into a
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rigid Dacron tube including the annulus of the aortic valve [3;4]. This technique however
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corrects and prevents annulus dilatation and such may also prevent development of aortic
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regurgitation in the long-term, therefore we preferred this technique in the last years [7].
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As one of the major determinants of treatment quality survival after valve sparing
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aortic root replacement was excellent being 72.6% (95% CI: 0.64 – 0.81) after 15 years,
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which is comparable to the normal population and the data of other groups [20-26]. Reasons
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for this favorable outcome are not only the physiological concept of valve sparing but also the
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close follow-up of these patients. Survival in the reimplantation group was comparable to the
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normal population and we found no difference in survival between the remodeling and the
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reimplantation groups. However, survival was lower than normal in the remodeling group.
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Whether this is related to the small number of patients, the lower ejection fraction and higher
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NYHA classification or the older age at the primary operation remains to be evaluated further.
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The rate of reoperation was acceptable till 10 years postoperatively as also reported by
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other groups [20;24;27] but thereafter we observed an obvious increase in the rate of
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reoperation especially in BAV patients compared to TAV patients as shown by the landmark
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analysis. It must be considered however that the number of patients is relatively small needing
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further evaluation by larger number of patients. Thus our results are less favorable compared
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with a cumulative incidence of reoperation of 21.7% at 15 years. It is possible that in general
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our repair techniques in BAV patients were insufficient although 10 of all reoperated BAV
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patients left the theatre at primary repair with no and one patient with trivial aortic
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regurgitation. Furthermore, at primary operation 10 of the 11 reoperated BAV patients had
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pliable leaflets, all were BAV type 1 left/right, only in one a small calcification was present at
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the commissural remnant between the fused left and right coronary cusp which was removed.
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In 5 patients a plication of the leaflets was required, in 6 patients none additional cusp
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intervention. We found no systematic technical issue in our reoperated patients demonstrating
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that our kind of repair would lead to later fibrotic tissue changes and calcification (10 of 11).
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Whether more coaptation area by using pericardial leaflet augmentation [28] leads to better
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results remains speculative in as much as the use of pericardium for cusp repair was reported
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to be a risk factor for earlier reoperation [25]. More innovative repair techniques with higher
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coaptation area, avoidance of symmetrical prolapse and more experience might result in better
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outcome as reported by Schneider et al. [27] with roughly 20% cumulative incidence of
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reoperation after 12 years. Furthermore circumferential annuloplasty as described by Lansac
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[29] or Schneider [27] may function as an additional protective effect against aortic
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insufficiency and as such improve the outcome. If the observed degenerative process is
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related to a genetic background or if the unphysiological morphology and hemodynamics in
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patients with a BAV are causative remains unknown. Another aspect that could have some
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influence on leaflet degeneration is the lack of sinuses in the reimplantation group especially
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for BAV leading to malrotation of the vortex behind the leaflets as recently shown by
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Oechtering et al. [30]. This degenerative process obviously accelerates in the second decade
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after surgery. These less optimal results prompted us to rethink BAV for valve sparing root
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replacement and in general may require a lot of more clinical and experimental research to
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shed light in this less favorable issue. In view of these data we more clearly inform our
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repair, confine the indication to absolute pliable leaflet tissue, perform more radical triangular
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resection of the thickened raphe with pericardial replacement extending on the free leaflet
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edges (right and left coronary cusps) to get more pliability and to increase coaptation area and
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do not use cusps for repair which show any signs of beginning calcification. Together this
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means some restriction in BAV indication. A Bio-Bentall procedure may be an alternative in
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those patients who do not like to take anticoagulation or a regular Bentall prosthesis with a
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mechanical valve. Nevertheless the results with valve sparing root repair are at least
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equivalent with a lower rate of composite events [31;32].
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Limitations of the study
This is a retrospective analysis and as such has a lot of flaws, weakening the
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comparability of the different groups. Nevertheless it is a clinical series with relatively long
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follow-up time providing us with some view on the results in the second decade. The number
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of patients is small especially in the second decade; however, the number of events (late death
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and reoperation) is around 10% of the total cohort and there is a clear trend for earlier
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degeneration in BAV compared to TAV supporting the theoretical background of BAV as a
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less physiological valve. Since the follow-up time of the reimplantation procedure was shorter
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than for the remodeling group it may explain the better survival compared to normal,
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however, this must be further evaluated.
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In the early years we did not use transesophageal echocardiography for analysis of
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intraoperative root dimensions and aortic valve function, and defined the valve competent
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when the root was pressurized after removal of the aortic clamp and no dilatation of the left
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ventricle
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echocardiography gaining more qualitative data. However, in most patients a transthoracic
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echocardiogram was performed pre-discharge providing some information on the valve
occurred.
Since
2003
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intraoperative
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It is possible that there are certain, unknown patients with significant valve lesion needing
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reoperation because of the incomplete echocardiographic late follow-up. Whether those
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shortcomings influence results remains speculative in as much as almost all reoperated BAV
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patients showed fibrous and calcifications of the leaflets at reoperation which is most likely an
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intrinsic process of the tissue of the leaflets.
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Conclusions
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In this series, survival was near normal in both, the remodeling and reimplantation
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aortic valve sparing root replacement techniques and the cumulative risk of reoperation
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remains stable up to 10 years postoperatively. In the second decade we observed an increase
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in reoperations particularly in BAV patients. Although the number of BAV patients in the
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second decade is small, our findings caused us to closely rethink our indication and technique
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for BAV valve sparing root replacement.
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The authors are thankful to Dr. Derek Robinson for his support regarding the statistical
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Acknowledgement
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ACCEPTED MANUSCRIPT Table 1. Perioperative characteristics of the patient population.
84.0 ± 27.8
2
6
9 (4.2)
2 (2.0)
2 (0.9) 8 (3.7) 56 (26.2) 10 (4.7)
19 (18.8)
2 (2.0)
7 (6.9)
30 (29.7)
3 (3.0)
35 (16.4) 33 (15.4) 2 (0.9)
12 (11.9) 12 (11.9) 0
43 (20.1)
28 (27.7)
27 (12.6) 28 (13.1) 66 (30.8) 93 (43.5) 0
31.9 ± 5.2
86 49.6 ± 9.6 42 41 ± 6.6 95
-11.1 -13.2 -0.6 -1.9
12.9
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p value <0.001 <0.001 0.082
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83.5 ± 23.3
Standardized difference 53.6 -48.3 22.0
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Remodeling (n=101) 61 (60.4) 55.9 ± 14.3 22 (21.8) 4 (4.0) 15 (14.9) 0 3 (3.0) 5 (5.0) 70 (69.3) 1 (1.0)
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Male gender Age (years) Bicuspid aortic valve Type 0 Type 1 Type 2 unknown Diabetes mellitus Hypertension Renal disease Serum creatinine (µmol/l) Unknown Previous cardiac surgery Coronary artery disease Peripheral artery disease Cerebrovascular disease Hyperlipidemia Chronic pulmonary disease CTD Marfan Loeys-Dietz Mitral valve insufficiency ≥ grade I Aortic valve insufficiency None / trace Mild Moderate Severe Unknown Annulus diameter (mm) Unknown Sinus diameter (mm) Unknown STJ diameter (mm) Unknown Ascending aorta diameter (mm) Unknown LVEF > 50%
Reimplantation (n=214) 179 (83.6) 48.9 ± 14.5 67 (31.3) 11 (5.1) 52 (24.3) 2 (0.9) 2 (0.9) 6 (2.8) 135 (63.1) 2 (0.9)
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Parameter
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-17.1 -8.7
-14.2
-7.9 8.9 12.9
-18.0 1.9
0.339 0.312 1
0.667
0.513 0.172 0.596 0.258 0.588 0.561 0.397
0.149 0.084
13 (12.9) 18 (17.8) 36 (35.6) 31 (30.7) 3 (3) 7.6 31.4 ± 7.5 72 51.7 ± 11.2 43 40.8 ± 8 82
-20.3
0.200
2.1
0.939
-49.9 50.2 ± 12.4 48
56.3 ± 12.3 18
174 (82.1)
66 (78.6)
0.739
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30% - 50% 38 (17.9) 18 (21.4) Unknown 2 17 NYHA 0.007 Class I 91 (42.9) 21 (25.6) 37.1 Class II 78 (36.8) 37 (45.1) -17.0 Class III 34 (16.0) 19 (23.2) -18.0 Class IV 9 (4.2) 5 (6.1) -8.4 Unknown 2 19 Atrial fibrillation 11 (5.1) 9 (8.9) -14.8 0.220 CTD: Connective tissue disease, LVEF: Left ventricular ejection fraction, NYHA: New York Heart Association, STJ: Sinotubular junction
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Leaflet intervention None Plication Pericardial extension Plication + pericardial extension Shaving Plication + shaving
Tricuspid aortic valve
Bicuspid aortic valve
155 (68.9) 67 (29.8) 1 (0.4) 1 (0.4) 0 1 (0.4)
23 (25.8) 54 (60.7) 8 (9.0) 3 (3.4) 1 (1.1) 0
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Table 3. Operative details of the patients. Parameter
Reimplantation Remodeling (n=214) (n=101) 196 (91.6) 87 (86.1)
p-value
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Elective surgery 0.162 Additional procedures Partial or total aortic arch 35 (16.4) 24 (23.8) 0.124 replacement Mitral valve intervention 8 (3.7) 7 (6.9) 0.258 CABG 23 (10.7) 11 (10.9) 1 Aortic valve cusp 107 (50.0) 31 (30.7) 0.002 intervention Size of prosthesis <0.001 24 mm 1 (0.5) 5 (5.0) 26 mm 8 (3.7) 14 (13.9) 28 mm 43 (20.1) 38 (37.6) 30 mm 123 (57.5) 38 (37.6) 32 mm 39 (18.2) 6 (5.9) Surgical data CPB time (min) 218.1 ± 51.0 177.1 ± 47.1 <0.001 Cross-clamp time (min) 180.0 ± 43.3 134.5 ± 43.9 <0.001 Circulatory arrest No. of patients 52 (24.3) 51 (50.5) Circulatory arrest time 29.4 ± 23.3 22.2 ± 14.1 0.022 (min) CABG: Coronary artery bypass grafting, CPB: Cardiopulmonary bypass
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Mortality Early mortality (≤ 30 days) Late mortality (>30 days) Cause of death Non-cardiac Cardiac Unknown Aortic valve reoperation Aortic valve phenotype BAV (n) TAV (n) Finding at reoperation Leaflet degeneration (fibrotic shrinkage, calcification) (n) Annulus dilatation (n)
Remodeling (n=101) 10.1 ± 5.6 0 – 19.8 26 (25.7) 2 (2.0) 24 (23.8)
7 (50.0) 6 (42.9) 1 (7.1) 13 (6.1)
11 (45.8) 9 (37.5) 4 (16.7) 14 (13.9)
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Reimplantation (n=214) 6.4 ± 4.2 0 – 21.9 17 (7.9) 3 (1.4) 14 (6.5)
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Total: 11 BAV: 7 TAV: 4 0
Total: 6 BAV: 3 TAV: 3 Total: 6 BAV: 1 TAV: 5 TAV: 1 TAV: 1
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Endocarditis (n) TAV: 1 Unknown (n) TAV: 1 Hemodynamic indication for reoperation Stenosis 3 1 Insufficiency 9 (1 Endocarditis) 11 (1 Endocarditis) Combined 1 2 n=61 Echocardiographic follow- n=104 up data1 5.9 ± 3.3 10.1 ± 4.4 Follow-up years Aortic regurgitation None/trace 60 (57.7) 23 (37.7) Mild 37 (35.6) 29 (47.5) Moderate 6 (5.8) 8 (13.1) Severe 1 (1.0) 1 (1.6) δp mean [mmHg] 6.5 ± 4.1 6.0 ± 3.4 1 Only patients with echocardiographic follow-up > 1 year; BAV: Bicuspid aortic valve, TAV: Tricuspid aortic valve
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Reference List
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[2] David TE, Feindel CM. An aortic valve-sparing operation for patients with aortic incompetence and aneurysm of the ascending aorta. J Thorac Cardiovasc Surg.
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[3] Leyh RG, Schmidtke C, Sievers HH, Yacoub MH. Opening and closing characteristics of the aortic valve after different types of valve-preserving surgery. Circulation.
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valve motion after the reimplantation type of valve-sparing procedure (David I) with a
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new aortic root conduit. Ann Thorac Surg. 2002;74:53-7.
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[8] Coselli JS, Volguina IV, LeMaire SA, Sundt TM, Connolly HM, Stephens EH, et al. Early and 1-year outcomes of aortic root surgery in patients with Marfan syndrome: a
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prospective, multicenter, comparative study. J Thorac Cardiovasc Surg. 2014;147:1758-
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[9] Shrestha M, Baraki H, Maeding I, Fitzner S, Sarikouch S, Khaladj N, et al. Long-term results after aortic valve-sparing operation (David I). Eur J Cardiothorac Surg.
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[12] David TE, Feindel CM, Bos J. Repair of the aortic valve in patients with aortic
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insufficiency and aortic root aneurysm. J Thorac Cardiovasc Surg. 1995;109:345-51. [13] Hanke T, Charitos EI, Stierle U, Robinson D, Gorski A, Sievers HH, et al. Factors associated with the development of aortic valve regurgitation over time after two
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different techniques of valve-sparing aortic root surgery. J Thorac Cardiovasc Surg.
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[14] Austin PC. Using the standardized difference to compare the prevalence of a binary
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variable between two groups in observational research. Communications in Statistics-
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[15] Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Stat Soc Ser B. 1995;57:289-300.
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[16] Yacoub MH, Kilner PJ, Birks EJ, Misfeld M. The aortic outflow and root: a tale of dynamism and crosstalk. Ann Thorac Surg. 1999;68:S37-S43. [17] Dagum P, Green GR, Nistal FJ, Daughters GT, Timek TA, Foppiano LE, et al. Deformational dynamics of the aortic root: modes and physiologic determinants.
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application to coronary flow. Nature. 1968;219:1059-61.
[19] Davies JE, Parker KH, Francis DP, Hughes AD, Mayet J. What is the role of the aorta in
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[18] Bellhouse BJ, Bellhouse FH, Reid KG. Fluid mechanics of the aortic root with
directing coronary blood flow? Heart. 2008;94:1545-7.
[20] David TE, David CM, Feindel CM, Manlhiot C. Reimplantation of the aortic valve at 20 years. J Thorac Cardiovasc Surg. 2017;153:232-8.
[21] Richardt D, Stierle U, Sievers HH. Long-Term Results after Aortic Valve-Sparing-
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Reimplantation Operation (David) in Bicuspid Aortic Valve. J Heart Valve Dis.
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2015;24:4-9.
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[22] Aicher D, Langer F, Lausberg H, Bierbach B, Schafers HJ. Aortic root remodeling: tenyear experience with 274 patients. J Thorac Cardiovasc Surg. 2007;134:909-15.
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[23] Malvindi PG, Cappai A, Basciu A, Raffa GM, Barbone A, Citterio E, et al. David
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operation: single center 10-year experience. J Cardiovasc Surg (Torino). 2015;56:639-
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45.
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[24] Kari FA, Doll KN, Hemmer W, Liebrich M, Sievers HH, Richardt D, et al. Survival and
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freedom from aortic valve-related reoperation after valve-sparing aortic root
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replacement in 1015 patients. Interact Cardiovasc Thorac Surg. 2016;22:431-8. 23
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[25] Schäfers HJ, Raddatz A, Schmied W, Takahashi H, Miura Y, Kunihara T, et al.
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Reexamining remodeling. J Thorac Cardiovasc Surg. 2015;149:S30-S36. [26] Kvitting JP, Kari FA, Fischbein MP, Liang DH, Beraud AS, Stephens EH, et al. David
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valve-sparing aortic root replacement: equivalent mid-term outcome for different valve
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types with or without connective tissue disorder. J Thorac Cardiovasc Surg.
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2013;145:117-26, 127.
[27] Schneider U, Feldner SK, Hofmann C, Schope J, Wagenpfeil S, Giebels C, et al. Two
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decades of experience with root remodeling and valve repair for bicuspid aortic valves. J
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Thorac Cardiovasc Surg. 2017;153:S65-S71.
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[28] Thudt M, Papadopoulos N, Monsefi N, Miskovic A, Karimian-Tabrizi A, Zierer A, et al. Long-Term Results Following Pericardial Patch Augmentation for Incompetent
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Bicuspid Aortic Valves: A Single Center Experience. Ann Thorac Surg. 2017;103:1186-
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92.
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[29] Lansac E, Di C, I, Sleilaty G, Lejeune S, Berrebi A, Zacek P, et al. Remodeling root repair with an external aortic ring annuloplasty. J Thorac Cardiovasc Surg.
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2017;153:1033-42.
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[30] Oechtering TH, Frydrychowicz A, Sievers HH. Malrotated sinus vortices in straight
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graft valve-sparing aortic root treatment: A matter of concern? J Thorac Cardiovasc
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Surg. 2017;154:794-7.
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[31] Vallabhajosyula P, Szeto WY, Habertheuer A, Komlo C, Milewski RK, McCarthy F, et
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al. Bicuspid Aortic Insufficiency With Aortic Root Aneurysm: Root Reimplantation
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Versus Bentall Root Replacement. Ann Thorac Surg. 2016;102:1221-8.
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[32] Price J, Magruder JT, Young A, Grimm JC, Patel ND, Alejo D, et al. Long-term
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outcomes of aortic root operations for Marfan syndrome: A comparison of Bentall
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versus aortic valve-sparing procedures. J Thorac Cardiovasc Surg. 2016;151:330-6.
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Figure legends
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Figure 1. Kaplan-Meier survival curve for reimplantation and remodeling technique. The
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dashed line at 16 years represents the threshold of a statistical meaningful sample size.
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Figure 2. Cumulative incidence of reoperation for reimplantation and remodeling technique.
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The dotted line at 16 years represents the threshold of a statistical meaningful sample size.
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Figure 3: Top: Cumulative incidence of reoperation for all BAV and TAV patients. Bottom:
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Landmark analysis: Cumulative incidence of reoperation for BAV and TAV patients in 10
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year survivors. The dotted lines at 16 years represent the threshold of a statistical meaningful
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sample size.
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Figure e1. Histogram, showing the annual numbers of the two operative techniques over
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time. The dotted line represents the time point when a change in our operative policy took
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place (see Methods section).
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Figure e2. Kaplan-Meier survival curve for BAV and TAV patients. The dashed line at 16
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years represents the threshold of a statistical meaningful sample size. Age at operation of
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TAV patients was 54.0 ± 14.8 years and that of BAV patients 44.0 ± 12.2 years.
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Video 1. This video shows a David reimplantation operation with a Sinus prosthesis. In detail:
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Transection of the aorta 1 cm above commissures, commissural suture 2/0 multifilament with
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pledget, dissection of sinus, sinus excision (non-coronary), left-coronary button preparation,
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preparation between aortic root and right ventricular outflow tract, sizing of the graft,
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preparing the sinus prosthesis, subannular implantation with multiple 2/0 multifilament Teflon 26
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area), commissure resuspension on the prosthesis with Teflon pledgets outside, sinus suture
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from inside the graft with 5/0 Prolene, knotting sinus suture over Teflon felt of commissure,
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left-coronary and right-coronary artery button anastomoses, central leaflet stitch for
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evaluating parallelism of the free edge of the leaflets, retracted right leaflet extension with
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glutaraldehyde prepared autologous pericardium, central plication of left coronary leaflet,
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postoperative 3D echocardiogram showing three sinuses, plication left leaflet and cusp
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extension of right leaflet, longitudinal echocardiogram showing central trace aortic
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insufficiency.
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S0022-5223(17)32847-7
DOI:
10.1016/j.jtcvs.2017.12.039
Reference:
YMTC 12366
To appear in:
The Journal of Thoracic and Cardiovascular Surgery
Received Date: 5 July 2017 Revised Date:
15 November 2017
Accepted Date: 5 December 2017
Please cite this article as: Klotz S, Stock S, Sievers H-H, Diwoky M, Petersen M, Stierle U, Richardt D, Survival and reoperation pattern after 20 years of experience with aortic valve sparing root replacement in patients with tricuspid and bicuspid valves, The Journal of Thoracic and Cardiovascular Surgery (2018), doi: 10.1016/j.jtcvs.2017.12.039. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Survival and reoperation pattern after 20 years of experience with aortic valve sparing
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root replacement in patients with tricuspid and bicuspid valves
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Stefan Klotz1, MD; Sina Stock1, MD; Hans-Hinrich Sievers, MD; Michael Diwoky; Michael
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Petersen, MD; Ulrich Stierle, MD; Doreen Richardt, MD
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Both authors contributed equally to this work
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Department of Cardiac and Thoracic Vascular Surgery, University Medical Center Schleswig-
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Holstein, Campus Lübeck, Germany
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Funding statement: This work received no funding
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Conflict of interest: none declared
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Corresponding author: Prof. Dr. Hans-H. Sievers, MD
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University Medical Center Schleswig-Holstein
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Department of Cardiac and Thoracic Vascular Surgery
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Ratzeburger Allee 160
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23538 Luebeck, Germany
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Tel: +49-451-500-42301
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Fax: +49-451-500-42304
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E-mail: [email protected]
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Total word count: 4045 1
Glossary of Abbreviations
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BAV: Bicuspid aortic valve
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CTD: Connective tissue disease
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HR: Hazard ratio
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TAV: Tricuspid aortic valve
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Central Picture Legend
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Cumulative incidence of reoperation after aortic valve sparing root replacement.
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(80 / 90 characters incl. spaces)
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Central Message
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Aortic valve sparing root replacement offers near normal survival. However, the risk of
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reoperation is increased in the second postoperative decade especially in patients with a
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bicuspid valve.
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(193 / 200 characters incl. spaces)
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Perspective statement
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Aortic valve sparing root replacement techniques are appealing options to treat aortic root
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dilatation with or without aortic valve disease. Data of other groups regarding reoperation in
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the second decade after the operation in patients with a bicuspid aortic valve are required to
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get further inside in the probably more complex issue of bicuspid aortic valve and surgical
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treatment.
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(384 / 405 characters incl. spaces)
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Objective. Remodeling or reimplantation are established operative techniques of aortic valve
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sparing root replacement. Long-term follow-up is necessary comparing tricuspid and bicuspid
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aortic valves.
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Methods. A total of 315 patients (tricuspid n=225, bicuspid n=89, quadricuspid n=1;
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remodeling n=101, reimplantation n=214) were evaluated. Mean follow-up was 10.1±5.6 and
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6.4±4.2 years for the remodeling and reimplantation group, respectively. Longest follow-up
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was 21.9 years with 99.2% completeness. Mean age of the patients was 55.9±14.3 for the
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remodeling group and 48.9±14.5 years for the reimplantation group.
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Results. There was no significant difference in survival between the remodeling and
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reimplantation group (p=0.11). Survival was comparable to the normal population in the
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reimplantation group (p=0.33). Risk factors for late death were age, diabetes and a higher
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NYHA classification. Cumulative incidence of reoperation at 10 years was 5.8% for the
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reimplantation and 11.7% for the remodeling group. (p=0.65). Overall there was no difference
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in the cumulative incidence of reoperation between tricuspid and bicuspid aortic valve
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patients (p=0.13), however a landmark analysis showed that in the second decade the
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cumulative incidence of reoperation was higher in bicuspid aortic valve patients (p<0.001). 10
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of 11 reoperated bicuspid aortic valves were degenerated.
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Conclusions. The remodeling and reimplantation aortic valve sparing root replacement
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techniques provided excellent long-term survival. Although the number of patients was
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relatively small we provide some hints that in the second decade after the operation especially
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in bicuspid aortic valve patients the risk of reoperation may be increased needing further
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evaluation. (Abstract word count: 243 / 250)
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Introduction In patients with aortic root aneurysm and macroscopic intact aortic valve leaflets a
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valve sparing root replacement may be indicated to prevent shortcomings of replacement
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substitutes like bioprostheses and mechanical valves. Such repair operations are performed in
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two different techniques: the remodeling (Yacoub) [1] and the reimplantation (David) [2]
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technique.
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hemodynamics, low thromboembolism and bleeding complications without the need for
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anticoagulation. The remodeling technique preserves more physiologically the aortic root
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distensibility and movement of the aortic cusps [3;4]. The clinical relevance of it however is
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unclear and may surface after decades only. Midterm results after both valve sparing
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techniques were reported to be excellent [5-9]. For further judgement of this surgical
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principle, however, results of long-term, preferably life-long follow-up are essential [10].
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Since survival and reoperation are the most relevant determinants for treatment quality we
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present survival and reoperation pattern in patients after aortic valve sparing root replacement
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comparing the remodeling and reimplantation technique including BAV and TAV.
are
aortic
valve
reconstructions
warranting
excellent
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Materials and methods
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From March 1994 to December 2016 434 patients were consecutively operated on
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with the valve sparing root replacement technique. After exclusion of patients with acute type
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A dissection 315 patients (240 males, 51.1 ± 14.8 years, mean follow-up: 7.5 ± 5.0 years,
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reverse Kaplan-Meier method: median follow-up = 7.9 years (95% CI 7.6-8.2 years), 2377.99
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patient*years) were left for the study. The remodeling technique was performed in 101
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patients; the reimplantation technique in 214 patients. A histogram with the annual number of
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the two procedures is depicted in Figure e1. After approval by the ethical committee patients’
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consent was obtained. Follow-up data were gained between 2015 and 2017 via written
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questionnaires to the patients or their family doctors and via outpatient visits. Longest follow-
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colleagues [11] - was 99.2%. Preoperative data are presented in Table 1. The choice for either
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of the two techniques at early days of valve sparing surgery was related to the surgeon’s
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preference, not to dimensions of the annulus or other pathologies. Only if the annulus appears
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enlarged (>28-30 mm) a David annuloplasty [12] was performed in the remodeling group
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(n=16). When we evaluated our results in 2008 we found that best hemodynamic results were
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obtained with the remodeling technique at lower annulus diameters and vice versa with the
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reimplantation technique [13]. Since then we used both the techniques according to annulus
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diameter. In patients with an annulus diameter of 28 – 30 mm the remodeling technique and in
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those with an annulus diameter > 30 mm the reimplantation technique was applied. Our
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operative technique was reported in detail previously [3]. Only leaflets which had a normal or
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near normal macroscopic appearance with good pliability were accepted for repair. Additional
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cusp intervention was performed in 137 patients (Table 2). A central leaflet stich was
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performed after root replacement in both remodeling and reimplantation. By this technique
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the absolute parallelism of the leaflets with respect to the normal appearing reference leaflet
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was judged and if additional length, which means some kind of prolapse, was present this
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amount of additional length was centrally plicated with 6/0 U-stiches. In some cases the
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thickened raphe of BAV type 1 LR was resected and replaced with a triangular autologous
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glutaraldehyde preserved pericardial patch with 6/0 running suture.
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Intraoperative or pre-discharge echocardiography revealed aortic insufficiency of
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grade none/trace in 287 patients (none n=230, trace n=57), mild in 20 patients, mild to
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moderate in 1 patient and unknown in 7 patients.
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Statistical analysis
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For statistical analysis the chi-square test, Fisher exact test, the Mann-Whitney U test,
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and the Student's t-test were used where appropriate. Nominal and ordinal data are presented 6
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deviations. Standardized differences were calculated using the definition recommended by
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Austin [14]. The method of Benjamini and Hochberg [15] was used to control the false
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discovery rate, resulting in a corrected significance level of 0.008. The calculations were
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performed using IBM SPSS Statistics (IBM Corp. Released 2013. IBM SPSS Statistics for
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Windows, Version 22.0. Armonk, NY: IBM Corp.) and SAS software (Version 9.4, SAS
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Institute Inc., Cary, NC, USA).
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Patient survival rates were analyzed by the Kaplan-Meier method and the log rank test
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and reoperation by the cumulative incidence function adjusting reoperation for the competing
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risk of death and Gray’s log-rank test. For patients living more than 10 years the reoperation
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rates in the remodeling and in the reimplantation group was calculated by the landmark
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analysis that is competing risk analysis considering only patients with the occurrence with
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reoperation or death conditional on neither having occurred in the first 10 years. The Cox
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proportional hazards model was used to compare survival for the two procedures while also
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allowing for other variables. The aim of the Cox models was to allow for potential imbalances
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between the groups when comparing the reimplantation and remodeling procedures. We
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started by just allowing for differences between the reimplantation and remodeling procedures
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and then also included age and then we looked at models including both the procedures, age
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and one other variable. The survival of patients in the study was compared with the predicted
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survival experience for equivalent members of the general population with respect to age and
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gender. The latter was determined using the German life-table, 2010/2012 (www.destatis.de).
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The subject-years method was used to compare the numbers of deaths for the two procedures
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with the expected (i.e. average) numbers of deaths in the general population with the same age
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and sex profile. The standardized mortality ratio was calculated by the actual number of
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deaths divided by expected number of deaths based on life tables.
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Clinical characteristics
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Clinical characteristics are presented in Table 3 and 4. Follow-up in the reimplantation group
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was 6.4+-4.2 years (range 0-21.9 years) and 10.1 +- 5.6 (range 0-19.8 years) in the
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remodeling group (p<0.001).
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Early mortality
There were 5 early deaths overall (Table 4). In the reimplantation group the causes for
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early death were sudden cardiac death, cardiac arrest with hemorrhagic shock and hypoxic
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brain injury and in the remodeling the causes were septic shock with multi-organ failure and
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cardiogenic shock.
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Late mortality
38 late deaths occurred during the study time (Table 4). There were 6 late cardiac
164
deaths in the remodeling group (3 patients with sudden cardiac death, 1 patient with heart
165
failure, 1 patient with cardiac arrest after suspected myocardial infarction, and 1 patient with
166
cardiac decompensation after pulmonary embolism). In the remodeling group 9 late cardiac
167
deaths occurred (2 patients with myocardial infarction, 2 patients with heart failure, 2 patients
168
with acute aortic dissection, 1 patient with sudden cardiac death, 1 patient with cardiac arrest
169
after descending aorta replacement and multiple bleedings, and 1 patient with cardiac
170
decompensation after systemic inflammatory response syndrome.
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171 172
Overall mortality
173
The
Cox
proportional
hazards
model
revealed
a
hazard
ratio
(HR)
174
remodeling/reimplantation of 1.68 (95% CI 0.89-3.19, p=0.111), indicating no significant
175
evidence of a difference in survival times (Figure 1). When age and gender were adjusted for, 8
ACCEPTED MANUSCRIPT 176
the estimated HR remodeling/reimplantation was smaller (HR: 1.23, 95% CI 0.63-2.41,
177
p=0.549) and age was a significant risk factor for survival (HR per year: 1.04, 95% CI 1.02-
178
1.07, p=0.001). Also including other imbalances between groups (Table 1) in the multivariate
179
Cox model did not reveal a difference in survival between the groups. Survival was comparable to the normal population in the reimplantation group
181
(Standardized mortality ratio: 1.26 ± 0.60, p=0.39) but was lower in the remodeling group
182
(Standardized mortality ratio: 1.64 ± 0.63, p=0.047).
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180
A multivariable Cox proportional hazards model using backward elimination
184
including the variables listed in Table 1 revealed age (HR 1.03, 95% CI 1.01-1.06, p=0.02),
185
diabetes (HR 3.04, 95% CI 1.06-8.73, p=0.039) and higher NYHA classification (HR per
186
increment 1.48, 95% CI 1.04-2.12, p=0.032) as risk factors for shorter survival time.
188
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There was not significant evidence of a difference in survival time between TAV and BAV patients (p=0.095, Figure e2).
2 (4.3%) patients with connective tissue disease (CTD) died in comparison to 41
190
(15.3%) patients of the non-CTD group. In the remodeling group 2 (15.5%) patients with
191
annuloplasty and 24 (28.2%) patients without annuloplasty died.
192
194
Reoperation
There was no statistically significant difference regarding reoperation in both groups
AC C
193
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189
195
(p=0.65, Figure 2). The cumulative incidence of reoperation at 10 years was 5.8% (95%CI
196
2.8-12.0) for the reimplantation group and 11.7% (95%CI 6.5-20.7) for the remodeling group.
197
27 patients (BAV: n=11; TAV: n=16) needed a reoperation. The cumulative incidence of
198
reoperation at 10 and 16 years was 5.3% (95% CI 1.7 - 15.4) and 48.4% (95% CI 27.7 - 74.1)
199
in BAV patients and 9.8% (95% CI 5.9 - 16.0) and 10.9% (95% CI 6.6 - 17.5) for TAV
200
patients respectively (p=0.13) (Figure 3). The landmark analysis showed that the difference
201
regarding reoperation between the BAV and TAV patients was only significant considering 9
ACCEPTED MANUSCRIPT patients living more than 10 years (p<0.001) (Figure 3). Causes for reoperation were different
203
(Table 4). 5 (10.6%) reoperations had to be performed in patients with CTD compared to 22
204
(8.2%) patients without CTD. 7 BAV and 2 Marfan patients needed reoperation in the
205
reimplantation group and 4 BAV and 3 Marfan patients in the remodeling group. 10 of 11
206
reoperated BAV patients developed fibrotic tissue shrinkage or calcification of the leaflets
207
causing predominantly aortic insufficiency with a lesser degree of stenosis. In the remodeling
208
group 3 (18.8%) patients with annuloplasty were reoperated and 11 (12.9%) patients without
209
annuloplasty. Two patients were reoperated due to aortic valve endocarditis.
SC
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202
210
Morbidity
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A stroke occurred in 8 (3.7%) patients of the reimplantation group and 2 (2.0%)
213
patients of the remodeling group. Major bleeding events were reported by 10 (4.7%) patients
214
of the reimplantation group and 4 (4.0%) patients of the remodeling group. 2 (0.9%) of the
215
reimplantation group and 2 (2.0%) patients of the remodeling group reported non-cerebral
216
embolic events.
218
Discussion
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In this retrospective study we found that the survival and cumulative incidence of
220
reoperation after the remodeling and reimplantation aortic valve sparing root replacement
221
techniques did not differ significantly. The same holds true for the probability of survival in
222
TAV and BAV patients. However, more reoperations were necessary in BAV patients in the
223
second decade after the reoperation especially in the reimplantation group.
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219
224
Normal anatomy warrants optimal function. Keeping this maxim in mind the
225
restoration of normal anatomy in general is appealing if the tissue is of favorable quality to
226
expect long-term function and durability. This is particularly important for the aortic valve
227
which plays a crucial role for left-ventricular to aortic coupling allowing for passage of blood 10
ACCEPTED MANUSCRIPT 228
at rest and exercise with low energy loss [16]. To achieve this goal the aortic valve performs
229
complex movements. It follows sophisticated 3D deformational dynamics thereby reducing
230
stress on the aortic cusps, minimizing transvalvular energy loss and optimizing coronary flow
231
[17-19]. Preserving the aortic leaflets and restoring physiological root dynamics theoretically
233
bear the potential to favorably influence long-term outcome of the patients. The remodeling
234
technique includes the resection of the sinuses only and does not touch the interleaflet
235
trigones and the annulus of the aortic valve which seems to restore some kind of distensibility
236
in this area in contrast the reimplantation technique which incorporates the aortic valve into a
237
rigid Dacron tube including the annulus of the aortic valve [3;4]. This technique however
238
corrects and prevents annulus dilatation and such may also prevent development of aortic
239
regurgitation in the long-term, therefore we preferred this technique in the last years [7].
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As one of the major determinants of treatment quality survival after valve sparing
241
aortic root replacement was excellent being 72.6% (95% CI: 0.64 – 0.81) after 15 years,
242
which is comparable to the normal population and the data of other groups [20-26]. Reasons
243
for this favorable outcome are not only the physiological concept of valve sparing but also the
244
close follow-up of these patients. Survival in the reimplantation group was comparable to the
245
normal population and we found no difference in survival between the remodeling and the
246
reimplantation groups. However, survival was lower than normal in the remodeling group.
247
Whether this is related to the small number of patients, the lower ejection fraction and higher
248
NYHA classification or the older age at the primary operation remains to be evaluated further.
249
The rate of reoperation was acceptable till 10 years postoperatively as also reported by
250
other groups [20;24;27] but thereafter we observed an obvious increase in the rate of
251
reoperation especially in BAV patients compared to TAV patients as shown by the landmark
252
analysis. It must be considered however that the number of patients is relatively small needing
253
further evaluation by larger number of patients. Thus our results are less favorable compared
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11
ACCEPTED MANUSCRIPT to those reported for the remodeling technique and BAV patients by the Schäfers group [27]
255
with a cumulative incidence of reoperation of 21.7% at 15 years. It is possible that in general
256
our repair techniques in BAV patients were insufficient although 10 of all reoperated BAV
257
patients left the theatre at primary repair with no and one patient with trivial aortic
258
regurgitation. Furthermore, at primary operation 10 of the 11 reoperated BAV patients had
259
pliable leaflets, all were BAV type 1 left/right, only in one a small calcification was present at
260
the commissural remnant between the fused left and right coronary cusp which was removed.
261
In 5 patients a plication of the leaflets was required, in 6 patients none additional cusp
262
intervention. We found no systematic technical issue in our reoperated patients demonstrating
263
that our kind of repair would lead to later fibrotic tissue changes and calcification (10 of 11).
264
Whether more coaptation area by using pericardial leaflet augmentation [28] leads to better
265
results remains speculative in as much as the use of pericardium for cusp repair was reported
266
to be a risk factor for earlier reoperation [25]. More innovative repair techniques with higher
267
coaptation area, avoidance of symmetrical prolapse and more experience might result in better
268
outcome as reported by Schneider et al. [27] with roughly 20% cumulative incidence of
269
reoperation after 12 years. Furthermore circumferential annuloplasty as described by Lansac
270
[29] or Schneider [27] may function as an additional protective effect against aortic
271
insufficiency and as such improve the outcome. If the observed degenerative process is
272
related to a genetic background or if the unphysiological morphology and hemodynamics in
273
patients with a BAV are causative remains unknown. Another aspect that could have some
274
influence on leaflet degeneration is the lack of sinuses in the reimplantation group especially
275
for BAV leading to malrotation of the vortex behind the leaflets as recently shown by
276
Oechtering et al. [30]. This degenerative process obviously accelerates in the second decade
277
after surgery. These less optimal results prompted us to rethink BAV for valve sparing root
278
replacement and in general may require a lot of more clinical and experimental research to
279
shed light in this less favorable issue. In view of these data we more clearly inform our
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12
ACCEPTED MANUSCRIPT patients on the increased probability of reoperation in the second decade especially after BAV
281
repair, confine the indication to absolute pliable leaflet tissue, perform more radical triangular
282
resection of the thickened raphe with pericardial replacement extending on the free leaflet
283
edges (right and left coronary cusps) to get more pliability and to increase coaptation area and
284
do not use cusps for repair which show any signs of beginning calcification. Together this
285
means some restriction in BAV indication. A Bio-Bentall procedure may be an alternative in
286
those patients who do not like to take anticoagulation or a regular Bentall prosthesis with a
287
mechanical valve. Nevertheless the results with valve sparing root repair are at least
288
equivalent with a lower rate of composite events [31;32].
290
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280
Limitations of the study
This is a retrospective analysis and as such has a lot of flaws, weakening the
292
comparability of the different groups. Nevertheless it is a clinical series with relatively long
293
follow-up time providing us with some view on the results in the second decade. The number
294
of patients is small especially in the second decade; however, the number of events (late death
295
and reoperation) is around 10% of the total cohort and there is a clear trend for earlier
296
degeneration in BAV compared to TAV supporting the theoretical background of BAV as a
297
less physiological valve. Since the follow-up time of the reimplantation procedure was shorter
298
than for the remodeling group it may explain the better survival compared to normal,
299
however, this must be further evaluated.
EP
AC C
300
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291
In the early years we did not use transesophageal echocardiography for analysis of
301
intraoperative root dimensions and aortic valve function, and defined the valve competent
302
when the root was pressurized after removal of the aortic clamp and no dilatation of the left
303
ventricle
304
echocardiography gaining more qualitative data. However, in most patients a transthoracic
305
echocardiogram was performed pre-discharge providing some information on the valve
occurred.
Since
2003
we
started
with
intraoperative
transesophageal
13
ACCEPTED MANUSCRIPT function. Furthermore a lot of patients had no records of aortic valve function and dimensions.
307
It is possible that there are certain, unknown patients with significant valve lesion needing
308
reoperation because of the incomplete echocardiographic late follow-up. Whether those
309
shortcomings influence results remains speculative in as much as almost all reoperated BAV
310
patients showed fibrous and calcifications of the leaflets at reoperation which is most likely an
311
intrinsic process of the tissue of the leaflets.
312
Conclusions
SC
313
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306
In this series, survival was near normal in both, the remodeling and reimplantation
315
aortic valve sparing root replacement techniques and the cumulative risk of reoperation
316
remains stable up to 10 years postoperatively. In the second decade we observed an increase
317
in reoperations particularly in BAV patients. Although the number of BAV patients in the
318
second decade is small, our findings caused us to closely rethink our indication and technique
319
for BAV valve sparing root replacement.
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14
ACCEPTED MANUSCRIPT
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analyses.
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322
The authors are thankful to Dr. Derek Robinson for his support regarding the statistical
EP
321
Acknowledgement
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320
15
ACCEPTED MANUSCRIPT Table 1. Perioperative characteristics of the patient population.
84.0 ± 27.8
2
6
9 (4.2)
2 (2.0)
2 (0.9) 8 (3.7) 56 (26.2) 10 (4.7)
19 (18.8)
2 (2.0)
7 (6.9)
30 (29.7)
3 (3.0)
35 (16.4) 33 (15.4) 2 (0.9)
12 (11.9) 12 (11.9) 0
43 (20.1)
28 (27.7)
27 (12.6) 28 (13.1) 66 (30.8) 93 (43.5) 0
31.9 ± 5.2
86 49.6 ± 9.6 42 41 ± 6.6 95
-11.1 -13.2 -0.6 -1.9
12.9
M AN U
27 (12.6)
p value <0.001 <0.001 0.082
RI PT
83.5 ± 23.3
Standardized difference 53.6 -48.3 22.0
SC
Remodeling (n=101) 61 (60.4) 55.9 ± 14.3 22 (21.8) 4 (4.0) 15 (14.9) 0 3 (3.0) 5 (5.0) 70 (69.3) 1 (1.0)
EP
Male gender Age (years) Bicuspid aortic valve Type 0 Type 1 Type 2 unknown Diabetes mellitus Hypertension Renal disease Serum creatinine (µmol/l) Unknown Previous cardiac surgery Coronary artery disease Peripheral artery disease Cerebrovascular disease Hyperlipidemia Chronic pulmonary disease CTD Marfan Loeys-Dietz Mitral valve insufficiency ≥ grade I Aortic valve insufficiency None / trace Mild Moderate Severe Unknown Annulus diameter (mm) Unknown Sinus diameter (mm) Unknown STJ diameter (mm) Unknown Ascending aorta diameter (mm) Unknown LVEF > 50%
Reimplantation (n=214) 179 (83.6) 48.9 ± 14.5 67 (31.3) 11 (5.1) 52 (24.3) 2 (0.9) 2 (0.9) 6 (2.8) 135 (63.1) 2 (0.9)
TE D
Parameter
AC C
323
-17.1 -8.7
-14.2
-7.9 8.9 12.9
-18.0 1.9
0.339 0.312 1
0.667
0.513 0.172 0.596 0.258 0.588 0.561 0.397
0.149 0.084
13 (12.9) 18 (17.8) 36 (35.6) 31 (30.7) 3 (3) 7.6 31.4 ± 7.5 72 51.7 ± 11.2 43 40.8 ± 8 82
-20.3
0.200
2.1
0.939
-49.9 50.2 ± 12.4 48
56.3 ± 12.3 18
174 (82.1)
66 (78.6)
0.739
8.8
<0.001 0.012 16
ACCEPTED MANUSCRIPT
RI PT
SC M AN U TE D EP AC C
324 325
30% - 50% 38 (17.9) 18 (21.4) Unknown 2 17 NYHA 0.007 Class I 91 (42.9) 21 (25.6) 37.1 Class II 78 (36.8) 37 (45.1) -17.0 Class III 34 (16.0) 19 (23.2) -18.0 Class IV 9 (4.2) 5 (6.1) -8.4 Unknown 2 19 Atrial fibrillation 11 (5.1) 9 (8.9) -14.8 0.220 CTD: Connective tissue disease, LVEF: Left ventricular ejection fraction, NYHA: New York Heart Association, STJ: Sinotubular junction
17
ACCEPTED MANUSCRIPT Table 2. Leaflet intervention in tricuspid and bicuspid aortic valves
Leaflet intervention None Plication Pericardial extension Plication + pericardial extension Shaving Plication + shaving
Tricuspid aortic valve
Bicuspid aortic valve
155 (68.9) 67 (29.8) 1 (0.4) 1 (0.4) 0 1 (0.4)
23 (25.8) 54 (60.7) 8 (9.0) 3 (3.4) 1 (1.1) 0
AC C
EP
TE D
M AN U
SC
327
RI PT
326
18
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Table 3. Operative details of the patients. Parameter
Reimplantation Remodeling (n=214) (n=101) 196 (91.6) 87 (86.1)
p-value
TE D EP AC C
329
M AN U
SC
RI PT
Elective surgery 0.162 Additional procedures Partial or total aortic arch 35 (16.4) 24 (23.8) 0.124 replacement Mitral valve intervention 8 (3.7) 7 (6.9) 0.258 CABG 23 (10.7) 11 (10.9) 1 Aortic valve cusp 107 (50.0) 31 (30.7) 0.002 intervention Size of prosthesis <0.001 24 mm 1 (0.5) 5 (5.0) 26 mm 8 (3.7) 14 (13.9) 28 mm 43 (20.1) 38 (37.6) 30 mm 123 (57.5) 38 (37.6) 32 mm 39 (18.2) 6 (5.9) Surgical data CPB time (min) 218.1 ± 51.0 177.1 ± 47.1 <0.001 Cross-clamp time (min) 180.0 ± 43.3 134.5 ± 43.9 <0.001 Circulatory arrest No. of patients 52 (24.3) 51 (50.5) Circulatory arrest time 29.4 ± 23.3 22.2 ± 14.1 0.022 (min) CABG: Coronary artery bypass grafting, CPB: Cardiopulmonary bypass
19
ACCEPTED MANUSCRIPT Table 4. Follow-up data.
Mortality Early mortality (≤ 30 days) Late mortality (>30 days) Cause of death Non-cardiac Cardiac Unknown Aortic valve reoperation Aortic valve phenotype BAV (n) TAV (n) Finding at reoperation Leaflet degeneration (fibrotic shrinkage, calcification) (n) Annulus dilatation (n)
Remodeling (n=101) 10.1 ± 5.6 0 – 19.8 26 (25.7) 2 (2.0) 24 (23.8)
7 (50.0) 6 (42.9) 1 (7.1) 13 (6.1)
11 (45.8) 9 (37.5) 4 (16.7) 14 (13.9)
7 6
4 10
RI PT
Follow-up years*
Reimplantation (n=214) 6.4 ± 4.2 0 – 21.9 17 (7.9) 3 (1.4) 14 (6.5)
SC
Parameter
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330
Total: 11 BAV: 7 TAV: 4 0
Total: 6 BAV: 3 TAV: 3 Total: 6 BAV: 1 TAV: 5 TAV: 1 TAV: 1
331 332
AC C
EP
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Endocarditis (n) TAV: 1 Unknown (n) TAV: 1 Hemodynamic indication for reoperation Stenosis 3 1 Insufficiency 9 (1 Endocarditis) 11 (1 Endocarditis) Combined 1 2 n=61 Echocardiographic follow- n=104 up data1 5.9 ± 3.3 10.1 ± 4.4 Follow-up years Aortic regurgitation None/trace 60 (57.7) 23 (37.7) Mild 37 (35.6) 29 (47.5) Moderate 6 (5.8) 8 (13.1) Severe 1 (1.0) 1 (1.6) δp mean [mmHg] 6.5 ± 4.1 6.0 ± 3.4 1 Only patients with echocardiographic follow-up > 1 year; BAV: Bicuspid aortic valve, TAV: Tricuspid aortic valve
20
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[32] Price J, Magruder JT, Young A, Grimm JC, Patel ND, Alejo D, et al. Long-term
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outcomes of aortic root operations for Marfan syndrome: A comparison of Bentall
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versus aortic valve-sparing procedures. J Thorac Cardiovasc Surg. 2016;151:330-6.
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Figure legends
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Figure 1. Kaplan-Meier survival curve for reimplantation and remodeling technique. The
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dashed line at 16 years represents the threshold of a statistical meaningful sample size.
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Figure 2. Cumulative incidence of reoperation for reimplantation and remodeling technique.
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The dotted line at 16 years represents the threshold of a statistical meaningful sample size.
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Figure 3: Top: Cumulative incidence of reoperation for all BAV and TAV patients. Bottom:
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Landmark analysis: Cumulative incidence of reoperation for BAV and TAV patients in 10
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year survivors. The dotted lines at 16 years represent the threshold of a statistical meaningful
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sample size.
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Figure e1. Histogram, showing the annual numbers of the two operative techniques over
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time. The dotted line represents the time point when a change in our operative policy took
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Figure e2. Kaplan-Meier survival curve for BAV and TAV patients. The dashed line at 16
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years represents the threshold of a statistical meaningful sample size. Age at operation of
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TAV patients was 54.0 ± 14.8 years and that of BAV patients 44.0 ± 12.2 years.
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Video 1. This video shows a David reimplantation operation with a Sinus prosthesis. In detail:
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Transection of the aorta 1 cm above commissures, commissural suture 2/0 multifilament with
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pledget, dissection of sinus, sinus excision (non-coronary), left-coronary button preparation,
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preparation between aortic root and right ventricular outflow tract, sizing of the graft,
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preparing the sinus prosthesis, subannular implantation with multiple 2/0 multifilament Teflon 26
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area), commissure resuspension on the prosthesis with Teflon pledgets outside, sinus suture
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from inside the graft with 5/0 Prolene, knotting sinus suture over Teflon felt of commissure,
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left-coronary and right-coronary artery button anastomoses, central leaflet stitch for
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evaluating parallelism of the free edge of the leaflets, retracted right leaflet extension with
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glutaraldehyde prepared autologous pericardium, central plication of left coronary leaflet,
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postoperative 3D echocardiogram showing three sinuses, plication left leaflet and cusp
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extension of right leaflet, longitudinal echocardiogram showing central trace aortic
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insufficiency.
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