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Eur J Cardiothorac Surg 2005;27:410-415
© 2005 Elsevier Science NL

Mid-term findings on echocardiography and computed tomography after RVOT-reconstruction: comparison of decellularized (SynerGraft) and conventional allografts

J.F. Matthias Bechtela, Joerg Gellissenb, Armin W. Erasmia, Michael Petersena, Alexander Hiobb, Ulrich Stierlea, Hans-Hinrich Sieversa,*

a Department of Cardiac Surgery, Universitaetsklinikum Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany
b Institute of Radiology, University of Luebeck, Germany

Received 5 October 2004; received in revised form 15 November 2004; accepted 1 December 2004.

* Corresponding author. Tel.: +49 451 500 2108; fax: +49 451 500 2051. (E-mail: sievers{at}medinf.mu-luebeck.de).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
 References
 
Objective: The immune response against human-leucocyte-antigens on donor-cells may be an important factor contributing to the degeneration of allograft-valves. We have previously reported that the use of the decellularized allograft SynerGraft (CryoLife®) reduces the immunologic response of the allograft-recipient. In this study we compare the echocardiographic and computed tomography angiographic (CTA) findings of SynerGrafts with conventional cryopreserved allografts. Methods: 22 patients who received a pulmonary SynerGraft (SG-group) (21 during a Ross-procedure) underwent CTA and resting echocardiography (median: 10 months postoperatively). 47 randomly chosen patients who underwent a Ross-procedure served as controls (C-group) (median: 32 months postoperatively). Results: Neither the pressure gradients (mean: SG=9±4 vs C=10±4mmHg; P=0.64) across the allograft, nor the effective orifice area (EOAI) (SG=0.93±0.80 vs C=0.93±0.42cm2/m2; P=0.96) differed between the groups. The EOAI showed a significant correlation with the smallest allograft-conduit-area measured on CTA (r=0.81; P<0.001) which was most frequently (n=34) found in the proximal postvalvular tubular part of the conduit. Calcifications (n=11) or a fibroproliferative reaction (n=15) were rarely observed. Overall, there were no radiologic differences between the groups. On CTA, the smallest diameter of the allograft-conduits was significantly smaller than the diameter given on the cryopreservation protocol (SG=16±3 and C=17±3mm vs 25mm in both groups; P<0.001 each) whereas the diameter of the distal part of the allograft was not (SG=24±2, P=0.066, and C=25±3mm, P=0.82). Conclusions: Despite a significant shorter follow-up in the SynerGraft-group, no functional or radiologic differences were observed as compared to control-patients. The smallest diameter is located almost exclusively at the proximal level of allograft-conduits.

Key Words: Calcification • Computed tomography • Echocardiography • Heart valve • Allograft • Imaging • Immunology


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
 References
 
Valvular allografts are used for reconstruction especially of the right (RVOT) and left ventricular outflow tract (LVOT) during surgery for congenital or acquired heart diseases. Unfortunately, valvular allografts degenerate in a significant number of patients necessitating reoperations.

Experimental data clearly indicate that valvular allografts are infiltrated by immunological active host cells causing allograft destruction [1–3]. Following implantation in humans, a specific cellular [4] and humoral immune [5] response directed against human leucocyte antigen (HLA) determinants of the valve donor has been detected. Accordingly, some indirect evidence from clinical studies suggests that allograft valve failure may be caused by immunological factors [6–8], although this is not supported by all available data [5,9,10] or universally accepted [11].

In an effort to reduce or even abolish the stimulation of the immune system, several groups are currently working on or have employed decellularization of valvular allografts. Cryolife Inc. (Kennesaw, GA, USA) has introduced a proprietary decellularization process (SynerGraft) for tissue valves that is followed by cryopreservation allowing world-wide distribution. Experimental and early clinical results obtained with the SynerGraft-treated valves were promising [12–15]. However, a high failure rate of SynerGraft-treated xenografts (some of which were sewn from three porcine non-coronary sinus with leaflets) in a pediatric patient population [16] has caused safety concerns and let to the offtake of this valve from the market.

This xenogenic SynerGraft must not be confused with allografts that have been decellularized by the SynerGraft-process. We have previously reported that implantation of such SynerGraft-treated allografts (SG-AG) is associated with a reduced immune response as compared to historic patients receiving conventional allografts (C-AG), but that no hemodynamic differences could be detected during the first 6 months postoperatively [17]. In this study, we sought to further follow the echocardiographic results of patients receiving a SG-AG. In addition, we studied whether computed-tomography with angiography (CTA) can be used to evaluate valve function after RVOT-reconstruction and whether the radiologic appearance of SG-AGs differs from that of C-AGs.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 Appendix A. Conference...
 References
 
2.1. Patients
As previously stated [17], a randomized comparison of SG-AG and C-AG was not possible at our department, mainly for logistic reasons. Of the 24 patients who had had pulmonary SG-AG-implantation included in the first study, two patients declined to undergo CTA. The remaining 22 patients form the basis of this study. The patients did not undergo CTA at a specific postoperative interval.

Patients of the control group who had received a C-AG were aquired from our large Ross-procedure data-base. Those patients who had their regular follow-up visit during the time-period in which the SG-AG-patients were evaluated by CTA were asked to undergo CTA, and 47 patients agreed to do so. The main characteristics of both study groups are given in Table 1. Informed consent was obtained from each patient. The study was performed in accordance with institutional guidelines.


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  		Table 1. Baseline characteristics and hemodynamic results at follow-up
 
2.2. Surgical technique
All operations were performed through a median sternotomy with hypothermic (26°C) cardiopulmonary bypass and cold crystalloid or blood cardioplegia for myocardial protection. For the Ross procedure, in brief, the diseased aortic valve was excised first. Then the pulmonary autograft was harvested from the RVOT and implanted as aortic valve substitute inside the aortic root in the subcoronary position.

Cryopreserved pulmonary allografts were then thawed and implanted into the RVOT. The distal suture line was made with 5–0 interrupted polypropylene sutures. For the proximal suture line, a 4–0 continuous polypropylene suture was used.

2.3. Echocardiography
For echocardiography, a Sonos 5 500 ultrasound system with a 2.5MHz ultrasound transducer (Agilent Technologies, Andover, MS) was used. Measurements performed included transvalvular flow velocity of the neo-aortic valve from the apical 5-chamber view with the use of continuous-wave (cw) Doppler, LVOT flow velocity with the use of pulsed-wave Doppler, and LVOT diameter. Flow characteristics across the RVOT were measured by cw Doppler from the left parasternal short axis view. Peak and mean transvalvular pressure gradients were determined by use of the modified Bernoulli equation ({Delta}P=4v2, where {Delta}p is the pressure gradient, and v is the maximal flow across the valve). Left ventricular stroke volume was calculated from the product of LVOT velocity-time integral and LVOT cross-sectional area. The neo-aortic and neo-pulmonary valve effective orifice area (EOA) were determined by the standard continuity equation with the use of LVOT stroke volume and then indexed for body-surface-area (BSA). Color flow Doppler was used to detect pulmonary regurgitation. The severity was semiquantitatively assessed on the basis of the length and width of the regurgitation jet and the distance it reaches into the RVOT and graded into none, trivial, mild, moderate, or severe. EOA was not calculated when there was more than mild pulmonary or aortic valve regurgitation.

2.4. Computed tomographic angiography
ECG-gated multidetector-CT of the heart was performed within a week of the echocardiographic measurements. Patients were in supine position, and scanning (Aquilion Multi, Toshiba Medical Systems) was performed during breath-holding. The ECG was simultaneously recorded. A first scan without contrast-material was used for identification of calcifications (120kV, 150mA, rotation time 0.5s). Thereafter, 120ml of a iodine-based, water-soluble contrast-agent (Ultravist 370) was injected into a cubital vein using a pump (3.5ml/s), and the second scan was started (120kV, 200–250mA, rotation time 0.5s). Slice collimation for calcium detection was 3mm and 2mm for contrast-enhanced CTA. The simultaneous acquisition of the ECG made it possible to use only data obtained during diastole for further evaluation (segmental retrospective gating). This technique minimizes artefacts due to movements. Images were then reconstructed by multiplanar reformatting along a defined curved path through the middle of the RVOT and the allograft. This technique allows visualization of the allograft in curved, i.e. virtual, planes. For evaluation, a paracoronal view and a parasagital view were computed (Fig. 1). The location of the smallest diameter on each view was identified. For description, the allograft is divided into the proximal anastomosis/valve region, and the conduit, which was further divided into the proximal and distal half. The smallest diameter was recorded, and measurements of the diameter were also taken from the other two regions. The cross-sectional area was derived from biplanar measurements. A fibroproliferative process was diagnosed if an increase of the densities along the boundary of the allograft or wall thickening was observed.



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  		Fig. 1. CTA of a conventional pulmonary allograft. The allograft is reconstructed along a curved path through its middle. This technique allows visualization of the allograft in virtual planes: (a) paracoronal view, (b) parasagital view. The location of the proximal anastomosis/valve region is marked as well as the tubular part of the conduit. CTA, computed tomography angiography; asc. aorta, ascending aorta; RPA, right pulmonary artery; LPA, left pulmonary artery; RVOT, right ventricular outflow tract.

 
2.5. Statistics
Categorial data are given as total numbers and relative frequencies and were compared using Fisher's exact test. Continuous data are presented as mean±standard deviation. Echocardiographic and CTA measurements were compared using paired and unpaired Mann-Whitney U-tests. Multiple comparisons were corrected for using Bonferoni's method. Correlations were assessed using Pearson's correlation coefficient. Linear regression analysis was used for assessing the association between EOA and CTA-area. Logistic regression analysis was applied to investigate the relation between the follow-up period and the diagnosis of fibroproliferation. A P-value <0.05 was considered to indicate statistical significance. All analyses were performed using SPSS for Windows (release 8.0; SPSS; Chicago, IL).


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 Appendix A. Conference...
 References
 
3.1. SG-AG: echocardiographic follow-up results at 12 months
12 Months after implantation, the maximal and mean pressure gradients were 18±9 and 10±6mmHg, respectively. The EAO (indexed for body-surface area) measured 0.96±0.32cm2/m2. When these results were seen as part of a serial examination, no significant change in valvular function was detected beyond 6 months postoperatively as exemplary illustrated for the EOA in Fig. 2.



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  		Fig. 2. Serial measurements of the EOA in SG-AG-patients. The main change of the effective orifice area (EOA) occurs during the first 6 postoperative months. Thereafter, no significant change was observed. BSA, body-surface area; n.s.: not significant.

 
3.2. SG-AG vs C-AG: comparison of baseline and echocardiographic results
In the SG-AG group, the CTA-examination was performed a median of 10 months postoperatively, whereas in the C-AG group, it was performed 32 months postoperatively (Table 1; P<0.001). As also shown in Table 1, the patients of the SG-AG group were significantly younger than the C-AG patients, but otherwise, there were no significant differences especially not regarding allograft valve function at the time of CTA.

3.3. Relation between echocardiographic and CTA measurements
The smallest area (indexed for BSA) on CTA measured 1.15±0.46cm2/m2 which is significantly larger than the indexed EOA (0.93±0.39, P<0.001). However, a significant, linear relation between the indexed EOA and the indexed smallest allograft-area on CTA was observed (Fig. 3). Fig. 3 also indicates that SG-AG and C-AG did not differ regarding this relation. The pressure gradients did not show a significant association with CTA-variables.



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  		Fig. 3. Relation between CTA and echocardiography. A significant, linear association exists between the effective orifice area (EOA) and the smallest area of the conduit as measured on computed tomography angiography (CTA). Closed symbols: conventional allografts, open symbols: SynerGraft-treated allografts, BSA: body-surface area.

 
3.4. SG-AG vs C-AG: comparison of CTA-results
In the majority of cases, the allografts had a quite symmetric appearance as the one shown in Fig. 1 (frequency of symmetric appearance, SG-AB vs C-AG: paracoronal view, 59 vs 50%, P=0.76; parasagital view, 57 vs 68%, P=0.81).

CTA revealed that in both groups, the smallest diameter of the allograft was most frequently located in the postvalvular, proximal part of the conduit (Table 2). The smallest diameter was 16.2±3.1 and 16.8±3.2mm in the SG-AGs and C-AGs, respectively (P<0.001 for both groups when compared with the diameter of the homograft as given on the cryopreservation protocol, see Table 1; P=0.36 for comparison of SG-AG and C-AG). At the level of the distal anastomosis, however, the homograft was not significantly smaller than the diameter given in the cryopreservation protocol (SG-AG: 24.4±1.9mm, P=0.066; C-AG: 25.4±2.5mm, P=0.82; P=0.073 for comparison of groups).


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  		Table 2. Main results on CTA
 
Irrespective of whether the narrowing of the conduit at its smallest level was symmetric or asymmetric, it could usually not be attributed to a specific process (fibroproliferation or calcifications; Table 2, Figs. 4 and 5). The presence of fibroproliferation appeared to be dependent on the follow-up period (Fig. 6, P=0.026), a shorter follow-up carrying a higher chance of detecting fibroproliferation. No thrombi were observed.



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  		Fig. 4. CTA of a SynerGraft-allograft showing fibroproliferation. In the paracoronal view (a), fibroproliferation (*) adjacent to the whole length of the allograf (and the aorta) is evident by the different intensities of the surrounding tissue. In the parasagital view (b), fibroproliferation is less evident. CTA: computed tomography angiography.

 


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  		Fig. 6. Time-dependency of the presence of fibroproliferation. Fibroproliferation was identified exclusively on CTAs performed during the first 2.3 years after surgery. CTA: computed tomography angiography, closed symbols: conventional allografts, open symbols: SynerGraft-treated allografts.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
Appendix A. Conference...
 References
 
In this study we provide further follow-up on patients who had had implantation of the decellularized SynerGraft-allograft (SG-AG), and compare the radiologic appearance of the SG-AG with that of conventional allografts (C-AG).

The necessity to withdraw the SynerGraft-treated xenograft from the market because of a high rate of early failure [16] has caused much concern recently regarding the stability and safety of decellularized valve-conduits. The functional results using a human valve decellularized by the SynerGraft-process reported herein are reassuring. When our results obtained 12 months after implantation of a SG-AG are compared to the results 6 months after implantation, no further significant change in valvular function was observed. A deterioration in valvular function can also be detected in recipients of conventional allografts [5,18,19], and the change in valvular function appears to be most pronounced in the first months after implantation [18–20].

In the first reports on human SG-AG implantation, it had been stated that valve function is ‘normal’ [14,15]. Our data support this statement, but longer follow-up and larger groups are needed for a definite conclusion. However, despite evidence that implantation of a SG-AG is associated with reduced immunization of the recipient [15,17,21], no advantage in valvular function is apparent—even in this study in which recipients of SG-AGs were compared to a random sample of recipients of C-AGs who had a significantly longer follow-up. This difference between the groups introduces bias in favour of the SG-AGs, but no differences in valvular function nor in the radiologic appearance was evident.

Recently, data supporting the role of the immune system in mediating allograft-failure have been added to the already existing experimental evidence [1–3]: Baskett et al. have reported that HLA-DR mismatch was associated echocardiographic valve failure (pulmonary insufficiency≥grade II or ≥50mmHg gradient) in a small study on 27 children who had had RVOT-reconstruction [6]. Dignan et al. [7] showed that the presence of HLA-class II antibodies was associated with a shorter time to structural aortic valve allograft deterioration (valve incompetence≥grade III or ≥50mmHg peak gradient) in 148 adults. In addition, studies by Pomplio et al. and Welters et al. [8,22] suggest that the intensity of the immune reaction against donor HLA-class I characteristics is associated with progressive functional valve deterioration or need for retransplantation.

In the light of this new clinical data, the fact that we as well as others [21] observed no difference regarding allograft function between SG-AGs and C-AGs should not be interpreted as no evidence for an immune-mediated deterioration of allograft valve function. Instead, it is suggested that the process of decellularization may cause damage to the allograft-matrix [23] that necessitates a repair-reaction of the donor that in turn is associated with a deterioration of allograft-function. As both, SG-AG and C-AG, had been cryopreserved, however, our data are also consistent with the interpretation that damage induced by cryopreservation and thawing [24] is mainly responsible for the fate of allografts.

In this study, we were able to correlate functional data (obtained by echocardiography) with radiologic data. CTA has been used for visualization of valves before, but we are unaware of any other study that visualized pulmonary valve allografts irrespective of function by either CTA or magnetic resonance imaging (MRI). We observed a significant association between the EOA and the minimal conduit-area on CTA which was most frequently located in the postvalvular, proximal part of the allograft-conduit. This location is in accordance with reports on the most frequent location of stenosis in failing allografts using echocardiography [19,25] and MRI [20].

Carr-White et al. [20] reported that in 11 of 15 patients, who underwent MRI because of a peak pressure gradient across a pulmonary valve allograft of ≥30mmHG, thick regions of nonfat tissue were present adjacent to the location of the stenosis. They interpret this finding as an excessive fibrotic reaction. Studying patients most of whom had normal valvular function, we were unable to detect any distinct radiologic pattern specific for either the location or the morphology of the smallest allograft-area or the type of allograft. Fibroproliferation or calcifications were only infrequently observed, and the smallest diameter of the allografts on CTA usually appeared to result from a mild, more or less homogenous narrowing of its proximal tubular part that could not be attributed to a specific process. MRI can be expected to be more sensitive than CTA in detecting fibroproliferative or fibrotic tissue, but CTA is more sensitive regarding calcifications. As a result, the frequency of calcifications observed in this study appears high on first sight, but all calcifications in this study were small isolated spots without any apparent functional relevance.

In conclusion, our data add to the existing evidence that implantation of SynerGraft-treated pulmonary valve allografts is safe and is associated with a valvular function no different from that of conventional allografts. CTA correlates with the EAO as determined by echocardiography, but no distinct radiologic pattern corresponding to the functional measurements could be elucidated. The smallest allograft-diameter may occur at any level of the allograft-conduit, but is usually in its postvalvular proximal part. We found some evidence that a fibroproliferative reaction is present in the first years after implantation, but vanishes with time. Therefore, serial studies, preferably by MRI, may help to more precisely characterize the donor-reaction to the implanted allograft.


   Appendix A. Conference discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
References
 
Dr J. Oury (Missoula, Montana): We applaud your results and certainly support your conclusions. Out of a total of 250 Rosses that we have done during the past 12 years, we have used the SynerGraft routinely in the past five years whenever available, and our overall rate of explant in the right ventricular outflow tract was approximately 2%. We have had no explants from the SynerGraft in the last five years that we have used that particular conduit. So I think it remains a work in progress, and further time is needed, of course, to definitively look at these results. I have two questions actually.

Do you attempt to oversize the right ventricular outflow tract when possible? I noted that the average size was about 25mm, and our average in our adult series, the average age being 33, the average size of the homograft is 27 or 28mm.

And secondly, do you use any specific drug therapy in order to try to ameliorate the inflammatory reaction in the first three months?

Dr Bechtel: The first question was regarding oversizing. We try to implant the largest possible homograft that would work and that is available. So we routinely took 25mm homografts for the SynerGrafts and conventional homografts.

The second question was regarding specific drug treatment. All our patients receive a course of non-steroidal, anti-phlogistic drugs for three months postoperatively. We are not sure whether this works or not, but we do so.

Dr C. Yankah (Berlin, Germany): The critical areas for calcification of the homografts are the anastomotic site, the main trunk followed by the valve leaflets. My question is; do you use special radiological scoring to grade the calcification in those areas. The scores might give an important information on the progression of the homograft calcification during the follow-up period. The grading of calcification will document wether there is an acceleration or not.

Dr Bechtel: No electronic beam CT was used. The calcium was assessed by visible inspection, not by measurement of calcium scores so far. This is a weakness of the study, but there is no obvious calcification.



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  		Fig. 5. CTA of a conventional allograft. The smallest diameter (arrow) is located very proximal, most likely at the level of the proximal anastomosis. No specific process causing the narrowing is apparent. CTA, computed tomography angiography.

 


   Footnotes
 
☆Presented at the joint 18th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 12th Annual Meeting of the European Society of Thoracic Surgeons, Leipzig, Germany, September 12–15, 2004.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
 References
 

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H. H. Sievers, T. Hanke, U. Stierle, M. F. Bechtel, B. Graf, D. R. Robinson, and D. N. Ross
A Critical Reappraisal of the Ross Operation: Renaissance of the Subcoronary Implantation Technique?
Circulation, July 4, 2006; 114(1_suppl): I-504 - I-511.
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 J. Thorac. Cardiovasc. Surg.Home page
F. Juthier, A. Vincentelli, J. Gaudric, D. Corseaux, O. Fouquet, C. Calet, T. L. Tourneau, V. Soenen, C. Zawadzki, O. Fabre, et al.
Decellularized heart valve as a scaffold for in vivo recellularization: Deleterious effects of granulocyte colony-stimulating factor
J. Thorac. Cardiovasc. Surg., April 1, 2006; 131(4): 843 - 852.
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