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Eur J Cardiothorac Surg 2003;23:1002-1006
© 2003 Elsevier Science NL

Early failure of the tissue engineered porcine heart valve SYNERGRAFT^TM in pediatric patients

^a Department of Cardiothoracic Surgery, AKH-University of Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria
^b Department of Surgery, AKH-University of Vienna, Vienna, Austria
^c Department of Pathology, AKH-University of Vienna, Vienna, Austria
^d Department of Pediatric Cardiology, AKH-University of Vienna, Vienna, Austria

Received 7 November 2002; received in revised form 21 January 2003; accepted 3 February 2003.

^* Corresponding author. Tel.: +43-1-40400-5620; fax: +43-1-40400-5640
e-mail: paul.simon{at}univie.ac.at

	Abstract

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

 
Objectives: The first tissue engineered decellularized porcine heart valve, Synergraft^TM (Cryolife Inc., USA) was introduced in Europe as an alternative to conventional biological valves. This is the first report of the rapid failure of these new grafts in a small series. Materials and methods: In 2001, 2 model 500 and 2 model 700 Synergraft^TM valves were implanted in four male children (age 2.5–11 years) in the right ventricular outflow tract as a root. Two patients had a Ross operation and two had a homograft replacement. Results: The cryopreserved Synergraft^TM valves appeared macroscopically unremarkable at implantation. Recovery from surgery was uneventful and good valve function was demonstrated postoperatively. Three children died, two suddenly with severely degenerated Synergraft^TM valves 6 weeks and 1 year after implantation. The third child died on the 7th day due to Synergraft^TM rupture. Subsequently the fourth graft was explanted prophylactically 2 days after implantation. Macroscopically all four grafts showed severe inflammation starting on the outside (day 2 explant) leading to structural failure (day 7 explant) and severe degeneration of the leaflets and wall (6 weeks and 1 year explant). Histology demonstrated severe foreign body type reaction dominated by neutrophil granulocytes and macrophages in the early explants and a lymphocytic reaction at 1 year. In addition significant calcific deposits were demonstrated at all stages. Surprisingly pre-implant samples of the Synergraft^TM revealed incomplete decellularization and calcific deposits. No cell repopulation of the porcine matrix occurred. Conclusion: The xenogenic collagen matrix of the Synergraft^TM valve elicits a strong inflammatory response in humans which is non-specific early on and is followed by a lymphocyte response. Structural failure or rapid degeneration of the graft occurred within 1 year. Calcific deposits before implantation and incomplete decellularization may indicate manufacturing problems. The porcine Synergraft^TM treated heart valves should not be implanted at this stage and has been stopped.

Key Words: Valve replacement • Congenital heart disease • Bioprosthesis • Tissue engineering • Matrix • Collagen

	1. Introduction

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

 
Currently available heart valve prostheses have major limitations which are mainly related to life-long anticoagulation in mechanical valves and to degeneration in biological prostheses particularly in the young. Homografts are the preferred valve substitute in the reconstruction of the right ventricular outflow tract in children with congenital heart disease. Limited durability, lack of growth and insufficient availability however remain problematic. Other types of conduits for reconstruction of the right ventricular outflow tract have either poor results by comparison to homografts or follow up is still short [1]. A decellularized porcine heart valve substitute was introduced in Europe with CE – mark by Cryolife Inc., USA. Porcine heart valves either aortic composite grafts (model 500) or whole pulmonary roots (model 700) are rendered cell free through a proprietary process – the Synergraft^TM technology. It is hypothesized by the inventors that this will significantly reduce antigenicity and will ideally allow for repopulation of the graft with recipient autologous cells and create a living tissue [2].

In 2001 we have implanted four porcine Synergraft^TM heart valves in children requiring right ventricular outflow tract reconstruction. This is the first report of the rapid failure of these grafts.

	2. Materials and methods

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

 
Four Synergraft^TM heart valves were implanted for reconstruction of the right ventricular outflow tract, two model 500 valves which were the first generation graft produced by Cryolife, Inc. and were constructed from three non-coronary segments of the aortic root. After Synergraft^TM pulmonary roots (model 700) became available we implanted an additional two grafts. The grafts were all shipped cryopreserved as the only means of preservation on dry ice well within the time limits recommended. The company guidelines for the thawing process before implantation were strictly adhered to. Macroscopically all four grafts appeared unremarkable in particular no cracks were seen in the leaflets or the wall of the conduits. In two cases length adjustment of the grafts allowed to obtain Synergraft^TM tissue samples before implantation for later analysis. In addition swaps of the grafts were sent for bacteriology as a standard procedure in all cases.

The details of patient characteristics are shown in Table 1. For patients who received these grafts a suitable pulmonary homograft was either not available from our own bank, international organ banks as well as Cryolife, Inc., or in one case the child had received a homograft in a previous operation with rapid degeneration of the homograft.

	3. Results

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

 
Surgery was uneventful in all patients. Intraoperative and early postoperative echocardiography demonstrated good function of the graft in three patients. In one the graft was not well seen at this point. Recovery from surgery was uncomplicated initially. In particular patients were afebril with no signs of infection. The bacterial swaps taken intraoperatively were negative in all patients.

3.1. Patients are described in chronology of implantation
Patient 1 died 6 weeks after implantation of a model 500 Synergraft^TM due to sudden cardiac death in hospital while awaiting urgent reoperation due to rapidly increasing gradients on echocardiography at the site of the distal anastomosis with deteriorating right ventricular function (Fig. 1C) . The peak Doppler gradient was 18 mmHg at discharge after implantation and increased to 75 mmHg within 1 month. Patient 2 died 1 year after implantation of the second series 500 Synergraft^TM again due to sudden cardiac death on the day of admission for graft replacement. Gradients gradually increased on Doppler echocardiography from a peak gradient 18 mmHg at discharge to 40 mmHg after 6 months and 75 mmHg after 9 months. Moderate pulmonary valve insufficiency developed after 6 months. Right ventricular function was normal on all follow up studies. A suitable pulmonary homograft could never be obtained for this child (Fig. 1D). Patient 3 died on the 7th postoperative day after implantation of a series 700 Synergraft^TM valve before discharge from the hospital due to rupture of the graft at the level of the commissures distant from the proximal or distal anastomosis (Fig. 1B). Explantation of the fourth Synergraft^TM valve was decided upon 2 days after implantation in light of the catastrophic graft failure with rupture (Fig. 1A). This graft was functioning normally without any abnormalities in the postoperative echocardiogram.

View larger version (93K): [in this window] [in a new window]   Fig. 1. Macroscopic findings in order of implant duration. (A) Two day implant: inflammatory changes seen on the outside of the graft only. (B) Seven day implant: severe inflammation mainly on the outside of the graft. The arrow indicates the site of rupture of the SynerGraftTM at the height of the commissures. (C) Six week implant: the conduit is completely covered with a thick fibrous sheath on the outside. On the inside the leaflets are markedly thickened and reddened as a sign of inflammation. There is a perforation of one leaflet cusp. No vegetations are seen. A fibrous ring at the site of the distal anastomosis with the pulmonary artery causes severe stenosis. (D) One year implant: The graft is completely encapsulated with a fibrous sheath on the outside. Starting at the distal suture a fibrous sheath is covering the inside extending down to the level of the commissures. The leaflets are virtually absent.

Histology (Figs. 2A–D) demonstrated a severe foreign body type reaction starting at the outside of the graft with dense neutrophil granulocyte and macrophage reaction in the fibrous sheath around the graft. In addition there was infiltration of the leaflet tissue. Only at the 1 year explant is a lymphocytic cell population seen. The matrix showed signs of significant calcium deposits located in the wall of the conduit but not in the leaflets. Interestingly the two pre-implant samples (Figs. 3A–D) taken from the two model 700 pulmonary Synergraft^TM valves revealed incomplete decellularization with patches of dense cell remnants in the case of graft rupture and significant calcium deposition in the conduit wall of the 2 day explant.

View larger version (79K): [in this window] [in a new window]   Fig. 2. Histologic findings. (A) Two day explant: inflammatory response on the outside of the graft with granulozytes. Within the matrix no cells are seen but multiple calcific deposits. (B) Seven day explant: severe inflammatory response seen on the outside of the graft with granulozytes and macrophages. (C) One year explant: in addition to the inflammatory response on the outside of the graft here already with neoangiogenesis a pseudointima which is disorganized has formed on the inside. Within the matrix calcific deposits are seen. There is no significant repopulation with cells. (D) One year explant: a disorganized thick pseudointimal layer can be demonstrated on the inside of the graft.

View larger version (101K): [in this window] [in a new window]   Fig. 3. Pre-implantation histologic and electron-microscopic findings. Samples of the two model 700 SynerGraftTM heart valves were examined. (A) The collagen structure of the sample is well preserved. (B) There are multiple calcific deposits within the matrix. (C) There is incomplete decellularization as documented by multiple cellular remnants within the matrix. The distribution of these patches with cell residues is irregular indicating uneven penetration and effectiveness of the decellularization process. (D) Electron microscopy demonstrates globular structures with a size of 5–10 µ. The origin and importance of these structures is at this point unclear.

	4. Discussion

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

Why did then the porcine Synergraft^TM valve not perform according to the expectations? We found in our series of four valve explants no signs of cell repopulation or of endothelialization of either the valve leaflets or the conduit wall up to 1 year. Unlike in experimental models it has been consistently impossible to achieve spontaneous post implantation re-endothelialization of prostheses in humans [10]. It is only with techniques of in vitro re-seeding under very controlled circumstances that successful seeding is obtained and pre-seeded grafts are successfully used clinically [11]. In our patients the collagen matrix induced a severe inflammatory response which subsequently led to early development of a thick fibrous sheath both on the inside and outside of the graft. At this point there is no sufficient explanation for this observation since it has been suggested that unlike the xenoantigenic cells of the leaflets the connective tissue of the porcine valve is not antigenic [12,13]. In contrast to the grafts treated with the Synergraft technology Steinhoff et al. [14] found in their experiments that decellularized porcine valve substitutes were not repopulated and contrasted to grafts which were pre-seeded with autologous myofibroblasts and endothelial cells. However they observed thickening of the leaflet after 12 weeks which is hypothesized to indicate excess matrix formation. This does not appear to be the mechanism in our human implants since there is no repopulation of the matrix with cells capable of matrix production. The fibroblasts seem unable to invade the matrix which is instead virtually encapsulated. The time course of changes reminds of the processes of wound healing. Blood contact to the collagen matrix activates a multitude of events which lead to thrombocyte activation, liberation of chemotactic and proliferation stimulating factors and within hours to polymorphnuclear neutrophil granulocyte and macrophage influx. This early inflammatory response may be responsible for significant weakening of the matrix structure of the wall and be the cause of the graft rupture which we experienced. However unlike in wound healing and in the animal studies in which some inflammatory response seems to be present as well [7] in the human implants there was no repopulation of the matrix with significant numbers of fibroblasts and myofibroblasts. Even after a year the matrix was virtually cell free and lined on the inside with a fibrous sheath and multi-layered disorganized pseudo-intima. In essence we observed the formation of fibrous hyperplasia both on the outside of the graft and the inside which caused valve failure. The mechanisms by which the collagen matrix triggers this process needs to be elucidated. There were also calcium deposits seen already before implantation in the conduit wall. We can only speculate that since collagen has in itself calcium binding properties these deposits may accumulate during the production process and form the nucleus for further calcification as was observed in all explants with time dependent increasing intensity.

In conclusion we observed rapid failure of the porcine Synergraft^TM aortic and pulmonary heart valves in a series of four children. Based on our experience we have recommended to stop implantation to the national regulatory board. The commonly used sheep model [15] has failed to predict the failures in humans. We feel that appropriate test models need to be developed to be able to further develop valves based on tissue engineering concepts which still hold great promise.

	Footnotes

 
Presented at the 16th Annual Meeting of the European Association for Cardio-thoracic Surgery, Monte Carlo, Monaco, September 22–25, 2002.

	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): First I would like to congratulate the authors for their courage in bringing these results to our attention, but also caution the authors, as well as all of us in the audience, not to throw out the baby with the bath water, in this case, the Synergraft technology.

In the Ross Registry series, which now numbers over 6000 cases, the Synergraft pulmonary homograft has been utilized in over 1000 cases during the past two and a half years. The explant rate has been less than 1% over this two and a half year period, which attests to at least the limited durability of that process. This is compared to an overall explant ratio of the pulmonary homograft over a 12-year period in the registry of approximately 4%, so at this point at least measures up to the standard pulmonary homograft.

We at our laboratory continue, along with others, as you have mentioned, to explore the possibility of utilizing a heterograft tissue in the tissue engineering lab with an alternative process. This, of course, is the Holy Grail that we are all looking for in terms of an inert matrix populated by host cells. I think this is worth continuing on an experimental basis and again caution that the basic process has certainly stood up to the midterm results as obtained in the registry.

Dr Simon: I totally agree with you. I am well aware of the results with the Synergraft-treated homografts, and that is why I am not against the Synergraft treatment. What I am just saying is we need to understand the difference in the collagen matrix between human tissue and xenograft tissue. That is what we need to understand, and I do not feel that we truly understand that. A lot of groups are pushing forward very much, and I am sure you were at the experimental session yesterday where different groups have shown their results and they are ready to go ahead to put those things into patients.

Dr Oury: I think your word of caution is appropriate. We are presenting elsewhere at this meeting similar results using heterograft tissue in experimental animals, similar in terms of our utilization, but with good midterm data in experimental animals, again, using the heterograft. So I think the interface that you speak of is very, very important to explore and hopefully to solve.

Dr H. Lindberg (Oslo, Norway): We also have implanted some Synergrafts and we had some bad experience. I think it is very courageous to publish these results. We have had to explant three of our ten Synergrafts, three out of 10, but the seven remaining grafts have been followed very closely and are working very nice. In our explants there were no calcium deposits. I would like to ask you, why do you think that not all grafts are ruined by the inflammatory process? Do you have any thoughts about that?

Dr S. Hoerstrup (Zurich, Switzerland): I would like to comment on the definition of tissue engineering concluding from these results. I think it is mandatory to restrain it to the original definition and concept, which is focused on biodegradable materials and autologous cell-seeding of these material. To my mind it is very broad to define the presented type of valves as a tissue engineered valves.

And a short question. Did you have any evidence that there is repopulation of the grafts with human cells?

Dr Simon: No, not in these explants, no, we did not have evidence of any cells going into the matrix.

To the other question from Oslo, I am aware of your implants. I have obviously no explanation why not all of the grafts failed. In our population, all four of them failed. I do not know what would have happened to the prophylactically explanted valve. That was functioning fine on the 2nd day. But after the other one ruptured, we just could not leave it in.

	References

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

 

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