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Ann Thorac Surg 2002;74:1438-1442
© 2002 The Society of Thoracic Surgeons

Original article: cardiovascular

Ross operation with a tissue-engineered heart valve

Pascal M. Dohmen, MDa*, Alexander Lembcke, MDb, Holger Hotz, MDa, Dietmar Kivelitz, MDb, Wolfgang F. Konertz, MD, PhDa

a Department of Cardiovascular Surgery, Berlin, Germany
b Department of Radiology, Charité, Humboldt University Berlin, Berlin, Germany

Accepted for publication June 7, 2002.

* Address reprint requests to Dr Dohmen, Department of Cardiovascular Surgery, Charité, Humboldt University Berlin, Schumannstrasse 20/21, D-10117 Berlin, Germany
e-mail: pascal.dohmen{at}charite.de


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. The Ross procedure has gained increasing acceptance due to excellent hemodynamic results by replacing the diseased aortic valve with the viable autologous pulmonary valve. Consequently, the right ventricular outflow tract (RVOT) has to be reconstructed. In this report a viable heart valve was created from decellularized cryopreserved pulmonary allograft that was seeded with viable autologous vascular endothelial cells (AVEC).

Methods. A 43-year-old patient suffering from aortic valve stenosis underwent a Ross operation on May 20, 2000, using a tissue engineered (TE) pulmonary allograft to reconstruct the RVOT. Four weeks before the operation a piece of forearm vein was harvested to separate, culture, and characterize AVEC. Follow-up was completed at discharge, 3, 6, and 12 months postoperatively by clinical evaluation, transthoracic echocardiography (TTE), and magnetic resonance imaging (MRI). Additionally, at 1-year follow-up a multislice computed tomographic scan was performed.

Results. After four weeks of culturing 8.34x106 AVEC were available to seed a 27-mm decellularized pulmonary allograft. Trypan blue staining confirmed 96.0% viability. Reendothelialization rate after seeding was 9.0x105 cells/cm2. TTE and MRI revealed excellent hemodynamic function of the TE heart valve and the neoaortic valve as well. Multislice computed tomography revealed no evidence of valvular calcification.

Conclusions. After 1 year of follow-up the patient is in excellent condition without limitation and exhibits normal aortic and pulmonary valve function.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Today’s biologic heart valves are far from optimal: gluteraldehyde preserved bioprostheses undergo degeneration due to their nonviable structure [1], while allografts, cryopreserved or fresh, are at risk for immunologic destruction [2]. Tissue engineered heart valves constructed from a matrix covered with autologous vascular endothelial cells (AVEC), are believed to have potential to overcome these obstacles without losing the excellent hemodynamics properties of biologic heart valves.

Extensive in vitro and in vivo investigations were performed [3] to prove the potential benefits of these new

generation heart valves after decellularization. Mechanical strength was maintained, and calcification and thrombogenicity have been proven to be absent after seeding with AVEC. At 3 months of implantation fibroblast ingrowth could be verified in the juvenile sheep model [4, 5]. Persistence of AVEC has been proven and their characterization as viable, fully functioning endothelium was performed.

With a clinical experience of more than 5 years with cell-seeded small caliber grafts for coronary artery revascularization [6], a trial to implant tissue engineered (TE) pulmonary valves during Ross procedures was started. This study reports the first clinical case of a tissue engineered heart valve to reconstruct the right ventricular outflow tract (RVOT).


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
After having obtained institutional review board approval and informed consent, the first implantation of a TE heart valve into a patient was performed on May 20, 2000. The matrix used to seed autologous viable endothelial cells was a commercially available cryopreserved pulmonary allograft.

Isolation and cultivation of autologous vascular endothelial cell
Four weeks preoperatively, 200 mL of blood was taken from the patient. A segment of a left forearm vein, 10 cm in length, was harvested under plexus anesthesia. The vein was cannulated at both sides, while the side branches were ligated. At the tissue laboratory the vein was carefully rinsed with DelBecco’s modified Eagle’s Medium (DMEM; Sigma Chemical Co, St. Louis, MO) and antibiotics (penicillin 100 U/mL, streptomycin 100 µg/mL; Sigma Chemical Co). Only AVECs were harvested by the use of Collagenase II 0.1% (Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT) for 10 minutes at 37°C. The AVEC and Collagenase solution was collected and centrifuged at 500g for 10 minutes. The AVEC were then seeded in 25 cm2 culture bottles (Falcon, Becton-Dickinson Labware, Mountain View, CA) with DMEM, 10 µg/mL basic fibroblast growth factor (Boehringer Ingelheim Pharmaceuticals, Inc), 10% of autologous serum, 100 U/mL penicillin and 100 µg/mL streptomycin in a humidified incubator (37°C, 5% CO2, and 98% air saturation). AVEC growth was evaluated by daily microscopical examination and after there was a confluent monolayer of AVEC seen, there was a passage performed until two culture bottles of 175 cm2 were fully seeded. Medium was changed every other day.

Decellularization of a cryopreserved pulmonary allograft
One week before implantation, a cryopreserved pulmonary allograft was shipped to the tissue laboratory. The pulmonary allograft was thawed according to instructions. Care was taken during this time with manipulations to avoid tissue destruction resulting in wall fracture or leaflet rupture. Then the valve was taken out of the bag and gross examination of the allograft was done. Fine dissection was performed to remove fat tissue as well as trimming of the muscle part at a minimum to allow for implantation without any further dissection. Additionally the allograft was sized and underwent a competence test. The tissue valve was decellularized by 1% deoxycholic acid (Sigma Chemical Co) at 37°C, followed by an extensive rinsing period in normal saline. The decellularized valve matrix (Fig 1) was stored in Hanks solution with antibiotics (penicillin 100 U/mL, Streptomycin 100 µg/mL). After the decellularization procedure was completed a second evaluation of the matrices was performed as well as resizing.



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  		Fig 1. A decellularized heart valve is illustrated. The collagen structure reveals no changes due to the deoxycholic acid treatment. Notice that not only all of the interstitial cells are eliminated but also no endothelial cells are seen any longer (Hematoxylin & eosin, x50).

 
Preparation of the tE heart valve
After a sufficient number of AVECs were available, seeding of the decellularized cryopreserved pulmonary allograft was performed. The acellular matrix was coated with Pronectine F (PAA Laboratories GmbH, Coelbe, Germany) over a period of 3 hours at 37°C. After this period the coated acellularized matrix was mounted into a special developed bioreactor (Fig 2) by two continuous suture lines using a no touch technique. The prepared AVEC suspension was given into the bioreactor, which was filled up with medium and deaired. The seeding procedure takes around 4 hours, using a sedimentation technique [7].



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  		Fig 2. The bioreactor is a transparent device with the valve attached to both ends for seeding.

 
Verification and quality control of the seeded tissue- engineered heart valve
To verify the cultured cells were free of contamination by interstitial cells, von Willebrandt factor staining was performed of the cell culture, just before seeding the graft. As the bioreactor was build by a bioinhenert material, AVEC bound only the coated decellularized matrix. The number of the cells binding at the matrix could be counted as the number of cells given into the bioreactor minus the cells which come out. Furthermore there were samples taken from the pulmonary wall matrix and examined by microscopy. Hematoxylin-Eosin staining of the wall was performed and kept as a document.

Case report
In March 2000, a 43-year-old man presented at our hospital with exceptional angina. At that time the NYHA classification was II. Clinical examination revealed a regular sinus rhythm of 85 beats per minute, blood pressure of 135/70 mm Hg in both arms. Parasternal and holosystolic 3/6 murmur could be heard. Abdominal findings were normal. His medical history revealed only pneumonia in 1970. Laboratory measurements were in normal ranges. Transthoracic echocardiography (TTE) illustrated a heavily calcified aortic valve and hemodynamic evaluation are reported in Table 1. Cardiac catheterization revealed an aortic valve surface area of 0.83 cm2, mean transvalvular pressure gradient of 45 mm Hg, left ventricular hypertrophy and left ventricular ejection fraction of 52%. There was no evidence of coronary heart disease. Magnetic resonance imaging was preoperatively performed to evaluated hemodynamic function and morphology of the native pulmonary heart valve.


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  		Table 1. Hemodynamic Evaluation of the Valve Function as Well as the Heart Function

 
Surgical technique
The Ross procedure has been described in detail [8] previously. On May 20, 2000, standard cannulation was used with normothermic cardiopulmonary. Cardiac arrest was performed with antegrade warm blood cardioplegia. The heavily calcified aortic valve was excised (Fig 3) and the aortic annulus was carefully decalcified. The native pulmonary heart valve was dissected free. The 27-mm TE heart valve was implanted into the RVOT using two running sutures in a no-touch technique. The native pulmonary heart valve was implanted into the aortic position using the modified subcoronary implantation technique. Both anastomoses were performed with a running suture. Aortic clamp-time was 99 minutes and total time on bypass was 123 minutes. Postoperatively, standard institutional care was given. Anticoagulation was performed for only three days with heparin.



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  		Fig 3. The heavily calcified aortic heart valve of the patient.

 
Follow-Up
For this patient who underwent a Ross procedure with RVOT reconstruction using a TE heart valve we performed close clinical evaluation up to discharge and thereafter. Hemodynamic evaluation was performed at discharge, 3, 6, and 12 months using TTE and MRI. MRI was performed to follow the valve morphology after implantation. The follow-up was then performed yearly and multislice computed tomography was performed to find out if there were any calcifications detectable at 1 year follow-up.

Clinical evaluation
The clinical evaluation was performed to detect if there was any evidence for immunologic activation, a leucocytosis, increasing of C-reactive protein or elevated temperatures during the first 2 weeks after the operation.

Transthoracic echocardiography
Transthoracic echocardiography was performed with a Hewlett Packard Sonos 5500 (Sunnyvale, CA) with a 2.5-MHz probe. During each echocardiographic examination, valve insufficiency was graded with color Doppler flow. The regurgitation of the pulmonary and aortic valve was measured by the length and the width of the jet into the right or left ventricular outflow tract. The gradation was 0 (none), 1+ (trace), 2+ (mild), 3+ (moderate), and 4+ (severe) for both heart valves. The maximum aortic and pulmonary flow velocities (AV max, PV max) were measured with continuous wave Doppler (normal: AV max = 1.0 to 1.8 m/s; PV max = 0.6 to 0.9 m/s). Pulse-wave Doppler was used for localization of the gradient drop between the RVOT and the TE heart valve and the LVOT and the neo-aortic heart valve.

Magnetic resonance imaging
MRI was performed with a 1.5 T scanner (Magnetom VISION; Siemens, Erlangen, Germany) and phased-array body coil for morphologic control of the TE heart valve at follow-up and to evaluate the right ventricular heart function. The patient was studied in the supine position, using a short- and long-axis cine MRI with an electrocardiographic triggering two-dimensional cine fast low-angle shot sequence with a slice thickness of 10 and 5 mm, respectively, without interslice gaps. The examination always started with breath-hold at the end-expiratory position. All examinations were completed within 45 to 60 minutes without complications.

Multislice computed tomography
Multislice computed tomography was performed with the Toshiba, Aquilion device (Toyko, Japan). A standard protocol for cardiac evaluation was used. The patient was again studied in the supine position, using an electrocardiographic triggering to indicate the R-R intervals with ca. 75 till 150 ms Zeitliche Auflösung depending about the heart frequency. The duration of the scanning phase was 30 to 45 seconds/breath-hold, using intravenous Ultravist 370 with a flow of 3 mL/s. The slice thickness is 1.0 mm.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Isolation and cultivation of autologous vascular endothelial cells
EC were cultured for 4 weeks in DMEM with 20% of patient serum and bFGF 10 µg/mL in a humidified incubator (37°C, 5% CO2 and 98% air saturation). DMEM was changed every second day and endothelial cell growth was evaluated by daily microscopical examination. After the third passage 8.34x106 endothelial cells were available, which was considered to be sufficient to cover a 27-mm heart valve. Trypan blue staining was used to test endothelial cells viability, which was 96% or 8.01x106 endothelial cells. The reendothelialization with the AVEC (Fig 4) in the bioreactor gave a density of 9.0x105 cells/cm2 after a duration 4 hours.



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  		Fig 4. Endothelial cell seeding of the tissue-engineered heart valve. At the inner surface, the specimen from the distal part of the pulmonary artery reveals a confluent endothelial cell layer covering the acellular matrix (Hematoxylin & eosin, x50).

 
Clinical evaluation
Leukocytes were between 9.180 and 15.200 cells/nL, C-reactive protein of 0.35 and 6.8 mg/dL, and maximum temperature of 37.4°C during the postoperative period.

Transthoracic echocardiography
The TTE revealed a well functioning neo aortic heart valve with a minimal mean pressure gradient at discharge and this continuous during the further follow-up (Table 1). There was no regurgitation seen of the neo aortic heart valve during the follow-up period. The left ventricular end diastolic diameter was reduced during the follow-up from initially 5.7 cm to 5.1 cm at 1-year follow-up. The TE heart at the RVOT demonstrated, from the beginning, a trivial central regurgitation that did not change during the time. The mean pressure gradient of the pulmonary heart valve was minimal of 1.6 mm Hg, which stayed stable up to 1 year.

Magnetic resonance imaging
Magnetic resonance imaging revealed a left ventricular mass reduction during the follow-up, starting immediately during the early postoperative period (Table 1). MRI supported the findings of the TTE as the aortic flow velocity decreased and remained stable during the follow-up period. MRI investigation demonstrated an easy access of the RVOT and the heart valve at this position which is less investigator depending (Fig 5).



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  		Fig 5. Magnetic resonance imaging of the tissue-engineered heart valve (1) with a measurement of the flow velocity at this heart valve.

 
Multislice computed tomography
Multislice computed tomography revealed no calcifications on both heart valves. Furthermore this investigation method revealed a normal functioning heart valve, demonstrating smoothly moving leaflets without any retraction and excellent leaflet (Fig 6).



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  		Fig 6. Multislice computed tomography of the tissue-engineered heart valve, which is fully open at this time and illustrates no calcification at any part of the heart valve.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
Preclinical results of this new generation of valve prostheses, which has been reported to be a living structure with potential for regeneration, exhibited excellent hemodynamics and no calcification in the juvenile sheep after 3 and 6 months. In the animal studies a confluent endothelium with regenerative potential could be seen on the inner surface of the valve [5].

Replacement of the pulmonary valve during the Ross operation can be performed with allografts [8] or xenografts [9]. Allografts may be targets to immunologic attack and may consequently fail. In fact most repeat surgery after the Ross operation are replacements of the pulmonary allograft due to calcification and degeneration [10]. In contrast to most other patients after allograft implantation this patient demonstrated no fever during his entire postoperative course. This may be a clue towards lacking antigenicity of this construct. As the matrix is completely acellular and no HLA antigen presenting cells are transmitted. The optimal matrix for TE heart valves, however, may be porcine valves, as they are relatively easy to obtain and cheap. Due to concern with transmission of porcine retrovirus into human, we used a human heart valve as a matrix at this time.

To the best of our knowledge, this study examined the first clinical case with implantation of a tissue-engineered heart valve.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

  1. Flameng W.J., Ozaki S., Yperman J., Herijgers P., Meuris B., Van Lommel A., Verbeken E. Calcification characteristics of porcine stented valves in a juvenile sheep model. Ann Thorac Surg 2001;71:S401-S405.[Abstract/Free Full Text]
  2. Oei F.B., Stegmann A.P., Vaessen L.M., Marquet R.L., Weimar W., Borgers A.J. Immunological aspects of fresh and cryopreserved aortic valve transplantation in rats. Ann Thorac Surg 2001;71:S379-S384.[Abstract/Free Full Text]
  3. Dohmen P.M., Meuris B., Flameng W., Konertz W. Influence of ischemic time and temperature on endothelial cell growth after transport. Int J Artif Organs 2001;24:281-285.[Medline]
  4. Dohmen P.M., Ozaki S., Yperman J., Flameng W., Konertz W. Lack of calcification of tissue engineered auto-xenografts in juvenile sheep. Semin Thorac Cardiovasc Surg 2001;13(Suppl. I):93-98.[Medline]
  5. Dohmen P.M., Ozaki S., Verbeken E., Yperman J., Flameng W., Konertz W. Tissue engineering of a pulmonary xenograft heart valve. Asian Cardiovasc Thoracic Surg 2002;10:25-30.
  6. Konertz W., Koch C., Dohmen P.M., Laube H., Rutsch W. Five year follow up of patients receiving tissue engineered coronary artery bypass grafts. Circulation 2001;104(Suppl II):362.
  7. Dohmen P.M., Stein-Konertz M., Erdbruegger W., Konertz W. A new pulsatile bioreactor for in vitro seeding and conditioning endothelial cells in tissue engineered heart valves. Int J Artif Organs 2001;24:558.
  8. Ross D.N. Technique of aortic valve replacement with a homograft: orthotopic replacement. Ann Thorac Surg 1991;52:154-156.[Abstract]
  9. Dohmen P.M., Hotz H., Lembcke A., Kivelitz D., Hamm B., Konertz W. Magnetic resonance imaging (MRI) of stentless xenografts for RVOT reconstruction during the Ross procedure. Semin Thorac Cardiovasc Surg 2001;13(Suppl I):24-27.[Medline]
  10. Carr-White G.S., Kilner P.J., Hon J.K., Rutledge T., Edwards S., Burman E.D., Pennell D.J., Yacoub M.H. Incidence, location, pathology, and significance of pulmonary homograft stenosis after Ross operation. Circulation 2001;104(Suppl I):8-16.



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