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Ann Thorac Surg 2000;70:1962-1969
© 2000 The Society of Thoracic Surgeons
a CryoLife, Inc, Kennesaw, Georgia, USA
b University of Colorado Health Science Center, Denver, Colorado, USA
c Prince Charles Hospital, Brisbane, Australia
Address reprint requests to Dr Goldstein, CryoLife, Inc, 1655 Roberts Blvd, NW, Kennesaw, GA 30144
e-mail: goldstein.steven{at}cryolife.com
Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000.
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Abstract |
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Methods. SynerGraft porcine heart valves (CryoLife Inc, Kennesaw, GA) were constructed from porcine noncoronary aortic valve cusp units consisting of aorta, noncoronary aortic leaflet, and attached anterior mitral leaflet (AML). After treatment to remove all histologically demonstrable leaflet cells and substantially reduce porcine cell-related immunoreactivity, three valve cusps were matched and sewn to form a symmetrical root utilizing the AML remnants as the inflow conduit. SynerGraft valves were evaluated by in vitro hydrodynamics, and by in vivo implants in the right ventricular outflow tract of weanling sheep for up to 336 days. Cryopreserved allograft valves served as control valves in both in vitro and in vivo evaluations. Valves were also implanted as aortic valve replacements in humans.
Results. In vitro pulsatile flow testing of the SynerGraft porcine valves demonstrated excellent valve function with large effective orifice areas and low gradients equivalent to a normal human aortic valve. Implants in sheep right ventricular outflow tracts showed stable leaflets with up to 80% of matrix recellularization with host fibroblasts and/or myofibroblasts, and with no leaflet calcification over 150 days, and minimal deposition at 336 days. Echocardiography studies showed normal hemodynamic performance during the implantation period. The human implants have proven functional for over 9 months.
Conclusions. A unique heart valve construct has been engineered to achieve the equivalent of an autograft. Short-term durability of these novel implants demonstrates for the first time the possibility of an engineered autograft.
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Introduction |
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Frequently underappreciated is the importance of the lack of cellular viability in such valves. Glutaraldehyde-crosslinked valves are, and remain, nonviable tissues without the opportunity for either tissue renewal or growth, explained by the cytotoxicity of residual aldehydes [6] and the inability of cells to migrate through the fixed, nondegradable matrix. It is clear that the cellular components of the native heart valve leaflet repair and modify the matrix resulting in lifetime durability. Over 20 years of experience with aortic homografts has shown that careful preservation of both matrix and cellular components correlates well with clinical durability. Antibiotic-stored grafts may not have had both matrix and cell integrity preserved, resulting in poor wear characteristics in comparison with cryopreserved homografts. Clearly nonviable homografts sterilized by chemical agents (ß-propiolactone [7]) or physical techniques (freeze drying and irradiation [8]) also demonstrated poor durability. These considerations suggest that a replacement valve design combining a stable leaflet connective tissue matrix with a viable cellular component would be optimal for producing long-term durability.
Additionally, a biologically engineered heart valve should have performance characteristics similar to the natural valve. Glutaraldehyde-crosslinked heart valve leaflets and conduit are markedly stiffened. Associated with the altered biomechanical characteristics are demonstrable changes in leaflet motion, which produce abnormal stress patterns and cause buckling, accelerated calcification, and eventual tissue failure. Fixation also affects the interaction of the leaflet/conduit unit resulting in limited valve orifice opening, which impairs valve performance. The normal aortic valve mechanics minimize leaflet stress during the cardiac cycle, especially as imposed at the commissural posts and leaflet free margins. A substantial advantage in terms of valve performance and durability should be anticipated with the use of non-glutaraldehyde-crosslinked tissue (normal matrix).
To optimize replacement heart valve characteristics, we have developed a decellularized (non-glutaraldehyde-fixed) composite porcine aortic valve. This valve was designed to provide the same leaflet-conduit interaction that allows optimal valvular mechanics and hemodynamics found in the human aortic valve, while at the same time sufficiently reducing the immunologic potential of the porcine valve by removing cellular constituents and soluble proteins. The low immunogenic potential of collagen in tissues is clear [9–11], and an acellular connective tissue matrix was hypothesized to be the basis of a stable replacement valve.
Valve design and performance was first assessed in an in vitro pulsatile flow loop system simulating physiologic aortic flow conditions. The premise of an immunologically neutral matrix was evaluated by using a porcine tissue-based graft in a weanling sheep pulmonary implant model of 5 or more months’ duration. Finally, the valves were implanted as intraaortic or pulmonary valves in human recipients with excellent near-term (9 months) results.
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Material and methods |
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Hydrodynamic testing
Human aortic valves and SHV were sewn into compliant silicone tubes and mounted as intact roots into a modified left heart model pulse duplicator (ViVitro Systems, Victoria, British Columbia, Canada). Flow evaluations were performed using a blood analog at ambient temperature, with system parameters adjusted to obtain standard adult aortic flow conditions (70 cycles per minute, 30% to 40% systolic fraction, nominal aortic pressures of 120/80 mm Hg, with mean aortic pressure of 100 mm Hg). Stroke volume was adjusted to achieve flow rates from 2 to 7 L per minute. A minimum of three test valves of each size and one equivalently sized reference valve were studied under all simulated cardiac outputs.
Aortic and left ventricular and aortic flow rates were digitally collected and averaged over 10 cycles. Additionally, average closure and leakage volumes (per stroke) were collected. High-speed video images of the outflow aspect were obtained (Phantom v.2.0; Vision Research, Wayne, NJ) using capture rates of 200 to 500 frames per second. Mean pressure gradient versus root-mean-square flow rate (Qrms) or simulated cardiac output were calculated and plotted. Effective orifice areas (EOA) were generated for each valve at each flow rate using the modified Gorlin equation, and were averaged to provide a nominal EOA over the range of flow rates investigated. Closure volume and net retrograde flow per cycle were reported for each valve at each flow rate.
Sheep implantation
Preclinical SynerGraft valve performance was evaluated by implantation into the right ventricular outflow tract (RVOT) of nine 4- to 6-month-old female or neutered male weanling Suffolk sheep. The choice of model was based on accessibility of the implant site, its suitability to stentless valve implantation, and studies of bioprosthetic valve performance in similar models recently summarized [13]. All implanted valves measured 19 mm at outer annulus diameter (OD); the internal diameter (ID) was 2 to 3 mm smaller depending on conduit wall thickness. For comparison with standard tissue valves used in pulmonary valve repair and replacement, 2 animals were implanted with a cryopreserved sheep aortic valve of similar annular dimensions. Exposure of the RVOT was obtained via a left thoracotomy, and the grafts were implanted as pulmonary valve conduit replacements.
All animals successfully weaned from bypass underwent open chest echocardiographic assessment of valvular function immediately after implant. At 3 months, and again just before sacrifice at 150 days, a closed chest echocardiogram was obtained with the animals standing. Complete examinations were obtained including four-chamber (two-dimensional [2D] and M-mode) and short-axis (2D and M-mode) views from the right side, short-axis views from the left side, and continuous-wave Doppler of the conduit from the left side. These views provided measurements of all wall thicknesses, chamber volumes, shortening fractions, and peak flow velocities, and allowed detection of any regurgitation. A single animal was evaluated at 150 days, and then allowed to survive until it died at 336 days of non-valve-related causes.
Hemodynamic studies were performed upon conclusion of the implant procedure and on all successful implants with the animal in the left decubitus position just before sacrifice and necropsy. A Swan catheter was passed through the jugular vein into the right heart and pulmonary artery to measure right atrium, right ventricle, pulmonary artery, and pulmonary wedge pressures. The same catheter was used to obtain cardiac output by thermodilution, and after repositioning, to determine transvalvular pulmonary valve gradient. The valve orifice area was determined utilizing a modified Gorlin equation.
All sheep involved in this study received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1985).
Histology/immunohistochemistry
At sacrifice, a portion of each leaflet was submitted for histologic evaluation, while a separate region was equilibrated in 20% sucrose in phosphate-buffered saline for 1 hour at 15°C, then trimmed and frozen in embedding compound (Tissue-Tek O.C.T. Compound, Sakura Finetek U.S.A., Inc, Torrance, CA) for cryosectioning and immunostaining. Antibodies for immunohistochemistry included monoclonal antibody to class II major histocompatibility antigen (H42A; VMRD, Inc, Pullman, WA), monoclonal antibody to fibroblastoid cells (RCV508B; VMRD, Inc), and monoclonal antibody to smooth muscle actin (VMRD, Inc). Specimens were scored on a five-point system (0 = minimal, 5 = high incidence).
Statistics
The significance of differences between treatment groups was evaluated by analysis of variance using the statistical program for the IBM-PC (SPSS for Windows, v. 8.0). Means with differences of p less than 0.05 were judged significant.
Clinical performance
Five patients have been implanted with the SHV at The Prince Charles Hospital, Brisbane, Australia. The study protocol was reviewed and approved by the Hospital Ethics Committee, and Clinical Trail Notification was filed with the Therapeutic Goods Administration of Australia.
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Results |
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In vivo valve performance: sheep RVOT model
Echocardiography
After implantation of the pulmonary valve graft and after weaning from cardiopulmonary bypass, 2D and M-mode ultrasound studies were performed on each animal through the left thoracotomy incision with the transducer placed directly upon the heart and/or great vessels. The long-axis and cross-sectional images of each sheep demonstrated excellent graft leaflet mobility. A 2D cross section of the SynerGraft conduit at the level of the valve demonstrated a valve area range of 1.82 to 3.18 cm2 in 8 sheep. The valve area of the 2 sheep with the control bioprosthesis was 2.09 and 3.57 cm2. These orifice areas were consistent with 15- to 21-mm pulmonary valve sizes and were reasonable for the conduit size implanted in each sheep. Valve orifice size determined by intraoperative ultrasound correlated well with Gorlin’s mathematical calculation of the valve size.
A complete ultrasound examination was performed approximately 3 months after device implant and at the time of valve explant. These ultrasonographic studies were performed with the animal awake and standing. In every instance but two, the sonographically determined orifice size remained correlated to the conduit diameter at the time of implantation. During the ultrasound examination, 22-satisfactory sonographic measurements of the conduit above the graft leaflets were obtained. Peak velocity of pulmonary artery blood flow in these sheep ranged from 1.8 to 2.77 m/s. There was no significant difference between SynerGraft and allograft measurements.
The estimated peak pulmonary artery valve gradient range of the sheep of this study as determined from the interim and preexplant echocardiographic studies was 5 to 25 mm Hg. The intraoperative gradient was lower and ranged from 0.8 to 3.3 mm Hg, as would be expected given the stress and the compromising affects of surgery on cardiac output and the fact that the animals had grown significantly in the interim.
Hemodynamic evaluation
At implantation and at explant, each animal had catheters placed through the left jugular vein into the right heart. Pressures were recorded from the right atrium, right ventricle, and pulmonary artery. Simultaneously, electrocardiography was recorded and cardiac output determined by thermodilution. The heart rate, valve orifice, and peak and mean gradient across the prosthetic heart valve were determined from recorded pressures and flows. The peak gradients measured directly across the bioprosthetic pulmonary valve at the time of implant and explant correlated well with the gradients determined by ultrasound. When measured directly, 2 sheep in the SynerGraft group had a measured gradient of less than 5 mm Hg, and the remaining 5 sheep had gradients between 10 and 19 mm Hg. As shown in Table 1, there was no statistical difference between average peak gradients or valve areas of sheep allograft implants and SynerGraft composite valves at 150 days postimplant. The relatively high gradients may be due to the fact that the animals were indeed growing during this period. Valve areas at 150 days postimplant were also the same.
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Microscopic valve appearance
Figure 2 compares the representative histologic appearance of preimplant SHV and fresh porcine leaflets showing the effective removal of virtually all histologically evident cells (fibroblast, myofibroblast, and endothelial). After implantation, there was a reappearance of cells within the SHV leaflets. At the earlier explant time (150 days), cells were found mainly toward the base of the leaflets near the aortic wall. After 336 days, there was a more widespread distribution of cells, with cellular elements found 60% to 80% of the distance to the free margin of the leaflets. The density of cells after 336 days resembled that of the fresh leaflet tissue.
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Comment |
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The present studies expand the previous successes in creating a cell-conductive matrix that generates a viable valve via the in-growth of host cells. In our sheep model, we have shown a progressive recellularization of the porcine leaflet matrix. With time, this recellularization takes on the character of interstitial cells present in the native leaflet, with fibroblasts and myofibroblasts as the predominant cell phenotypes present. A small complement of inflammatory cells present in the 150 explant leaflets had disappeared by the 336-day time point, suggesting that an early phase of remodeling had been completed by the later time.
The histological findings with the decellularized SHV contrast with those of cryopreserved allograft tissues used as controls. Though cellular at implantation, the explanted allograft leaflets contained only narrow cellular areas near the leaflet base and along the leaflet margins (Fig 3). Because the grafts were allogeneic, it was impossible within this study to assess whether the cells originated in the implant or from the recipient. The cell numbers and distribution appeared to be following the pattern observed with human allograft valve implants as reported by Mitchell and associates [17] and Armiger [18], who report a steady decline in the cellularity of cryopreserved allografts eventually leaving a cell-free, but structurally intact, matrix. These findings imply that the cryopreserved allograft matrix is not cell conductive.
A viable cell complement is vital to the turnover of extracellular matrix components of the leaflet [19]. The relevant cells have been identified as having characteristics of fibroblasts [20] or myofibroblasts [21] with respect to their synthesis of fibrillar collagens and/or smooth muscle actin. The synthesis of types I, III, and V collagen is considered most important to the long-term durability of the leaflets, whereas the participation of these interstitial cells in the moment-to-moment contractile function of the leaflets remains speculative [20]. Myofibroblasts also participate in wound healing, providing contraction or retraction phases of tissue remodeling [22]. Thus, it is expected that the cells of the repopulated leaflets would contain cells having characteristics of smooth muscle cells (Fig 5) as well as fibroblasts. Through immunohistochemical staining, actin-positive cells were typically found in the leaflet spongiosa, representative of normal leaflet hierarchy. At 150 days, a small complement of inflammatory cells were still present in the leaflets, making it difficult to specify either a functional (contractile) role for these cells, or a matrix remodeling role from a porcine to sheep collagenous base. However, it is important to note that smooth muscle cells are a part of the cell complement of normal heart valve leaflets, and the implanted SynerGraft matrix was able to serve as the scaffold for in vivo recellularization with appropriate cell phenotypes.
The SynerGraft porcine heart valve design incorporates several attributes of human aortic heart valves that confer optimal functionality and performance. Among these are leaflet symmetry, native leaflet-conduit-sinus geometry, and natural tissue biomechanics. The principal focus of the in vitro hydrodynamic studies was to demonstrate the integrity of the valve design. In these investigations, SynerGraft porcine heart valves viewed under aortic pulsatile parameters using high-speed digital video recordings showed excellent leaflet symmetry and valve function under all flow rates evaluated. Leaflet motion upon opening was even and smooth, with full leaflet retraction to yield a large flow orifice. Dilation of the conduit was noted, resulting in leaflet-free margin tensioning. Valves closed symmetrically showing no significant central insufficiency or retrograde flow and a smooth regular coaptive margin. In each instance, leaflet behavior was shown to be analogous to that found with human aortic valves. In contrast, stented fixed porcine valves showed no systolic annular dilation and thus a restricted flow orifice, often with asymmetric leaflet motion and significant folding of the free margin during maximal ejection.
Pressure gradients for SynerGraft porcine heart valves were substantially lower than the same clinically sized stented bioprosthetic heart valves (eg, 19-mm SHV and a 19-mm stented porcine heart valve) over all flow rates tested. The measured gradients for the SHVs, and thus their calculated effective orifice areas, were statistically indistinguishable from similar clinically sized human aortic heart valves. Calculated EOA (modified Gorlin equation) yielded values of 2.52 and 2.40 cm2 for the 19-mm OD/16-mm ID SynerGraft and 16-mm ID human aortic valves, respectively. Under similar flow conditions, the calculated EOA for a 19-mm Hancock MO (model 250) stented porcine valve was found to be 1.41 cm2. The ability of the compliant SHV to respond to changing pressures of the cardiac cycle results in normal valvular function and flow efficiency equal to the native aortic valve. For larger sized SHVs and human aortic valves (annular diameters 23 mm and greater), mean pressure gradients were very low, often below 5 mm Hg, at simulated cardiac outputs of 6 L/min and above. The similarities in tissue mechanics and valve geometry between the SHVs and native human aortic valves resulted in this close matching of the measured hydrodynamic performance.
Typical of all trileaflet tissue valves, retrograde flow fractions of the SHVs evaluated were small, generally less than 5% of the forward flow volume, and were independent of cardiac output. All regurgitation was attributable to closure of the valve mechanism, with no measurable leakage through the closed valve or through the SHV conduit construction suture lines. As expected, closure volumes increased modestly as the valve size increased. Variations in cardiac output or cycle rate did not significantly affect closure volumes or leakage for a given valve size. Regurgitant flow parameters for the SHVs were similar to size-matched human aortic valves. Based on these hydrodynamic findings, we concluded that the design of the SHV produces performance characteristics indistinguishable from normal human aortic valves.
The weanling sheep have proven to be an excellent model for evaluation of candidate heart valves, and its relevance to valve implantation in humans is well understood [23]. Cuspal calcification is a major cause of glutaraldehyde-crosslinked valve failure in humans, and this leaflet pathology can be demonstrated even after short-term (3-month) implants of typical fixed bioprostheses. We previously reported that the SHV leaflet undergoes no calcification over 5 months of implantation [12]. Therefore, we anticipate that valve performance similar to that shown for the SHV in this study will be replicated in human surgery. The short-term clinical experience of this valve in human patients (Table 2) lends credibility to this assertion.
In summary, animal connective tissue can be made nonimmunogenic, and thus acceptable for xenografting, by means other than chemical crosslinking. As shown in this report, the residual connective tissue matrix is stable in two xenogeneic species. This stability is not gained at the cost of creating a crosslinked matrix into which cells cannot migrate. We found that the acellular matrix supports recellularization with interstitial cells that apparently are capable of remodeling the implant. When chemical fixation is avoided, the natural biomechanical properties of the tissue are retained, thus enabling construction of a composite valve with human aortic valve-like properties. In total, these features demonstrate significant progress toward the engineering of an ideal tissue-based replacement heart valve. The SynerGraft valve is nonthrombogenic, nonhemolytic, has excellent performance characteristics, and repopulates in vivo to create a viable matrix. As a result, this valve design provides the greatest opportunity to clinically demonstrate extended durability and growth, two characteristics long sought after in replacement heart valves.
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Acknowledgments |
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This work was supported, in part, by grant number IR44HL53088-02 from the National Institutes of Health to CryoLife, Inc.
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Discussion |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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DR CLARKE: Well, I think in order for the durability to be maintained, that has to be replenished over time. I also think that we still have some problems to deal with, particularly in the aortic conduit. The leaflets seem to be doing extremely well, however, there was some slight calcification in the conduits. It was not nearly as much as in the wall of the homograft conduit, however.
DR AXEL HAVERICH (Hannover, Germany): You may know that we follow a similar concept in our laboratory, with the exception that we try to recellularize those porcine matrices ex vivo prior to implantation. We feel this might be the better approach because we have full endothelialization of the graft at the time of implantation. My questions for you would be: Did you see full reendothelialization of the grafts in all anatomical aspects at the time of explantation long term, and did you see calcification of the matrix or the valve leaflets in your long-term implants? Thank you.
DR CLARKE: In answer to your first question, no, we did not see extensive endothelialization. The cells were identified as almost exclusively fibroblasts and smooth muscle cells. In terms of calcification, there was absolutely no calcification observed in the leaflet portion of the graft at all. The only calcification that was observed was in the aortic wall, and this calcification, as I mentioned, was significantly less than the calcification in the corresponding controls.
DR RICHARD D. WEISEL (Toronto, Canada): This is truly a remarkable way of approaching things. Have you tried the valve in the immature sheep to see if it does in fact grow?
DR CLARKE: These were weanling sheep, and, as a matter of fact, there is some evidence that in this model they did not really grow since the gradients increase, and that may be because the valve did not increase in size as the animal grew.
DR WEISEL: Did you see any clots in the valves at all?
DR CLARKE: The only one that clotted was the 77-day death, which probably clotted as a result of a fungal infection at the time of surgery, and it had a thrombosis in the conduit, but there was no evidence of thrombosis in any of the others.
DR WEISEL: Do you think there will be endothelialization eventually?
DR CLARKE: I do not know the answer to that. It is certainly possible.
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