Ann Thorac Surg 2005;80:1610-1614
© 2005 The Society of Thoracic Surgeons
Original article: Cardiovascular
Superior Durability of Synergraft Pulmonary Allografts Compared With Standard Cryopreserved Allografts
Zarry Tavakkol, MD
a
,
Sarah Gelehrter, MD
b
,
Caren S. Goldberg, MD, MS
b
,
Edward L. Bove, MD
c
,
Eric J. Devaney, MD
c
,
Richard G. Ohye, MD
c
,
*
a Department of Surgery, University of Washington, Seattle, Washington
b Department of Pediatrics and Communicable Diseases, Ann Arbor, Michigan, USA
c Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan
Accepted for publication April 6, 2005.
* Address correspondence to Dr Ohye, F7830 Mott/0223, 1500 East Medical Center Dr, Ann Arbor, MI 48109 (Email: ohye{at}umich.edu).
Presented at the Poster Session of the Forty-first Annual Meeting of The Society of Thoracic Surgeons, Tampa, FL, Jan 24–26, 2005.
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Abstract
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BACKGROUND: The ideal pulmonary valve replacement for children and adolescents remains elusive. Although favored by many surgeons, the cryopreserved pulmonary allograft tends to become rapidly incompetent and elicits an immune response. The SynerGraft process (Cryolife Inc, Kennesaw, GA) decellularizes a pulmonary allograft, leaving a scaffold of connective tissue. These grafts have been shown to decrease immune reactivity and become populated with host cells. Although theoretically these traits may improve durability, few data comparing SynerGraft-processed allografts (SynAs) (Cryolife Inc) with standard cryopreserved allografts are available.
METHODS: A single institution review was performed for all SynAs implanted from their introduction in 2001 to January 2003. Twenty-six patients with SynAs and 26 age and diagnosis-matched controls receiving cryopreserved allografts were evaluated. Subjects were analyzed for demographics, survival, reintervention, and echocardiographic findings.
RESULTS: There were no significant differences between groups in age, weight, valve diameter, orthotopic and heterotopic allograft position, or follow-up. On echocardiogram there was no difference in initial degree of allograft insufficiency or gradient. However, at mean follow-up of 19 ± 13 months, SynAs were significantly less regurgitant than cryopreserved allografts (p = 0.017). Although all gradients were low, a significant difference between SynAs (7.6 ± 14 mm Hg) and cryopreserved allografts (14.6 ± 15.6 mm Hg; p = 0.012) had emerged. Survival was identical at 85% (22 of 26). Rates of reintervention were similar at 7% (2 of 26) for cryopreserved allografts and 3.8% (1 of 26) for SynAs (p = 0.98).
CONCLUSIONS: At intermediate follow-up, the SynA demonstrated greater durability with less insufficiency and lower gradients. These characteristics are important to many patients with complex congenital heart disease; however, long-term effects on survival and reintervention remain unknown.
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Introduction
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The ideal conduit for replacement of the pulmonary artery and valve remains elusive, particularly for the child or young adult. A prosthesis that achieves the characteristics of durability, ease of implantation, availability readiness in small sizes, freedom from the need for anticoagulation, limited antigenicity, low risk of thromboembolic complications, and growth potential remains to be realized. The currently available options may have strengths in some areas that are offset by disadvantages in others.
Many congenital heart surgeons favor cryopreserved pulmonary allografts for reconstruction of the pulmonary outflow tract in children and adults [1–5]. As with all the options for reconstruction of the right ventricular outflow tract, the cryopreserved pulmonary allograft has advantages and disadvantages. The favorable tissue handling characteristics and small sizes of cryopreserved pulmonary allografts are balanced by their limited availability and tendency toward early incompetence [6–8]. Cryopreserved pulmonary allografts also elicit a host immune response. This immune system activation appears to be at least partially responsible for the limited durability of the allografts [8–11]. In addition, congenital heart disease is one of the most common indications for cardiac transplantation in childhood, and the development of antibodies limits the potential donor pool [12].
To address these disadvantages inherent in cryopreserved pulmonary allografts, CryoLife Inc (Kennesaw, GA) developed the SynerGraft process that reduces the cellularity of the allografts, leaving an intact extracellular scaffold (Fig 1) [13]. The resulting valved conduit (CryoValve SG [CryoLife, Inc]) is then cryopreserved using a proprietary freezing method [14]. Although the SynerGraft process may theoretically improve durability, few data are available comparing the CryoValve SG (CryoLife Inc) with the standard cryopreserved pulmonary allograft. The standard grafts from CryoLife are preserved in the same manner as the CyroValve SG allografts (CryoLife Inc), with the exception of the decellularizing process.
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Patients and Methods
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A retrospective, single institution review of the patients receiving a CryoValve SG (CryoLife Inc) pulmonary allograft from their introduction in 2001 to January 2003 was conducted. After obtaining Institutional Review Board approval, data were reviewed for 26 patients with CryoValve SG valves (CryoLife Inc) implanted in the pulmonary outflow tract and 26 contemporary controls who received standard cryopreserved pulmonary allografts. Controls were case matched first by age in an attempt to achieve a cohort similar in immunologic maturity and allograft diameter. The second discriminator used (when more than 1 patient of a similar age was available) was whether the allograft was placed in a heterotopic or orthotopic position. Data were collected through review of patient charts and operative reports regarding patient demographics (sex, age, height, and weight), pulmonary allograft size, patient factors (allograft position, previous valve replacement), and operative procedure. Other factors that were reviewed included length of follow-up, valve function immediately after the operation, and at the time of the last follow-up, as well as postoperative complications and mortality. No histologic evaluations of explanted allografts were available in this retrospective study. No attempt was made at blood group matching, and no immunosuppression was used in either group.
Valve function was evaluated by a single echocardiographer who was blinded to the type of valve being evaluated who reviewed postoperative and follow-up echocardiograms. These echocardiograms were assessed for degree of pulmonary stenosis by measurement of Doppler peak instantaneous pressure gradient. Pulmonary insufficiency grades were assigned according to a subjective scale of 0 to 4, in which 0 = none, 1 = trivial, 2 = mild, 3 = moderate, and 4 = severe/free.
Normally distributed data are expressed as mean ± standard deviation and non-normal data as median (range). Student's t tests were applied to normally distributed, continuous variables, such as valve gradient at last follow-up. Non-normal continuous variables, such as degree of pulmonary insufficiency, were analyzed by the Wilcoxon rank list. Time to event data are expressed by Kaplan-Meier curves and were subjected to log-rank testing.
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Results
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The CryoValve SG allograft (CryoLife Inc) and standard cryopreserved allograft groups had no significant differences in patient age, weight, diameter of the valve used, orthotopic versus heterotopic position of the allograft, or time of follow-up (Table 1; Fig 1). At the discharge echocardiographic evaluation, both allograft types revealed no difference in the degree of valve insufficiency between the two groups, with the CryoValve SG allografts (CryoLife Inc) and standard cryopreserved allografts both demonstrating a median degree of pulmonary insufficiency of 1+ (ranges, 0 to 3+ and 0 to 2+, respectively; p = 0.35) (Table 2). Median gradient postoperatively was also similar for the CryoValve SG allografts (CryoLife Inc) (0 mm Hg; range, 0 to 15 mm Hg) and the standard cryopreserved allografts (0 mm Hg; range, 0 to 0 mm Hg) (Table 2).
However, at a mean follow-up of 19 ± 14 months, the median degree of insufficiency of the CryoValve SG valves (CryoLife Inc) was significantly less than that of the standard grafts. The CryoValve SG valve (CryoLife Inc) median degree of pulmonary insufficiency was 1+ (range, 0 to 4+), whereas the standard valve median degree of pulmonary insufficiency was 3+ (range, 0 to 4+; p = 0.017) (Table 2). In addition, although all the gradients were low, a significant difference in valve gradient between the two groups (CryoValve SG [CryoLife Inc], 7.6 ± 14 mm Hg vs standard valve, 14.6 ± 15.6 mm Hg; p = 0.012) had already developed (Table 2).
The frequency of reintervention was similar between the two groups (CryoValve SG [CryoLife Inc], 3.8% [1 of 26] vs standard, 7.7% [2 of 26]; p = 0.98) (Fig 2). One patient in the CryoValve SG (CryoLife Inc) cohort required reintervention. The patient who had undergone a neonatal complete repair for truncus arteriosus and discontinuous pulmonary arteries with a 9-mm CryoValve SG (CryoLife Inc) (patient weight, 2.5 kg) had bilateral branch pulmonary artery stenoses develop at 9 months post-procedure. The patient underwent patch augmentation of the branch pulmonary arteries and conduit upsizing, although the conduit gradient was 0 mmHg and the degree of insufficiency was 1+ at the time of reoperation. Two patients required reintervention in the standard cryopreserved allograft group. One patient with critical aortic stenosis, an interrupted aortic arch, and a ventricular septal defect, who had undergone a neonatal Rastelli procedure with a 13-mm standard allograft (patient weight, 3.1 kg), required balloon dilatation of bilateral branch pulmonary artery stenoses 24 months after the procedure. At that time, the peak allograft gradient was 26 mm Hg and the degree of insufficiency was 3+. The second patient also had critical aortic stenosis, an interrupted aortic arch, and a ventricular septal defect, and underwent a neonatal Rastelli procedure with a 9-mm standard allograft at a birth weight of 2.3 kg. The patient progressed to a peak gradient of 60 mm Hg with grade 0 insufficiency at 26 months post-procedure. A moderate-sized right ventricular outflow tract aneurysm was also noted on catheterization. The patient underwent allograft replacement with the findings of a saccular aneurysm at the proximal suture line, likely due to a contained suture line dehiscence.
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Fig 2. Actuarial freedom from reintervention of CryoValve (Cryolife Inc, Kennesaw, GA) versus standard valve.
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Mean survival at follow-up was identical between the CryoValve SG (CryoLife Inc) patients and the standard allograft patients (85%; 22 of 26) (Fig 3). Of the CryoValve SG (CryoLife Inc) patients, there were 3 hospital deaths and 1 late death. Of the standard allograft patients, there were 2 hospital deaths and 2 late deaths.
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Comment
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Cryopreserved pulmonary allografts have been shown to be very effective conduits for reconstruction of the right ventricular outflow tract in both children and adults [1–5]. These allografts have favorable tissue handling characteristics, including the ability to conform readily to various shapes without compressing underlying structures such as coronary arteries. The suture lines are rapidly hemostatic with little needle hole bleeding. They are available in very small sizes, although the smallest sizes are in relatively short supply. Although they tend to be relatively resistant to stenosis, they are prone to becoming rapidly regurgitant, particularly in the pediatric population [6–8].
This limited durability appears to be due at least in part to immunologic factors. The standard cryopreserved allograft is strongly antigenic and elicits a rapid host immune response. Shaddy and associates [9] prospectively measured the frequency of human leukocyte antigen (HLA) class I panel-reactive alloantibodies (PRA) in children undergoing open heart surgery with or without the implantation of allograft material. They found that in patients receiving an allograft, the PRA increased from 3.2% ± 2.7% before surgery to 63.3% ± 12% at 25 days ± 2 days after surgery, and 99.7% ± 3.4% at 3.4 months ± 0.3 months. The control group had no significant change in PRA. This immune response is believed to have been a contributory factor to the early degradation of allograft function. Christenson and colleagues [1] evaluated 59 children receiving a pulmonary allograft and found that ABO blood group incompatibility resulted in accelerated fibrocalcification, particularly in patients less than 3 years of age. Similarly, Baskett and colleagues [11] found that both ABO blood group and HLA-DR mismatch was associated with echocardiographic failure, defined as regurgitation greater than or equal to grade 2/4 or peak gradient greater than or equal to 50 mm Hg.
To decrease the intensity of the immune response (CryoLife, Inc) developed a decellularization technique for allograft tissue. This proprietary process (SynerGraft) entails incubating the tissue in sterile water to promote cell lysis. The allografts are then exposed to ribonuclease and deoxyribonuclease and are repeatedly washed in an isotonic solution prior to cryopreservation. This process removes greater than 95% of all cellular debris by hematoxylin and eosin staining [13]. Similarly the resulting valves show minimal immunostaining for HLA class I or II [15]. Initial testing of the decellularization process entailed implantation of porcine valve constructs into weanling sheep. The weanling sheep model is characterized by rapid calcification of untreated xenografts. After explantation at 150 days, the decellularized valves showed no calcification by histology or spectrophotometry and no increase in valve gradient at catheterization performed just prior to sacrifice [13]. The decellularized grafts were also analyzed for cellular repopulation in a xenograft pig-to-sheep model with graft explanation at 3, 4, 5, 6, and 11 months post-implantation [16]. A rapid cellular infiltrate was noted, replaced in time by mature host interstitial cells. By 3 months post-implantation, functional host fibroblasts were demonstrated, which synthesized type I procollagen. At 11 months, the leaflets had no identifiable inflammatory infiltrate and were 80% repopulated with host cells, including fibroblasts and smooth muscle actin positive cells distributed in an architecture similar to natural leaflets. An in vitro comparison of decellularized human allografts (CryoValve SG [CryoLife, Inc]) with standard cryopreserved allografts revealed similar tissue mechanics and hemodynamic performance. Uni-axial tension loading demonstrated no difference in conduit failure, leaflet failure, or suture retention. In vitro hemodynamic testing revealed no differences in valve gradient, valve closure volume, or diastolic regurgitation [15].
Elkins and colleagues [17] demonstrated a low incidence of HLA class I PRA positivity (commonly defined as less than or equal to 10%) in patients receiving decellularized allografts. Of 57 patients with a negative preoperative PRA receiving decellularized tissue, 91% (52 of 57) remained negative at 1 month and 88% (43 of 49) at 3 months. There was no difference in valve gradient or regurgitation compared with 73 patients receiving a standard cryopreserved valve at a limited median follow-up of 4 months. Hawkins and colleagues [10] evaluated the HLA class I and class II PRA of 14 patients receiving decellularized valved conduits or tissue patches. In comparison with 20 historic controls receiving standard cryopreserved tissue, both HLA class I and II PRA percentages were significantly lower at all time periods. The 8 patients implanted with a decellularized valved conduit were compared with 8 historical control patients at a mean follow-up of 8 months. No difference was found in valve gradient or degree of regurgitation.
Unlike the previous studies previously described, at an intermediate follow-up of 16.3 ± 10.5 months our cohort of CyroValve (CryoLife, Inc) patients demonstrated a notable difference in the degree of regurgitation compared with case-matched controls receiving a standard cryopreserved allograft. A small, but statistically significant difference in gradient was also found, although it is important to note that these results are not independent, as the volume load imposed by regurgitation may increase the gradient. Although the most obvious explanations for the failure of the studies by Elkins and colleagues [17] and Hawkins and colleagues [10] to find similar functional differences are the length of follow-up and sample size, there are other important differences. The patients were slightly older in the study by Hawkins and colleagues [10] (8.5 ± 7.9 years) and markedly older in the study by Elkins and colleagues [17] (median, 34 years; range, 3 months to 59 years). In the study by Hawkins and colleagues [10], only 57% (8 of 14) of their patients had a valved conduit compared with 100% in the current group. Ninety-five percent (55 of 58) of the patients in the Elkins and colleagues' [17] cohort had the decellularized pulmonary allograft placed in an orthotopic position during a Ross procedure compared with only 31% in our current group. Valves placed in an orthotopic position tend to have greater longevity than valves placed in a heterotopic position, possibly due to the effects of laminar versus non-laminar flow. In contrast with the other studies, the patients in our cohort were younger and all required the placement of a valved conduit, the majority of which were in a heterotopic position. It is precisely this group of infants and young children with active immune response, rapid growth, and complex congenital heart disease requiring heterotopic allograft placement who would benefit the most from any improvement in allograft durability. Although the average patient may tolerate pulmonary regurgitation very well, patients in this group, including those infants with tetralogy of Fallot and absent pulmonary valve or elevated pulmonary vascular resistance, may well benefit from the greater intermediate-term competence of the decellularized allograft. Whether these relatively subtle improvements will translate into a decrease in the absolute number of conduit reinterventions, an improvement in cardiovascular function, or an increased survival in the long-term remains to be determined.
This study is limited by several factors. The study is not prospective. To minimize this shortcoming, a contemporary group of case-matched controls was utilized. Despite this technique, many interesting factors that may affect the longevity of the allografts, such as the histology or the effect of blood group matching, could not be assessed. The relatively small number of patients may not allow for the detection of small differences between groups. The intermediate nature of the follow-up does not allow for the determination of long-term outcomes.
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Abstract
Introduction
