SynerGraft® (SG) decellularized-cryopreserved cardiac valve allografts have been developed to provide a valve replacement option that has reduced antigenicity, retained structural integrity, and the ability to be stored long-term until needed for implantation. However, it is critical to ensure that both the SG processing and cryopreservation of these allografts do not detrimentally affect the extracellular matrix architecture within the tissue. This study evaluates the effects of SG decellularization and subsequent cryopreservation on the extracellular matrix integrity of allograft heart valves. Human aortic and pulmonary valves were trisected, with one-third of each either left fresh (no further processing after dissection), decellularized, or decellularized and cryopreserved. Two-photon laser scanning confocal microscopy was used to visualize collagen and elastin in leaflets and conduits. The optimized percent laser transmission (OPLT) required for full dynamic range imaging of each site was determined, and changes in OPLT were used to infer changes in collagen and elastin signal intensity. Collagen fiber crimp period and collagen and elastin fiber diameter were measured in leaflet tissue. Statistically significant differences in OPLT and the dimensional characteristics of collagen and elastin in study groups were determined through single factor ANOVA. The majority of donor-aggregated average OPLT observations showed no statistically significant differences among all groups, indicating no difference in collagen or elastin signal strength. Morphometric analysis of collagen and elastin fibers revealed no significant alterations in treated leaflet tissues relative to fresh tissues. Collagen and elastin structural integrity within allograft heart valves are maintained through SynerGraft® decellularization and subsequent cryopreservation.

Background. Aortic root replacement with cryopreserved allografts is associated with excellent hemodynamics, little endocarditis, low thromboembolic event rates, and no need for anticoagulation. There is, however, concern regarding the long-term durability of this valve substitute, especially in younger patients. Meta-analysis and microsimulation were used to calculate age-specific long-term prognosis after allograft aortic root replacement based on current evidence. Methods. Our center's experience with cryopreserved allograft aortic root replacement in 165 adult patients was combined in a meta-analysis with reported and individual results from four other hospitals. Using this information, the microsimulation model predicted age- and gender-specific total and reoperation-free and event-free life expectancy. Results. The pooled results comprised 629 patients with a total follow-up of 1860 patient-years (range 0 to 12.8 years). Annual risks were 0.6% for thromboembolism, 0.05% for bleeding, 0.5% for endocarditis, and 0.5% for nonstructural valve failure. Structural allograft failure requiring reoperation occurred in 15 patients, and a patient age-specific Weibull function was constructed accordingly. Calculated total life expectancy varied from 27 years in a 25-year-old to 12 years in a 65-year-old male; corresponding actual lifetime risk of reoperation was 89% and 35%, respectively. Conclusions. Cryopreserved aortic allografts have an age-related limited durability. This results in a considerable lifetime risk of reoperation, especially in young patients. The combination of meta-analysis and microsimulation provides an appropriate tool for estimating individualized long-term outcome after aortic valve replacement and can be useful both for patient counseling and prognostic research purposes. (C) 2003 by The Society of Thoracic Surgeons.

Objective: This study compared clinical outcomes of patients receiving CryoValve SG decellularized pulmonary valves with those of patients receiving conventionally processed CryoValve pulmonary valves.Methods: All consecutive patients undergoing Ross procedures and right ventricular outflow tract reconstructions with SG valves at 7 institutions (February 2000-November 2005) were assessed retrospectively (193 Ross procedures, 149 right ventricular outflow tract reconstructions). Patient, procedural, and outcome data were compared with those from 1246 conventional implants (665 Ross procedures, 581 right ventricular outflow tract reconstructions). Hemodynamic function was assessed at latest follow-up.Results: Follow-up was complete for 99% in SG group and 94% in conventional group, with mean follow-ups of 4.0 years (range, 0-6.7 years) for SG and 3.7 years (range, 0-6.7 years) for conventional. Five-year cumulative survivals and freedoms from adverse events were comparable between SG and conventional valves. Among patients undergoing Ross procedures, peak gradient at last follow-up was lower with SG valves (P<.01); no difference was observed in the right ventricular outflow tract reconstruction population. Pulmonary insufficiency was significantly reduced with SG valves in patients undergoing both Ross procedures (P<.01) and right ventricular outflow tract reconstructions (P<.01). Valve type was not a significant predictor of valve-related failure in propensity-adjusted analysis of either procedure.Conclusions: CryoValve SG decellularized pulmonary valves have acceptable clinical outcomes and favorably compare with conventionally processed valves. Improved hemodynamic function observed with SG valves could signify improved long-term outcomes and may be due to the decreased antigenicity of these valves. (J Thorac Cardiovasc Surg 2010; 139: 339-48)

OBJECTIVE:We performed a review of a consecutive series of 487 patients undergoing the Ross operation to identify surgical techniques and clinical parameters that affect outcome.METHODS:We performed a prospective review of consecutive patients from August 1986 through June 2002 and follow-up through August 2004. Patient age was 2 days to 62 years (median, 24 years), and 197 patients were less than 18 years of age. The Ross operation was performed as a scalloped subcoronary implant in 26 patients, an inclusion cylinder in 54 patients, root replacement in 392 patients, and root-Konno procedure in 15 patients. Clinical follow-up in 96% and echocardiographic evaluation in 77% were performed within 2 years of closure.RESULTS:Actuarial survival was 82% +/- 6% at 16 years, and hospital mortality was 3.9%. Freedom from autograft failure (autograft reoperation and valve-related death) was 74% +/- 5%. Male sex and primary diagnosis of aortic insufficiency (no prior aortic stenosis) were significantly associated with autograft failure by means of multivariate analysis. Freedom from autograft valve replacement was 80% +/- 5%. Freedom from endocarditis was 95% +/- 2%. One late thromboembolic episode occurred. Freedom from allograft reoperation or reintervention was 82% +/- 4%. Freedom from all valve-related events was 63% +/- 6%. In children survival was 84% +/- 8%, and freedom from autograft valve failure was 83% +/- 6%.CONCLUSIONS:The Ross operation provides excellent survival in adults and children willing to accept a risk of reoperation. Male sex and a primary diagnosis of aortic insufficiency had a negative effect on late results.

Background and aim of the study: Endocarditis with aortic root abscess is one of the most complicated surgical problems. Methods: An 8-year-old girl was presented with dyspnea, high fever, and fatigue. She had stenotic bicuspid aortic valve with endocarditis and aortic root abscess. Ross procedure was performed with fresh autologous pericardial tube and pericardial monocusp valve. Right internal mammary artery to right coronary artery bypass was also done due to destructed right coronary artery ostium. Results: Four years after the operation she is in excellent clinical condition without medications. Echocardiography reveals mild autograft regurgitation and mildly stenotic right ventricular outflow tract. Conclusions: If homografts are not available, total reconstruction of RVOT with autologous fresh pericardium may offer reasonable early and mid-term results especially when active endocarditis and aortic root abscess is involved.

Background. Coarctation repair in the neonate (.28 days) is associated with higher mortality and increased incidence of restenosis compared with older infants. It has been suggested that resection of pericoarctation ductal tissue may reduce this risk of restenosis. Methods and Results. To further clarify these issues, we reviewed our experience with 111 consecutive neonates undergoing primary repair between 1973 and 1991. Hospital mortality was 14.4% (16 of 111) and was not significantly different for the type of repair. resection and end-to-end anastomosis (RETE) 10.7% (6 of 56), subclavian flap angioplasty (SFA) 16.7% (6 of 36), and patch angioplasty (PA) 16.7% (3 of 18). Associated complex cardiac pathology was associated with higher operative risk.. 25% (10 of 40) versus 8.4% (6 of 71) (P=.02). Median follow-up of 4.2 years (range, 0.1 to 18.5 years) was 99%o complete. Late mortality was 13.6% (13 of 95), of which 92% occurred within 1 year of repair. Twenty percent (19 of 95) needed reintervention for restenosis, RETE 16% (8 of 50), SFA 13% (4 of 30), and PA 47% (7 of 15) (P=.02). Of these, 84.2% (16 of 19) required reintervention within 1 year of repair. Freedom from reintervention 1 and 8 years after operation was 80±4% and 77±5%, respectively. Actuarial survival 8 years after operation was 73±4%; for simple coarctation, this was 90±4%. By multivariate analysis, survival was negatively influenced only by presence of associated cardiac pathology (P=.002) and reintervention only by patch angioplasty technique of repair (P=.007). Conclusions. In the neonate, resection of coarctation (RETE) does not diminish the risk for reintervention compared with SFA. The risk for both late death and recurrent coarctation are highest within the first year after repair, and follow-up should be particularly vigilant during this period. (Circulation. 1993;88[part 21:198-204.)

Instantaneous ascending aortic blood flow was recorded at operation in five patients with severe, pure mitral regurgitation, and in nine dogs in which mitral regurgitation was produced experimentally under controlled conditions. In both the patients and the experimental animals, the pattern of aortic flow was abnormal during mitral regurgitation: peak flow occurred early, the percentage of total forward flow

The term ‘valvular heart disease’ incorporates a wide range of conditions. The gold-standard diagnostic techniques, the natural history, and the interventional, as well as surgical, techniques which are available for treatment should be known by the clinician. The surgical management of valvular heart disease involves a series of operations and techniques. The aim of this review is to describe valvular pathology and the available surgical techniques.

BACKGROUND AND AIM OF THE STUDY:Patient-related factors, aortic insufficiency, bicuspid aortic valve, aortic annulus dilatation, ascending aortic dilatation or aneurysm, and aortic valve endocarditis have been suggested as affecting the results of the Ross operation. The study aim was to assess the impact of prior aortic valve intervention on early and late results of a Ross operation.METHODS:A total of 399 patients who underwent surgery between August 1986 and September 2000 were reviewed retrospectively. The patients were grouped as: no prior aortic valve intervention (NOAVI, n = 219); prior aortic valvuloplasty (AVP, n = 106); prior balloon aortic valvuloplasty (AVB, n = 40); and prior aortic valve replacement (AVR, n = 34). Details of operative and late mortality, autograft valve function, and homograft valve function were analyzed.RESULTS:Operative mortality was higher for AVB (10%; three deaths in neonates) than the other groups (from 2.3% to 5.9%) (p = 0.084). Freedom from autograft valve degeneration, defined as severe autograft valve insufficiency, non-endocarditis autograft valve reoperation or valve-related death, ranged from 93 +/- 3% for AVP to 76 +/- 8% for NOAVI at 10 years (p = 0.43). Freedom from homograft reoperation in the pulmonary position was 100% for AVB at six years, and 99 +/- 1% for AVP, 82 +/- 8% for NOAVI, and 70 +/- 13% for AVR at 10 years (p = 0.0026).CONCLUSION:There appears to be no significant difference between patients with and without prior aortic valve surgery, with respect to operative mortality or late autograft function. However, patients with prior AVR appear to have a significantly higher homograft reoperation rate after a Ross operation, the reasons for which are uncertain.

Tissue engineering of a heart valve has progressed dramatically in three different arenas: a biodegradable stented valve seeded with autogenous cells, decellularized allograft and xenograft valves that are seeded with autogenous cells, and decellularized allograft and xenograft valves that repopulate by adaptive remodeling in vivo. Preclinical evaluation and implants in sheep have been accomplished in each of these arenas, and clinical use of this emerging technology is occurring in the latter two. The clinical use of decellularized allografts that repopulate in vivo is expanding; however, its impact on allograft durability remains unknown.

Dr Elkins discloses that he has a conflict of interest with CryoLife, Inc. Dr Elkins discloses that he has a conflict of interest with CryoLife, Inc. The development of a tissue-engineered heart valve has been the goal of many cardiac surgeons for decades. The original implants of allograft heart valves were hoped to be permanent valve implants, especially if they could be implanted with viable intrinsic cells. However, these valves slowly develop progressive structural degeneration and at explantation are noted to be acellular. This loss of cellularity is thought to be immunologically mediated, as valvular tissue of organ transplants retain their normal cellular architecture if appropriate immune suppressive therapy is utilized. This recognition that maintenance of viability was important for long-term durability led to the use of the pulmonary autograft valve as a replacement for the aortic and mitral valve. The long-term function of the pulmonary valve in the systemic circulation and the requirement of a biological substitute for the pulmonary valve that converts single valve disease to two valves at risk of degeneration and failure are major deterrents to acceptance of the pulmonary autograft as the ideal aortic valve replacement. Continued interest in development of a tissue-engineered valve has been focused in three different arenas: (1) Seeding a biodegradable valve matrix with autologous endothelial or fibroblast cells [1Shinoka T Shum-Tim D Ma P.X., et al Creation of viable pulmonary artery autografts through tissue engineering.J Thorac Cardiovasc Surg. 1998; 115: 536-546Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar]; (2) seeding a decellularized allograft valve with vascular endothelial cells or dermal fibroblasts [2Dohmen P.M Ozaki S Yperman J et al.Lack of calcification of tissue engineered heart valves in juvenile sheep.SeminThorac Cardiovasc Surg. 2001; 13: 93-98PubMed Google Scholar, 3Bader A Schilling T Teebken O.E., et al Tissue engineering of heart valves human endothelial cell seeding of detergent acellularized porcine valves.Eur J Cardiothorac Surg. 1998; 14: 279-284Crossref PubMed Scopus (325) Google Scholar, 4Zeltinger J Landeen L.K Alexander H.G et al.Development and characterization of tissue-engineered aortic valves.Tissue Engineer. 2001; 7: 9-22Crossref PubMed Scopus (129) Google Scholar]; and (3) use of a decellularized allograft with maintained structural integrity as a valve implant that will be repopulated by adaptive remodeling [5Elkins R.C Goldstein S Hewitt C.W et al.Recellularization of heart valve grafts by a process of adaptive remodeling.SeminThorac Cardiovasc Surg. 2001; 13: 87-92PubMed Google Scholar, 6Elkins R.C Lane M.M Capps S.B et al.Humoral immune response to allograft valve tissue pretreated with an antigen reduction process.SeminThorac Cardiovasc Surg. 2001; 13: 82-86PubMed Google Scholar, 7Elkins R.C Dawson P.E Goldstein S et al.Decellularized human valve allografts.Ann Thorac Surg. 2001; 71: 428-432Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar]. Dohmen and coauthors[8Dohmen P.M Lembcke A Hotz H et al.Ross operation with a tissue-engineered heart valve.Ann Thorac Surg. 2002; 74: 1438-1442Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar] report their experience with their first successful implant of a decellularized allograft seeded with autologous vascular endothelial cells with 1-year follow-up. They are to be congratulated on this success, but there are also several questions still to be answered. Does their decellularization process render all allograft valves immunologically inert? Will the seeded vascular endothelial cells penetrate the matrix and differentiate into fibroblasts and myo-fibroblasts that are biologically active, and will they regenerate the collagen and elastin matrix of the allograft such that the valve will maintain structural integrity? Can their decellularization process be utilized on other cardiac valves such as the aortic valve, which has significant structural differences, especially the aortic root and ascending aorta? Decellularized allografts are now being utilized as pulmonary and aortic valve replacements with anticipated repopulation of the leaflet tissue and of the conduit. Early assessment of valve function has been excellent, with evidence of reendothelialization and repopulation of the matrix with fibroblasts and myo-fibroblasts in a limited number of explants. In some patients, a humoral antibody response similar to the humoral immune response seen in most patients who receive a cryopreserved allograft has been demonstrated. It is anticipated that repopulation of the decellularized allograft will be associated with improved long-term function; however, this is still unknown. This is an exciting development in tissue valve engineering, but even if it would ultimately demonstrate that an allograft valve can be a permanent valve without late degeneration, its use is still limited by the availability of allograft valves. The adaptation of these processes to xenograft tissue or the development of a biodegradable matrix that is seeded with autogenous endothelial or fibroblasts cells is the present hope for an unlimited supply of tissue-engineered heart valves. In vitro studies have been conducted and limited in vivo implants have been accomplished utilizing these techniques. Early results are promising, and we await further elucidation of these ongoing investigations in the hope of having a tissue-engineered valve that will meet the need for clinical heart valve replacement.

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 8.34×10 6 AVEC were available to seed a 27-mm decellularized pulmonary allograft. Trypan blue staining confirmed 96.0% viability. Reendothelialization rate after seeding was 9.0×10 5 cells/cm 2 . 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.

The humoral immune response to allograft heart valves as measured by PRA was absent in 52 of 57 (91%) patients at 1 month and was absent in 43 of 49 (88%) at 3 months in allograft valves treated with the SynerGraft process for antigen reduction. Short-term valve function is satisfactory. This may be associated with improved durability and long-term function.

The objective of this study was to investigate if function and durability of connective tissue grafts stems from in vivo revascularization and recellularization. Viability is important for durable valve performance, demonstrated by pulmonary autografts. A pattern of in vivo recellularization occurs in xenogeneic or allogeneic heart valves decellularized prior to implantation, dictated by the tissue matrix and functional biomechanics. Porcine or sheep heart valves were decellularized with the SynerGraft antigen reduction process (a common treatment process to remove all histologically demonstrable leaflet cells), and implanted as pulmonary (n = 11) or aortic valve (n = 9) replacements in sheep. Sheep allograft pulmonary valves (n = 4) were implanted as pulmonary valve replacements. Recellularization was evaluated histologically after 3, 4, 5, 6, and 11 months, with cell phenotypes identified using specific antibodies. SynerGraft heart valves were progressively recellularized beginning with an initial cellular infiltrate, and subsequent repopulation with mature interstitial cells. This process occurs in the conduit and then in the leaflet, and is associated with revascularization of the graft. Functional, fully developed fibrocytes, actively synthesizing type I procollagen (antibody probe) were present within 3 months. As the process matured cell density and distribution became similar to native valve leaflets with localization of smooth muscle actin positive cells at the ventricularis/spongiosa interface. After 11 months, leaflet explants had no detectable inflammatory cells, were as much as 80% repopulated, and had a distribution of smooth muscle actin positive cells similar to that of the natural leaflet. SynerGraft- treated heart valve implants are repopulated by a process typical of adaptive remodeling following implantation. This antigen reduction treatment is the first successful tissue engineering effort obtaining an implant with mature recipient cells capable of matrix protein synthesis. Normal early valve function and durability is maintained.

BACKGROUND AND AIM OF THE STUDYThe clinical evaluation and comparison of St. Jude Medical (SJM) and CarboMedics (CM) prosthetic heart valves implanted between 1988 and 1997 is presented.METHODSIn total, 648 SJM valves were implanted in 641 patients, and 601 CM valves in 591 patients. There were 684 mitral valve replacements, 256 aortic valve replacements, 252 mitral and aortic (double) valve replacements, 16 triple valve replacements, and 41 other tricuspid-related valve replacements. Total follow up was 98%. The overall incidence of valve-related events was compared before and after establishment of a 'valve clinic' in 1993.RESULTSThe overall hospital mortality was 3.4%; late mortality was 8.2%. The five- and ten-year survival for all patients was 92.1% and 86.2%, respectively. There were 31 episodes of thromboembolism in 27 patients (including valve thrombosis in three), 21 episodes of bleeding events in 20 patients, and 18 re-replacements of implanted valves. No structural valve deterioration was observed. Freedom from thromboembolism was 97.8% at five years and 96.3% at ten years; freedom from bleeding episodes was 98.1% and 97.6%, respectively. In terms of hospital and late mortality, and incidence of thromboembolism, hemorrhagic episodes and structural valve failure, no statistically significant differences were found between the SJM and CarboMedics patient groups. Freedom from thromboembolism was 96.7% at five years before initiation of an intensive follow up program, and 99.0% thereafter (p = 0.031). In contrast, freedom from bleeding episodes fell from 99.3% to 96.1% during the same time period (p = 0.0004).CONCLUSIONBoth the SJM and CM prosthetic heart valves performed well in our study, and no discernible differences in clinical performance of the two valves were detected. The intensive follow up program resulted in a reduced incidence of thromboembolism, but an increased number of bleeding complications. An optimum anticoagulation regimen to manage these two conflicting problems has yet to be elucidated.

Background. Variable performance of allograft tissues in children and some adults may be linked to an immune response and could be mitigated by reducing implant antigenicity. Methods. As endothelial and fibroblast cells are the likely source of valve antigenicity, human (CryoValve SG) and sheep pulmonary valves were decellularized using the SynerGraft treatment process. Treated valves were evaluated in vitro using histochemical, biomechanical, and hydrodynamic methods, and compared with standard cryopreserved valves. Four SynerGraft-treated and two cryopreserved sheep pulmonary valves were implanted as root replacements in the right ventricular outflow tract of growing sheep and monitored echocardiographically and histologically at 3 and 6 months. CryoValve SG human pulmonary valves were implanted in 36 patients. Results. SynerGraft treatment reduced tissue antigen expression but did not alter human valve biomechanics or strength. Decellularized sheep allograft valves were functional during the implantation period, and, they became progressively recellularized with recipient cells. In humans, CryoValve SG pulmonary valves did not provoke a panel reactive antibody response. Conclusions. SynerGraft decellularization leaves the physical properties of valves unaltered and substantially diminishes antigen content. Reduction in implant cellularity enables host recellularization of the matrix, which should favorably impact long-term graft durability.

BACKGROUND AND AIM OF THE STUDY Although the Ross operation has become the accepted aortic valve replacement in children, the long-term fate of the pulmonary autograft valve remains unknown. To assess mid-term and late results of autograft valve durability, patient survival and valve-related morbidity, a retrospective review of patients (age range: 3 days to 17 years) having a Ross operation between November 1986 and May 2001 were reviewed. METHODS Medical records and patient contacts with all but two of 167 current survivors of 178 consecutive patients having an aortic valve replacement as a Ross operation have been completed during the past two years. The most recent echocardiographic evaluation was reviewed for autograft valve and homograft valve function. RESULTS Operative mortality was 4.5% (8/178), with three late deaths (two were non-valve-related) for an actuarial survival of 92+/-3% at 12 years. Actuarial freedom from autograft valve degeneration (reoperation or severe insufficiency of autograft valve or valve-related death) was 90+/-4% at 12 years. Autograft valve degeneration was not affected by technique of insertion (141 root replacement, 37 intra-aortic), aortic valve morphology (157 bicuspid or unicuspid, 26 tricuspid), or age at operation. Autograft valve degeneration was worse in patients with a primary lesion of aortic insufficiency than in those with aortic stenosis (p = 0.03). Autograft valve reoperation was required in 12 patients, with autograft valve replacement in seven. Actuarial freedom from autograft replacement was 93+/-3% at 12 years. Homograft valve replacement was required in seven patients, with actuarial freedom from replacement of 90+/-4% at 12 years. Eight additional patients have homograft valve obstruction (gradient > or =50 mmHg), and seven have severe pulmonary insufficiency. CONCLUSION Survival and freedom from aortic valve replacement are excellent in children. Homograft valve late function remains a concern, and efforts to improve homograft durability should be encouraged.

Young patients with complex aortic valve disease involving the aortic root or ascending aorta are a challenge to manage. To use the Ross operation and realize its benefits, the operative technique must include aortic annulus reduction and fixation and replacement of ascending aortic pathology. Special techniques must be used when the cause of the complex disease is active endocarditis of the valve and aortic root. Surgical techniques that allow the use of the Ross operation in these settings and the midterm results in 84 patients are reviewed.