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The Stented Porcine Bioprosthesis: A 50-Year Journey Through Hopes and Realities

2019; Elsevier BV; Volume: 108; Issue: 1 Linguagem: Inglês

10.1016/j.athoracsur.2019.03.015

1552-6259

Uberto Bortolotti, Aldo Milano, Marialuisa Valente, Gaetano Thiene,

Electrospun Nanofibers in Biomedical Applications

The year 2018 marked the 50th anniversary of the first implant of a commercially manufactured stented porcine bioprosthesis. During the subsequent years considerable clinical and pathologic research was done to evaluate the overall performance of such devices and to identify the leading causes of failure. This brief review covers 5 decades, summarizing the initial hopes and the realities faced by surgeons who have believed from the start in these cardiac valve substitutes. From reported failures and long-term results a new generation of durable and reliable stented porcine bioprosthetic valves is currently available. The year 2018 marked the 50th anniversary of the first implant of a commercially manufactured stented porcine bioprosthesis. During the subsequent years considerable clinical and pathologic research was done to evaluate the overall performance of such devices and to identify the leading causes of failure. This brief review covers 5 decades, summarizing the initial hopes and the realities faced by surgeons who have believed from the start in these cardiac valve substitutes. From reported failures and long-term results a new generation of durable and reliable stented porcine bioprosthetic valves is currently available. The year 2018 marked the 50th anniversary of the first implant of a commercially manufactured stented porcine bioprosthesis (PB). In a Letter to the Editor published some years ago, Warren Hancock, replying to an observation of Alain Carpentier, stated that the first stented PB was implanted in October 1968 [1Hancock W.D. Valvular xenograft to bioprosthesis.Ann Thorac Surg. 1990; 49: 170Google Scholar]. This was a formalin-fixed PB produced by Hancock Laboratories. In the ensuing 50 years several changes were adopted in valve manufacturing, yielding the current generations of this and other PBs. Therefore, besides celebrating what can be really considered as an historical event in valve surgery, a brief overview of what has happened thereafter in the field of PB appears timely (Table 1).Table 1Evolution of Stented Porcine Bioprostheses 1968–2018StudyEventDateBinet and colleagues 10Binet J.P. Duran C.G. Carpentier A. Langlois J. Heterologous aortic valve transplantation.Lancet. 1965; 2: 1275Google ScholarFirst implant of an unstented porcine xenograft for AVR1965Hancock 1Hancock W.D. Valvular xenograft to bioprosthesis.Ann Thorac Surg. 1990; 49: 170Google ScholarFirst implant of a formaldehyde-fixed stented porcine bioprosthesis manufactured in Hancock Labs1968Carpentier and colleagues 11Carpentier A. From valvular xenograft to valvular bioprosthesis: 1965-1970.Ann Thorac Surg. 1989; 48: S73-S74Google Scholar, 12Carpentier A. Lemaigre G. Robert L. Carpentier S. Dubost C. Biological factors affecting long-term results of valvular heterografts.J Thorac Cardiovasc Surg. 1969; 58: 467-483Google ScholarImportance of glutaraldehyde and stent in tissue fixation and mounting; introduction of the term bioprosthesis1969Gallucci and colleagues 15Gallucci V. Bortolotti U. Milano A. Valfrè C. Mazzucco A. Thiene G. Isolated mitral valve replacement with the Hancock bioprosthesis: a 13-year appraisal.Ann Thorac Surg. 1984; 38: 571-578Google ScholarFirst implant of a glutaraldehyde-fixed Hancock bioprosthesis for MVR1969Angell and colleagues 17Angell W.W. Angell J.D. Sywak A. The Angell-Shiley porcine xenograft.Ann Thorac Surg. 1979; 28: 537-553Google ScholarImplant of the Angell-Shiley porcine bioprosthesis1970Reis and colleagues 14Reis R.L. Hancock W.D. Yarbrough J.W. Glancy D.L. Morrow A.G. The flexible stent. A new concept in the fabrication of tissue heart valve prostheses.J Thorac Cardiovasc Surg. 1971; 62: 683-689Google ScholarIntroduction of the flexible polypropylene stent1971Jamieson and colleagues 18Jamieson W.R. Hayden R.I. Miyagishima R.T. et al.The Carpentier-Edwards standard porcine bioprosthesis: clinical performance to 15 years.J Card Surg. 1991; 6: 550-556Google ScholarImplant of the Carpentier-Edwards porcine bioprosthesis1975Cohn and colleagues 25Cohn L.H. Di Sesa V. Collins Jr., J.J. The Hancock modified-orifice porcine bioprosthetic valve: 1976-1988.Ann Thorac Surg. 1989; 48: S81-S82Google ScholarImplant of the Hancock modified-orifice bioprosthesis1976Bortolotti and colleagues 28Bortolotti U. Milano A. Mazzucco A. et al.Influence of prosthetic design on durability of the Liotta porcine valve in the mitral position.Ann Thorac Surg. 1990; 50: 734-738Google ScholarAvailability of the Liotta low-profile porcine bioprosthesis for clinical use1976Wright and colleagues 29Wright J.T.M. Eberhardt C.E. Gibbs M.L. Saul T. Gilpin C.B. Hancock II – an improved bioprosthesis.in: Cohn L.H. Gallucci V. Cardiac Bioprostheses. Yorke Med Books, New York, NY1982: 425-444Google ScholarDavid and colleagues 31David T.E. Armstrong S. Maganti M. Hancock II bioprosthesis for aortic valve replacement: the gold standard of bioprosthetic valves durability?.Ann Thorac Surg. 2010; 90: 775-781Google ScholarClinical introduction of the Hancock II bioprosthesis with the surfactant T6 as anticalcification treatment1982Milano and colleagues 19Milano A. Bortolotti U. Talenti E. et al.Calcific degeneration as the main cause of porcine bioprosthetic valve failure.Am J Cardiol. 1984; 53: 1066-1070Google ScholarDemonstration of dystrophic tissue calcification as main cause of porcine bioprosthesis failure1984Veseli 34Veseli I. Analysis of the Medtronic Intact bioprosthetic valve. Effects of "zero pressure" fixation.J Thorac Cardiovasc Surg. 1991; 101: 90-99Google ScholarFavorable effects of zero-pressure fixation on porcine cusps elasticity1991Celiento and colleagues 36Celiento M. Ravenni G. Tomei L. Pratali S. Milano A. Bortolotti U. Excellent durability of the Mosaic aortic bioprosthesis at extended follow up.J Heart Valve Dis. 2018; 27: 97-103Google ScholarMore than 20-year follow-up with the Medtronic Mosaic third-generation porcine bioprosthesis2018AVR = aortic valve replacement; MVR = mitral valve replacement. Open table in a new tab AVR = aortic valve replacement; MVR = mitral valve replacement. The use of mechanical prostheses, using the caged-ball principle, as reported by Harken and colleagues [2Harken D.E. Soroff H.S. Taylor W.J. Lefemine A.A. Gupta S.K. Lunzer S. Partial and complete prostheses in aortic insufficiency.J Thorac Cardiovasc Surg. 1960; 40: 744-762Google Scholar] and Starr and Edwards [3Starr A. Edwards M.L. Mitral replacement: clinical experience with a caged-ball prosthesis.Ann Surg. 1961; 154: 726-740Google Scholar] in 1960, has dramatically changed the outlook of patients with mitral or aortic valve disease [2Harken D.E. Soroff H.S. Taylor W.J. Lefemine A.A. Gupta S.K. Lunzer S. Partial and complete prostheses in aortic insufficiency.J Thorac Cardiovasc Surg. 1960; 40: 744-762Google Scholar, 3Starr A. Edwards M.L. Mitral replacement: clinical experience with a caged-ball prosthesis.Ann Surg. 1961; 154: 726-740Google Scholar]. In fact, until then such patients could only benefit from closed commissurotomy for mitral stenosis or implantation of rudimentary prostheses into the descending aorta to treat aortic regurgitation, in most situations quite often with rather unpredictable results [4Hanlon C.R. Kaiser G.C. Mudd J.G. Willman V.L. Closed mitral commissurotomy for mitral stenosis.Ann Surg. 1968; 167: 796-800Google Scholar, 5Hufnagel C.A. Harvey W.P. The surgical correction of aortic regurgitation preliminary report.Bull Georgetown Univ Med Cent. 1953; 6: 60-61Google Scholar]. After several years of clinical use it became evident that mechanical prostheses, regardless of their design, were associated with variable rates of thromboembolic complications, despite the absolute need for life-long anticoagulation. Moreover, other dismal events such hemorrhages, mostly related to an incorrect management of anticoagulants, could jeopardize both early and late postoperative survival [6Edmunds Jr., L.H. Thrombotic and bleeding complications of prosthetic heart valves.Ann Thorac Surg. 1987; 44: 430-445Google Scholar]. Tissue prosthetic valves were therefore devised to overcome such evident drawbacks of mechanical valve substitutes. Initially, bioprostheses were obtained by suturing on stent segments of fascia lata [7Senning A. Rothlin M. Reconstruction of the aortic valve with fascia lata. Initial and long-term results.Vasc Surg. 1973; 7: 29-35Google Scholar] or dura mater [8Zerbini E.J. Results of replacement of cardiac valves by homologous dura mater valves.Chest. 1975; 67: 706-710Google Scholar] to replicate the tricuspid shape of the human aortic valve. Such tissues once mounted on a frame were found to be unable to resist both mechanical stresses and fibrocalcific degeneration leading to premature valve failure. It must be remembered, however, that homografts had already been used to replace the aortic valve [9Ross D.N. Homograft replacement of the aortic valve.Lancet. 1962; 2: 487Google Scholar]. The first insertion of a xenograft in the aortic position was performed by Binet and colleagues in 1965 [10Binet J.P. Duran C.G. Carpentier A. Langlois J. Heterologous aortic valve transplantation.Lancet. 1965; 2: 1275Google Scholar]. Early failures of such implants occurring mainly because of inflammatory reaction and cellular ingrowth demonstrated the need for both tissue preservation, with adequate chemical treatment and an external mechanical protection [11Carpentier A. From valvular xenograft to valvular bioprosthesis: 1965-1970.Ann Thorac Surg. 1989; 48: S73-S74Google Scholar]. The research and the seminal studies by Carpentier [11Carpentier A. From valvular xenograft to valvular bioprosthesis: 1965-1970.Ann Thorac Surg. 1989; 48: S73-S74Google Scholar] and his group [12Carpentier A. Lemaigre G. Robert L. Carpentier S. Dubost C. Biological factors affecting long-term results of valvular heterografts.J Thorac Cardiovasc Surg. 1969; 58: 467-483Google Scholar] demonstrated the efficacy of glutaraldehyde in decreasing the antigenicity and increasing the stability of the heterologous tissue; moreover, mounting the tissue on a stent provided adequate protection to cellular ingrowth. After such modifications, the valve could not be considered as a graft anymore but became a bioprosthesis [12Carpentier A. Lemaigre G. Robert L. Carpentier S. Dubost C. Biological factors affecting long-term results of valvular heterografts.J Thorac Cardiovasc Surg. 1969; 58: 467-483Google Scholar]. The first PBs, coming from Hancock Laboratories, were fixed in formaldehyde and mounted on a rigid metallic stent. Such devices showed high rates of early failures due to structural valve deterioration (SVD), a term that would become familiar among all cardiac surgeons in the years to come. Although an unexpected extended resistance of this PB model to SVD was observed in some series [13Bortolotti U. Milano A. Mazzucco A. et al.Longevity of the formaldehyde-preserved Hancock porcine heterograft.J Thorac Cardiovasc Surg. 1982; 84: 451-453Google Scholar], two major modifications were introduced into the manufacturing process of Hancock PBs: replacement of the rigid metallic stent with a flexible one made of polypropylene (Fig 1), aiming to reduce mechanical stresses on commissures and cusps [14Reis R.L. Hancock W.D. Yarbrough J.W. Glancy D.L. Morrow A.G. The flexible stent. A new concept in the fabrication of tissue heart valve prostheses.J Thorac Cardiovasc Surg. 1971; 62: 683-689Google Scholar], and the use of glutaraldehyde in tissue processing, fixation, and storage. The first Hancock I PB was implanted in March 1970 in Padua, Italy; the group of Padua University was credited for the first implant as Lawrence H. Cohn stated in the discussion of a paper presented at the 20th Anniversary Meeting of The Society of Thoracic Surgeons in San Antonio, Texas, in 1984 [15Gallucci V. Bortolotti U. Milano A. Valfrè C. Mazzucco A. Thiene G. Isolated mitral valve replacement with the Hancock bioprosthesis: a 13-year appraisal.Ann Thorac Surg. 1984; 38: 571-578Google Scholar]. Thereafter, this device gained immediately a worldwide acceptance with an increasing number of implants both in the mitral and aortic position; this premature enthusiasm led sometimes to an indiscriminate use of such devices regardless of patient age and underlying valve pathologic process. The initial results were, however, extremely gratifying with a negligible incidence of reoperations for SVD and thromboembolic complications at a medium-term follow-up [16Cèvese P.G. Gallucci V. Morea M. Fasoli G. Dalla Volta S. Casarotto D. Heart valve replacement with the Hancock bioprosthesis. Analysis of long-term results.Circulation. 1977; 56: II111-II116Google Scholar]. At that time other companies joined the market and other stented PBs became clinically available; some of them were abandoned quite early, whereas others were implanted until the more recent years [17Angell W.W. Angell J.D. Sywak A. The Angell-Shiley porcine xenograft.Ann Thorac Surg. 1979; 28: 537-553Google Scholar, 18Jamieson W.R. Hayden R.I. Miyagishima R.T. et al.The Carpentier-Edwards standard porcine bioprosthesis: clinical performance to 15 years.J Card Surg. 1991; 6: 550-556Google Scholar]. However, as clinical follow-up progressed, the number of patients presenting with a failing PB that required reoperation started to increase. Analysis of PBs explanted at reoperation showed various modes of failure, but tissue mineralization, leading to cusp rigidity with stenosis or commissural dehiscence with incompetence, was soon identified as the leading cause of SVD [19Milano A. Bortolotti U. Talenti E. et al.Calcific degeneration as the main cause of porcine bioprosthetic valve failure.Am J Cardiol. 1984; 53: 1066-1070Google Scholar, 20Schoen F.J. Levy R.J. Piehler H.R. Pathological considerations in replacement cardiac valves.Cardiovasc Pathol. 1992; 1: 29-52Google Scholar] (Fig 2). Many clinicopathologic studies from various institutions indicated that the Hancock I had a limited durability because of dystrophic calcification of the tissue and that the benefits for most patients were lost within the first postoperative decade [21Gallucci V. Mazzucco A. Bortolotti U. Milano A. Guerra F. Thiene G. The standard Hancock porcine bioprosthesis: overall experience at the University of Padova.J Cardiac Surg. 1988; 3: 337-345Google Scholar]. This was particularly evident for patients who were considered to have peculiar risk factors for calcification such as young age, renal failure, and pregnancy [22Thandroyen F.T. Whitton I.N. Pirie D. Rogers M.A. Mitha A.S. Severe calcification of glutaraldehyde-preserved porcine xenografts in children.Am J Cardiol. 1980; 45: 690-696Google Scholar, 23Kuzela D.C. Huffer W.E. Coinger J.D. Winter S.D. Hammond W.S. Soft tissue calcification in chronic dialysis patients.Am J Pathol. 1977; 86: 403-424Google Scholar, 24Bortolotti U. Milano A. Mazzucco A. et al.Pregnancy in patients with a porcine bioprosthesis.Am J Cardiol. 1982; 50: 1051-1054Google Scholar]. The Hancock I PB revealed after harvesting a suboptimal hemodynamic performance in the small sizes. This was caused by a rigidity of the right coronary cusp of the porcine aortic valve with a retained muscle septal bar. To overcome this problem, a new model was produced in which the right aortic cusp was replaced by a normal cusp from another porcine aortic valve. This PB with a modified orifice was reported to have a similar durability compared with the traditional model, despite the more complex fabrication procedure [25Cohn L.H. Di Sesa V. Collins Jr., J.J. The Hancock modified-orifice porcine bioprosthetic valve: 1976-1988.Ann Thorac Surg. 1989; 48: S81-S82Google Scholar]. Furthermore, the Hancock I valve was mounted on a stent with a quite high profile with potential risk of left ventricular tract obstruction and left ventricular rupture when implanted in the mitral position because of prosthesis–left ventricular disproportion [26Jones M. Eidbo E.E. Rodriguez E.R. Ferrans V.J. Clark R.E. Ventricular aneurysms and other lesions produced by the struts of bioprosthetic valves implanted in sheep.J Thorac Cardiovasc Surg. 1988; 95: 729-733Google Scholar, 27Jett G.K. Jett M.D. Bosco P. van Rijk-Swikker G.L. Clark R.E. Left ventricular outflow obstruction following mitral valve replacement: effect of strut height and orientation.Ann Thorac Surg. 1986; 42: 299-303Google Scholar]. Such complications were eliminated by a low-profile PB that, however, showed a high rate of commissural tearing because of its peculiar design [28Bortolotti U. Milano A. Mazzucco A. et al.Influence of prosthetic design on durability of the Liotta porcine valve in the mitral position.Ann Thorac Surg. 1990; 50: 734-738Google Scholar]. The results of gross, histologic, and ultrastructural evaluation of explanted Hancock I PBs indicated that improvement in tissue selection and changes in the valve manufacturing process were mandatory. This led to a new generation of PBs provided with a stent more resistant to creep and of lower profile but, most importantly, treated with an anticalcification agent. The detergent sodium dodecyl sulphate (known as T6) was found to reduce significantly tissue mineralization in juvenile sheep and in subcutaneous implantation in rats; therefore, it was added to the tissue treatment [29Wright J.T.M. Eberhardt C.E. Gibbs M.L. Saul T. Gilpin C.B. Hancock II – an improved bioprosthesis.in: Cohn L.H. Gallucci V. Cardiac Bioprostheses. Yorke Med Books, New York, NY1982: 425-444Google Scholar, 30Arbustini E. Jones M. Moses R.D. Eidbo E.E. Carrol R.J. Ferrans V.J. Modification of the Hancock T6 process of calcification of bioprosthetic cardiac valves implanted in sheep.Am J Cardiol. 1984; 53: 1388-1396Google Scholar]. The Hancock I was then replaced by the Hancock II PB which was shown to be clearly superior to its predecessor with a considerable increase in durability [31David T.E. Armstrong S. Maganti M. Hancock II bioprosthesis for aortic valve replacement: the gold standard of bioprosthetic valves durability?.Ann Thorac Surg. 2010; 90: 775-781Google Scholar]. The ultrastructural observation that the fixation process could kill the porcine cells inside the cusps, with membrane fragmentation and leakage of cytoplasmatic organelles, which represent the initial site of calcium phosphate deposition [32Valente M. Bortolotti U. Thiene G. Ultrastructural substrates of dystrophic calcification in porcine bioprosthetic valve failure.Am J Pathol. 1985; 119: 12-21Google Scholar], led to the production of a stented PB with decellularized tissue. This device has been reported to be resistant to calcification, but more consistent data are lacking [33Bortolotti U. Celiento M. Della Barbera M. Pratali S. Thiene G. Valente M. Long-term durability of a St. Jude Medical X-Cell bioprosthesis.Ann Thorac Surg. 2012; 93: 972-974Google Scholar]. It was evident that various modifications were required to obtain a more durable PB. These modifications included the use of new materials for the supporting stent, more accurate quality control of the porcine aortic valve by more rapid harvesting and selecting those with a less prominent muscular shelf, and the use of calcium-retarding agents. Furthermore, the technique of pressure fixation of the cusps needed to be changed to introduce the concept of zero-pressure fixation that was shown to maintain the normal collagen waveness of the porcine cusps, preserving their elasticity and normal function [34Veseli I. Analysis of the Medtronic Intact bioprosthetic valve. Effects of "zero pressure" fixation.J Thorac Cardiovasc Surg. 1991; 101: 90-99Google Scholar]. All such modifications led to a new generation of PBs. Although many of the original manufacturers have abandoned the market, three PB models, incorporating the previously described changes and with significant follow-up data, are still currently available (Fig 3). Some of these have shown excellent durability after mitral or aortic valve replacement with freedom from SVD more than 90% at 15 and 20 years [35Celiento M. Blasi S. De Martino A. Pratali S. Milano A. Bortolotti U. The Mosaic mitral valve bioprosthesis: a long-term clinical and hemodynamic follow-up.Texas Heart Inst J. 2016; 43: 13-19Google Scholar, 36Celiento M. Ravenni G. Tomei L. Pratali S. Milano A. Bortolotti U. Excellent durability of the Mosaic aortic bioprosthesis at extended follow up.J Heart Valve Dis. 2018; 27: 97-103Google Scholar]. Furthermore, in some of these models valve dimensions and geometry might facilitate subsequent valve-in-valve procedures when needed. The gratifying results obtained with the most recent PB models should detect further methods to increase durability and valve performance well beyond the 20-year limit indicated by the most recent studies. This would allow a lower age threshold for tissue valve implantation that is currently generally set at more than 70 to 75 years and, therefore, to expand the benefits of avoidance of long-term anticoagulation and related complications to a younger patient population. In this field the research is currently concentrated on evaluating the potential use of genetically modified pigs to obtain PBs or in the development of tissue engineering of cardiac valves [37Cheung D.Y. Duan B. Butcher J.T. Current progress in tissue engineering of heart valves: multiscale problems, multiscale solutions.Expert Opin Biol Ther. 2015; 15: 1155-1172Google Scholar]. Because mineralization in the long term is the main critical issue of bioprosthetic valves from cell death caused by glutaraldehyde fixation, removal of cell debris through pre-implantation tissue treatment with alcohol has also been found to be quite effective in enhancing valve durability [38Pettenazzo E. Valente M. Thiene G. Octanediol treatment of glutaraldehyde fixed bovine pericardium: evidence of anticalcification efficacy in the subcutaneous rat model.Eur J Cardiothorac Surg. 2008; 34: 418-422Google Scholar]. This, together with tissue decellularization with ionic detergents or enzyme extraction, followed by endogenous cell repopulation after implantation [39Della Barbera M. Valente M. Basso C. Thiene G. Morphologic studies of cell endogenous regulation in decellularized aortic and pulmonary homografts implanted in sheep.Cardiovasc Pathol. 2015; 24: 102-109Google Scholar], may also represent the future in the field. The role of PB and other tissue valves might be questioned by further developments of less-invasive valve replacement techniques such as transcatheter aortic valve implantation (TAVI). However, although the mid-term results available for TAVI are encouraging, little is known about durability of TAVI devices beyond 5 years from implantation. From previous clinical and pathologic experience with surgically implanted bioprostheses, follow-up studies at 10 or more years in large populations are requested to endorse the use of TAVI in young patients or in patients with a low-risk profile even as possible future valve-in-valve treatment [40Bagur R. Pibarot P. Otto C.M. Importance of the valve durability-life expectancy ratio in selection of a prosthetic aortic valve.Heart. 2017; 103: 1756-1759Google Scholar]. The past year marked the 50th anniversary of the implant of the first commercially manufactured PB. Since then enough clinical and pathologic experience was accumulated to identify tissue calcification as the major cause of SVD and PB failure and to suggest the most important innovations needed to eliminate or at least delay such complication to increase PB durability. Today, PBs are devices that still have an important role in the surgical treatment of valvular heart disease. Demonstration of more extended durability by further follow-up studies may allow a decreased age limit for implantation to younger subjects. This should contrast effectively the rapidly expanding role of catheter-based interventions, trying to reserve such techniques at a later age as valve-in-valve procedures, should PB failure require a reintervention.