Morphologic findings and causes of failure in 24 explanted Ionescu-Shiley low-profile pericardial heart valves.

From 1981 to 1987 just over 608 Ionescu-Shiley low-profile bovine pericardial bioprostheses were implanted at the Toronto Hospital. Twenty-four prostheses (11 aortic and 13 mitral) were surgically explanted from 1988 to 1990 from 20 adults (10 men and 10 women). Prosthesis failure was caused by primary tissue failure in 17 valves or by other mechanisms in seven valves. Variable degrees of tissue failure were also seen in four of the seven valves from the latter group. Primary tissue failure was characterized by fluid insudation between collagen bundles, para stent post tears (alignment stitch related, 20 valves), cusp perforation with prolapse, and calcification. The earliest cusp tears occurred at 28 months. Calcification (10 of 24 cases) was minimal in seven of 10 valves (occurring primarily at the margins of the torn cusp), moderate in two, and severe in one. Tissue overgrowth (pannus) was seen in all but three prostheses. Like its predecessor, the Ionescu-Shiley standard pericardial valve, this prosthesis failed at 2 to 5 years largely due to design-related (alignment stitch) causes and tissue degeneration. Calcification was less prominent, while tissue overgrowth (pannus) was more marked.     

Novel "biomechanical" polymeric valve prostheses with special design for aortic and mitral position: a future option for pediatric patients?

In children, systemic heart valve replacement with bioprostheses is associated with accelerated valve degeneration, and mechanical prostheses require permanent anticoagulation. Novel "biomechanical" polymeric valve prostheses ("bio" = flexible, "mechanical" = synthetic), solely made of polycarbonate urethane (PCU), were tested in vitro and in a growing animal (calf) model with the aim of improved durability without permanent anticoagulation. The trileaflet aortic prosthesis has diminished pressure loss and reduced stress and strain peaks. The asymmetric bileaflet mitral valve mimics natural nonaxial inflow. The valves underwent long-term in vitro testing and in vivo testing in growing calves for 20 weeks [mitral (7), aortic (7)] with comparison to different commercial bioprostheses [mitral (7), aortic (2)]. In vitro durability of PCU valves was proved up to 20 years. Survival of PCU valves versus bioprostheses was 7 versus 2 mitral and 5 versus 0 aortic valves, respectively. Two animals with PCU aortic valves died of pannus overgrowth causing left ventricular outflow tract obstruction. Degeneration and calcification were mild (mitral) and moderate (aortic) in PCU valves but were severe in biological valves. There was no increased thrombogenicity of the PCU valves compared to bioprostheses. The novel polymeric valve prostheses revealed superior durability compared to current bioprostheses in growing animal model without permanent anticoagulation and thus, may be a future option for pediatric patients.     

An analysis of autopsy findings in 108 patients who died after valve replacement

The pathological findings and the causes of death were reviewed in 108 patients who had received 142 heart valve prostheses (52 mechanical and 90 bioprostheses) at the National Cardiovascular Center in Osaka, Japan, from 1977 to 1991. Rheumatic heart disease was the major underlying disease (60.2%), and the age distribution at death ranged from 21 to 80-year-old. Survival duration after the surgery extended from 0 day to 9 years. Thirty-three patients (30.6%) died of perioperative complications such as myocardial haemorrhage and damage, or from heart failure which had been evident prior to the operation, a cause of death which predominated in patients who died within 1 week of surgery (15/17; 88.2%). Thirty-eight patients (35.2%) died of prostheses-related problems such as prosthetic valve failure (cuspal tears and calcifying destruction of the xenograft), thromboembolism, and prosthetic valve endocarditis. Endocarditis was frequent in patients who had survived longer than 1 year (25/33; 75.8%). None of the patients died of prostheses-related problems within 1 week. Non-infectious valve failure was more common in patients with bioprostheses than in those with mechanical valves; thromboembolism showed the opposite association. Prosthetic valve infective endocarditis was nearly equal in frequency in both types of valve.     

Stability and function of glycosaminoglycans in porcine bioprosthetic heart valves

Glycosaminoglycans (GAGs) are important structural and functional components in native aortic heart valves and in glutaraldehyde (Glut)-fixed bioprosthetic heart valves (BHVs). However, very little is known about the fate of GAGs within the extracellular matrix of BHVs and their contribution to BHV longevity. BHVs used in heart valve replacement surgery have limited durability due to mechanical failure and pathologic calcification. In the present study we bring evidence for the dramatic loss of GAGs from within the BHV cusp structure during storage in saline and both short- and long-term Glut fixation. In order to gain insight into role of GAGs, we compared properties of fresh and Glut-fixed porcine heart valve cusps before and after complete GAG removal. GAG removal resulted in significant morphological and functional tissue alterations, including decreases in cuspal thickness, reduction of water content and diminution of rehydration capacity. By virtue of this diminished hydration, loss of GAGs also greatly increased the "with-curvature" flexural rigidity of cuspal tissue. However, removal of GAGs did not alter calcification potential of BHV cups when implanted in the rat subdermal model. Controlling the extent of pre-implantation GAG degradation in BHVs and development of improved GAG crosslinking techniques are expected to improve the mechanical durability of future cardiovascular bioprostheses.     

The effect of glycosaminoglycan stabilization on tissue buckling in bioprosthetic heart valves

Bioprosthetic valves are used in thousands of heart valve replacement surgeries. Existing glutaraldehyde-crosslinked bioprosthetic valves fail due to either calcification or degeneration. Glutaraldehyde crosslinking does not stabilize valvular glycosaminoglycans (GAGs). GAGs, predominantly present in the medial spongiosa layer of native heart valve cusps, play an important role in regulating physico-mechanical behavior of the native cuspal tissue during dynamic motion. The primary objective of this study was to identify the role of cuspal GAGs in valve tissue buckling. Glutaraldehyde-crosslinked cusps showed extensive buckling compared to fresh, native cusps. Removal of GAGs by treatment with GAG-degrading enzymes led to a marked increase in buckling behavior in glutaraldehyde-crosslinked cusps. We demonstrate that the retention of valvular GAGs by carbodiimide crosslinking together with chemical attachment of neomycin trisulfate (a hyaluronidase inhibitor), prior to glutaraldehyde crosslinking, reduces the extent of buckling in bioprosthetic heart valves. Furthermore, following exposure to GAG-digestive enzymes, neomycin-trisulfate-bound cusps experienced no alterations in buckling behavior. Such moderate buckling patterns mimicked that of fresh, untreated cusps subjected to similar bending curvatures. Thus, GAG stabilization may subsequently improve the durability of these bioprostheses.     

Amyloid deposits in bioprosthetic cardiac valves after long-term implantation in man. A new localization of amyloidosis

Congo red staining with microscopic examination under polarized light was performed in 30 porcine bioprosthetic cardiac valves and one autologous fascia lata valve explanted from 31 patients in order to detect the presence of amyloid. Microdeposits of amyloid were present in the sewing ring of the fascia lata valve and in 10 porcine bioprostheses, and this finding was confirmed by transmission electron microscopy in 3 porcine bioprostheses. All amyloid-laden porcine valves had been implanted for at least 33 months before removal, and all except two showed dysfunction and/or severe degeneration of cuspal tissue. Statistical analyses failed to establish any correlation between the presence of amyloid and patient-related factors. In a majority of porcine bioprostheses amyloid was permanganate-sensitive and tryptophan-positive. The pathogenesis of this new form of heart valve amyloidosis might consist in penetration of human macrophages in deteriorated bioprosthetic cusps and their interaction with blood-borne amyloid precursors.     

Inflammation and infection in nine surgically explanted Medtronic Freestyle stentless aortic valves.

BACKGROUND: The Medtronic Freestyle valve is fixed in glutaraldehyde at zero pressure on the cusps and treated with alpha-amino oleic acid. This valve reportedly has excellent clinical and hemodynamic results, but little has been reported about its long-term pathology. METHODS AND RESULTS: Nine Freestyle valves explanted between 2003 and 2005 were reviewed to assess the reasons for bioprosthesis failure (six implanted at our institution). All valves were examined in detail, using histochemistry and immunohistochemistry to identify the cellular response. One Freestyle valve, explanted for mitral valve endocarditis on the fifth postoperative day, was excluded from analysis. Average implant duration was 52.8+/-35.5 months. Four valves were explanted for infective endocarditis, three for aortic insufficiency, two for aortic stenosis with cusp calcification seen in five valves, pannus and thrombus in all valves and a chronic inflammatory reaction involving the xenograft arterial wall seen in eight of nine valves. This was associated with significant damage to the porcine aortic wall in seven cases, and cusp myocardial shelf damage in six cases. CONCLUSIONS: In this series of valves, we found (1) infective endocarditis; (2) pannus, thrombus, and calcification; and (3) unusual and significant inflammatory reaction and aortic tissue damage, which could by itself lead to aortic incompetence.     

Pathological findings in explanted prosthetic heart valves from ventricular assist devices

AIMS: Ventricular assist devices (VADs) are now a mainstay in the management of patients with end-stage heart failure. An important consideration in the long-term durability of these devices is the structural integrity of the prosthetic valves. Herein, we report the morphological findings in inflow and outflow explanted bioprostheses from seven such devices. METHODS: The porcine bioprostheses (n = 7; HeartMate, Novacor) were examined from inflow and outflow valve conduits. Cusp tears were assessed on gross examination. Tissues were then processed for histology and graded for pannus, thrombus, and calcification. Immunohistochemistry was performed using anti-CD68 (macrophages), CD45 (leukocytes) and CD31 (endothelial cells) antibodies to assess inflammation. RESULTS: There was no evidence of infection, host tissue growth, or calcification in either the inflow or the outflow valves in any case. A mild-to-moderate mononuclear cell 'deposit' was present on all porcine bioprostheses, largely on the non-flow surface of the valve cusps. In the case of the longest implant (HeartMate, duration 567 days), a significant mononuclear cell infiltrate was seen on the flow surface, the non-flow surface, as well as the base of the cusp tissue. Variably sized cusp tears were found in all inflow porcine bioprostheses at and beyond 3 months post-implantation, with the longest duration implant showing multiple tears. No tears were identified in the outflow valves. Histology revealed thrombus deposition in all inflow and outflow porcine valves. In addition, inflow valve cusps were characterised by the presence of longitudinally running 'cystic' spaces, which seem to increase in size with increasing implant duration. CONCLUSION: Bioprosthetic heart valves in VADs show significant changes which appear to correlate with duration post-implantation. These changes suggest that haemodynamic forces and the inflammatory reaction may play a significant role in the long-term durability of the porcine bioprostheses in these devices.     

Morphological findings in explanted Toronto stentless porcine valves.

BACKGROUND: Stentless porcine valves have many documented advantages over stented valves. Since its introduction in 1991, the Toronto stentless porcine valve (T-SPV) has shown excellent hemodynamic performance. METHODS: A total of 332 T-SPVs have been implanted at our institution up to December 2003, 25 of which have been explanted at surgery. Herein, we report a study of 30 explanted T-SPVs seen at our institution over a 5-year period. RESULTS: The mean patient age at explant was 61.2+/-11.8 years with a mean implant duration of 100.7+/-27.8 months (after excluding one valve removed early postoperatively for infective endocarditis). Twenty-seven of 30 valves (90%) showed structural deterioration characterized by tissue degeneration, cusp tears, calcification, and lipid insudation. Eight valves (26.7%) showed evidence of calcification on gross inspection and a total of 23 valves (76.7%) showed at least one microscopic focus of calcification, located primarily in the basal and commissural regions of the cusp. Twenty valves (66.6%) showed cusp tears. Pannus was visible grossly on the surface of 27 of 30 valves (90%), while histologically, at least some degree of pannus was observed on both the inflow and outflow surfaces of all but two valves. Twelve T-SPV (40.0%) showed calcification in the porcine aortic tissue, four of which involved calcification of the porcine muscle shelf in the right coronary cusp. Two T-SPV showed no significant structural deterioration. Their clinical reason for explantation was incompetence or infective endocarditis. CONCLUSION: With a freedom from reoperation of about 87.0% at up to 10 years, the T-SPV shows excellent durability. The majority of explanted valves show structural valve deterioration similar to that seen in other porcine heart valves.     

Amyloid deposits in aortic and mitral valves

Summary The material from 100 consecutive aortic and mitral valve operations has been studied histologically with particular reference to the presence of amyloid deposits. Sixty seven per cent were positive (aortic 88%, mitral 45%).The simultaneous occurrence of calcification of the valves and amyloid degeneration as well as of calcification and hyalinization was significant. Similarly there was significantly more amyloid in the older age groups, as well as a significant correlation between the degree of hyalinization of the valve and amyloid.]Thirty-two patients had previously suffered from rheumatic fever. The heart valves of these patients did not differ histologically from the others, whereas significantly more amyloid was observed in the stenotic mitral valves than in the mitral valves which were insufficient.     

Periodate-mediated glycosaminoglycan stabilization in bioprosthetic heart valves

Bioprosthetic heart valves (BPHVs) derived from glutaraldehyde-crosslinked porcine aortic valves are frequently used in heart valve replacement surgeries. However, the majority of bioprostheses fail clinically because of calcification and degeneration. We have recently shown that glycosaminoglycan (GAG) loss may be in part responsible for degeneration of glutaraldehyde-crosslinked bioprostheses. In the present studies, we used a mild reaction of periodate-mediated crosslinking to stabilize glycosaminoglycans in the bioprosthetic tissue. We demonstrate the feasibility of periodate reaction by crosslinking major components of extracellular matrix of bioprosthetic heart valve tissue, namely type I collagen and hyaluronic acid (HA). Uronic acid assay of periodate-fixed HA-collagen matrices showed 48% of HA disaccharides were bound to collagen. Furthermore, we show that such reactions are also feasible to fix glycosaminoglycans present in the middle spongiosa layer of bioprosthetic heart valves. The periodate reactions were compatible with conventional glutaraldehyde crosslinking and showed adequate stabilization of extracellular matrix as demonstrated by thermal denaturation temperature and collagenase assays. Moreover, uronic acid assays of periodate-fixed BPHV cusps showed 36% reduction in the amount of unbound GAG disaccharides as compared with glutaraldehyde-crosslinked cusps. We also demonstrate that calcification of BPHV cusps was significantly reduced in the periodate-fixed group as compared with the glutaraldehyde-fixed group in 21-day rat subdermal calcification studies (periodate-fixed tissue Ca 72.01 +/- 5.97 microg/mg, glutaraldehyde-fixed tissue Ca 107.25 +/- 6.56 microg/mg). We conclude that periodate-mediated GAG fixation could reduce structural degeneration of BPHVs and may therefore increase the useful lifetime of these devices.     

Collagen fiber disruption occurs independent of calcification in clinically explanted bioprosthetic heart valves

The durability of bioprosthetic heart valves (BHV) is severely limited by tissue deterioration, manifested as calcification and mechanical damage to the extracellular matrix. Extensive research on mineralization mechanisms has led to prevention strategies, but little work has been done on understanding the mechanisms of noncalcific matrix damage. The present study tested the hypothesis that calcification-independent damage to the valvular structural matrix mediated by mechanical factors occurs in clinical implants and could contribute to porcine aortic BHV structural failure. We correlated quantitative assessment of collagen fiber orientation and structural integrity by small angle light scattering (SALS) with morphologic analysis in 14 porcine aortic valve bioprostheses removed from patients for structural deterioration following 5-20 years of function. Calcification of the explants varied from 0 (none) to 1+ (minimal) to 4+ (extensive), as assessed radiographically. SALS tests were performed over entire excised cusps using a 0.254-mm spaced grid, and the resultant structural information used to generate maps of the local collagen fiber damage that were compared with sites of calcific deposits. All 42 cusps showed clear evidence of substantial noncalcific structural damage. In 29 cusps that were calcified, structural damage was consistently spatially distinct from the calcification deposits, generally in a distribution similar to that noted in porcine BHV subjected to in vitro durability testing. Our results suggest a mechanism of noncalcific degradation dependent on cuspal mechanics that could contribute to porcine aortic BHV failure.     

Matrix metalloproteinases in the pathology of natural and bioprosthetic cardiac valves

Degenerative dysfunction of cardiac valves may be accounted for by uncontrolled extracellular matrix degradation processes in which matrix metalloproteinases could play a major role. In this study, 24 pathologic human valves and 26 pericardial-derived bioprostheses were analysed for metalloproteinases by gelatin zymography. Compared to controls, human stenotic valves and bioprostheses explanted because of either calcifying or noncalcifying degeneration revealed three notable biochemical aspects: (1) an amplification in the levels of metalloproteinase 9 (gelatinase B), suggestive of its active role in valvular pathology; (2) minimal modifications in the gelatinolytic levels of metalloproteinase 2 (gelatinase A), indicative of a constitutive secretion; and (3) activation products derived from both gelatinase A and B. All gelatinolytic activities identified in pathologic specimens were inhibited in vitro by zinc and calcium chelators (captopril, doxycycline, dithiothreitol, and ethylenediaminotetraacetic acid), suggesting potential therapeutic approaches. High levels of beta-glucuronidase (a lysosomal marker enzyme for phagocytic cells) were found in human calcified stenotic valves and in ruptured and calcified pericardial-derived bioprostheses. Mononuclear recruitment was minimal to moderate in pathologic human valves, and in noncalcified ruptured bioprostheses infiltrating mononuclear cells were concentrated in large numbers at the cuspal free edge. These findings suggest the involvement of infiltrating phagocytic cells and putative common mechanisms in the degeneration of both the natural and the bioprosthetic valvular extracellular matrix (ECM).     

猪主动脉生物瓣远期损坏的病理学观察

对３６ 例植入人体内１０７ 个月以上的损坏瓣膜作病理学观察。基本病损：９４－４４ ％ 为钙化、３６－１１％ 为撕裂、１３－２９％ 为穿孔。结果表明,首先瓣叶应力集中区胶原纤维变性产生钙化,新的应用集中区的形成,导致瓣叶撕裂与穿孔,相互促进。早期损坏以钙化为主,而后期常以钙化和撕裂、钙化和穿孔等多种病损因素的复合结果为主。     

Structural changes of glutaraldehyde- treated porcine bioprosthetic valves

Gross anatomic, histologic, and transmission and scanning electron microscopic observations were made of 29 bioprosthetic valves that had been implanted in patients for up to 115 months. On the basis of these morphologic data, no significant evidence of tissue rejection was seen. However, the durability of these valve bioprostheses is still questionable. Our observation primarily emphasize three factors: (1) disruption of the endothelial cell barrier and the lack of significant host endothelialization even 115 months after transplantation; (2) increased permeability that eased diffusion of circulating host plasma proteins into valve tissue, and increased activity of infiltration processes, eg. calcification and lipid accumulation; and (3) biodegradation of the collagen framework. Each of these factors may contribute further to valve dysfunction. Development of an intimal fibrous sheath seems to occur in porcine bioprostheses that have been implanted for the longest periods of time, but the rate of host tissue ingrowth varies.     

Founder's Award, 25th Annual Meeting of the Society for Biomaterials, perspectives. Providence, RI, April 28-May 2, 1999. Tissue heart valves: current challenges and future research perspectives.

Substitute heart valves composed of human or animal tissues have been used since the early 1960s, when aortic valves obtained fresh from human cadavers were transplanted to other individuals as allografts. Today, tissue valves are used in 40% or more of valve replacements worldwide, predominantly as stented porcine aortic valves (PAV) and bovine pericardial valves (BPV) preserved by glutaraldehyde (GLUT) (collectively termed bioprostheses). The principal disadvantage of tissue valves is progressive calcific and noncalcific deterioration, limiting durability. Native heart valves (typified by the aortic valve) are cellular and layered, with regional specializations of the extracellular matrix (ECM). These elements facilitate marked repetitive changes in shape and dimension throughout the cardiac cycle, effective stress transfer to the adjacent aortic wall, and ongoing repair of injury incurred during normal function. Although GLUT bioprostheses mimic natural aortic valve structure (a) their cells are nonviable and thereby incapable of normal turnover or remodeling ECM proteins; (b) their cuspal microstructure is locked into a configuration which is at best characteristic of one phase of the cardiac cycle (usually diastole); and (c) their mechanical properties are markedly different from those of natural aortic valve cusps. Consequently, tissue valves suffer a high rate of progressive and age-dependent structural valve deterioration resulting in stenosis or regurgitation (>50% of PAV overall fail within 10-15 years; the failure rate is nearly 100% in 5 years in those <35 years old but only 10% in 10 years in those >65). Two distinct processes-intrinsic calcification and noncalcific degradation of the ECM-account for structural valve deterioration. Calcification is a direct consequence of the inability of the nonviable cells of the GLUT-preserved tissue to maintain normally low intracellular calcium. Consequently, nucleation of calcium-phosphate crystals occurs at the phospholipid-rich membranes and their remnants. Collagen and elastin also calcify. Tissue valve mineralization has complex host, implant, and mechanical determinants. Noncalcific degradation in the absence of physiological repair mechanisms of the valvular structural matrix is increasingly being appreciated as a critical yet independent mechanism of valve deterioration. These degradation mechanisms are largely rationalized on the basis of the changes to natural valves when they are fabricated into a tissue valve (mentioned above), and the subsequent interactions with the physiologic environment that are induced following implantation. The "Holy Grail" is a nonobstructive, nonthrombogenic tissue valve which will last the lifetime of the patient (and potentially grow in maturing recipients). There is considerable activity in basic research, industrial development, and clinical investigation to improve tissue valves. Particularly exciting in concept, yet early in practice is tissue engineering, a technique in which an anatomically appropriate construct containing cells seeded on a resorbable scaffold is fabricated in vitro, then implanted. Remodeling in vivo, stimulated and guided by appropriate biological signals incorporated into the construct, is intended to recapitulate normal functional architecture.     

Bioprosthetic heart valves: modes of failure

Valve replacement started in 1960, with the surgeon now having a significant variety of prosthetic heart valves from which to choose. These valves are broadly divided into mechanical heart valves (MHV) and bioprosthetic heart valves (BHV). Improvements in the performance and ease of usage of BHV without the need for anticoagulant therapy are among the desired features of BHV and hence the increasingly preferred choice over their mechanical counterparts. However, with increased use the post-implantation complications have become more apparent, and these include: calcification, cusp tears, pannus growth, infective endocarditis, valve thrombosis and other factors specific to valve type. In this review we describe these complications in order to bring awareness among surgeons, clinicians and pathologists. Diagnosis, treatment and preventive measures, if taken in a timely manner, can help reduce their impact and further enhance the quality of life of patients with prosthetic heart valves.     

Ionescu-Shiley bovine pericardial bioprostheses. Histologic and ultrastructural studies.

Studies were done on the structural changes that develop in Ionescu-Shiley valves that are used as replacement heart valves for 4 to 8 years. These changes were compared with those found in similarly used porcine aortic valve (PAV) bioprostheses. A variety of morphologic differences were observed between bovine pericardial valve (BPV) and PAV bioprostheses after orthotopic implantation including: primary tissue failure associated with the use of an alignment suture, thickening of valve leaflet, leaflet tissue delamination, leaflet calcification, and dystrophic alterations of collagen. These findings indicate that valve design criteria directly influence the durability of pericardial valves. However, other factors unique to pericardial tissue also affect the durability and performance of BPVs. These factors include the inability of pericardial tissue to accommodate dynamic stresses; the extensive insudation of plasma proteins and lipids; and the inability to reduce leaflet calcification using agents that effectively mitigate calcification in PAV bioprostheses.     

Mechanisms of bioprosthetic heart valve failure: fatigue causes collagen denaturation and glycosaminoglycan loss.

Bioprosthetic heart valve (BPHV) degeneration, characterized by extracellular matrix deterioration, remodeling, and calcification, is an important clinical problem accounting for thousands of surgeries annually. Here we report for the first time, in a series of in vitro accelerated fatigue studies (5-500 million cycles) with glutaraldehyde fixed porcine aortic valve bioprostheses, that the mechanical function of cardiac valve cusps caused progressive damage to the molecular structure of type I collagen as assessed by Fourier transform IR spectroscopy (FTIR). The cyclic fatigue caused a progressive loss of helicity of the bioprosthetic cuspal collagen, which was evident from FTIR spectral changes in the amide I carbonyl stretching region. Furthermore, cardiac valve fatigue in these studies also led to loss of glycosaminoglycans (GAGs) from the cuspal extracellular matrix. The GAG levels in glutaraldehyde crosslinked porcine aortic valve cusps were 65.2 +/- 8.66 microg uronic acid/10 mg of dry weight for control and 7.91 +/- 1.1 microg uronic acid/10 mg of dry weight for 10-300 million cycled cusps. Together, these molecular changes contribute to a significant gradual decrease in cuspal bending strength as documented in a biomechanical bending assay measuring three point deformation. We conclude that fatigue-induced damage to type I collagen and loss of GAGs are major contributing factors to material degeneration in bioprosthetic cardiac valve deterioration.