Pulmonary site bioprostheses: morphologic findings in 40 cases.
Abstract: Context.--From January 1995 to June 2003, there were 514 patients who underwent pulmonary valve replacements at either the Hospital for Sick Children or Toronto General Hospital. Fifty-four (10.5%) of these adults returned for replacement of their prostheses because of failure. Forty (74.1%) of the 54 explants were bioprostheses, and 14 (25.9%) were homografts.

Objective.--To present the morphologic findings from this consecutive series of 40 pulmonary-site bioprostheses.

Design.--Data were obtained by review of pathologic, clinical, and surgical records for all 40 patients with bioprosthetic pulmonary valves explanted from 1995 to June of 2003.

Results.--The mean duration of valve implantation was 14.3 [+ or -] 5.2 years (2-26 years). Median age at implantation was 16.7 [+ or -] 10.3 years (range, 3 months to 53 years). Structural valve deterioration was found in 39 (97.5%) of the valves. Morphologic evidence of stenosis was found in all valves, whereas incompetence was found in 28 (70.0%). Calcification was present in 32 (80.0%) of the valves and was severe and diffuse in 22 (55.0%). Host tissue overgrowth, or pannus, was present on 39 (97.5%) of the valves and was severe in 35 (87.5%). Tears were present in 19 (47.5%) of the valves.

Conclusions.--Explanted bioprostheses showed a high degree of calcification and pannus, which together led to stenosis. Cusp immobilization, involving all 3 cusps, was frequent and was more common in patients younger than 30 years of age at explantation (P < .001). Host-tissue overgrowth is a significant problem with bioprostheses, and pulmonary-site bioprostheses are no exception.

(Arch Pathol Lab Med. 2009;133:797-802)
Article Type: Clinical report
Subject: Cardiovascular instruments, Implanted (Usage)
Cardiovascular instruments, Implanted (Health aspects)
Children's hospitals (Research)
Congenital heart disease (Diagnosis)
Congenital heart disease (Care and treatment)
Congenital heart disease (Patient outcomes)
Morphology (Analysis)
Authors: Soor, Gursharan S.
Leong, Shaun W.
Butany, Jagdish
Shapero, Jonathan L.
Williams, William G.
Pub Date: 05/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: May, 2009 Source Volume: 133 Source Issue: 5
Topic: Event Code: 310 Science & research
Product: SIC Code: 3842 Surgical appliances and supplies
Geographic: Geographic Scope: Canada Geographic Code: 1CANA Canada
Accession Number: 230152003
Full Text: Although many previous studies (1-11) have reported findings in bioprosthetic heart valves, very few have focused on right-sided valves. Herein, we report a series of pulmonary-site tissue valves explanted between January 1995 and June 2003, with an emphasis on morphologic findings.

The Toronto General Hospital and Toronto's Hospital for Sick Children have a long history of pulmonary valve replacement surgery for congenital heart disease, with a total of 1081 patients receiving 1335 pulmonary valve implants (including valves in conduits), as allografts or bioprostheses. There were 514 living, adult patients (age >18 years) who underwent valve replacement from January 1995 to June 2003 at these facilities. Fifty-four (10.5%) of these adults required reoperation and valve replacement because of failed prosthetic valves. Forty (74.1%) of the explanted valves were bioprostheses, and 14 (25.9%) were allografts.

MATERIALS AND METHODS

Data were obtained by review of pathologic, clinical, and surgical records. All pulmonary valve bioprostheses explanted from January 1995 to June 2003 at Toronto General Hospital have been included in the current study. Most of these prosthetic heart valves had not been treated with antimineralization agents.

All explanted prostheses were examined radiologically, grossly and histologically, by one author (J.B.). The biologic parts of the valves were removed from the superstructure (plastic-metal-fabric framework) and decalcified. Sections were then submitted for histologic processing. Paraffin-embedded sections were cut at 4 to 5 [micro]m and stained with hematoxylin-eosin. A Movat pentachrome stain (for collagen and elastic tissue) was obtained. Additional sections for microorganisms (Gram stain and Gomori methenamine silver) were obtained if infective endocarditis was suspected. Histologic examination was performed to document the severity and location (cusps and/or porcine aorta) of pannus, calcification, thrombus, inflammation, and tissue degeneration. The sections were examined using a Leica DMRB microscope (Leica Systems, Toronto, Ontario, Canada), and photomicrographs were obtained using a Leica digital camera (DC 500, Leica).

Cusp tears were classified according to Ishihara et al. (12) Type I tears involved the free edges of the cusps. Type II lesions were linear perforations along the base of the cusps parallel to the sewing ring. Type III lesions were large perforations in the center of the cusps, and type IV lesions were pinholelike perforations in the cusps.

Host-tissue overgrowth, or pannus, was classified according to Butany et al. (13) In this system, pannus covering part of the circumference of the valve sewing ring was classified as mild. Pannus covering the whole width of the ring and up to 2 mm of the cuspal tissue was considered moderate, and severe pannus was indicated with coverage of greater than 2 mm of the basal portion of a valve cusp.

[FIGURE 1 OMITTED]

Fisher exact test was used for contingency analysis of categoric variables. Student t test was used for analysis of continuous variables. All statistical tests were performed at a significance level of P < .05.

RESULTS

The 40 bioprosthetic valves were explanted from 19 (47.5%) women and 21 (52.5%) men. They were implanted for a mean of 14.3 [+ or -] 5.2 years (range, 2 to 26 years). The average patient age at the time of valve implantation was 16.7 [+ or -] 10.3 years (range, 3 months to 53 years). For many patients, the explanted valve was not their first prosthetic valve in that position, and hence, the average age of patients at the time of the first implant would be somewhat younger, 10.3 [+ or -] 8.0 years. For all cases, significant valvular dysfunction was seen on echocardiography, before explantation.

The primary indication for valve implantation was tetralogy of Fallot (n = 22; 55.0%) followed by transposition of the great arteries (n = 7; 17.5%), pulmonary atresia (n = 5;12.5%), double outlet right ventricle (n = 4;10.0%), and truncus arteriosus (n = 2; 5.0%). Nineteen (47.5%) of the explanted bioprostheses were of the Hancock variety (Medtronic Heart Valve Division, Irvine, Calif), 13 (32.5%) were Ionescu-Shiley valves (Shiley Heart Valve Research Center, Irvine, Calif), and 8 (20%) were Carpentier-Edwards bioprostheses (Baxter Healthcare Corporation, now Edwards Life Sciences, Irvine, Calif; Figure 1).

[FIGURE 2 OMITTED]

The morphologic features associated with structural valve deterioration (SVD) included collagen degeneration, calcification, prolapse, increased cusp stiffness/cusp immobilization, fluid insudation, fibrosis and cusp tears (Figures 2 through 4). A total of 39 (97.5%) of the valves showed evidence of SVD (97.5%). The only valve that did not show evidence of SVD was a Hancock valve that had been in place for 2 years (the shortest duration in this series) and was explanted because of severe pannus-causing valvular stenosis. Evidence of stenosis was found in all 40 (100.0%) of the cases. Valvular incompetence was determined based on cusp tears and cusp immobilization. In total, 28 (70.0%) of the valves were incompetent. The average implant duration of incompetent valves was 13.2 [+ or -] 4.6 years, and the average implant duration of nonincompetent valves was 16.8 [+ or -] 6.0 years. This difference was statistically significant (P = .04). Overall, 27 (67.5%) of the valves showed all 3: SVD, stenosis, and incompetence. One valve in this series was explanted because of infective endocarditis. This valve had been in place for 12 years, and also showed SVD, stenosis and incompetence. Morphologic findings are summarized in the Table.

Calcification

Calcification was present in 32 (80.0%) of the valves (Figure 3). The calcification was severe and diffuse in 22 (55.0%) of the cases. In 2 (5.0%) of the cases, the calcification was so severe that it formed a plate or platelike layer over the valve cusps. A third case showed areas of both platelike and nodular calcification in separate areas.

Valves with calcification had been implanted for a mean of 14.7 [+ or -] 4.9 years (range, 7 to 26 years). Among the 9 (22.5%) prostheses implanted for less than 10 years, calcification was severe and diffuse in 3 (33.3%) of the cases, whereas among the 31 (77.5%) prostheses implanted for more than 10 years, calcification was severe and diffuse in 19 (61.3%) (P = .25).

[FIGURE 3 OMITTED]

Pannus

Pannus was present on 39 (97.5%) of the explanted specimens. The one case where there was no evidence of pannus was a conduit in which most of the cuspal tissue had been destroyed. Severe pannus was found on 35 (87.5%) of the specimens, often covering both the flow and non-flow surfaces, with extensions to the free margins. Of the remaining valves, 1 (2.5%) demonstrated moderate pannus, 1 (2.5%) of the valves displayed mild pannus, and 2 (5.0%) of the cases could not be categorized because of partial destruction of cusp tissue.

Cusp Immobilization

Significant pannus led to valve cusps immobilization in 22 (55.0%) of the specimens. All 3 cusps were immobilized in 17 (42.5%) of the cases, and all 17 of these had calcification in addition to pannus. Nine (52.9%) of these 17 specimens had all 3 cusps immobilized in a partially open position. Pannus extending onto both the flow and non-flow cuspal surfaces led to retraction of collagen and shortening of the cusp (Figure 2). In 4 (10.0%) of the 40 cases, all 3 cusps were immobilized in the fully open position. There were 2 (5.0%) of the cases with all 3 cusps immobilized in a closed position.

Tears

Tears were present in 18 (45.0%) of the valves. These valves were in place for an average of 14.3 [+ or -] 4.3 years. Nine (22.5%) of the valves showed multiple tears. Overall, there was one type III tear, with the rest of the tears being type I. The type III tear was an oval perforation at the center of one cusp of a Carpentier-Edwards porcine valve, measuring 0.4 cm by 0.2 cm. This valve had been in place for 18 years and was heavily calcified, with all cusps immobilized in the open position.

Infective Endocarditis

In 1 (2.5%) of the cases, the primary mode of valve failure was infective endocarditis. The explanted device was a conduit with a Carpentier-Edwards porcine bioprosthesis that had been in place for 12 years. Gram positive cocci were present in thrombi on the cusps. The cuspal tissue was not calcified. The wall of the conduit was acutely inflamed and showed signs of necrosis.

Other Changes

In 3 (7.5%) of the cases, structural deterioration was so severe that little cuspal tissue remained at explantation. These valves were implanted for 26, 19, and 9 years. At the time of bioprosthetic valve explantation, these patients were 32, 25, and 24 years old, respectively.

Evidence of thrombi (generally small) was discovered in 11 (27.5%) of the explanted valves. These valves were implanted for 13.1 [+ or -] 4.6 years (range, 7 to 21 years). Cusp prolapse was present in 5 (12.5%) of the cases, of which 2 also demonstrated calcification. In 3 (60.0%) of the 5 cases, only one cusp was prolapsed. All of these valves had tears. In 1 (20.0%) of the cases, 2 cusps were prolapsed, and there was extensive calcification and pannus formation. All 3 cusps were prolapsed in 1 (20.0%) of the cases, and this valve also showed broad pannus formation and extensive calcification.

There was only one case of paravalvular leak. This valve was in place for 13.5 years in a conduit. Two tears were present in this valve, measuring 0.6 cm and 0.3 cm in length, respectively. Despite this finding, there was no evidence of any calcification. The valve did display evidence of thrombus and severe pannus.

[FIGURE 4 OMITTED]

Valve Type

In total, 24 (60.0%) of the valves were porcine aortic (Hancock/Carpentier-Edwards) and 16 (40.0%) were bovine pericardial (Ionescu-Shiley low-profile). The porcine bioprostheses were in place 15.3 [+ or -] 5.8 years, whereas the pericardial valves were in place for 12.7 [+ or -] 3.6 years. Calcification was present in 20 (83.3%) of the porcine valves as compared with 12 (75.0%) of the pericardial valves; severe calcification was seen in 12 (50.0%) versus 10 (62.5%) of the valves, respectively. Cusp immobilization was similar in both groups as well, with 54.2% (n = 13) of the porcine valves having one cusp immobilized versus 56.3% (n = 9) in the pericardial group. All 3 cases of severe SVD causing cusp destruction were from porcine valves, comprising 18.8% of the porcine group. Differences in the above morphologic changes of porcine versus bovine pericardial valves did not reach statistical significance.

Nineteen (47.5%) of the explanted pulmonary valves were in conduits. These valves were in place for 15.9 [+ or -] 5.0 years. The remaining 21 (52.5%) bioprostheses were orthotopic implants. The orthotopic implants were in place for 12.8 [+ or -] 4.9 years. Pannus was severe in 15 (78.9%) of the conduits, and mild in 1 (5.3%), whereas the remaining 3 (15.8%) of the valves in conduits could not be assessed because of extensive cusp destruction. In the orthotopically placed series, pannus was severe in 20 (95.2%) of the 21 cases and moderate in 1 (4.8%). Evidence of pannus extending to, or near, the free margin was found on 10 (52.6%) of the 19 valve conduits and 6 (28.6%) of the 21 orthotopically placed valves. Fourteen (73.7%) of the 19 valve conduits were calcified compared with 18 (85.7%) of the 21 orthotopically placed valves. Differences in morphologic features of valves from conduits versus orthotopic implants did not demonstrate statistical significance.

Nineteen (47.5%) of the 40 patients were younger than 30 years at the time of valve explantation. Fourteen (73.7%) of these 19 patients had immobilization of all 3 valve cusps. In those older than 30 years of age, 3 (14.3%) had immobilization of all 3 cusps, a statistically significant difference (P < .001). In the younger age group, 11 (57.9%) of the explanted valves showed severe and diffuse calcification as did 11 (52.4%) of the valves in the older age group. Eight (42.1% and 38.1%, respectively) of the valves from each age group showed evidence of cusp tears. These differences did not reach statistical significance.

COMMENT

The 40 explanted valves in this series had a relatively long period of bioprosthesis survival (14.3 [+ or -] 5.2 years) in a fairly young patient population. Although left-sided valve explants ranged in duration from 2.2 to 8.5 years in various older studies, (1-3,11,14) we recently reported on a series of Carpentier-Edwards supraannular (Baxter Healthcare Corporation, now Edwards Life Sciences) and Hancock-II (Medtronic Heart Valve Division) porcine bioprostheses that were in place for 13.9 [+ or -] 3.9 and 10.0 [+ or -] 5.1 years, respectively. (13) In the current series of pulmonary explants, the lower pressure load in the right side of the heart likely enhanced the survival of some valves, as 8 (20.0%) of our valve explants were in place for 20 or more years.

Infective endocarditis has been demonstrated as a significant cause of failure in aortic and mitral valve bioprostheses. The occurrence of infective endocarditis has been reported at a linearized rate of 0.6% per patient-year in Carpentier-Edwards porcine valves in the aortic and mitral positions. (15) However, endocarditis was the cause of valve failure in only 1 (2.5%) of the valves in our study. In addition, the only case of paravalvular leak in our patient group occurred in this patient with infective endocarditis, consistent with the theory that paravalvular leak often occurs as a complication of endocarditis. (10) Paravalvular leaks may, in part, be caused by ventricular closing pressures and are, therefore, more common on the left side.

We found pannus almost universally (97.5%) in our cases, with severe pannus present in 87.5% of these explanted valves. These findings are consistent with our recent study of porcine explants, in which pannus was found in 93.9% of cases. (13) Exuberant pannus may be worsened by the longevity of implants, the relatively young age of the patient population, and the narrower right ventricular outflow tract (especially in those with the tetralogy of Fallot) and may be exacerbated by the differences in hemodynamics in the right versus the left side of the heart. Indeed, in early term analysis of pulmonary conduits, a susceptibility to obstruction from pannus formation, in conjunction with the effects of SVD (such as calcification and thrombosis), has been observed. (16) Furthermore, the thickness of pannus has been reported to increase dramatically in valved conduits compared with nonvalved conduits. (17) In a large-scale study of children younger than 18 years of age, more than 90% of prosthetic pulmonary valve re-replacements were due to stenosis. (18) In a separate study of porcine-valved conduits for right ventricular outflow tract reconstruction, a small patient group (n = 16) was found to have a 60% prevalence of severe conduit stenosis at 9 years after implant. (19) A relatively large bioprosthesis, when placed in a comparatively narrow right ventricular outflow tract, likely allows greater tissue-prosthesis contact and more rapid and extensive host-tissue overgrowth. Clearly, the extent of host-tissue overgrowth in pulmonary-valved conduits and orthotopic pulmonary implants is problematic. The exact impact of age and hemodynamic differences compared with the left side is, however, difficult to determine.

Another interesting finding in this series of explanted valves is their low incidence of cusp tears, considering the longevity of the valves and the high incidence of other features of structural deterioration. In our previous series of porcine bioprosthesis, tears were found in 76.1% of explants, compared with 45.0% in the current series. In many cases, severe pannus entirely covered one or more cusps, possibly providing a coating or sheath to the bioprosthesis cusps, thus protecting it from collagen fiber damage that would normally cause tearing. The lower incidence of tearing may also be related to decreased pressures on the right side of the heart compared with the left.

Calcification was found in 80.0% of the pulmonary bioprostheses, most often with severe deposits spread throughout the cuspal tissue. The progression of calcific deposits has been shown to increase with length of implantation. (1) Furthermore, calcification of bioprostheses has been shown to be accelerated in patients younger than 20 years of age (4) and to be less extensive in patients older than 35 years of age. (20) The high degree and severity of calcification and calcification-related changes seen in our study would, therefore, be expected, considering the young patient group analyzed and the relatively long duration of valve implant. Whether or not the lower pressures in the right ventricular outflow tract have any impact on this is difficult to determine. Our study also found a marked increase in cusp immobilization, with a significant rate of cusp immobilization involving all 3 cusps in patients younger than 30 years old at the time of valve explantation. The high incidence of calcification, pannus, and cusp immobilization would have led to clinically significant stenosis in the majority of valves in this series.

CONCLUSION

We have presented data from an 8-year review of explanted pulmonary site bioprostheses, implanted in a young population, mainly for congenital heart disease. There were no statistically significant differences in morphologic findings between different valve types (porcine aortic vs. bovine pericardial). The explanted bioprostheses had a high rate of severe calcification and pannus over-growth, and these changes together led to valve orifice stenosis. Severe cusp immobilization was also a frequent finding, with the immobilization of all 3 cusps being more common in patients younger than 30 years of age (at the time of explantation). The valves in our series were in place for considerably long periods of time. Host-tissue overgrowth is a significant problem with bioprosthetic valves, particularly pulmonary site implants, and needs further evaluation.

Accepted for publication August 19, 2008.

References

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(4.) Milano A, Bortolotti U, Talenti E, et al. Calcific degeneration as the main cause of porcine bioprosthetic valve failure. Am J Cardiol. 1984;53:1066-1070.

(5.) Schoen FJ, Hobson CE. Anatomic analysis of removed prosthetic heart valves: causes of failure of 33 mechanical valves and 58 bioprostheses, 1980 to 1983. Hum Pathol. 1985;16:549-559.

(6.) Schoen FJ, Collins JJ Jr, Cohn LH. Long-term failure rate and morphologic correlations in porcine bioprosthetic heart valves. Am J Cardiol. 1983;51:957 964.

(7.) Valente M, Bortolotti U, Arbustini E, et al. Glutaraldehyde-preserved porcine bioprosthesis: factors affecting performance as determined by pathologic studies. Chest. 1983;83:607-611.

(8.) Valente M, Ius P, Bortolotti U, et al. Fathology of the pericarbon bovine pericardial xenograft implanted in humans. J Heart Valve Dis. 1998;7:180-189.

(9.) Ius P, Thiene G, Minarini M, et al. Low-profile porcine bioprosthesis (Liotta): pathologic findings and mode of failure in the long-term. J HeartValve Dis. 1996; 5:323-327.

(10.) Grabenwoger M, Grimm M, Leukauf C, et al. Failure mode of a new pericardial valve prosthesis (Sorin pericarbon): a morphological study. Eur J Cardiothorac Surg. 1994;8:470-476.

(11.) Isomura T, Yanai T, Akagawa H, et al. Late pathological changes of Carpentier-Edwards porcine bioprostheses in the mitral position. J Cardiovasc Surg (Torino). 1986;27:307-315.

(12.) Ishihara T, Ferrans VJ, Boyce SW, et al. Structure and classification of cuspal tears and perforations in porcine bioprosthetic cardiac valves implanted in patients. Am J Cardiol. 1981;48:665-678.

(13.) Butany J, Leong SW, Cunningham KS, et al. A 10-year comparison of explanted Hancock-II and Carpentier-Edwards supraannular bioprostheses. Car diovasc Pathol. 2007;16:4-13.

(14.) Bernal JM, Rabasa JM, Lopez R, et al. Durability of the Carpentier-Edwards porcine bioprosthesis: role of age and valve position. Ann Thorac Surg. 1995; 60(suppl):248-252.

(15.) Jamieson WRE, Burr LH, Munro AI, et al. Carpentier-Edwards standard porcine bioprosthesis: a 21-year experience. Ann Thorac Surg. 1998;66:S40-43.

(16.) Agarwal KC, Edwards WD, Feldt RH, et al. Clinicopathological correlates of obstructed right-sided porcine-valved extracardiac conduits. J Thorac Cardiovasc Surg. 1981;81:591-601.

(17.) Fiore AC, Peigh PS, Robison RJ, et al. Valved and nonvalved right ventricular-pulmonary arterial extracardiac conduits. J Thorac Cardiovasc Surg. 1983; 86:490-497.

(18.) Caldarone CA, McCrindle BW, Van Arsdell GS, et al. Independent-factors associated with longevity of prosthetic pulmonary valves and valved conduits. J Thorac Cardiovasc Surg. 2000;120:1022-1031.

(19.) Albert JD, Bishop DA, Fullerton DA, et al. Conduit reconstruction of the right ventricular outflow tract. J Thorac Cardiovasc Surg. 1993;106:228-236.

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Gursharan S. Soor, BSc; Shaun W. Leong, BSc; Jagdish Butany, MBBS, MS, FRCPC; Jonathan L. Shapero, MD; William G. Williams, MD

From the Departments of Pathology and Cardiovascular Surgery, Toronto General Hospital and University of Toronto (Messrs Soor and Leong and Drs Butany and Shapero); and the Division of Cardiovascular Surgery, The Hospital for Sick Children, University of Toronto (Dr Williams), Toronto, Ontario. Dr Shapero is now with the Department of Dermatology, University of British Columbia, Vancouver, British Columbia.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Jagdish Butany, MBBS, MS, FRCPC, Department of Pathology, 11E-420, Toronto General Hospital, 200 Elizabeth St, Toronto, ON, Canada M5G 2C4 (e-mail: jagdish.butany@uhn.on.ca).
Morphologic Findings in Explanted Pulmonary
        Bioprosthetic Valves

Morphologic Finding              Total (%)

Stenosis                          40 (100)
Structural valve deterioration   39 (97.5)
Pannus                           39 (97.5)
 Severe and diffuse              35 (87.5)
Incompetence                     28 (70.0)
Calcification                    32 (80.0)
 Severe and diffuse              22 (55.0)
Cusp immobilization              22 (55.0)
 Involving all 3 cusps           17 (42.5)
Cusp tears                       18 (45.0)
Thrombus                         11 (27.5)
Cusp prolapse                     5 (12.5)
Infective endocarditis            1 (2.5)
Paravalvular leak                 1 (2.5)
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