THORACIC AND CARDIOVASC SURGE

Transcription

1 Volume 95, Number 5 The Jqurnal of THORACIC AND CARDIOVASC SURGE Official organ The American Association for Thor The Western Thoracic Surgical Association Editor JOHN W. KIRKLIN, Birmingham, Ala. Associate editor EUGENE H. BLACKSTONE, Birmingham, Ala. THE AMERICAN ASSOCIATION FOR THORACIC SURGERY Next Meeting, May 8-1, 1989 Headquarters, Sheraton HoteljHynes Convention Center, Boston, Massachusetts (See page 943) THE WESTERN THORACIC SURGICAL ASSOCIATION Next Meeting, June 22-25, 1988 Headquarters, Sheraton Royal Waikoloa Hotel, Hawaii (For Program see page 947) Published by The C V. Mosby Company St. Louis, Mo. ISSN University of Michigan Exhibit 23 St. Jude Medical v. University of Michigan IPR

2 Exh. 23 Page 1 Volume 95, Number 5 The Jqurnal of THORACIC AND CARDIOVASC SURGE Official organ The American Association for Thor The Western Thoracic Surgical Association Editor JOHN W. KIRKLIN, Birmingham, Ala. Associate editor EUGENE H. BLACKSTONE, Birmingham, Ala. THE AMERICAN ASSOCIATION FOR THORACIC SURGERY Next Meeting, May 8-1, 1989 Headquarters, Sheraton HoteljHynes Convention Center, Boston, Massachusetts (See page 943) THE WESTERN THORACIC SURGICAL ASSOCIATION Next Meeting, June 22-25, 1988 Headquarters, Sheraton Royal Waikoloa Hotel, Hawaii (For Program see page 947) Published by The C V. Mosby Company St. Louis, Mo. ISSN

3 Exh. 23 Page 2 1 THORAC CARDIOYASC SuRa 1988;95:912-9 Hemodynamic and pathologic evaluation of a unileaflet pericardia! bioprosthetic valve This study investigate<i the in vivo hemodynamics and pathologic changes. of a unileaflet pericardia( bioprosthetic valve 3 to 5 months after implantation in juvenile sheep. Group 1 had 1 sheep with tricuspid valve replacement. 2 had nine sheep with mitral valve replacement. Group 3 served as a control with 1 sheep that had valve replacement with a trileaftet. porcine bioprosthesis. Hemodynamic performance was satisfactory in all three groups despite prominent. pathologic changes, particularly in unileaftet valves. Intrinsic cuspal calcification was present il_l 66% of the unileaftet tricuspid, 88 % unileaftet mitral, and 25 % porcine tricuspid valves. Neither cuspal tearing nor perforations were However, cuspal stretching and redundancy of the mobile cusp was present in six tricuspid, seven mitral unileaftet valves, and. no porcine valves. Gross pericardial redundancy correlated with the microscopic appearance of distorted and separated. collagen bundles. These findings suggest that multiple modes of primary tissue failure may limit the durability of this unileaftet pericardia} valve. Richard J. Shemin, MD, Frederick J. Schoen, MD, PhD, Robert Hein, MD, John Austin, MD, and Lawrence H. Cohn, MD, Boston, Mass. Bioprostheses have advantages over mechanical prostheses including a near-physiologic central flow orifice and superior thromboresistance, usually without longterm anticoagulation. 1-3 Nevertheless, clinically used bioprostheses fabricated from either porcine aortic valve or bovine pericardium fail frequently, often through degenerative processes, most prominently mineralization, which cuspal stiffening or tearing, or both.4-1 Attempts to enhance durability have included improved procurement techniques, low-pressure glutaraldehyde fixation, calcification-retarding substances,. and careful intraoperative handling Recently, new structural designs have appeared that present a of theoretical he!jlodynamic advantages, especially in small annular sizes. The novel unileaflet pericardia! bioprosthesis, developed by Meadox Medicals, Inc. (Oakland, N.1.) has a single leaflet. fabricated from glutaraldehyde-preserved bovine pericardium that in closing meets a pericardiumcovered flexible. Delrin stent. 13 The pericardia! covering of the stent provides a smooth; nonabrasive and throm- From the Departments of Surgery and Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. Received for publication Feb. 17, Accepted for publication June 11, Address for reprints: Lawrence H. Cohn, MD, Division of Cardiac Surgery, 75 Francis St., Boston, MA 2115 boresistant surface for coaption. The primary goal of a "unicusp" design was to enable the fuil available orifice area at low cardiac outputs (Fig. 1). This study evaluated the hemodynamics and pathologic changes of this valve after mitral and tricuspid valve replacements in sheep. Methods Twenty-nine juvenile sheep weighing 22 to 33 kg (3 to 5 months of age) underwent replacement of the mitral or tricuspid valve. The sheep were divided into three groups. Group 1 was composed of 1 sheep that underwent tricuspid valve replacement with a unileaflet per.icardial valve. Group 2 was composed of nine sheep that underwent mitral valve replacement with a unileaflet pericardia! valve. Group 3 (control) consisted of 1 sheep underwent a tricuspid valve replacement with a trileaflet porcine bioprosthesis. These valves (23 mm) were manufactured by Hancock Extracorporeal, Inc. (Anaheim, Calif.) and were outdated for clinical use (6 years). The animals were anesthetized with thiopental sodium (Pentothal, 25 mgfkg) and anesthesia was maintained with.5% halothane. Cefamandole (5 mgfkg) was administered preoperatively and continued 24 hours postoperatively every 8 hours for antibiotic prophylaxis. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by National Institutes of Health (NIH Publication No. 8-23, revised 1978). Groups 1 and 3: triscupid valve replacement. Animals 912

4 Exh. 23 Page 3 Volume 95 Number 5 May 1988 Unileaflet pericardia/ bioprosthetic valve underwent a right thoracotomy for tricuspid valve replacement. The valve replacement was performed with standard cardiopulmonary bypass technique at normothermia. The tight atrium was opened to expose the tricuspid valve. The leaflets and chordae tendineae were excised. Nonabsorbable pledget-supported suture material was used to suture the valves into the tricuspid valve anulus. Each valve was positioned with the strut posteriorly to avoid outflow tract obstruction. After atriotomy closure, the sheep were weaned from cardiopulmonary bypass. Group 2: Mitral valve replacement. The animals underwent mitral valve replacement via a left thoracotomy. Cardiopulmonary bypass was maintained at 32ac. The aorta was cross-clamped and the heart arrested with 3 ml of cold crystalloid cardioplegic solution. The mitral valve was exposed through a left atriotomy. The valve was excised and the prosthesis sutureq into the mitral valve anulus. The prosthetic valve strut was oriented posteriorly to prevent left ventricular outflow tract obstruction. After 3 months the animals underwent hemodynamic evaluation. The data were collected under basal conditions and then after volume loading with 7 ml of Ringer's lactate. Cardiac output was measured by thermodilution technique. Micromanometer catheters (Millar Instruments, Inc., Houston, Texas) were used to measure intracardiac chamber pressures. Valvular gradients and valve areas were calculated from the h_emodynamic data. 14 Animals were killed at postoperative intervals of 3 to 5 months. The hearts were removed and fixed in 1% formalin. After fixation of the hearts for at least 1 week, the valve prostheses were carefully dissected from the surrounding myocardium with a 1 em cuff of annular tissue. Valves were photographed from the inflow and outflow aspects, roentgenograms were made (25 kv for 1 minute, Faxitron, Hewlett- Packard, McMinnville, Ore.), and sections were taken for histologic examination from the cuspal free edge, both lateral attachments, the cuspal basal attachment; and the inside and outside pericardia! covering of the stationary support. Specimens were dehydrated in graded concentrations of ethanol, embedded in JB-4 glycol methacrylate medium (Polysciences, Inc., Warrington, Pa.), sectioned 2 to 3 P,m thick, and stained by hematoxylin and eosin for overall structure and von Kossa stain for the demonstration of calcium phosphates. The degree of calcification and degree of cuspal stretching and redundancy for each valve were graded as = not present; 4+ = most severe. Gross, microscopic, and radiographic data were recorded on a form designed specifically for analysis of this valve configuration. In vivo hemodynamics Hemodynamic performance of the valves is presented in Table I. The three groups had a mean resting cardiac output of 2.1 ±.15 Ljmin. Mter volume loading with 1 L of Ringer's lactate, the cardiac output was increased in all groups. The 2 f mm unileaflet valve in the tricuspid position had a mean resting gradient of 1.3 ±.6 mm Hg arid a valve area of ±.84 cm 2 Mter volume loading the gradient increased. to 6. ± 1.4 mm Hg and the valve area-increased to 2.63 ±.73 cm 2 The 23 mm unileaftet valve in the mitral position Fig. l. Meadox Medicals heart valve as shown from the outflow aspect (A} and inflow aspect (B). had a resting gradient of 2.4 ±.3 mm Hg and a valve area of 1.97 ±.21 cm 2, which increased to 3.26 ±.41 cm 2 with a rise in gradient to 6.7 ±.6 mm Hg after volume loading. The tricuspid 23 mm porcine bioprosthetic valve in the tricuspid valve position had a resting gradient of 1.8 ±.3 mm Hg and an associated valve area of 1.3 ±.15 _cm 2, which increased to 2.4 ±.32 cm 2 with a rise in valvular gradient to 3.6 ±.9 rrim Hg. Morphology The summary of gross pathologic findings is shown in Table II. Four tricuspid and one mitral unileaftet valve and two porcine tricuspid valves had endocarditis (24%); all were characterized by bulky vegetations involving the cusps of the prosthesis, causing near-complete obstruction. In four of these cases, calcific deposits were noted extrinsic to the cusps, but within the vegetations. These were associated with inflammatory cells or bacteria, or

5 Exh. 23 Page Shemin et a!. The Journal of Thoracic and Cardiovascular Surgery Table I. Hemodynamic evaluation Position size Style (mm) Basal Pericardia! Mitral ±.9 unileaflet Pericardia! Tricuspid ±.22 unileaflet Porcine Tricuspid ±.13 trileaflet *Mean ± standard error of the mean. output (L/min)* Stimulated 3.83 ± ± ±.42.. :; area Basal Stimulated 1.97 ± ± ± ± ± ±.32 Basal Stimulated 2.4 ± ± ±.6 6. ± ± ±.9 Table IT. Summary of pathologic results Thrombosis Endocarditis Calcification* Cuspal stretching* Porcine (T} 2/1 2/8 T, Tricuspid position; M, mitral position. *Includes noninfected specimens only. tone with paravalvular leak. Unileaflet (T) 4/1 4/6 6/6 Unileaflet (M) 1/9 7/8 7f8t both. Valves with infection are not included in the subsequent analysis. No instance of thrombotic occlusion was encountered and there were no grossly visible valvular thrombotic deposits. The mean (range) implantation intervals for noninfected porcine tricuspid, unileaflet tricuspid, and unileaflet mitral valves were 132 (17 to 161) days, 17 (99 to 119) days, and 123 (14 to 159) days, respectively. Intrinsic cuspal calcification was noted grossly, radiographically, and histologically in four of six unileaflet tricuspid valves, seven of eight unileaflet mitral valves, but only two of eight porcine tricuspid valves (Figs. 2, 3, and 4). Gross and radiographic features of valve mineralization are illustrated in Fig. 2. Although the number of valves is relatively small, the degree of calcification graded radiographically, and summarized in Fig. 3, was greater in mitral (range to 3+, median 2+) than tricuspid replacements (range to 1 +, median 1 + ); both were more than that noted in the porcine control valves in this study (range to 1 +,median ). Three of eight unileaflet mitral but no unileaflet or porcine tricuspid valves had 3+ calcification. The major site of calcification of the unicuspal pericardia! bioprosthesis was along the linear attachments of the mobile cusp to the fixed strut. Histologic examination revealed that calcium phosphate deposition in unileaflet bioprostheses was generally intrinsic to the cuspal pericardium (Fig. 4), but occasionally extrinsic where calcium ulcerated through the cuspal surface. Extrinsic mineralization was often associated with focal microscopic thrombotic deposits. The stationary pericardia! covering of the fixed strut had minimal and focal intrinsic microscopic calcification, which was limited to the sites of suture compression. There was,. in general, good correlation noted in the degree of mineralization revealed by the various techniques used for analysis. Neither cuspal tearing nor perforations were noted. However, most pericardia! unileaflet valves (six tricuspid, seven mitral) had some degree of stretching and redundancy of the mobile cusp, particularly at its free edge (Figs. 5 and 6), the severity varying among specimens (tricuspid, range 1 + to 3+, median 2+; mitral, range 1 + to 4+, median 2 +). In some cases, cuspal stretching appeared to be sufficient to have caused valvular incompetency, although not of a degree sufficient to cause prolapse of the mobile cusp. Gross pericardia! cuspal redundancy correlated well with the microscopic appearance of distorted and separated collagen bundles (Fig. 5). This was not associated with inflammation or calcification. Redundancy of cusps was not encountered in the porcine bioprostheses studied. Tissue overgrowth was generally mild and did not contribute to dysfunction of any _prosthesis. In one case, calcification was also seen as extrinsic microfoci, associated with tissue overgrowth at the proximal portion of the mobile cusp. Small foci of fibrous tissue were frequently noted overlying the proximal attachment sites and distal free edges of cusps. Microscopically, especially at the free edges, there was inflammatory infiltration of the cuspal tissue by mononuclear cells, predominantly macrophages, which interdigitated among the cuspal collagen bundles and focally destroyed the cuspal architecture (Fig. 7). Cuspal inflammatory activity, gross

6 Exh. 23 Page 5 Volume 95 Number 5 May 1988 Unileaflet pericardia! bioprosthetic valve Fig. 2. Gross and radiographic features of the mineralization of unileaflet pericardia! valves used. Unileaflet pericardia! bioprostheses implanted in the tricuspid (A) and mitral (C) positions, with their associated specimen radiographs, B and D, respectively. Mineralization sites are indicated by arrows in radiographs. distortion with microscopic architectural disruption, and deposition of calcific nodules appeared to be independent processes, each feature generally noted separately from the others. Discussion The present study provides a detailed hemodynamic and pathologic analysis of a new unileaflet glutaraldehyde-pretreated pericardia! bioprosthesis implanted into and harvested from growing sheep. The methods used demonstrate a comprehensive approach to the study of a new bioprosthesis of any configuration. All animals did well during the period of observation, with each animal at least doubling its body weight. Congestive heart failure or thromboembolic episodes were not present. The hemodynainic performance of the PORCINE VALVE (T) z 4 8 UNILEAFLET (T) A UNILEAFLET (M) -u LL..- -I 3 Ua_...Jq: <ta:: Ue> u...o oo w<f: wa:: (!) w 2,. A I.u..e, 1 eo, QO DURATION (DAYS) A- 161 o-- Q 15 MEAN VALUES Fig. 3. Summary of radiographically determined degree of calcification versus duration of implant for the valves analyzed. T, Tricuspid position; M, mitral position..a

7 Exh. 23 Page Shemin eta!. The Journal of Thoracic and Cardiovascular Surgery Fig. 4. Microscopic features of unileaflet pericardia! valve mineralization. A, Intrinsic cuspal calcification (from specimen shown in Fig. 2, C and D). B, Extrinsic calcification (e) (valve cusp noted by asterisk), superimposed on intrinsic calcification (i). C, Focal mineralization associated with the anchoring suture (s) in pericardium covering stationary strut. (Von Kossa's reagent [calcium phosphate black]; original magnifications; A, Xl35; B, and C, X 5.) pericardia! unileafiet valve was satisfactory in both the mitral and tricuspid positions. All groups had low resting gradients and responded to volume loading with an increase in the effective valve orifice area. This finding has been noted in tissue valves and is probably due to improved leaflet excursion at higher cardiac output. 15 The trileafiet porcine valve in the tricuspid position demonstrated satisfactory hemodynamics. During the limited period of observation, the hemodynamic function of the prosthesis was not significantly affected by the pathologic changes. However, the morphologic results suggest that this prosthesis may be subject to several distinct degenerative processes in clinical use. Calcification was prominent, especially in the mitral valve replacements. Since presently used clinical porcine and pericardia! bioprostheses fail frequently by calcific degeneration, the results of this study suggest that the durability of the unileafiet pericardia! bioprosthesis would be limited by this pathologic process Recent studies of calcification of glutaraldehyde-preserved pericardium implanted subcutaneously in rats have suggested that. the potential for and the mechanisms of mineralization of bovine pericardium are identical to those of similarly prepared porcine aortic valves, 2 despite the structural differences between these materials The present study also suggests that calcification of the stationary pericardia! strut covering, which occurred only focally in association with sutures, will not be an important problem. Local inflammatory tissue destruction and pericardia! stretching with redundancy were unexpected findings of this study. The significance of pericardia! inflammation

8 Exh. 23 Page 7 volume 95 Number 5 MaY 1988 Unileaflet pericardia/ bioprosthetic valve '.. '. Fig. 5. Stretching of pericardium. Gross photographs (A and B) and photomicrograph (C) showing severe cuspal stretching and redundancy, associated with local pericardia! architectural disruption and separation of collagen bundles. C, Hematoxylin and eosin; original magnification X 15.) and gross stretching with redundancy is unknown. Superficial mononuclear cells are frequently noted in clinical porcine aortic valve bioprostheses implanted for long intervals, but neither inflammatory destruction nor cuspal distortion has been previously reported in orthotopic experimental, human pericardia!, or porcine valve explants. 19 However, these processes have recently been noted in failed clinical pericardia! bioprostheses. 24 The cause of pericardia! stretching is unknown. It could be a general property of this tissue, or it could be a product of peculiarities of tissue selection site or orientation, or of changes during tissue preparation. In this regard, a recent study demonstrated that the extensibility of tissue harvested from one particular site within the calf pericardium was significantly greater than that from all <.!) ' z 4 J: " w ::>- 1-u 3 rnz...jc:x c:xa -e-, a.z (f)::> =>a 2 uw IJ...cr yb- w w ::. <.!) w a PORCINE (T) UNICUSPID(T) UNICUSPID (M) Fig. 6. Summary of degree of pericardia! stretching/redundancy for the valves examined. T, Tricuspid position; M, mitral position.

9 Exh. 23 Page Shemin et a/. The Journal ot Thoracic and Cardiovascular Surgery report demonstrating a significant decrease in amount of calcification in porcine valve and pericardia! tissues stored in glutaraldehyde for increasing periods after 15 months. 3 Thus, despite favorable hemodynamics, the unicusp pericardia! valve will likely have limited durability because of multiple modes of tissue degeneration. The reported herein support accumulating data that pericardium may be. less durable than porcine aortic valve, and that valves fabricated from bovine pericardium may be subject to a variety of potentially deleterious degenerative processes Fig. 7. Photomicrograph of fibrous capsule associated with inflammatory infiltration and local cuspal destruction. Individual collagen bundles are noted by arrows. (Hematoxylin and eosin; original magnification X375.) other positions. 25 Tissue from this site, however, was not unusual with respect to thickness or structure on light and electron microscopic study. Destruction of pericardium by inflammation has been also noted in studies of subcutaneous implants of pericardium. 2. Although bioprosthetic valve mineralization does riot appear to have an immunologic basis, 26 it is possible that noncalcific inflammatory reactivity may be related to an immunologic reaction directed toward collagen or some other component of pericardia! tissue. Orthotopic experimental valve replacements in calves, sheep, and dogs have been used recently as an adjunct to prosthetic valve development. Since the durability of clinical bioprosthetic valves is most significantly limited by mineralization, with or without associated cuspal tearing, a modd used to investigate the suitability of a new bioprosthetic valve configuration must use an immature subject of a species that potentiates calcification.27 Growing sheep, as used in the present study, have been found to be a convenient and reliable model for bioprosthesis evaluation, in which valves of 21 to 23 mm may be inserted in both the tricuspid and mitral positions, and the animals observed for periods of 3 to 6 months. A previous investigation of the unileaflet valve configuration in dogs did riot demonstrate significant calcification despite 2 years of valve function The dog is not generally considered to be a useful model for accelerated calcification. The minimal pathologic changes in all the porcine valves studied were striking. The8e valves were outdated for clinical use. This observation is consistent with a REFERENCES 1. Carpentier A, Deloche A, Relland J, et al. Six-year follow-up of glutaraldehyde-preserved heterografts. J THORAC CARDIOVASC SURG 1974;68: Oyer PE, Stinson EB, Griepp RB, Shumway NE. Valve replacement with the Edwards and Hancock prosthesis: comparative analysis of late morbidity and mortality. Ann Surg 1977;186: Pipkin RJ), Buch WS, Fogarty TJ. Evaluation of aortic valve replacement with a porcine xenograft without long-term anticoagulation. J THORAC CARDIOVASC SURG 4. Ferrans VJ, Boyce SW, Billingham ME, Jones M, Ishihara T, Roberts WC. Calcific deposits in porcine bioprostheses: structure and pathogenesis. Am J Cardiol 198;46: Ferrans VJ, Spray TL, Billingham ME, Roberts WC. Structural changes in glutaraldehyde-treated porcine heterografts used as substitute cardiac valves. Am J Cardiol 1978;41: Fishbein MC, Gissen SA, Collins JJ, Barsamian EM, Cohn LH. Pathologic findings after cardiac valve replacement with glutaraldehyde-fixed porcine valves. Am J Cardiol 1977;4: Riddle JM, Magilligan DJ Jr, Stein PD. Surface morphology of degenerated porcine bioprosthetic valves four to seven years following implantation. J THORAC CARDIO VASCSURG 1981;81: Magilligan DJ Jr, Lewis JW Jr, Jara FM, et al. Spontaneous degeneration of porcine bioprosthetic valves. Ann Thorac Surg 198.;3: Sanders SP, Levy RJ, Freed MD, Norwood WI, Castaneda AR. Use of Hancock porcine xenografts in children and adolescents. Ani J Cardiol 198;46: Kutsche LM, Oyer P, Shumway N, Baum D. An important complication of Hancock mitral valve replacement in children. Circulation 1979;6(Pt 2): Carpentier A, Dubost C, Lane E, et al. Continuing improvements in valvular bioprostlieses. J THoRAC CAR DIOVASC SURG 1982;83: Levy RJ, Hawley MA, Schoen FJ, Lund SA, Liu PY.

10 Exh. 23 Page 9 volume 95 Number 5 MaY 1988 Unileaflet pericardia! bioprosthetic valve Inhibition by diphosphonate compounds of calcification of porcine bioprosthetic heart valve cusps implanted subcutaneously in rats. Circulation 1985;71 : Gabbay S. Ionescu-Shiley pericardia! xenograft: followup of 1 year to 6 years. Ann Thorac Surg 1985;39: Gorlin R, Gorlin SG. Hydraulic formula for calculation of the area of the stenotic mitral valve, other cardiac valves, and central circulatory shunts. Am Heart J 1?51;41: Ubago JL, Figueroa A, Colman T, Revuelta JM, Ochoteco A, Duran CMG. Hemodynamic evaluation of the Hancock bioprosthesis in the mitral position: a 1-7 year follow-up. In: Cohn LH, Gallucci V, eds. Cardiac biopros.:. theses. New York: Yorke Medical Books, 1982: Schoen FJ, Levy RJ. Bioprosthetic heart valve failure: pathology and pathogenesis. Cardiol Clin 1984;2: Milano A, Bortolotti U, Talenti E, et al. Calcific degeneration as the main cause of porcine bioprosthetic valve dysfunction. Am J Cardiol 1984;53: Schoen FJ, Hobson CE. Anatomic analysis of removed prosthetic heart valves: causes of failure of 33 mechanical valves and 58 bioprostheses, Hum Pathol 1985; 16: Schoen FJ. Cardiac valve prosthesis: pathological and bioengineering considerations. J Cardiac Surg 1987;2: Schoen FJ, Tsao JW, Levy RJ. Calcification of bovine pericardium used in cardiac valve bioprosthesis: implications for the mechanisms of bioprosthetic tissue mineralization. Am J Pathol 1986;123: Ishihara T, Ferrans VJ, Jones M, Boyce SW, Kawanami, Roberts WC. Histologic and ultrastructural featuresof normal human parietal pericardium. Am J Cardiol 198; 46: Ishihara T, Ferrans VJ, Jones M, Boyce SW, Roberts WC. Structure of bovine parietal pericardium and of unimplanted Ionescu-Shiley pericardia! valvular bioprostheses. J THORAC CARDIOVASC SURG 1981;81: Allen DJ, DiDio LJ, Zacharias A, et al. Microscopic study of normal parietal pericardium and unimplanted Puig-Zerbini pericardia! valvular heterografts. J THoRAc CARDIOVASC StiRG 1984;87: Schoen J, Gonzalez-Lavin L, Cernaianu A. Causes of m1d pathologic findings in surgically removed standard bovine pericardia! heart valve emphasis on progressive structural deterioration. Circulation 1987;76: Trowbridge EA, Roberts KM, Crofts CE, Lawford PV. Pericardia! heterografts: toward quality control of the mechanical properties of glutaraldehyde-fixed leaflets. J THORAC CARDIOVASC SURG 1986;92: Levy RJ, Schoen FJ, Howard SL. Mechanism of calcification of porcine bioprosthetic aortic valve cusps: role of T-lymphocytes. Am J Cardiol 1983;52: Jones M, Barnhart GR, Chavez JM, et al. Experimental evaluation of bioprosthetic valves implanted in sheep. In: Cohn LH, Gallucci V, eds. Cardiac bioprotheses. New York: Yorke Medical Books, 1982: Gabbay S, Frater RWM. The unileaflet heart valve bioprosthesis: new concept. In: Cohn LH, Gallucci V, eds. Cardiac bioprostheses. New York: Yorke Medical Books, 1982: Gabbay S, Frater RWM. The Meadox uni-cusp heart valve bioprosthesis. L'Informaticin Cardiol 1983 (July- August): Schryer PJ, Tomasek ER, Starr JA, Wright JTM. Anti-calcification effect of glutaraldehyde-preserved valve tissue stored for increasing time in glutaraldehyde, In: Bodnar E, Yacoub M, eds. Biologic and bioprosthetic valves, New York: Yorke Medical Books, 1986: Reul GJ, Cooley DA, Duncan JM, et al. Valve failure with the Ionescu-Shiley bovine pericardia! bioprosthesis: analysis of 268 patients. J Vase Surg 1985;2: Galioto FM, Midgley FM, Kapur S, et al. Early failures of Ionescu-Shiley bioprosthesis after mitral valve replacement in children. J THORAC CARDIOVASC SuRG 1982; 83: Gallo I, Nistal F, Revuelta JM, Garcia-Satue E, Artifiano E, Duran CG. Incidence of primary tissue valve failure with the Ionescu-Shiley pericardia! valve. J THORAC CARDIOVASC SURG 1985;9: Walley VM, Bedard P, Brais M, Keon WJ. Valve failure caused by cusp tears in low-profile Ionescu-Shiley bovine pericardia! bioprosthetic valves. J THo RAe CARDiov ASC SuRG 1987;93:583-6.