Calcific degeneration as the main cause of porcine bioprosthetic valve failure

Calcific Degeneration as the Main Cause of Porcine Bioprosthetic Valve Failure ALDO MILANO, MD, UBERTO BORTOLOTTI, MD, ENRICO TALENTI, MD, CARLO VALFRE, MD, ELOISA ARBUSTINI, MD, MARIALUISA VALENTE, MD, ALESSANDRO MAZZUCCO,

MD, VINCENZO GALLUCCI, MD, and GAETANO THIENE, MD

Sixty-seven glutaraldehyde-processed porcine bioprostheses (PBS), recovered at autopsy or reoperation from 65 patients, were evaluated by roentgenologic and pathologic examination. Seven patients with 6 PBS were younger than 20 years of age. The time interval of function was 2 to 138 months (average 62). Pathologically, 53 explants had signs of intrinsic dysfunction, which was ascribed to calcification in 36 (68 % ). By x-ray examination, calcific deposits were found in 55 of 67 PBS (82% ). The mean duration of function was 70 f 32 months in calcified PBS vs 27 f I8 months in noncalcified PBS (p
in 41 (75 % ), at the free margin in 37 (67 % ) and at the aortic wall in 37 (67%). When mild, Ca++ deposits involved the commissures in 90% of cases, the body of cusps in 30 % and the free margin only in 10%. Forty-seven calcified PBS were mounted on a flexible stent, and 8 had a rigid stent, with an average time of function of 63 f 28 and I I3 f I8 months, respectively (p
When porcine bioprostheses (PBS) became available in clinical practice as cardiac valve substitutes, the durability of the collagen structures and antigenic acceptance by the host were considered the main determinants of adequate long-term performance. Glutaraldehyde was introduced in the processing of porcine valves, as a stronger cross-linking agent, to solve the problem of antigenicity.l Early failures were considered to be caused by collagen breakdown, as suggested by histologic and electron microscopic investigations.“m4 Subsequently, as experience on explanted PBS increased, primary calcification was identified as one of

the major determinants of porcine bioprosthetic failure, mainly in children.“-I1 We studied 67 consecutive xenografts explanted 2 months or longer after insertion to determine the incidence and extent of calcification. Our findings suggest that Ca++ degeneration is a progressive and time-related phenomenon and represents the leading cause of late dysfunction in both children and adults.

From the Departments of Cardiovascular Surgery, Pathology and Radiology, University of Padova, Medical School, Padova, Italy. This study was supported by Grant 81.01818.04 of Consiglio Nazionale delle Ri~erche, Rome, Italy. Manuscript received September 16, 1983; revised manuscript received November 21. 1983, accepted November 23, 1983. Address for reprints: Gaetano Thiene, MD, lstituto di Anatomia Patologica. Via Gabelli, 61, 35100 Padova, Italy.

Methods Sixty-seven glutaraldehyde-preserved PBS (48 mitral, 18 aortic and 1 tricuspid) were explanted from 65 consecutive patients and form the basis of the present report. The patients, 37 men and 28 women, ranged in age from 8 to 66 years (average 39) at the time of PB implantation. Seven patients were younger than 20 years of age (mean 14 years) and 58 were older (mean 41 years). Sixteen PBS were recovered at necropsy from 14 patients and 51 were obtained from 51 patients at reoperation; 6 PBS were referred to us for pathologic evaluation from other institutions. The explants had been in place 2 to 138 months

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(average 62). Figure 1 displays the distribution of the explants according to duration of function and site of implantation. Twenty-six PBS had been in place longer than 6 years. Patients who died in the early postoperative period were excluded from this investigation. In all patients the clinical records were reviewed to analyze the factors possibly predisposing to PB calcification and consequently to identify groups of patients at higher risk. Before being processed for morphologic study, all PBS were submitted to radiographic investigation using a beryllium microradiographic set, high-resolution films and close contact. The following technique was employed: focus-film distance 40 cm, time of exposure 40 seconds, voltage 45 kV and amperage 5 mA. The sites of calcification were recorded by dividing each prosthetic cusp into 4 regions: body, free edge, commissures and porcine aortic wall Accordingly, 12 regions were evaluated for every PB. Cal&c deposits were graded as absent when microradiography was negative, mild when they were l mm in size or involved more than 4 regions.

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Subsequently, detailed gross examination was carried out and all data were reported on graphic protocols, reproducing cusps, commissures and aortic wall. Multiple photographs were taken of the xenografts, with close-up views of specific lesions. All data are presented as mean f standard deviation. Continuous variables were comparedby the Student t teat and categorical variables by chi-square or Fisher’s exact test contingency analysis. Two-tailed p values <0.05 were considered significant.

Results Causes of porcine bioprosthetic failure: Seven xenografts were obtained from 6 patients who died or were reoperated on for causes unrelated to PB dysfunction. All other xenografts were removed because of dysfunction: 53 because of tissue failure (intrinsic dysfunction) and 7 because of paravalvular leak (extrinsic dysfunction). The causes of intrinsic dysfunction were calcification in 36 explants (68%), endocarditis in 5 (9.5%), thrombosis in 4 (7.5%), primary cuspal tears in 4 (7.5%), fibrous sheathing in 3 (5.7%) and thick intracuspal hematoma in 1 (1.8%) (Fig. 2). The results of detailed pathologic examination in cases of endocarditis, thrombosis, fibrous tissue overgrowth and primary cusp tears without calcification have previously been reported by our groupls-17 and will not be presented here.

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FfGURE 1. Number and type of porcine bioprosthesis (PBS) distributed according to the time of function and site of implantation. Forty-eight PBS were mitral (M). 18 aortic (A) and 1 tricuspid (T). Only PBS in place

longerthan2monthswereconsideredinthegoupwithlessthanlyear of function.

FlGURE 2. Causes of intrinsic dysfunction in 53 porcine bioprostheses. Calcification accounts for 66% of cases of failure.

FIGURE 3. Mitral porcine bioprosthesis in place 59 months, removed from a man who was 18 years old at the time of native valve replacement. Calcific vegetations are mainly located at the commissures, causing torn leaflets and valve incompetence.

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Roentgenologic findings: Of the 67 PBS examined, 55 were calcified (82%) and 12 were not; the average time of function in these 2 groups of PBS was 70 f 32 and 27 f 18 months, respectively (p
Age: All 8 PBS explanted from patients younger than 20 years of age at implantation were calcified; they had been in place an average of 50 f 21 months, compared with 73 f 33 months for the 47 calcified PBS implanted in patients older than 20 years of age (p <0.05). The mean duration of function of PBS from patients (n = 32) older than 35 years of age and from those (n = 14) 20 to 35 years of age was identical (74 f 34 vs 73 f 33 months). Sex: Calcification of PBS did not appear to be sexrelated. Site of im~la~tatioR: Of 55 calcified PBS, 37 were mitral, 17 aortic and 1 was tricuspid. The mean time of function was 54 f 24 months for aortic PBS and 77 f 34 months for mitral PBS (p
FIGURE 4. X-ray of a rigid stent mitral porcine bioprosthesis in place 125 months, explanted from a man who was 29 years old at the time of vafve replacement. Massive involvement of all cusp corn~~nts caused combined stenosis and incompetence.

FIGURE 5. Aortic porcine bioprosthesis in place 51 months, removed from a man who was 53 years old at the time of valve replacement. A massive calcification involves a ~mmissure and has caused tears in 2 leaflets, resulting in valve incompetence.

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with calcified PBS, 15 had not (difference not significant). Other factors: Calcific dysfunction developed 94 months after mitral valve replacement in a man with chronic renal failure. Two xenografts explanted from 2 women who became pregnant after operation were severely calcified after 26 to 88 months of function, respectively. Among the 5 PBS that failed because of endocarditis, 2 appeared calcified at 19 and 86 months after implantation, respectively. Discussion We have evaluated calcific degeneration of PBS from 2 standpoints: its potential for inducing PB dysfunction and its extent and occurrence with the progression of time, regardless of its role in determining porcine bioprosthetic failure. Calcification accounted for 68% of the cases of intrinsic dysfunction and can be considered the main factor influencing the long-term durability of PBS. In our experience, other causes, such as fibrous tissue ovprimary ergrowth, I2 thrombosis ls endocarditis,14 tears15 and cuspal hematoma, apparently have less important influences on porcine valve performance. On x-ray study, 82% of the overall series of PBS were calcified, whereas 18% were not. The noncalcified PBS had been in place a significantly shorter time than had the calcified PBS (27 f 18 vs 70 f 32 months, p
153 % 92 ‘,.

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FIGURE 6. Progression of incidence of calcification. x-ray examination, in the 67 porcine bioprostheses place longer than 6 years were calcified.

as assessed by (PBS). All PBS in

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and unavoidable in current porcine xenografts. Furthermore, our data confirm that patients younger than 20 years of age have a propensity to undergo accelerated calcific degeneration of PBS. We cannot find the same propensity in patients between 20 and 35 years of age when compared with those older than 35 years, as observed by Magilligan et al. ls Thus, on the basis of our results, calcification does not spare adult patients and seems to affect in a similar manner all patients older than 20 years of age. As to the site of implantation, PBS in the aortic position seem to undergo earlier calcification compared with those in the mitral position; this finding was noted in both the overall series and in the group with dysfunction. These findings were reported in a recent review of patients operated on at our institutionlg; similar results were noted in the experience of Henry Ford Hospital.20 Schoen et al,” in contrast, reported rates of primary dysfunction of 6.8% for mitral PBS and 4.1% for aortic PBS in their clinical series. Moreover, Warnes et a1,22 studying PBS implanted in the aortic and mitral position and explanted simultaneously at reoperation, described more severe degenerative changes in mitral than in aortic xenografts. The commissures were involved in almost all calcified PBS followed by the body of the cusps, free margin and aortic wall. This was true also when calcification was mild, suggesting that the calcific degeneration usually starts at the leaflet commissural attachments, which are the structures bearing the greatest closing stresses.23 Isolated, heavy calcific deposits at the commissures can be critical because they can cause cuspal detachment and valvular incompetence. We were surprised to find that some PBS with a rigid stent had a long durability, particularly because the flexible stent was introduced to reduce commissural stresses and to enhance valve performance.24 The explanation for this apparent paradox is not clear. We were interested to verify whether the presence of calcification in the native valve could predict earlier calcific degeneration in the PB used as a valve substitute. We found a significantly lower incidence of native valve calcification in patients in whom calcification of the PB did not develop (p <0.05). To confirm this finding, which might influence the choice of prosthetic device at the time of valve replacement, further investigations are required. Plasma protein insudate containing y-carboxy-glutamic acid (Gla), an amino acid whose synthesis is mediated by vitamin K, was noted as an early site of calcific deposits in tissue valves.2” Accordingly, the routine use of oral anticoagulants was suggested by some investigators8 to delay the onset of bioprosthetic calcification. In our experience, patients who underwent long-term anticoagulant treatment with vitamin K antagonists, such as sodium warfarin, did not show less calcific degeneration compared with nontreated patients. Thus, the pathogenesis of calcific deposition, although mediated by Gla, does not appear to be influenced by maintaining the patients on oral anticoagulants.

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In conclusion, calcification is the leading cause of late PB failure; calcification is progressive and timerelated, involving all PBS implanted more than 6 years; commissures are the first structures to be affected by Ca++ deposits; calcific failure occurs earlier in the aortic than in the mitral position; calcific degeneration is accelerated in patients younger than 20 years of age, whereas no difference in behavior is seen in patients older than 20 years; and chronic warfarin therapy does not influence the onset of calcification. References 1. Carpentler A, Lemaigre G, Robert L, Carpentier S, Dubost C. Biological factors affecting long-term results of valvular heterografts. J Thorac Cardiovasc Sum 1969:58:467-464. 2. spray TL, Roberts WC. Structural changes in porcine xenografls used as substitute cardiac valves. Gross and histologic observations in 51 glutaraldehyde preserved Hancock valves in 41 patients. Am J Cardiol 1977: 40:319-330. 3. Fisbbeln MC, Gissen SA, Colllns JJ, Barsamlan EM, Cohn LH. Pathologic findings after cardiac valve replacement with glutaraldehyde-fixed porcine valves. Am J Cardiol 1977;40:331-337. 4. Ferrans VJ, Spray TL, Billingham ME, Roberts WC. Structural changes in glutaraldehyde-treated porcine heterografts used as substitute cardiac valves. Transmission and scanning electron microscopy observation in 12 patients. Am J Cardiol 1978;41:1159-1184. 5. Ferraus VJ, Boyce SW, Biiiingham ME, Jones M, ishihara T, Roberts WC. Calcific deposits in porcine bioprostheses: structure and pathogenesis. Am J Cardiol 1960;46:721-734, 6. Cipiano PR, Blllingham ME, Oyer PE, Kutsche LM, Stlnsen EB. Calcification of porcine prosthetic heart valves. A radiographic and light microscopic study. Circulation 1982;66:1100-1104. 7. Geha AS, Laks H, Stansei HC, Cornhill JF, Kilman JW, Buckley MJ, Roberts WC. Late failure of porcine valve heterografts in children. J Thorac Cardiovasc Surg 1979;78:351-364. 8. Sanders SP, Levy RJ, Freed MD, Norwood WI, Castaneda AR. Use of Hancock porcine xenografts in children and adolescents. Am J Cardiol 1980;46:429-438. 9. Silver MY, Poiiock J, Silver MD, Williams WG, Trusler GA. Calcification in porcine xenografl valves in children. Am J Cardiol 1980;45:685-689.

10. Thandroyen FT, Whitton IN, Pirie D, Rogers MA, Mltha AS. Severe calcification of glutaraldehyde-preserved porcine xenografts in children. Am J Cardiol 1980;45:690-696. 11. Bortoiotli U. Thlene G. Calcification of oorcine heteroarafts imolanted in children. Chest 1981;80:117-118. ’ 12. Berlolotti U, Galfuoci V, Casarotlo D, Thlene G. Fibrous tissue overgrowth on Hancock mitral xenografts. A cause of late prosthetic stenosis. Thorac Cardiovasc Sure 1979;27:316-318. 13. Thiene G, Borlotolti U, Panlzzon G, Milan0 A, Gallucci V. Pathological substrates of thrombus formation after heart valve reolacement with the Hancock bioprosthesis. J Thorac Cardiovasc Surg 1960;80:414-423. 14. Borloiottl U,~Thlene G, Milan0 A, Panizzon 0, Valente M, Galtuccl V. Pathological study of infective endocarditis on Hancock porcine bioprostheses. J Thorac Cardiovasc Surg 1981;81:934-942, 15. Thlene G, Arbustinl E, Borloiotti U, Talenti E, Miiano A, Vaiente M, Molln G, Gaiiuocl V. Pathol ic substrates of porcine valve dysfunction. In: Cohn LH. Gallucci V. eds. 7 ardtac Bioorostheses. New York: Yorke Medical. 16. Arbustini E, Bortolotti U, Valente M, Milan0 A, Gatlucci V, Pennelll N, Thfene G Cuss disruotion bv massive liDid infiltration. A rare case of ocrcine valve dysfunction. J’Thorac Cardiovasc Surg 1982;84:738-743. 17. Valente Y, Bortolotti U, Arbustlni E, Talent1 E, Thiene 0, Galtucci V. Glutarafdehydepresened porcine bioprosthesis: factors affecting performance as determined by pathologic studies. Chest 1983;83:607-611. 18. Magllligan DJ Jr, Lewis JW Jr, Jara FM, Lee MW, Alam M, Riddle JM, Stein PD. Spontaneous degeneration of the porcine bioprosthetic valve. Ann Thorac Surg 1980;30:259-266. 19. Galluccl V, Valfre C, Mazzucco A, Bortolotti U, Milan0 A, Chloin R, Dalla Volta S, Cevese PG. Heart valve replacement with the Hancock bioprosthesis: a 5-11 year follow-up. In: Cohn LH, Gallucci V, ads. Cardiac Bioprostheses. New York: Yorke Medical, 1982:9-24. 20. Lakler JB, Khaja F, MagKiigan DJ Jr, GoldsteM S. Porcine xenograft valves. Long-term (60-89 month) followup. Circulation 1980;62:313-318. 21. Schoen FJ, Collins JJ, Cohn LH. Long-term failure rate and morphologic correlations in porcine bioprosthesic heart valves. Am J Cardiol 1983; 51:957-964. 22. Warnes CA, Scott ML, Silver GM, Smith CW. Ferrans VJ, Roberts WC. Comparison of late degenerative changes in porcine bioprostheses in the mitral and aortic valve oosition in the same Datient. Am J Cardiol 1983: 51:965-968. 23. Broom ND. Fatigue-induced damage in glutaraldehyde-preserved heart valve tissue. J Thorac Cardiovasc Surg 1978;78:202-211. 24. Reis RI_, Hancock WD, Yarbreugh JW, Glanoy DL, Morrow AG. The flexible stent. A new concept in the fabrication of tissue heart valve prosthesis. J Thorac Cardiovasc Suro 1971:62:683-889. 25. Levy RJ, Lian JB. Stud&s on etiology of calcific aortic valve disease: the role of the calcium binding amino-acid-carboxy-glutamic acid (abstr). Circulation 1978;58:suppl ll:ll-54.