Relation of Calcification to Tom Leaflets

Transcription

1 Relation of Calcification to Tom Leaflets of Spontaneously Degenerated Porcine Bioprosthetic Valves Paul D. Stein, M.D., Stephen R. Kemp, Ph.D., Jeanne M. Riddle, Ph.D., Min W. Lee, M.D., Joseph W. Lewis, Jr., M.D., and Donald J. Magilligan, Jr., M.D. BSTRCT The gross appearance of 54 spontaneously degenerated porcine bioprosthetic valves was evaluated to determine the relation of calcium deposition to cusp disruption. Tears or perforations were shown in 89% (48) of the degenerated valves. The most common site of tears or perforations was near the commissural attachment (6% of all tears). Grossly visible deposits of calcium salts that ruptured to the surface of the cusps or caused changes in the topography were observed in 7% (38) of the 54 valves. Calcification was adjacent to tears or perforations in 56% (27) of the 48 valves with torn cusps. mong the valves that showed calcification, the deposits of calcium salts were adjacent to tears or perforations in 71% (27 of 38). The location of deposits of calcium did not relate to the age or sex of the patient or to the position of the valve, but valves with calcium were inserted longer than valves with no calcium (87 f 4 versus 58 f 7 months; p <.1). The outflow surfaces showed more calcification than the inflow surfaces, irrespective of whether the valves were in the aortic or mitral position. mong the 38 valves with calcification, 92% (35) showed calcification at the commissural attachments, 53% (2) showed calcification in the body of 1 or more cusps, 11% (4) near the base, and 8% (3) near the free edge. In conclusion, most patients with spontaneous porcine valve degeneration showed calcification. The calcification was associated with tears or perforations of the cusps in 5% of all degenerated valves, in 56% of valves with torn cusps, and in 71% of valves that showed gross calcification. Many spontaneously degenerated porcine bioprosthetic valves show gross calcification, and the structure and pathogenesis of this calcification have been investigated in detail (1, 21. The relation of gross calcification to cusp disruption, however, is unclear. This article examines the incidence and location of gross calcific deposits in spontaneously degenerated porcine valves and determines the relation of gross calcium deposits to cusp disruption. From the Departments of Medicine, Surgery, and Pathology, Henry Ford Hospital, Detroit, M1. ccepted for publication Oct 1, ddress reprint requests to Dr. Stein, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI Material and Methods Color slides of the inflow and outflow surfaces of 54 spontaneously degenerated porcine bioprosthetic valves removed from 53 patients were examined to determine the location of tears, perforations, and gross calcification and their relation to each other. ll but 3 valves were removed at the time of replacement for spontaneous degeneration; 3 were obtained at autopsy. The valves had been inserted in the mitral position in 38 patients and in the aortic position in 16 patients. Fifty-two of the 54 spontaneously degenerated porcine bioprosthetic valves were fabricated by Hancock Laboratories (naheim, C) and 2 were Carpentier- Edwards prostheses (Edwards Laboratories, Santa na, C). ll of the valves had a standard orifice; the right coronary cusp of all valves contained a muscular shelf. Only valves that underwent spontaneous degeneration were studied. Valves were excluded if the patients had perivalvular regurgitation or if they, at any time, had prosthetic valve endocarditis. valve was considered to have undergone spontaneous degeneration if there was valvular incompetence or stenosis accompanied by tears, perforations, or calcification of 1 or more cusps in the absence of an identifiable cause. Valves in the aortic position were inserted for 66 t 7 months (range, 15 to 112 months) and valves in the mitral position, 83 & 5 months (range, 12 to 135 months). ll of the patients were adults (mean age, years; range, 21 to 75 years). ges of patients were listed as the age at the time of removal of the valve because of spontaneous degeneration. The mean age of patients with valves removed from the mitral position ( years) was comparable to the mean age of patients whose valves were removed from the aortic position (48 * 5 years) (not significant [NS]). There were 2 men and 33 women. The valves were thoroughly washed with isotonic saline solution within minutes after removal, and photographs were obtained within one or two hours after the valve was removed. Gross appearance of all the valves was examined, and the presence or absence of calcium was evaluated by palpation and inspection. In every instance in which the photograph showed calcification, calcification was confirmed by gross examination of the specimen. In two instances the photographs did not reveal any calcification, but a small amount was identified by palpation and inspection. These valves were reported as calcified. Forty of 54 valves were examined histologically for microscopic evidence of calcium. Microscopic sections were obtained from 26 of 38 valves that showed gross 1 75

2 176 The nnals of Thoracic Surgery Vol 4 No 2 ugust 1985 Fig I. () Example of a heardy calcified spontaneous/y degenerated porcine bioprosthetic vuhe. The idzw (Hancock) 7ws rernoued from the rnitral position after 48 ~nonths of insertion. Calcium ulns particirlady heavy at the comn~issures. (B) Example of a spontaneously dl*- generated porcine bioprosthetic z~alzie (Hancock) that shorc~cd 11 calcification. The r~a/rie 7~~11s reniorw-d from the aortic position after 88 months of insertion. verticai tear ruas present at the free edge of the cusp. calcification, and the presence of calcium was confirmed by microscopic examination in all. mong 16 valves that showed no gross calcification, microscopic examination of sections of the cusps were obtained in 13. Five showed microscopic foci of calcium. Regarding the techniques of microscopic sectioning of the valves, in 5 of the valves, serial sections were cut perpendicular to the free edge of the cusp and parallel to the edge at the commissural attachment. n average of twenty-one paraffin sections from the 3 cusps of each of these 5 valves was examined. Von Kossa and alizarin red stains were obtained when indicated. Calcification was localized from photographs according to a scheme suggested by Cipriano and associates [3] (Fig 1). Specific areas identified were the base of the cusp, the body of the cusp, the portion near the free edge of the cusp, and the commissural attachment. Tears were localized according to a method described by Ishihara and colleagues [4], which we modified somewhat. We identified the following: vertical tears at or near the commissural attachment; vertical tears near the midportion of the cusp; horizontal tears near the margin of the attachment; oval or circular perforations of the body of the cusp; pinhole perforations; and complete destruction of a cusp. ll data were reported as the mean 2 the standard B error of the mean. Statistical analyses were based on either the Student unpaired t test, the chi-square test, or a two-tailed test of proportion. Results Gross Calcification Grossly visible deposits of calcium salts that ruptured to the surface of the cusps or caused changes in the surface topography were observed in 38 (7%) of the 54 degenerated valves (Fig 2). The presence of calcification was not related to the site of insertion (aortic or mitral position). Gross calcification was observed in 3 (79%) of the 38 degenerated valves in the mitral position and in 8 (5%) of the 16 in the aortic position (NS). The presence of calcification did not relate to the age (Fig 3) or sex of the patient. The mean age of patients 54 DEGENERTED VLVES 38 MITRL (16 ORTIC 1 I, 48 TERS OR 6 STIFF PERFORTIONS NO TERS OR PERFORTIONS + 34 CLCIFIED 14 NON- 4 CLCIFIED 2 NON- CLCIFIED CLClFlEC 27 CLCIUM 7 CLCIUM SSOCITED NOT SSOCITED WITH TERS WITH TERS

3 177 Stein et al: Bioprosthetic Valve Degeneration U w > 4 Y w 4 3 zoi :* 1 : Table 1. Location of Deposits of Calcium Location ortic Mitral Position Position (no. of (no. of valves) valves) Total Predominantly on inflow 5 5 surface Predominantly on outflow surface Equal on both surfaces 2 2 No information 1 1 Total lo] Table 2. Location of Calcification CL~IFIED NON-C'LCIFIED Valves cusps VLVES VLVES Location (N = 38) (N = 114) Fig 3. ge of patients in rchorir spontaneously degenerated porcine bioprosthetic valiies werc calcified compared with age in those in whom the valves zuere not calcified. The difference in age betroeen Commissural attachment Body of cusp 2 32 these groups zuas not si,ynificant. Base of cusp 4 12 Near free edge r" 12-5 I s 1- Z 8- w ' 6-8 I U ** CLCIFIED VLVES ** NON-CLCIFIED VLVES Fix 4. Duratioii of illserfion of calcified and izoncalcified spontarirously degenerated purcine hioprosthetic ualves. Calcified rinlves iiiere inserted longer (p <.1). with calcified valves was 49 * 3 years, and the mean age of patients with noncalcified valves was 53 f 14 years (NS). If patients 35 years old and younger were eliminated, the mean age of patients with calcified valves (56 f 2 years) remained not significantly different from that of patients with noncalcified valves (6 2 2 years). Of the patients with calcified valves, 14 (26%) were men and 23 (43%) were women (NS). Valves that showed gross calcification were inserted longer than valves that showed no gross calcification (87 f 4 months versus 58 f 7 months; p <.1) (Fig 4). Even if patients 35 years of age and younger were eliminated, the duration of insertion of valves that showed gross calcification was significantly longer than those that showed no gross calcification (86 f 5 months versus 6 f 7 months; p <.1). Deposits of calcium were more prominent on the outflow surface of the valve than the inflow surface, irrespective of whether the valves were in the aortic or mitral position. mong the 38 patients with grossly calcified valves, 3 (79%) showed more prominent deposits of calcium on the outflow surface (p <.1) (Table 1). Calcification, when present, usually involved more than one cusp. mong the valves that showed calcification, 19 (5%) of 38 showed involvement of all 3 cusps, 8 (21%) showed involvement of 2 cusps, and 11 (29%) showed involvement of only 1 cusp. We could not determine from the photographs if the cusp that was singly involved was the right coronary cusp, which contained the muscular shelf. The usual site of calcification was the commissural attachment; 35 (92%) of the 38 calcified valves showed the calcification at that site (Table 2). mong the 38 valves that were grossly calcified, 62 (54%) of 114 cusps showed calcium in the region of the commissural attachment, 32 (28%) showed calcification in the body, 12 of 114 leaflets (11%) showed calcification at the base, and 12 of 114 cusps (11%) showed calcification near the free edge.

4 178 The nnals of Thoracic Surgery Vol 4 No 2 ugust 1985 Table 3. Incidence of Tears or Perforations" ortic Valves Mitral Valves ll Valves Type of Tear or Perforation (no. of tears) (no. of tears) (no. of tears) Vertical tear near commissure extending to free edge Vertical tear near midportion of cusp extending to free edge Pinhole perforation Large perforation Tear parallel to base of attachment Completely destroyed "U tears and perforations were listed. More than one tear or perforation of each type and more than one type may have occurred in any cusp. Tears or Perforations Tears or perforations were present in 48 (89%) of the 54 degenerated valves (see Fig 2). Only 6 valves, 5 of which were removed from the mitral position and 1 from the aortic position, showed no tears or perforations. Four of these valves were insufficient because the cusps were unable to coapt, and 2 were stenotic but not regurgitant. mong valves with tears or perforations, 4 (8%) of 48 showed tears in 3 cusps, 2 (42%) showed tears in 2 cusps, and 24 (5%) had a tear in only 1 cusp. The most prevalent type of tear was a vertical tear near the commissural attachment (Table 3). Such tears constituted 6% (49182) of all tears or perforations. The incidence of such tears was greater in valves removed from the mitral position, but the difference was not statistically significant. Forty-nine (88%) of the 56 vertical tears that extended to the free edge of the cusp occurred near the commissural attachment (see Table 3). Together, tears parallel to the base of attachment and large perforations constituted only 1% of all tears. Sixty-three percent (3454) of spontaneously degenerated valves showed vertical tears near the commissural attachment in 1 or more cusps (Table 4). Such tears occurred in 56% of aortic valves and 66% of mitral valves (W. ssociation of Calcification with Tears OY Perforations Gross deposits of calcium salts were observed in 71% (34/48) of valves that showed tears or perforations, but the calcification often was not in close proximity to the tear (see Fig 2). Calcification was in close proximity to tears or perforations in 5% (27/54) of all spontaneously degenerated valves and was in close proximity to the tear or perforation in 56% (27148) of valves that had tears or perforations. Some valves showed calcification with tears of more than 1 cusp, and some cusps showed more than one deposit of calcium. The most frequent location of gross calcification in close proximity to a tear was the commissural attachment. Calcification associated with vertical tears near the commissural attachment occurred in 22 valves (Table 5). The next most common site was the body of the cusp, where calcification occurred in close proximity to a tear or perforation in 8 valves. Calcification associated with a tear or perforation near the free edge occurred in only 3 valves and occurred at the base of the leaflet in only 2 valves. Comment This study demonstrated that tears or perforations are the most usual cause of dysfunction of spontaneously Table 4. Tear or Perforations ccording to Number of Valves Involved" ortic Valves Mitral Valves ll Valves Type of Tear or Perforation (N = 16) (N = 38) (N = 54) Vertical tear near commissure extending to free edge Vertical tear near midportion of cusp extending to free edge Pinhole perforation Large perforation 2 2 Tear parallel to base of attachment Completely destroyed "Each type of tear or perforation was listed only once in a given valve.

5 ~~ ~ 179 Stein et al: Bioprosthetic Valve Degeneration Table 5. Location of Gross Deposits of Calcium in Values with a Tear or Perforation No. of No. of Location Valves cusps Commissural attachment Body of cusp 8 11 Near free edge 3 3 Near base 2 2 degenerated bioprosthetic valves and occurred in 89% of such valves. Gross calcification was frequently found in degenerated valves (present in 7%). Calcification was in close proximity to the tears or perforations in about half (56%) of the valves that were torn. Therefore, calcification was not a necessary feature of degeneration. Often in spontaneously degenerated valves, tears occurred in the absence of calcification. We observed this in 14 (26%) of the 54 valves. It is reasonable to presume that the tissue was adversely affected and stresses were greater in calcified valves. The association of calcification with tears has not been assessed in the past, although the common occurrence of calcification with tears has been recognized and the lesions were thought to be interrelated [5]. The occurrence of spontaneous degeneration in the absence of tears or perforations did not necessarily imply an absence of regurgitation. In fact, 4 valves that showed no tears or perforations were clinically found to be primarily regurgitant, presumably due to an inability of the cusps to properly coapt. The 68% incidence of gross calcification of spontaneously degenerated valves noted by Milano and associates [2] is similar to the 7% incidence we observed. This incidence is also comparable to that observed by Ferrans and associates [l], who found gross calcification in 79% of spontaneously degenerated valves. Calcification seems to be a time-related event, which we and others observed. The average duration of insertion of valves that showed calcification in this study was more than two years longer than the average duration of insertion of valves that showed no calcification. In an adult population, Cipriano and associates [3] showed calcification in 3% of valves inserted less than three years, in 82% inserted three to five years, and in 96% inserted five years or longer. In the present study as in others [l-31, the most common site of calcification was the commissural attachments. Thubrikar and associates [6] suggested that the earliest sites of calcification occurred predominantly in the area of attachment where the leaflet was subjected to maximum flexion. Presumably, the mechanical stresses initiated calcification by damaging the structural integrity of the leaflet tissue (61. Regarding the association of tears with calcification, mathematical modeling of stresses that act on the closed valve leaflets suggests that the development of focal calcification can induce local stress gradients between the site of calcification and the immediately surrounding tissue [6a]. These stress gradients would favor local tissue disruption [6a]. The calcification process seems, in part, to relate to the local deposition of proteins that contain y- carboxyglutamic acid, a calcium-binding amino acid [7]. y-carboxyglutamic acid containing protein has been found in the leaflets of calcified natural human aortic valves and calcified porcine bioprosthetic valves [7] as well as a number of other tissues that have undergone ectopic calcification, including atherosclerotic plaques [8]. s calcification occurred in glutaraldehyde-treated porcine aortic valve cusps implanted subcutaneously in rabbits, levels of y-carboxyglutamic acid in the leaflets also increased [9]. Warfarin sodium inhibits synthesis of y-carboxyglutamic acid. Spontaneously degenerated porcine bioprosthetic valves removed from patients treated with warfarin in usual clinical doses showed less calcification than valves removed from patients who did not receive warfarin [lo]. lthough tears or perforations were usually present in the spontaneously degenerated valves that we observed, others have found a somewhat lower occurrence. Schoen and co-workers [ll] found tears in 11 (79%) of 14, and Pomar and associates [5] noted tears in 18 (69%) of 26. The most common location of tears, as observed by Pomar [5], Ishihara [4], and their colleagues, was a vertical tear at the free edge. Our observations were similar; 68% of all tears or perforations were vertical tears that extended to the free edge. Most of these (6% of all tears) were vertical tears near the commissural attachment. Primary tissue failure due to disruption of the fibrocollagenous framework of the valve may be a factor in tears without calcification. Ishihara and co-workers [4] postulated that tears may occur as a consequence of tissue failure where mechanical forces are exerted in a highly localized manner, either because of the patterns of opening and closure of the bioprosthetic cusps or because of the presence of calcium deposits. Supported in part by the United States Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute Grant HL References 1. Ferrans VJ, Boyce SW, Billingham ME, et al: Calcific deposits in porcine bioprostheses: structure and pathogenesis. m J Cardiol46:721, Milano, Bortolotti U, Talenti E, et al: Calcific degeneration as the main cause of porcine bioprosthetic valve failure. m J Cardiol 53:166, Cipriano PR, Billingham ME, Oyer PE, et al: Calcification of porcine prosthetic heart valves: a radiographic and light microscopic study. Circulation 66:11, Ishihara T, Ferrans VJ, Boyce SW, et al: Structure and classification of cuspal tears and perforations in porcine bioprosthetic cardiac valves implanted in patients. m J Cardiol 48:665, 1981

6 18 The nnals of Thoracic Surgery Vol 4 No 2 ugust Pomar JL, Bosch X, Chaitman BR, et al: Late tears in leaflets of porcine bioprostheses in adults. nn Thorac Surg 37:78, Thubrikar MJ, Deck JD, ovad J, Nolan SP: Role of mechanical stress in calcification of aortic bioprosthetic valves. J Thorac Cardiovasc Surg 85:115, a. Sabbah HN, Hamid MS, Stein PD: Estimation of mechanical stresses on closed leaflets of porcine bioprosthetic valves: effects of stiffening, focal calcification and focal thinning. m J Cardiol 55:19, Levy RJ, Zenker J, Lian JB: Vitamin K-dependent calcium binding proteins in aortic valve calcification. J Clin Invest 65563, Levy RJ, Lian JB, Gallop PM: therocalcin, a gammacarboxyglutamic acid containing protein from atherosclerotic plaque. Biochem Biophys Res Commun 91:41, Fishbein MC, Levy RJ, Ferrans VJ, et al: Calcification of cardiac valve bioprostheses: biochemical, histologic, and ultrastructural observations in a subcutaneous implantation model system. J Thorac Cardiovasc Surg 83:62, Stein I'D, Riddle JM, Kemp SR, et al: Effect of warfarin on calcification of spontaneously degenerated porcine bioprosthetic valves. J Thorac Cardiovasc Surg (in press, 1985) 11. Schoen FJ, Collins JJ, Cohn LH: Long-term failure rate and morphologic correlations in porcine bioprosthetic heart valves. m J Cardiol 51:957, 1983 Notice from the merican Board of Thoracic Surgery The merican Board of Thoracic Surgery began its recertification process in Diplomates interested in participating in recertification should maintain a documented list of the cardiothoracic operations they performed during the year prior to application for recertification. They should also keep a record of their attendance at thoracic surgical meetings and other continuing education medical activities for the two years prior to application for recertification. In place of a cognitive examination, candidates for recertification will be required to complete both the general thoracic and cardiac portions of the SESTS I1 Syllabus (Self-Educationiself-ssessment in Thoracic Surgery). It is not necessary for candidates to purchase SESTS I1 prior to applying for recertification. SESTS I1 booklets will be forwarded to candidates after their applications have been received. Diplomates whose ten-year certificates will expire in 1988 may begin the recertification process in This new certificate will be dated ten years from the time of expiration of the original certificate. Recertification is also open to any Diplomate with an unlimited certificate. The deadline for submission of applications for recertification is July 1, recertification brochure outlining the rules and requirements for recertification in thoracic surgery is available on request from the merican Board of Thoracic Surgery, 1464 E Seven Mile Rd, Detroit, MI 4825.