Late incidence and determinants of reoperation in patients with prosthetic heart valves q

European Journal of Cardio-thoracic Surgery 25 (2004) 364 370 www.elsevier.com/locate/ejcts Abstract Late incidence and determinants of reoperation in patients with prosthetic heart valves q Marc Ruel a,b, *, Alexander Kulik a, Fraser D. Rubens a, Pierre Bédard a, Roy G. Masters a, Andrew L. Pipe a, Thierry G. Mesana a a Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Suite 3403, Ottawa, Ont., Canada K1Y 4W7 b Department of Epidemiology and Community Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5 Received 19 October 2003; received in revised form 7 December 2003; accepted 15 December 2003 Objectives: Reoperation is a relatively common event in patients with prosthetic heart valves, but its actual occurrence can vary widely from one patient to another. With a focus on bioprosthetic valves, this study examines risk factors for reoperation in a large patient cohort. Methods: Patients ðn ¼ 3233Þ who underwent a total of 3633 operations for aortic (AVR) or mitral valve replacement (MVR) between 1970 and 2002 were prospectively followed (total 21179 patient-years; mean 6.6 ^ 5.0 years; maximum 32.4 years). The incidence of prosthetic valve reoperation and the impact of patient- and valve-related variables were determined with actual and actuarial methods. Results: Fifteenyear actual freedom from all-cause reoperation was 94.1% for aortic mechanical valves, 61.4% for aortic bioprosthetic valves, 94.8% for mitral mechanical valves, and 63.3% for mitral bioprosthetic valves. In both aortic and mitral positions, current bioprosthesis models had significantly better durability than discontinued bioprostheses (15-year reoperation odds-ratio 0.11 ^ 0.04; P, 0:001 for aortic, and 0.42 ^ 0.14; P ¼ 0:009 for mitral). Current bioprostheses were significantly more durable in the aortic position than in the mitral position (14.3 ^ 6.8% more freedom from 15-year reoperation; P ¼ 0:018). Older age was protective, but smoking was an independent risk factor for reoperation after bioprosthetic AVR and MVR (hazard ratio for smoking 2.58 and 1.78, respectively). In patients with aortic bioprostheses, persistent left ventricular hypertrophy at follow-up and smaller prosthesis size predicted an increased incidence of reoperation, while this was not observed in patients with mitral bioprostheses. Conclusions: These analyses indicate that current bioprostheses have significantly better durability than discontinued bioprostheses, reveal a detrimental impact for smoking after AVR and MVR, and indicate an increased reoperation risk in patients with a small aortic bioprosthesis or with persistent left ventricular hypertrophy after AVR. q 2003 Elsevier B.V. All rights reserved. Keywords: Valves; Follow-up studies; Prosthesis; Surgery; Complications 1. Introduction Reoperation following valve replacement surgery is a relatively common event, particularly in patients with bioprosthetic valves. Freedom from reoperation for currently available mechanical valves is greater than 95% at 10 years and greater than 90% at 15 years. Bioprostheses, q Presented at the Joint 17th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 11th Annual Meeting of the European Society of Thoracic Surgeons, Vienna, Austria, October 12 15, 2003 * Corresponding author. Address: Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Suite 3403, Ottawa, Ontario, Canada K1Y 4W7. Tel.: þ1-613-761-4893; fax: þ1-613- 761-4713. E-mail address: mruel@ottawaheart.ca (M. Ruel). however, have a significantly higher rate of reoperation secondary to structural valve deterioration (SVD). In large series, freedom from reoperation has been greater than 95% at 5 years, greater than 90% at 10 years, but less than 70% at 15 years [1]. Although long-term anticoagulation is avoided with tissue valves, the risk of SVD, reoperation, and subsequent morbidity and mortality remain their major disadvantages [2]. Although some risk factors for earlier reoperation in patients with bioprosthetic valves are known, such as younger age [3] and mitral valve position [4], potential others such as poor ventricular function, valve model, and prosthesis size have been controversial [3,5 8]. This study aims at better defining the determinants of reoperation from a large cohort of patients with prosthetic heart valves followed longitudinally after aortic (AVR) or 1010-7940/$ - see front matter q 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.ejcts.2003.12.013

M. Ruel et al. / European Journal of Cardio-thoracic Surgery 25 (2004) 364 370 365 mitral valve replacement (MVR), with an emphasis on reoperation for SVD of bioprostheses. 2. Methods 2.1. Patients, prostheses and follow-up Adult patients ($18 years of age) who underwent AVR or MVR between 1970 and 2002 at our institution were followed annually in a dedicated valve clinic. Patients had a history focused on the determination of functional status and the occurrence of valve-related complications, physical examination, ECG and chest radiograph, complete blood count, serum chemistries, and international normalized ratio determinations when applicable. The study cohort included 3233 consecutive adult patients who underwent a total of 3633 operations for replacement of the aortic, mitral, or both valves. Of these 3233 patients, no information is available on 291 (9.0%) who did not attend the follow-up valve clinic at any point in time, and only partial information could be obtained on an additional 350 patients (10.8%) who were later lost to follow-up at a mean of 4.7 ^ 4.3 years after valve replacement. Total follow-up was 21179 patient-years (mean 6.6 ^ 5.0 years; maximum 32.4 years). The preoperative characteristics of the cohort by site of implant are presented in Table 1. Two thousand three hundred forty-eight operations consisted of AVR, 1062 of MVR, and 223 of concomitant AVR and MVR. Table 2 shows the types of prostheses implanted in the study population. 2.2. All-cause reoperation and reoperation for structural valve degeneration In accordance with the Guidelines for Reporting Morbidity and Mortality after Cardiac Valvular Operations [9], reoperation was defined as any operation that repaired, altered, or replaced a previously operated valve. Since this series excluded primary valve repair procedures, reoperation was performed for a previously implanted prosthesis in Table 1 Prevalence and mean values of preoperative variables, by implant site Aortic ðn ¼ 2348Þ Mitral ðn ¼ 1062Þ Double valve ðn ¼ 223Þ Gender Female (%) 31.8* 60.0 56.5 Age (years) 61.9 ^ 13.6* 59.2 ^ 12.4 58.5 ^ 12.4 Body surface area (m 2 ) 1.87 ^ 0.24* 1.76 ^ 0.24 1.78 ^ 0.25 Coronary artery disease (%) 36.2* 30.4 19.8* Chronic atrial fibrillation (%) 5.3* 23.9 22.0 Values reported as percentages or mean ^ SD. *P, 0:05 versus other subgroups. Table 2 Number and current commercial availability of implanted valve prostheses, by site all cases. The indication for reoperation was available for all patients. Reoperation for SVD was defined as a reoperation performed primarily because of an intrinsic abnormality of the valve that caused stenosis or regurgitation, exclusive of infection or thrombosis. Other prosthesis-related complications were recorded according to the guidelines [9]. 2.3. Statistical analyses Aortic* ðn ¼ 2571; %Þ Mitral* ðn ¼ 1285; %Þ Mechanical valves (%) 47.1 59.3 St Jude Medical 413 (16.1) 253 (19.7) Y a Medtronic Hall 338 (13.2) 286 (22.3) Y Carbomedics 276 (10.7) 124 (9.7) Y Harken 83 (3.2) 58 (4.5) N Lillehei Kaster 69 (2.7) 20 (1.6) N Bjork Shiley 18 (0.7) 8 (0.6) N MCRI On-X 16 (0.6) 13 (1.0) Y Bioprosthetic valves (%) 52.9 40.7 Medtronic Hancock II 441 (17.2) 140 (10.9) Y Ionescu Shiley 254 (9.9) 130 (10.1) N Ionescu Shiley low profile 205 (8.0) 102 (7.9) N Medtronic Hancock I 138 (5.4) 86 (6.7) Y Homograft 98 (3.8) Y Medtronic Intact 96 (3.7) 33 (2.6) N Edwards Perimount 79 (3.1) 30 (2.3) Y St Jude X-Cell 23 (0.9) 1 (0.1) N Stentless Porcine b 17 (0.7) Y Carpentier Edwards Standard 7 (0.3) 1 (0.1) Y Current availability *Prostheses implanted during double valve replacement were redistributed according to their individual implant site. N, no; Y, yes. a Includes 57 Silzone TM -coated aortic prostheses, which are now discontinued. b Denotes either a St Jude Toronto stentless or a Medtronic Freestyle prosthesis. Data were imported and analyzed in Intercooled Stata 8.0 (Stata, College Station, TX). For actuarial analyses, patients were censored at the time of their last follow-up visit or death if they had not yet been reoperated. Censoring was assumed to be independent of predictors and outcomes. Actual freedom from all-cause reoperation or reoperation for SVD was determined for each site of implantation and each class (i.e. mechanical versus bioprosthetic) of valve prostheses [6,10]. Crude actuarial reoperation rates are not reported. To increase the study s generalizability with respect to current cardiac surgical practice, separate analyses were also performed that only included patients who were implanted with currently available prostheses. Potential univariate predictors were individually tested for equality of actuarial freedom from reoperation with a Log-Rank test. These predictors were also tested for 15-year

366 M. Ruel et al. / European Journal of Cardio-thoracic Surgery 25 (2004) 364 370 actual freedom from reoperation with logistic regression. Univariate effect estimates and P-values were used to guide multivariate model selection and are not reported. 2.3.1. Reoperation due to structural valve deterioration hazard (actuarial) No a priori distributional assumption was made with respect to the freedom from reoperation over time, and the proportional hazard assumption was tested for each covariate with generalized Cox Snell residuals and 2 ln[2ln(survival)] probabilities. Cox proportional hazards models were developed by incorporating variables that had a P-value of 0.10 or less on univariate analysis; in order to account for positive or negative confounding, no automated model selection procedure was used and all reported variables, unless collinear with a Spearman s rank correlation coefficient $ 0.30 and a P-value, 0.005, were used simultaneously. When collinear covariates were identified, the one most readily interpretable was selected for entry in the final models. Non-significant variables used in the models are presented in the footnotes of Tables 3 and 4. Each model was evaluated with a score test and rejected if P $ 0:05: 2.3.2. Reoperation due to SVD at 15 Years (actual) The impact on the 15-year reoperation incidence of variables that had a P-value of 0.10 or less on univariate analysis or that were significant on multivariate actuarial analysis was validated with logistic regression. Only variables that predicted reoperation for SVD by using both actuarial and actual methods are reported in Tables 3 and 4. Table 3 Actuarial predictors of reoperation for structural valve deterioration aortic bioprostheses Adjusted hazard ratio 95% CI P Significant predictors a Female gender 0.67 0.46, 0.98 0.038 Age (per year) 0.97 0.96, 0.98,0.001 Body surface area (per m 2 ) 1.84 1.08, 3.16 0.026 Smoking 2.58 1.85, 3.60,0.001 Persistent LVH at follow-up 2.38 1.61, 3.51,0.001 Current bioprosthesis 0.39 0.17, 0.91 0.030 (versus discont.) Prosthesis size 0.82 0.70, 0.98 0.010 (per manufacturer size unit) Prosthesis size/bsa #10th percentile b 1.79 1.11, 2.87 0.017 BSA, body surface area; Discont., discontinued bioprosthesis model; LVH, left ventricular hypertrophy. a Non-significant variables included in the model were atrial fibrillation, coronary disease, diabetes mellitus, preoperative New York Heart Association class, redo aortic valve replacement, and aspirin use. b Separate model. Table 4 Actuarial predictors of reoperation for structural valve deterioration mitral bioprostheses No automated selection procedure was used, and collinearity was handled as previously described. 3. Results Adjusted hazard ratio 95% CI P Significant predictors a Age (per year) 0.98 0.96, 0.99 0.039 Coronary artery disease 0.35 0.15, 0.85 0.020 Smoking 1.79 1.01, 3.19 0.048 a Non-significant variables included in the model were female gender, atrial fibrillation, diabetes mellitus, body surface area, preoperative New York Heart Association class, redo mitral valve replacement, current mitral bioprosthesis (versus discontinued), mitral prosthesis size, persistent left ventricular hypertrophy at follow-up, and aspirin use. 3.1. Cumulative incidence of reoperation after valve replacement 3.1.1. All-cause reoperation Actual freedom from all-cause reoperation at 10, 15 and 20 years was 96.2, 94.1, and 93.8% for aortic mechanical valves, 76.1, 61.4, and 59.6% for aortic bioprosthetic valves (P, 0:001; versus aortic mechanical), 96.4, 94.8, and 94.2% for mitral mechanical valves, and 79.8, 63.3, and 57.6% for mitral bioprosthetic valves (P, 0:001; versus mitral mechanical), respectively. 3.1.2. Reoperation for structural valve deterioration Fig. 1 displays the actual freedom from reoperation for SVD in patients with aortic (A) and mitral (B) bioprostheses, and separately depicts discontinued and current bioprosthesis models. In both aortic and mitral positions, current bioprostheses had significantly better durability than discontinued bioprostheses (odds-ratio of 15-year reoperation for SVD 0.11 ^ 0.04; 95% CI 0.06, 0.23; P, 0:001 for current versus discontinued aortic bioprostheses, and 0.42 ^ 0.14; 95% CI 0.22, 0.80; P ¼ 0:009 for current versus discontinued mitral bioprostheses, respectively). Current bioprostheses were significantly more durable in the aortic position than in the mitral position (14.3 ^ 6.8% more freedom from 15-year reoperation for SVD; 95% CI 1.1, 27.7%; P ¼ 0:018; current aortic versus mitral bioprostheses). For example, in 91 patients at risk 10 years after AVR with the Medtronic Hancock II aortic prosthesis, 95.8% were free (94.8 ^ 3.2% by actuarial methods) from reoperation due to SVD. There was no significant difference in the durability of discontinued bioprosthesis between aortic and mitral implant positions.

M. Ruel et al. / European Journal of Cardio-thoracic Surgery 25 (2004) 364 370 367 Fig. 1. Actual freedom from reoperation due to structural valve deterioration in patients with discontinued versus current aortic (A) and mitral (B) bioprostheses. 3.2. Risk factors for reoperation due to structural valve deterioration (Tables 3 and 4) 3.2.1. Gender Women had a lower incidence of reoperation for SVD after AVR (hazard ratio 0.67). This, however, was not the case after MVR, where a non-significant reverse trend was observed (hazard ratio, female versus male gender 1.50; 95% CI 0.88, 2.55; P ¼ 0:14). 3.2.4. Coronary artery disease Concomitant coronary artery disease was protective against reoperation in patients undergoing bioprosthetic MVR. The hazard ratio was 0.35. 3.2.5. Smoking Smoking was an independent risk factor for reoperation due to SVD after AVR as well as after MVR. The hazard ratios were 2.58 and 1.78, respectively. 3.2.2. Age Older age was protective against reoperation for SVD after bioprosthetic AVR and MVR, with a hazard ratio of 0.97 and 0.98 per year increase in age, respectively. 3.2.3. Body surface area A larger body surface area (BSA) was associated with a lower freedom from reoperation for SVD after AVR (hazard ratio 1.84 per m 2 increase), but not after MVR. 3.2.6. Left ventricular hypertrophy Persistent left ventricular hypertrophy at follow-up was associated with a significantly higher incidence of subsequent reoperation for SVD in patients with aortic bioprostheses (hazard ratio 2.38). 3.2.7. Prosthesis size In patients with aortic bioprostheses, larger prosthesis size significantly predicted an increased freedom from

368 M. Ruel et al. / European Journal of Cardio-thoracic Surgery 25 (2004) 364 370 reoperation due to SVD. Both a linear effect with respect to manufacturer prosthesis size (hazard ratio 0.82 per increase of one valve size, independent of BSA), and a dichotomous effect of the ratio of prosthesis size over BSA at or below the 10th percentile value of the cohort were observed (hazard ratio 1.79 for patients with prosthesis size/bsa ratio smaller or equal to the 10th percentile value of the cohort). These relationships were not observed in patients with mitral bioprostheses. 4. Discussion This study identified three main new findings with respect to the late incidence of reoperation for SVD in patients with bioprosthetic heart valves. First, it formally demonstrated that current models of bioprostheses have markedly better durability than older models that are discontinued. This is an encouraging finding for clinicians and patients, and provides basis for the initiation of a reconsideration process on the existing guidelines regarding the generally recommended minimum age for the implantation of biological versus mechanical prostheses. Secondly, the study indicated that smoking has a detrimental effect on bioprosthetic valve durability, regardless of implant site. A related finding had previously been reported in patients with native aortic valve stenosis [11], but so far not in patients with bioprosthetic valves, and this provides another mandate for the cessation of smoking in all valve patients, notwithstanding the other effects of smoking on cancer and coronary disease risk. In this regard, one can speculate that smoking might play a role on calcium metabolism or accelerate SVD by a mechanism not unrelated to atherosclerosis. Finally, the study also showed that larger aortic bioprostheses have a lower incidence of reoperation. This may be due to patients with larger prostheses tolerating stenosis or regurgitation secondary to SVD better, or relate to a true beneficial impact of larger prosthesis size on SVD because of lower flow velocities and lower transprosthesis gradients. The study also identified a relationship between persistent left ventricular hypertrophy determined by objective ECG criteria at follow-up after AVR, and a higher incidence of reoperation for aortic SVD. Although the mechanistic basis of this relationship is unclear, it could relate to the coprevalence of left ventricular hypertrophy in patients with smaller aortic prostheses, in itself a risk factor for reoperation, or to the coprevalence of left ventricular hypertrophy with hypertension, which may cause chronically increased diastolic closure stress on the bioprosthesis. BSA also correlated with the risk of reoperation for aortic SVD. This is in contrast with a previous study that showed an inverse relationship between body mass index and native aortic valve stenosis (although valve disease-related weight loss could have confounded this relationship) [12], and could potentially be explained by higher hemodynamic stresses on the prosthesis in patients with an elevated BSA or by their lower tolerance to the effects of stenosis or regurgitation as the bioprosthesis progressively fails. Coexistent coronary artery disease at the time of bioprosthetic MVR resulted in a significantly increased freedom from reoperation in this study. This has been identified by other authors previously [10], and likely relates to competing risks of death in patients with concomitant mitral and coronary disease rather than to a true protective biological effect of coronary disease on the development of SVD. 4.1. Previous related work Structural deterioration of a bioprosthesis is the leading cause and most frequent indication for reoperation in patients with tissue valves [13 16]. Bioprosthetic valves are known to undergo a time-dependent process of structural deterioration secondary to stress-related tears, perforations or dystrophic calcifications [17]. Independent risk factors previously found to be associated with bioprosthetic SVD include younger age, mitral valve position [18 23], renal insufficiency [21], and poor ventricular function [3], although no relationship between left ventricular function and freedom from reoperation was demonstrated in the present study. Larger valve size had previously been suspected to be a possible predictor of SVD [6,24], but other studies have found the opposite to be true, with small valve size being associated with increased calcification [7] and stenotic failure [8]. 4.2. Limitations The findings of this cohort study may not necessarily be generalizable to all patients with bioprosthetic valves, because the study represents a single institution s experience and may have been affected by regional referral and patient management patterns. In addition, unsuspected demographic and selection factors unique to the cohort may have resulted in overfitted statistical associations. Finally, generalizability to current bioprostheses may be in part limited by the fact that most reoperations for SVD occurred in older generation bioprostheses, despite this factor having been accounted for in the analyses. No prospective data was available from the present cohort on serum cholesterol level and statin treatment status. Evidence suggests that hypercholesterolemia plays a role in the progression of native aortic stenosis [11,25], and recent findings unpublished as of this writing have identified a potential benefit for statins in preventing reoperation in patients with bioprosthetic valves. The impact of serum creatinine and renal failure could also not be evaluated, as too few dialysis-dependent patients had, until recently, been implanted with bioprosthetic valves at our institution. Because this study was observational it is possible, despite the use of a hard end-point like reoperation, that

M. Ruel et al. / European Journal of Cardio-thoracic Surgery 25 (2004) 364 370 369 clinical factors or selection bias may have influenced results, such as in those patients for whom reoperation might have been delayed because of patient preferences or perceived surgical risk. In addition, although the effect of multiple potential confounders was forced into the statistical models, it remains possible that unknown confounders may ultimately have impacted on some findings. 4.3. Conclusions Despite the aforementioned limitations, this study identified several risk factors for reoperation due to structural valve dysfunction in patients with aortic and mitral bioprostheses. A major, potentially modifiable factor shown to be of detrimental impact in both aortic and mitral implant positions was smoking. In addition, the study revealed that larger aortic bioprosthesis size was associated with an increased freedom from late reoperation for SVD, therefore constituting an additional impetus to implant as large a valve as possible in all patients undergoing bioprosthetic AVR. Other risk factors for reoperation due to SVD included younger age, male gender, BSA, and persistent left ventricular hypertrophy for patients with aortic bioprostheses, and younger age and coronary artery disease for patients with mitral bioprostheses. The study also formally determined that current models of bioprostheses have markedly better durability than older models that are now discontinued, suggesting that a revision process on the recommended minimum age guidelines for the implantation of tissue versus mechanical prostheses may be indicated. Overall, the results of this study may provide useful information for clinicians and patients in determining what prosthesis class may be best suited for a given patient, how the prosthesis may fare with respect to reoperation for SVD, and how some risk factors for reoperation due to SVD may potentially be avoided. Acknowledgements The authors wish to extent their gratitude to Mary Thomson for her assistance with the organization of the valve clinic and management of the database. References [1] Poirer NC, Pelletier LC, Pellerin M, Carrier M. 15-year experience with the Carpentier Edwards pericardial bioprosthesis. Ann Thorac Surg 1998;66(Suppl 6):S57 S61. [2] Rahimtoola SH. Choice of prosthetic heart valve for adult patients. J Am Coll Cardiol 2003;41(6):893 904. [3] David TE, Ivanov J, Armstrong S, Feindel CM, Cohen G. Late results of heart valve replacement with the Hancock II bioprosthesis. J Thorac Cardiovasc Surg 2001;121(2):268 77. 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370 M. Ruel et al. / European Journal of Cardio-thoracic Surgery 25 (2004) 364 370 in the mitral position: a 20-year experience. J Heart Valve Dis 2001; 10(4):443 8. [23] Helft G, Tabone X, Georges JL, Lomama E, Nematalla H, Metzger JP, Heulin A, Vacheron A. Bioprosthetic valve replacement in the elderly. Eur Heart J 1995;16(4):529 33. [24] Glower DD, White WD, Hatton AC, Smith LR, Young WG, Wolfe WG, Lowe JE. Determinants of reoperation after 960 valve replacements with Carpentier-Edwards prostheses. J Thorac Cardiovasc Surg 1994;107(2):381 92. discussion 392 3. [25] Boon A, Cheriex E, Lodder J, Kessels F. Cardiac valve calcification: characteristics of patients with calcification of the mitral annulus or aortic valve. Heart 1997;78(5):472 4. Appendix A. Conference discussion Dr P. Skarsgard (Vancouver, Canada): Did you find any increased rate of structural valve deterioration according to size in the mitral position? Dr Ruel: No, we did not. The relationship we observed with aortic bioprostheses was not present with mitral bioprostheses; there was not even a trend. Dr S. Bolling (Ann Arbor, Michigan): Were you able to analyze how many of these patients were on statins? There is sort of a trend in some of the literature now to analyze reoperative rates, valve degeneration rates on the basis of statins, and even statin dose in some of these patients. If this is a modern series we should be able to analyze which patients were on statins and does that have an influence on valve degeneration. Dr Ruel: You are absolutely right that both native and prosthetic valve literatures now suggest that hypercholesterolemia may have a detrimental effect on valve deterioration. Unfortunately we do not have this data available. Dr K. Wrobel (Krakow, Poland): Did you analyze the rate of urgency reoperation compared between the groups and did you try to identify any risk factors for urgent reoperation in both groups? Dr Ruel: No, we did not look at that. As one would expect, the vast majority of those reoperations were electively performed for progressive structural valve deterioration. There were a few urgent reoperations, especially with discontinued models like the Ionescu-Shiley whose failure could happen very suddenly, but in the recent part of the series there were quite few reoperations which were performed urgently. Dr E. Al-Mashat (Baghdad, Iraq): Have you tried to correlate the degeneration with the possibility of the etiologic cause for the pathology? It has been our observation in Iraq that no matter how good the bioprosthesis is, it gets degenerated quicker, perhaps our main pathology being rheumatic heart disease and age of our patients is much younger than yours. What is your comment on this? Dr Ruel: It is an interesting hypothesis that perhaps some preformed antibodies as the result of rheumatic fever may play a role in bioprosthetic valve degeneration, but we have not been in a position to look at this in our series.